阅读说明：本技术 杂芳基二氢嘧啶衍生物和治疗乙型肝炎感染的方法 (Heteroaryl dihydropyrimidine derivatives and methods for treating hepatitis b infection ) 是由 万昭奎 蒋益民 戴学东 刘谦 W.S.张 邓刚 付利强 于 2018-06-26 设计创作，主要内容包括：本文提供了可用于在有需要的受试者中治疗HBV感染的化合物,其药物组合物以及在所述受试者中抑制、阻遏或预防HBV感染的方法。(Provided herein are compounds useful for treating HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in said subject.)

1. A compound having the formula I

Including any possible deuterated isomer, stereoisomer, or tautomeric form thereof, wherein:

R¹selected from aryl or heteroaryl, each optionally substituted with one or more halogens;

R²selected from the group consisting of: a 4-7 membered unsubstituted saturated ring, a 3-7 membered substituted saturated ring, and a 5-12 membered fused, spiro or bridged bicyclic unsubstituted or substituted saturated ring, each of which optionally contains one or more heteroatoms, and wherein the substituted saturated ring is substituted with one or more substituents each independently selected from the group consisting of: halogen, oxo, hydroxy, cyano, C₁-C₃Alkyl radical, C₁-C₃Alkoxy, hydroxy C₁-C₃Alkyl or-X-R⁷；

R³Is C₁-C₄An alkyl group;

R⁴、R⁵and R⁶Independently selected from the group consisting of: hydrogen, C₁-C₃Alkyl and halogen;

-X-R⁷selected from the group consisting of: -SO₂-R⁷、-SO₂-R⁸-(CH₂)_n-R⁷、-SO₂NR⁸R⁷、-NR⁸S(＝O)(＝NH)-R⁷、-NR⁸S(＝O)NR⁸-R⁷、-NR⁸C(＝O)NR⁸-R⁷、-S(＝O)(＝NH)NR⁸-R⁷、-S(＝O)(＝NH)-R⁷、-NR⁸-(CH₂)_n-SO₂-R⁷、-NR⁸SO₂-NR⁸R⁷、-OC(＝O)-R⁷、-C(＝O)-R⁷、-(CH₂)_n-C(＝O)O-R⁷、-C(＝O)NR⁸-R⁷、-NR⁸C(＝O)-R⁷、-NR⁸C(＝O)O-R⁷、-OC(＝O)NR⁸-R⁷and-NR⁸-R⁷；

R⁷And R⁸Each independently selected from hydrogen or from a substituent selected from the group consisting of: c₁-C₄Alkyl, aryl, heteroaryl and 3-7 membered saturated rings optionally containing one or more heteroatoms, each such substituent from the group may optionally be substituted with one or more R⁹And R¹⁰Substitution;

or R⁷And R⁸When attached to nitrogen, may be taken together to form a 3-7 membered saturated ring;

R⁹and R¹⁰Each independently selected from-OR¹¹Oxo, optionally substituted by one or two R¹¹Substituted C₁-C₄Alkyl, -NHC (═ O) OR¹¹、-C(＝O)R¹¹、-(CH₂)_n-C(＝O)OR¹¹、-C(＝O)NH₂-CN, halogen, or phenyl;

each R¹¹Independently is C₁-C₄Alkyl, - (CH)₂)_n-OR¹¹Or hydrogen;

each n is independently an integer from 0 to 4;

or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, wherein-X-R⁷represents-SO₂-R⁷、-SO₂NH-R⁷or-C (═ O) O-R⁷。

3. The compound of claim 1 or 2, wherein R⁴、R⁵And R⁶Independently selected from fluorine, chlorine or bromine.

4. A compound according to claim 3, wherein R⁴And R⁵Is fluorine and R⁶Is hydrogen.

5. A compound according to any one of the preceding claims, wherein R¹Is thiazolyl.

6. A compound according to any one of the preceding claims, wherein R²Selected from the group comprising 3-7 membered saturated rings optionally containing one or more heteroatoms and optionally substituted with one or more halogen, oxo, hydroxy or-X-R⁷And (4) substitution.

7. A compound according to any one of the preceding claims, wherein R²Selected from the group comprising a 4-6 membered saturated ring optionally containing one or more heteroatoms and optionally substituted with one or more halogen, oxo, hydroxy or-X-R⁷And (4) substitution.

8. A compound according to any one of the preceding claims, wherein R²Is a 5-or 6-membered saturated ring optionally containing one or more heteroatoms, said ring being further substituted by-X-R⁷And (4) substitution.

9. The compound of claim 8, wherein the saturated ring comprises nitrogen or oxygen.

10. A compound according to any one of the preceding claims, wherein R³Is methyl.

11. The compound of claim 1 selected from the group consisting of compounds having the formula:

12. a pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

13. A compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 for use as a medicament.

14. A compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 for use in the prevention or treatment of HBV infection in a mammal.

15. A product containing (a) a compound as defined in any one of claims 1 to 11 and (b) another HBV inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment of HBV infection.

Background

Chronic Hepatitis B Virus (HBV) infection is a serious global health problem affecting more than 5% of the world population (more than 3.5 million people worldwide, 1.25 million people in the united states).

Despite the availability of prophylactic HBV vaccines, the burden of chronic HBV infection remains a significant unmet global medical problem because treatment options are not ideal in most areas of developing countries and the rate of new infections continues to be constant.

HBV capsid protein plays an important role in the life cycle of the virus. HBV capsid/core protein forms a metastable viral particle or protein shell that protects the viral genome during intercellular passage and also plays a central role in viral replication, including genome encapsidation, genome replication, and virion morphogenesis and egress. The capsid structure also reacts to environmental cues to allow non-encapsulation after viral entry. Consistently, it has been found that proper timing of capsid assembly and disassembly, proper capsid stability, and function of the core protein are critical for viral infectivity.

There is a need in the art for therapeutic agents that increase the inhibition of viral production and can treat, ameliorate or prevent HBV infection. Administration of such therapeutic agents to HBV infected patients as monotherapy or in combination with other HBV treatments or adjunctive therapies will result in significantly reduced viral load, improved prognosis, reduced disease progression and enhanced seroconversion rates.

Background art for dihydropyrimidine for the treatment of HBV includes WO 2013/102655 and WO 9954326.

Disclosure of Invention

Provided herein are compounds useful for treating HBV infection in a subject in need thereof. Accordingly, in one aspect, provided herein is a compound having formula I:

including any possible deuterated isomer, stereoisomer, or tautomeric form thereof, wherein:

R¹selected from aryl or heteroaryl, each optionally substituted with one or more halogens;

R²is selected from the group consisting ofGroup (c): a 4-7 membered unsubstituted saturated ring, a 3-7 membered substituted saturated ring, and a 5-12 membered fused, spiro, or bridged bicyclic unsubstituted or substituted saturated ring, each of which optionally contains one or more heteroatoms, and wherein the substituted saturated ring is substituted with one or more substituents each independently selected from the group consisting of: halogen, oxo, hydroxy, cyano, C₁-C₃Alkyl radical, C₁-C₃Alkoxy, hydroxy C₁-C₃Alkyl or-X-R⁷。

R³Is C₁-C₄An alkyl group;

R⁴、R⁵and R⁶Independently selected from the group consisting of: hydrogen, C₁-C₃Alkyl and halogen;

-X-R⁷selected from the group consisting of: -SO₂-R⁷、-SO₂-R⁸-(CH₂)_n-R⁷、-SO₂NR⁸R⁷、-NR⁸S(＝O)(＝NH)-R⁷、-NR⁸S(＝O)NR⁸-R⁷、-NR⁸C(＝O)NR⁸-R⁷、-S(＝O)(＝NH)NR⁸-R⁷、-S(＝O)(＝NH)-R⁷、-NR⁸-(CH₂)_n-SO₂-R⁷、-NR⁸SO₂-NR⁸R⁷、-OC(＝O)-R⁷、-C(＝O)-R⁷、-(CH₂)_n-C(＝O)O-R⁷、-C(＝O)NR⁸-R⁷、-NR⁸C(＝O)-R⁷、-NR⁸C(＝O)O-R⁷、-OC(＝O)NR⁸-R⁷and-NR⁸-R⁷；

R⁷And R⁸Each independently selected from hydrogen or from a substituent selected from the group consisting of: c₁-C₄Alkyl, aryl, heteroaryl and 3-7 membered saturated rings optionally containing one or more heteroatoms, each such substituent from the group may optionally be substituted with one or more R⁹And R¹⁰Substitution;

or R⁷And R⁸When attached to nitrogen, may be taken together to form a 3-7 membered saturated ring;

R⁹and R¹⁰Each independently selected from-OR¹¹Oxo, optionally substituted by one or two R¹¹Substituted C₁-C₄Alkyl, -NHC (═ O) OR¹¹、-C(＝O)R¹¹、-(CH₂)_n-C(＝O)OR¹¹、-C(＝O)NH₂-CN, halogen (more specifically fluorine), or phenyl;

each R¹¹Independently is C₁-C₄Alkyl, - (CH)₂)_n-OR¹¹Or hydrogen;

each n is independently an integer from 0 to 4;

or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, R²Selected from the group consisting of: a 3-7 membered saturated ring and a 5-12 membered fused, spiro or bridged bicyclic saturated ring, each of which optionally contains one or more heteroatoms, and each such saturated ring is optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, oxo, hydroxy, cyano, C₁-C₃Alkyl radical, C₁-C₃Alkoxy, hydroxy C₁-C₃Alkyl or-X-R⁷；

-X-R⁷Selected from the group consisting of: -SO₂-R⁷、-SO₂NR⁸R⁷、-NR⁸S(＝O)(＝NH)-R⁷、-NR⁸SO₂NR⁸R⁷、-NR⁸C(＝O)NR⁸-R⁷、-S(＝O)(＝NH)NR⁸-R⁷、-S(＝O)(＝NH)-R⁷、-NR⁸SO₂-R⁷、-OC(＝O)-R⁷、-C(＝O)-R⁷、-C(＝O)O-R⁷、-C(＝O)NR⁸-R⁷、-NR⁸C(＝O)-R⁷、-NR⁸C(＝O)O-R⁷、-OC(＝O)NR⁸-R⁷and-NR⁸-R⁷；

R⁹represents-OR¹⁰Oxo, C₁-C₄Alkyl, -NHC (═ O) OR¹⁰、-C(＝O)R¹⁰、-C(＝O)OR¹⁰；

R¹⁰Is C₁-C₄Alkyl or hydrogen.

In another aspect, provided herein is a pharmaceutical composition comprising at least one compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another aspect, provided herein is a pharmaceutical composition comprising at least one disclosed compound and a pharmaceutically acceptable carrier. In another aspect, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of inhibiting or reducing the formation or presence of HBV-containing DNA particles or HBV-containing RNA particles in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

In one embodiment, any of the methods provided herein may further comprise administering to the individual at least one additional therapeutic agent selected from the group consisting of: HBV polymerase inhibitors, immunomodulators, interferons, viral entry inhibitors, viral maturation inhibitors, capsid assembly modulators, reverse transcriptase inhibitors, cyclophilin/TNF inhibitors, TLR agonists, HBV vaccines and any combination thereof.

Detailed Description

Provided herein are compounds, e.g., compounds having I or pharmaceutically acceptable salts thereof, useful for treating and preventing HBV infection in a subject.

Without being bound by any particular mechanism of action, it is believed that these compounds modulate or disrupt HBV assembly and other HBV core protein functions necessary for HBV replication or infectious particle production and/or can disrupt HBV capsid assembly, producing empty capsids with greatly reduced infectivity or replication capacity. In other words, the compounds provided herein can act as capsid assembly modulators.

The compounds provided herein have potent antiviral activity, exhibit advantageous metabolic profiles, tissue distribution, safety and drug profile, and are suitable for use in humans. The disclosed compounds can modulate (e.g., accelerate, delay, inhibit, disrupt, or reduce) normal viral capsid assembly or disassembly, bind capsids, or alter cellular polyprotein and precursor metabolism. Regulation may occur when the capsid protein is mature or during viral infection. The disclosed compounds can be used in methods of modulating the activity or properties of HBV cccDNA, or the production or release of HBV RNA particles from infected cells.

In one embodiment, the compounds described herein are suitable for monotherapy and are effective against natural or native HBV strains and HBV strains that are resistant to currently known drugs. In another embodiment, the compounds described herein are suitable for use in combination therapy.

Definition of

The following sets forth definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification and claims, either individually or as part of a larger group, unless otherwise limited in specific instances.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well known and commonly employed in the art.

As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element. Furthermore, the use of the term "including" as well as other forms such as "including", "includes" and "included" is not limiting.

As used herein, the term "about" will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. As used herein, the term "about" when referring to a measurable value such as an amount, duration, etc., is intended to include variations of ± 20% or ± 10% (including ± 5%, ± 1%, and ± 0.1%) relative to the specified value, as such variations are suitable for performing the disclosed methods.

As used herein, the term "capsid assembly modulator" refers to a compound that disrupts or accelerates or inhibits or hinders or retards or reduces or modifies normal capsid assembly (e.g., during maturation) or normal capsid disassembly (e.g., during infection) or perturbs capsid stability thereby inducing aberrant capsid morphology and function. In one embodiment, the capsid assembly modulator accelerates capsid assembly or disassembly, thereby inducing aberrant capsid morphology. In another embodiment, the capsid assembly modulator interacts with (e.g., binds to at an active site, binds to at an allosteric site, modifies or hinders folding, etc.) a major capsid assembly protein (CA), thereby disrupting capsid assembly or disassembly. In yet another embodiment, the capsid assembly modulator causes perturbation of the structure or function of the CA (e.g., the ability of the CA to assemble, disassemble, bind to a substrate, fold into a proper conformation, etc.), which reduces viral infectivity or is lethal to the virus.

As used herein, the term "treatment" is defined as administering or administering a therapeutic agent, i.e., a disclosed compound (alone or in combination with another agent), to a patient suffering from an HBV infection, symptoms of an HBV infection, or the likelihood of suffering from an HBV infection, with the goal of curing, healing, reducing, alleviating, altering, remedying, ameliorating, improving, or affecting an HBV infection, symptoms of an HBV infection, or the likelihood of suffering from an HBV infection, or administering a therapeutic agent (e.g., for diagnostic or ex vivo applications) to a patient. Such treatments can be specifically tailored or modified based on knowledge gained from the pharmacogenomics field.

As used herein, the term "prevention" means no disorder or disease development (if no disorder or disease occurs), or no further disorder or disease development (if the disorder or disease has already occurred). The ability to prevent some or all of the symptoms associated with a disorder or disease is also contemplated.

As used herein, the term "patient", "individual" or "subject" refers to a human or non-human mammal. Non-human mammals include, for example, farm animals as well as companion animals such as ovine, bovine, porcine, canine, feline, and murine mammals. Preferably, the patient, subject or individual is a human.

As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to an amount of a pharmaceutical agent that is non-toxic but sufficient to provide the desired biological result. The result may be a reduction and/or alleviation of signs, symptoms or causes of disease, or any other desired change in a biological system. The appropriate therapeutic amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

As used herein, the term "pharmaceutically acceptable" refers to a material (e.g., carrier or diluent) that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of a composition in which it is contained.

As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by conversion of an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include mineral or organic acid salts of basic residues, such as amines; basic or organic salts of acidic residues such as carboxylic acids and the like. Pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; nonaqueous media, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred. A list of suitable salts is found in Remington's pharmaceutical Sciences [ ramington's pharmaceutical Science ], 17 th edition, Mack Publishing Company [ mark Publishing Company ], easton, pa, 1985, p. 1418 and Journal of pharmaceutical Science [ Journal of pharmaceutical Science ],66,2(1977), each of which is incorporated herein by reference in its entirety.

As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful in the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. There are a variety of techniques in the art for administering compounds including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent or encapsulating material, involved in carrying or transporting or carrying or delivering a compound useful in the present invention in a patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compounds useful in the present invention, and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; a surfactant; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; a phosphate buffer solution; and other non-toxic compatible materials used in pharmaceutical formulations.

As used herein, "pharmaceutically acceptable carrier" also includes any and all coating agents, antibacterial and antifungal agents, and absorption delaying agents, and the like, that are compatible with the activity of the compounds useful in the present invention and are physiologically acceptable to a patient. Supplementary active compounds may also be incorporated into the compositions. The "pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of the compounds useful in the present invention. Other additional ingredients that may be included in pharmaceutical compositions for practicing the present invention are known in the art and are described, for example, in Remington's pharmaceutical sciences [ pharmaceutical science of Remington ] (genro editors, mark Publishing company (Mack Publishing Co.), 1985, easton, pa), which is incorporated herein by reference.

As used herein, unless otherwise specified, the term "alkyl" by itself or as part of another substituent means a straight or branched chain hydrocarbon (i.e., C) having the specified number of carbon atoms₁-C₃Alkyl means an alkyl group having 1 to 3 carbon atoms, C₁-C₄Alkyl means an alkyl group having 1 to 4 carbons), and includes straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl.

As used herein, unless otherwise specified, the term "halo" or "halogen" alone or as part of another substituent means a fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

As used herein, the term "3-7 membered saturated ring" refers to a monocyclic non-aromatic saturated group in which each atom (i.e., backbone atom) forming the ring is a carbon atom, unless the ring contains one or more heteroatoms, if so further defined. A 3-7 membered saturated ring includes groups having 3 to 7 ring atoms. Monocyclic 3-7 membered saturated rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

As used herein, a 3-7 membered saturated ring optionally containing one or more heteroatoms refers to a heteroalicyclic group containing one or more, more particularly one, two or three, even more particularly one or two, and most particularly one ring heteroatom each selected from O, S and N. In one embodiment, each heterocyclyl group has from 3 to 7 atoms in its ring system, with the proviso that the ring of the group does not contain two adjacent O or S atoms. Unless otherwise specified, the heterocyclic ring system may be attached to the rest of the molecule at any heteroatom or carbon atom that provides a stable structure.

Examples of 3-membered heterocyclyl groups include, but are not limited to, aziridine.examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidine and β lactam.examples of 5-membered heterocyclyl groups include, but are not limited to, pyrrolidine, oxazolidine, and thiazolidinedione.examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidine, morpholine, and piperazine.

Other non-limiting examples of heterocyclyl groups include monocyclic groups such as aziridine, oxirane, epithiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, tetrahydrofuran, thiophenane, piperidine, piperazine, morpholine, thiomorpholine.

As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings and having aromatic character, i.e., having (4n +2) delocalized pi (pi) electrons, where n is an integer.

As used herein, unless otherwise specified, the term "aryl", used alone or in combination with other terms, means a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), wherein such rings may be attached together in a pendant manner (e.g., biphenyl), or may be fused (e.g., naphthalene). Aryl radicalsExamples of groups include phenyl, anthracyl and naphthyl. A preferred example is phenyl (e.g., C)₆Aryl) and biphenyl (e.g. C)₁₂-aryl). In some embodiments, the aryl group has from 6 to 16 carbon atoms. In some embodiments, the aryl group has from 6 to 12 carbon atoms (e.g., C)₆-C₁₂-aryl). In some embodiments, the aryl group has 6 carbon atoms (e.g., C)₆-aryl).

As used herein, the term "heteroaryl" or "heteroaromatic" refers to a heterocyclic ring having aromatic character. Heteroaryl substituents may be defined by the number of carbon atoms, e.g. C₁-C₉-heteroaryl indicates the number of carbon atoms contained in the heteroaryl group and does not include the number of heteroatoms. E.g. C₁-C₉Heteroaryl will comprise a further 1 to 4 heteroatoms. The polycyclic heteroaryl group may include one or more partially saturated rings. Non-limiting examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (including, e.g., 2-and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (including, e.g., 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (including, e.g., 3-and 5-pyrazolyl), isothiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,3, 4-triazolyl, tetrazolyl, 1,2, 3-thiadiazolyl, 1,2, 3-oxadiazolyl, 1,3, 4-thiadiazolyl, and 1,3, 4-oxadiazolyl.

Non-limiting examples of polycyclic heterocycles and heteroaryls include indolyl (including, e.g., 3-, 4-, 5-, 6-and 7-indolyl), indolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl (including, e.g., 1-and 5-isoquinolinyl), 1,2,3, 4-tetrahydroisoquinolinyl, cinnolinyl, quinoxalinyl (including, e.g., 2-and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1, 8-naphthyridinyl, 1, 4-benzodioxanyl, coumarin, dihydrocoumarin, 1, 5-naphthyridinyl, benzofuranyl (including, e.g., 3-, 4-, 5-, 6-and 7-benzofuranyl), 2, 3-dihydrobenzofuranyl, 1, 2-benzisoxazolyl, Benzothienyl (including, for example, 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (including, for example, 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl (including, for example, 2-benzimidazolyl), benzotriazolyl, thioxanthyl, carbazolyl, carbolinyl, acridinyl, pyrroledialkyl, and quinolizinyl.

As used herein, the term "substituted" means that an atom or group of atoms replaces hydrogen as a substituent attached to another group.

As used herein, the term "selected from …" (e.g., "R⁴Selected from A, B and C ") is to be understood as equivalent to the term" selected from the group consisting of: … "(e.g.," R ")⁴Selected from the group consisting of: A. b and C ").

One embodiment relates to a compound having formula I as defined herein, wherein-X-R⁷represents-SO₂-R⁷、-SO₂NH-R⁷or-C (═ O) O-R⁷。

One embodiment relates to compounds having formula I as defined herein, wherein R is⁴、R⁵And R⁶Independently selected from fluorine, chlorine or bromine.

One embodiment relates to compounds having formula I as defined herein, wherein R is⁴And R⁵Is fluorine and R⁶Is hydrogen.

One embodiment relates to compounds having formula I as defined herein, wherein R is¹Is thiazolyl.

One embodiment relates to compounds having formula I as defined herein, wherein R is²Selected from the group comprising 3-7 membered saturated rings optionally containing one or more heteroatoms and optionally substituted with one or more halogen, oxo, hydroxy or-X-R⁷And (4) substitution.

One embodiment relates to compounds having formula I as defined herein, wherein R is²Selected from the group comprising a 4-6 membered saturated ring optionally containing one or more heteroatoms and optionally substituted with one or more halogen, oxo, hydroxy or-X-R⁷And (4) substitution.

One embodiment relates to compounds having formula I as defined herein, wherein R is²Is optionally composed ofA 5-or 6-membered saturated ring of one or more heteroatoms, said saturated ring being further substituted by-X-R⁷And more particularly wherein the saturated ring comprises nitrogen or oxygen.

One embodiment relates to compounds having formula I as defined herein, wherein R is³Is methyl.

One embodiment relates to a compound selected from the group consisting of compounds satisfying the formula:

the disclosed compounds may have one or more stereocenters, and each stereocenter may independently exist in the R or S configuration. In one embodiment, the compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein include racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof, having the therapeutically useful properties described herein.

The preparation of the optically active form is effected in any suitable manner, including by way of non-limiting example, by resolution of the racemic form by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In one embodiment, a mixture of one or more isomers is used as a disclosed compound described herein. In another embodiment, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis or separation of enantiomeric or diastereomeric mixtures. Resolution of the compounds and their isomers is achieved by any means, including by way of non-limiting example, chemical methods, enzymatic methods, fractional crystallization, distillation, and chromatography.

Where the absolute R or S stereochemistry of a compound cannot be determined, it can be determined by the retention time after chromatography under specific chromatographic conditions, as determined by the column, eluent, etc.

In one embodiment, the disclosed compounds may exist as tautomers. All tautomers are included within the scope of the compounds provided herein.

Compounds described herein also include isotopically-labeled compounds in which one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include, but are not limited to²H、³H、¹¹C、¹³C、¹⁴C、³⁶Cl、¹⁸F、¹²³I、¹²⁵I、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³²P and³⁵and S. In one embodiment, isotopically labeled compounds are useful for drug and/or substrate tissue distribution studies. In another embodiment, substitution with a heavier isotope such as deuterium provides greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).

In yet another embodiment, positron emitting isotopes such as¹¹C、¹⁸F、¹⁵O and¹³n substitution is useful in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds are prepared by any suitable method or by employing an appropriate isotopically labeled reagent in place of an unlabeled reagent otherwise employed.

In one embodiment, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

The compounds described herein and other related compounds having different substituents are synthesized using the techniques and materials described herein and techniques known to those skilled in the art. The general methods for preparing the compounds described herein are modified by the use of appropriate reagents and conditions in order to introduce the various moieties shown in the formulae provided herein.

Starting from compounds that are available from commercial sources or prepared using the procedures described herein, the compounds described herein are synthesized using any suitable procedure.

Method of producing a composite material

Provided herein are methods of treating an HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Also provided herein are methods of eradicating an HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the disclosed compounds.

Provided herein are methods of reducing the viral load associated with HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Additionally, provided herein are methods of reducing the recurrence of HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the disclosed compounds.

Provided herein are methods of inhibiting or reducing the formation or presence of HBV-containing DNA particles or HBV-containing RNA particles in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

In certain aspects, the methods and/or compositions described herein are effective for inhibiting or reducing the formation or presence of HBV-associated particles in vitro or in vivo (e.g., in a cell, in a tissue, in an organ (e.g., in the liver), in an organism, etc.). HBV-associated particles can contain HBV DNA (i.e., linear and/or covalently closed circular DNA (cccdna)) and/or HBV RNA (i.e., pregenomic RNA and/or subgenomic RNA). Thus, HBV-associated particles include HBV-containing DNA particles or HBV-containing RNA particles.

As used herein, "HPV-associated particle" refers to both infectious HBV virions (i.e., daniella particles) and non-infectious HBV subviral particles (i.e., HBV filaments and/or HBV spheres). The HBV virion comprises an envelope comprising a surface protein, a nucleocapsid comprising a core protein, at least one polymerase protein and an HBV genome. HBV filaments and HBV spheres comprise HBV surface proteins but lack core protein, polymerase and HBV genome. HBV filaments and HBV bodies are also collectively referred to as surface antigen (HBsAg) particles. HBV spheres comprise a small neutralizing HBV surface protein. HBV filaments also include medium, small and large HBV surface proteins.

HBV subviral particles may include non-particulate or secreted HBeAg as a marker for active replication of HBV.

Provided herein are methods of reducing the adverse physiological effects of HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Also provided herein are methods of reducing, alleviating, or inhibiting HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Provided herein are methods of inducing reversal of liver damage from HBV infection in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Provided herein are methods of reducing the physiological effects of a long-term antiviral treatment of HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Provided herein are methods of prophylactically treating an HBV infection in an individual in need thereof, wherein said individual has a latent HBV infection, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

In one embodiment, the individual is refractory to other therapeutic classes of HBV drugs (e.g., HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly modulators, antiviral compounds of different or unknown mechanisms, and the like, or combinations thereof). In another embodiment, the disclosed methods reduce the viral load in an individual having an HBV infection to a greater extent or at a faster rate than the extent to which other therapeutic classes of HBV drugs reduce the viral load in the individual.

In one embodiment, administration of the disclosed compounds or pharmaceutically acceptable salts thereof allows for administration of at least one additional therapeutic agent at a lower dose or frequency than the sole administration of the at least one additional therapeutic agent required to achieve a similar result in the prophylactic treatment of HBV infection in an individual in need thereof.

In one embodiment, administration of the disclosed compound or pharmaceutically acceptable salt thereof reduces the viral load in the individual to a greater extent or at a faster rate than administration of a compound selected from the group consisting of: HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, different capsid assembly modulators, antiviral compounds of different or unknown mechanisms, and any combination thereof.

In one embodiment, the disclosed methods reduce the viral load in individuals with HBV infection, thereby allowing for lower doses or different regimens of combination therapy.

In one embodiment, the disclosed methods result in a lower incidence of viral mutations or viral resistance compared to other classes of HBV drugs, thereby allowing for long-term treatment and minimizing the need for treatment regimen changes.

In one embodiment, administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, results in a lower incidence of viral mutation or viral resistance as compared to administration of a compound selected from the group consisting of: HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, different capsid assembly modulators, antiviral compounds of different or unknown mechanisms, and combinations thereof.

In one embodiment, the disclosed methods increase the seroconversion rate from HBV infection to non-HBV infection or from detectable HBV viral load to undetectable HBV viral load to a seroconversion rate beyond current treatment regimens. As used herein, "seroconversion" refers to the period of time during which HBV antibodies are produced and become detectable.

In one embodiment, the disclosed methods increase or normalize or restore normal health, cause a complete restoration of normal health, restore life expectancy, or address a viral infection in an individual in need thereof.

In one embodiment, the disclosed methods eliminate or reduce the number of HBV RNA particles released from HBV infected cells, thereby enhancing, prolonging or increasing the therapeutic benefit of the disclosed compounds.

In one embodiment, the disclosed methods eradicate HBV in an HBV-infected individual, thereby avoiding the need for long-term or life-long treatment, or reducing the duration of treatment, or allowing for reduced administration of other antiviral agents.

In another embodiment, the disclosed methods further comprise monitoring or detecting the HBV viral load of the subject, and wherein the method is performed for a period of time, comprising until the HBV virus is undetectable.

Thus, in one embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

Thus, in one embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of table 1 or a pharmaceutically acceptable salt thereof.

In one embodiment of any of the methods provided herein, the method can further comprise monitoring the HBV viral load of the subject, wherein the method is performed for a period of time such that the HBV virus is undetectable.

Combination therapy

The disclosed compounds may be used in combination with one or more additional compounds for the treatment of HBV infection. These additional compounds may include other disclosed compounds and/or compounds known to be useful in treating, preventing, or reducing the symptoms or effects of HBV infection. Such compounds include, but are not limited to, HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly modulators, reverse transcriptase inhibitors, immune modulators, TLR agonists, and other agents with different or unknown mechanisms that affect HBV life cycle or affect the outcome of HBV infection.

In non-limiting examples, the disclosed compounds may be used in combination with one or more drugs (or salts thereof) selected from the group consisting of:

HBV reverse transcriptase inhibitors, and DNA and RNA polymerase inhibitors, including but not limited to lamivudine (3TC, Zeffix, Heptovir, episir, and episir-HBV), entecavir (Baraclude, Entavir), adefovir dipivoxil (Hepsara, Preveon, bis-POM PMEA), tenofovir fumarate (tenofovir disoproxil fumarate) (Viread, TDF, or PMPA);

interferons, including but not limited to interferon α (IFN- α), interferon β (IFN- β), interferon lambda (IFN-lambda), and interferon gamma (IFN-gamma);

a viral entry inhibitor;

inhibitors of viral maturation;

capsid assembly modulators described in the literature, such as, but not limited to, BAY 41-4109;

a reverse transcriptase inhibitor;

immune modulators, such as TLR agonists; and

agents of different or unknown mechanism, such as but not limited to AT-61((E) -N- (1-chloro-3-oxo-1-phenyl-3- (piperidin-1-yl) prop-1-en-2-yl) benzamide), AT-130((E) -N- (1-bromo-1- (2-methoxyphenyl) -3-oxo-3- (piperidin-1-yl) prop-1-en-2-yl) -4-nitrobenzamide), and similar analogs.

In one embodiment, the additional therapeutic agent is an interferon, the term "interferon" or "IFN" refers to any member of a family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune responses human interferons are divided into three classes, type I, which includes interferon- α (IFN- α), interferon- β (IFN- β), and interferon- ω (IFN- ω), type II, which includes interferon- γ (IFN- γ), and type III, which includes interferon- λ (IFN- λ), as used herein the term "interferon" includes recombinant forms of interferons that have been developed and are commercially available, as used herein the term "interferon" also includes subtypes of interferons, such as chemically modified or mutated interferons.

Thus, in one embodiment, a compound of formula I may be administered in combination with an interferon selected from the group consisting of interferon α (IFN- α), interferon β (IFN- β), interferon lambda (IFN-lambda), and interferon gamma (IFN-gamma). in one embodiment, the interferon is interferon- α 0-2a, interferon- α -2b, or interferon- α -n1.. in another embodiment, interferon- α -2a or interferon- α -2b is pegylated.in a preferred embodiment, interferon- α -2a is pegylated interferon- α -2a (PEGASYS).

In another embodiment, the additional therapeutic agent is selected from an immunomodulatory or immunostimulatory therapy comprising a biological agent belonging to the interferon class.

In addition, the additional therapeutic agent may be an agent of a different or unknown mechanism, including an agent that disrupts the function of one or more other essential viral proteins or host proteins required for HBV replication or persistence.

In another embodiment, the additional therapeutic agent is an antiviral agent that blocks viral entry or maturation or targets HBV polymerase, such as a nucleoside or nucleotide or non-nucleoside (nucleotide) polymerase inhibitor. In another embodiment of the combination therapy, the reverse transcriptase inhibitor or DNA or RNA polymerase inhibitor is zidovudine, didanosine, zalcitabine, ddA, stavudine, lamivudine, abacavir, emtricitabine, entecavir, aricitabine, adefovir dipivoxil (Atevirapine), ribavirin, acyclovir, famciclovir, valacyclovir, valganciclovir, tenofovir, adefovir, PMPA, cidofovir, efavirenz, nevirapine, delavirdine, or etravirine.

In other words, the immunomodulator may affect maturation of antigen presenting cells, proliferation of T cells, and cytokine release (e.g., IL-12, IL-18, IFN- α, IFN- β, and IFN-. gamma., TNF- α, etc.).

In another embodiment, the additional therapeutic agent is a TLR modulator or TLR agonist, such as a TLR-7 agonist or a TLR-9 agonist. In further embodiments of the combination therapy, the TLR-7 agonist is selected from the group consisting of: SM360320 (9-benzyl-8-hydroxy-2- (2-methoxy-ethoxy) adenine) and AZD 8848([ methyl 3- ({ [3- (6-amino-2-butoxy-8-oxo-7, 8-dihydro-9H-purin-9-yl) propyl ] [3- (4-morpholinyl) propyl ] amino } methyl) phenyl ] acetate).

In any of the methods provided herein, the method can further comprise administering to the individual at least one HBV vaccine, nucleoside HBV inhibitor, interferon, or any combination thereof. In one embodiment, the HBV vaccine is at least one of RECOMBIVAX HB, ENGERIX-B, ELOVAC B, GENEVAC-B, or SHANTVAC B.

In one embodiment, the methods described herein further comprise administering at least one additional therapeutic agent selected from the group consisting of: nucleotide/nucleoside analogs, entry inhibitors, fusion inhibitors, and any combination of these or other antiviral mechanisms.

In another aspect, provided herein is a method of treating an HBV infection in an individual in need thereof, the method comprising reducing the HBV viral load by: administering to the individual a therapeutically effective amount of the disclosed compounds, alone or in combination with a reverse transcriptase inhibitor; and further administering to the individual a therapeutically effective amount of an HBV vaccine. The reverse transcriptase inhibitor may be at least one of zidovudine, didanosine, zalcitabine, ddA, stavudine, lamivudine, abacavir, emtricitabine, entecavir, aliscitabine, altiveline, ribavirin, acyclovir, famciclovir, ganciclovir, valganciclovir, tenofovir, adefovir, PMPA, cidofovir, efavirenz, nevirapine, delavirdine, or etravirine.

In another aspect, provided herein is a method of treating an HBV infection in an individual in need thereof, the method comprising reducing the HBV viral load by: administering to the individual a therapeutically effective amount of the disclosed compounds, alone or in combination with an antisense oligonucleotide or RNA interfering agent targeting HBV nucleic acid; and further administering to the individual a therapeutically effective amount of an HBV vaccine. Antisense oligonucleotides or RNA interfering agents are sufficiently complementary to the target HBV nucleic acid to inhibit replication of the viral genome, transcription of viral RNA, or translation of viral proteins.

In another embodiment, the disclosed compounds and at least one additional therapeutic agent are co-formulated. In yet another embodiment, the disclosed compounds and at least one additional therapeutic agent are co-administered.

For any combination therapy described herein, a suitable method can be used to calculate the synergistic effect, e.g., Sigmoid-E_maxEquation (Holford)&Scheiner,19981, clin. pharmacokinet. [ clinical pharmacokinetics]6:429-&Musschnek, 1926, arch, exp, pathol Pharmacol [ experimental pathology and pharmacology archives]114:313-326) and the median effect equation (Chou)&Talalay,1984, adv. EnzymeRegul. [ progress in enzyme regulation]22:27-55). Each of the above-mentioned equations can be applied to experimental data to generate a corresponding graph to help assess the effect of the drug combination. The corresponding graphs associated with the above equations are the concentration-effect curve, the isobologram curve, and the joint index curve, respectively.

In one embodiment of any of the methods of administering a combination therapy provided herein, the method can further comprise monitoring or detecting the HBV viral load of the subject, wherein the method is performed for a period of time, comprising until such time as the HBV virus is rendered undetectable.

Application/dose/formulation

In another aspect, provided herein is a pharmaceutical composition comprising at least one disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The actual dosage level of the active ingredient in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, but which is not toxic to that patient.

In particular, the selected dosage level will depend upon a variety of factors including the activity of the particular composition employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, body weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A physician (e.g., physician or veterinarian) having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can begin administration of the pharmaceutical composition to administer the disclosed compound at a level below that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is particularly advantageous to formulate the compounds in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the patients to be treated; each unit containing a predetermined amount of a compound of the present disclosure calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The dosage unit form of the invention is determined by and directly dependent on the following factors: (a) the unique features of the disclosed compounds and the particular therapeutic effect to be achieved, and (b) limitations inherent in the art of compounding/formulating such disclosed compounds for the treatment of HBV infection in a patient.

In one embodiment, the compositions of the present invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition of the invention comprises a therapeutically effective amount of the disclosed compounds and a pharmaceutically acceptable carrier.

In some embodiments, the dose of the disclosed compounds is from about 1mg to about 2,500 mg. In some embodiments, the dose of the disclosed compounds for use in the compositions described herein is less than about 10,000mg, or less than about 8,000mg, or less than about 6,000mg, or less than about 5,000mg, or less than about 3,000mg, or less than about 2,000mg, or less than about 1,000mg, or less than about 500mg, or less than about 200mg, or less than about 50 mg. Similarly, in some embodiments, the dose of the second compound (i.e., another drug for HBV treatment) as described herein is less than about 1,000mg, or less than about 800mg, or less than about 600mg, or less than about 500mg, or less than about 400mg, or less than about 300mg, or less than about 200mg, or less than about 100mg, or less than about 50mg, or less than about 40mg, or less than about 30mg, or less than about 25mg, or less than about 20mg, or less than about 15mg, or less than about 10mg, or less than about 5mg, or less than about 2mg, or less than about 1mg, or less than about 0.5mg, and any and all whole or partial increments thereof.

In one embodiment, the present invention relates to a packaged pharmaceutical composition comprising a container containing a therapeutically effective amount of the disclosed compound, alone or in combination with a second agent; and instructions for using the compound to treat, prevent or reduce one or more symptoms of an HBV infection in a patient.

The route of administration of any of the compositions of the present invention includes oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the present invention may be formulated for administration by any suitable route, such as for oral or parenteral administration, e.g., transdermal, transmucosal (e.g., sublingual, lingual, (per) buccal, (per) urethral, vaginal (e.g., per and around the vagina), nasal (intra) and (per) rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, capsules, lozenges, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, creams, lozenges, creams, pastes, plasters, lotions, wafers, suppositories, liquid sprays for nasal or oral administration, dry or nebulized formulations for inhalation, compositions and formulations for intravesical administration, and the like. It should be understood that the formulations and compositions useful in the present invention are not limited to the specific formulations and compositions described herein.

For oral administration, particularly suitable are tablets, dragees, liquids, drops, suppositories or capsules, caplets and gelatin capsules. Compositions intended for oral administration may be prepared according to any method known in the art, and such compositions may contain one or more agents selected from the group consisting of: inert, non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents, such as lactose; granulating and disintegrating agents, such as corn starch; binders, such as starch; and lubricating agents, such as magnesium stearate. Tablets may be uncoated or they may be coated by known techniques to provide an elegant or delayed release of the active ingredient. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

For parenteral administration, the disclosed compounds can be formulated for injection or infusion, e.g., intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion. Suspensions, solutions or emulsions in oily or aqueous vehicles, optionally containing other formulating agents such as suspending, stabilizing or dispersing agents, may be used.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of the invention and are covered by the appended claims. For example, it is understood that modifications to reaction conditions (including but not limited to reaction times, reaction size/volume) and experimental reagents such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, using only routine experimentation, using art-recognized alternatives, are within the scope of the present application.

It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed within the value and range of values are intended to be included within the scope of the invention. Moreover, all values falling within these ranges, as well as upper or lower limits of value ranges, are also contemplated by this application.

The following examples further illustrate aspects of the invention. However, they are in no way limiting of the teachings or disclosure of the present invention described herein.

Examples of the invention

Exemplary compounds useful in the methods of the invention will now be described with reference to the following illustrative synthetic schemes for their general preparation and the specific examples that follow. The skilled artisan will recognize that, in order to obtain the various compounds herein, the starting materials may be suitably selected such that the ultimately desired substituent will be carried through the reaction scheme with or without suitable protection to yield the desired product. Alternatively, it may be necessary or desirable to replace the ultimately desired substituent with a suitable group which may be carried through the reaction scheme and appropriately replaced with the desired substituent. Variables are as defined above with reference to formula (I), unless otherwise specified. The reaction may be carried out between the melting point of the solvent and the reflux temperature, preferably between 0 ℃ and the reflux temperature of the solvent. Conventional heating or microwave heating may be employed to heat the reaction. The reaction can also be carried out in a sealed pressure vessel above the normal reflux temperature of the solvent.

Preparation examples

Exemplary compounds useful in the methods of the invention will now be described with reference to the following illustrative synthetic schemes for their general preparation and the specific examples that follow.

General scheme

General synthesis of compounds having general formula I is described in scheme 1 and scheme 2. Compounds having the general formula III can be synthesized as described in scheme 1 (method A or method B), using conditions that depend on the substituent R on the compound having the general formula III₂And R₃. As described in method a, an acid having the general formula II is converted to an active ester by reaction with N, N-carbonyldiimidazole CDI, which is then coupled under basic conditions with monomethyl malonate potassium salt to produce an intermediate, which in turn undergoes decarboxylation to produce a ketoester having the general formula III. Alternatively, as described in method B, the compound having formula III can be converted from the acid having formula II and 2, 2-dimethyl-1, 3-dioxan by a similar conversion sequence as method aAlkane-4, 6-diones. The final product having general formula I can be synthesized as described in scheme 2 (method C or method D). The former is a common chemical method for multicomponent reactions with compounds having the general formulas III, IV and V in a selected solvent (but not limited to ethanol EtOH) in the presence of a base (but not limited to sodium acetate NaOAc). Alternatively, a step-wise method as described in method D is provided. The compounds having general formulae III and IV undergo condensation to produce a conjugated intermediate having formula X, which is then reacted with a compound having general formula V in a basic reaction medium at elevated temperature to produce the final product dihydropyrimidine having general formula I.

Scheme 1

Method A₁

To an acid of general formula II (1 equivalent) in acetonitrile was added N, N-carbonyldiimidazole (1.1 equivalent) at room temperature. The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere (mixture a). To a suspension of potassium monomethyl malonate (2 equivalents) in acetonitrile was added magnesium chloride (2.5 equivalents) and triethylamine (3.2 equivalents) at room temperature. After stirring for 2 hours under a nitrogen atmosphere, mixture a was added thereto and stirred at 80 ℃ to 100 ℃ overnight. The resulting reaction mixture was cooled to room temperature and concentrated to give a residue which was purified by silica gel column chromatography to give the ketoester having the general formula III.

Method A₂

In the method A₁In the above, potassium monoethylmalonate was used instead of potassium monomethyl malonate.

Method B

To a solution of an acid of general formula II (1 eq), 2-dimethyl-1, 3-dioxane-4, 6-dione (1.2 eq) and 4-dimethylaminopyridine (1.5 eq) in dichloromethane was added N-ethyl-N' - (3-dimethylaminopropyl) at room temperatureBase) carbodiimide hydrochloride (1.2 equivalents). After stirring overnight under nitrogen, the mixture was diluted with dichloromethane, washed with 5% wt aqueous potassium hydrogen sulfate, followed by brine, over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure to give an intermediate of formula IIa.

A solution of the intermediate of formula IIa in methanol was stirred at 90 ℃ for 3 hours. After cooling to room temperature, the mixture is concentrated under reduced pressure to give the ketoester of the general formula III.

Scheme 2

Method C

To a solution of the ketoester of formula III (1 equivalent) in ethanol was added the aldehyde of formula IV (1 equivalent), the formamidine hydrochloride of formula V (1 equivalent) and sodium acetate (1-1.2 equivalents). The mixture was brought to 80-100 ℃ and stirred under nitrogen overnight. After cooling to room temperature, it was concentrated to dryness. The residue was taken up in dichloromethane, washed with water, brine and over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography to provide a dihydropyrimidine product of general formula I. Chiral chromatography is used, where applicable, to separate and purify the stereoisomers of the dihydropyrimidine product having the general formula I.

Method D

To a solution of a ketoester of formula III (1 equivalent) in isopropanol, an aldehyde of formula IV (1-1.5 equivalents), piperidine (0.1 equivalent) and glacial acetic acid (a few drops) were added at room temperature under a nitrogen atmosphere. After stirring overnight, the mixture was concentrated under reduced pressure to leave a residue which was purified by silica gel column chromatography to give an intermediate having general formula X.

To a solution of the intermediate of formula X in N, N-dimethylformamide was added formamidine hydrochloride of formula V (1-1.2 equivalents) and sodium bicarbonate (3-4 equivalents). After stirring at 100 ℃ to 110 ℃ for a reaction time ranging from 4 hours to overnight, the mixture was cooled to room temperature and concentrated under reduced pressure to leave a residue which was purified by silica gel column chromatography to give the dihydropyrimidine product of general formula I.

Chiral chromatography is used, where applicable, to separate and purify the stereoisomers of the dihydropyrimidine product having the general formula I.

Preparation of acids, aryl aldehydes (P1) and formamidines (P2) having the general formula II:

part I: preparation of acids having the general formula II

Acid 1

Intermediate a 1: tert-butyl 1- ((2-methoxy-2-oxoethyl) sulfonyl) piperidine-4-carboxylate

To a solution of piperidine-4-carboxylic acid hydrochloride (500mg, 2.26mmol) and triethylamine (2.29g, 22.6mmol) in 1, 2-dichloroethane (50mL) was added methyl 2- (chlorosulfonyl) acetate (1.17g, 6.78mmol) at 0 ℃ under a nitrogen atmosphere. After stirring at 0 ℃ for 4 hours, the mixture was poured into water (40mL) and extracted three times with dichloromethane (50 mL). The combined organic layers were washed twice with brine (100mL) and Na₂SO_4(s)Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 9:1 to 3:1) to give the title compound as a yellow solid (475mg, 65% yield).¹H NMR(400MHz,CDCl₃)δ3.92(s,2H),3.79(s,3H),3.75-3.70(m,2H),3.04-2.98(m,2H),2.39-2.32(m,1H),1.98-1.92(m,2H),1.81-1.71(m,2H),1.44(s,9H)。

Intermediate a 2: 1- (2-Methoxycarbonylpropane-2-sulfonyl) -piperidine-4-carboxylic acid tert-butyl ester

To a solution of 1- ((2-methoxy-2-oxoethyl) sulfonyl) piperidine-4-carboxylic acid tert-butyl ester intermediate A1(100mg, 0.312mmol) in N, N-dimethylformamide (5mL) at 0 ℃ under a nitrogen atmosphere was added 60% wt hydrogenated in mineral oilSodium (31mg, 0.780mmol) and iodomethane (111mg, 0.780 mmol). After stirring at room temperature for 4 hours, the mixture was poured into water (20mL), followed by extraction four times with ethyl acetate (20 mL). The combined organic layers were washed twice with brine (30.0mL) and Na₂SO_4(s)Dried, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to give the title compound as a brown oil (114mg,>100% yield). LC-MS (ESI): r_T＝1.71min，C₁₅H₂₇NO₆Calculated mass of S349.2, found value of M/z 294.1[ M + H-56]⁺。¹H NMR(400MHz,CDCl₃)δ3.77(s,3H),3.73-3.70(m,2H),3.02(t,J＝13.2Hz,2H),2.38-2.31(m,1H),1.91-1.87(m,2H),1.76-1.68(m,2H),1.60(s,6H),1.43(s,9H)。

Acid 1: 1- ((1-methoxy-2-methyl-1-oxopropan-2-yl) sulfonyl) piperidine-4-carboxylic acid

To a solution of 1- (2-methoxycarbonyl-propane-2-sulfonyl) -piperidine-4-carboxylic acid tert-butyl ester intermediate a2(1.23g, 3.52mmol) in dichloromethane (50mL) was added trifluoroacetic acid (50mL) at room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give the crude title compound as a yellow solid (1.20g,>100% yield) was used directly in the next step. LC-MS (ESI): r_T＝0.26min，C₁₁H₁₉NO₆Calculated mass of S293.1, M/z found value 294.0[ M + H [ ]]⁺。

Acid 2

Intermediate a 3: 3-oxabicyclo [3.3.1] nonane-2, 4-dione

A solution of cyclohexane-1, 3-dicarboxylic acid (10.0g, 58.1mmol) in acetic anhydride (100mL) was stirred at 120 ℃ for 1.5 h. The solvent was removed to give a residue as a yellow solid (11.8g, crude). The residue was used in the next step without further purification.¹H NMR(400MHz,DMSO-d₆)δ2.35-2.27(m,1H),2.26-2.22(m,1H),1.88-1.85(m,2H),1.82-1.70(m,4H),1.66-1.60(m,0.5H),1.53-1.44(m,0.5H),1.30-1.17(m,1H)。

Acid 2: cis-3- (methoxycarbonyl) cyclohexanecarboxylic acid

Reacting 3-oxabicyclo [3.3.1]]A solution of nonane-2, 4-dione intermediate A3(12.9g, 83.8mmol) in methanol (100mL) was stirred at 70 deg.C overnight. The solvent was removed to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1 to 3:1) to give the title compound as a yellow solid (8.3g, 54% yield).¹H NMR(400MHz,CDCl₃)δ3.68(s,3H),2.38-2.30(m,2H),2.28-2.25(m,1H),2.05-1.98(m,2H),1.93-1.89(m,1H),1.62-1.52(m,1H),1.42-1.30(m,3H)。

Similarly using a similar procedure, the acid esters were prepared as follows:

acid 3: 3- (methoxycarbonyl) cyclopentanecarboxylic acid

¹H NMR(400MHz,DMSO-d₆)δ12.10(s,1H),3.60(s,3H),2.90-2.70(m,2H),2.16-1.65(m,6H)。

Acid 4

Intermediate a 4: 4- (2-ethoxy-2-oxoethylene) cyclohexanecarboxylic acid

To a solution of 4-oxocyclohexanecarboxylic acid (2.0g, 14mmol) in anhydrous ethanol (100mL) was added sodium methoxide (0.9g, 16mmol) followed by ethyl 2- (diethoxyphosphoryl) acetate (3.5g, 15mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was cooled to 4 ℃ in an ice bath, then another batch of sodium methoxide (800mg, 15mmol) was added. After stirring at 4 ℃ for 1 hour under a nitrogen atmosphere, the reaction mixture was allowed to warm to room temperature and adjusted to pH 5 with glacial acetic acid (3 ml). The acidified mixture was concentrated and the remaining oil was partitioned between ethyl acetate (100mL) and 1M aqueous hydrochloric acid (100 mL). The organic phase was separated, washed twice with water (100mL), over anhydrous Na₂SO₄₍s₎Dried, filtered and concentrated to give the title compound as a yellow oil(3.0g, 100% yield), used directly in the next reaction without further purification.¹H NMR(400MHz,DMSO-d₆)δ12.12(s,1H),5.65(s,1H),4.06(q,J＝7.2Hz,2H),3.45(dt,J＝13.6,4.0Hz,1H),2.54-2.50(m,1H),2.36-2.26(m,1H),2.24-2.15(m,2H),1.97-1.94(m,2H),1.57-1.41(m,2H),1.19(t,J＝7.2Hz,3H)。

Acid 4: 4- (2-ethoxy-2-oxoethyl) cyclohexanecarboxylic acid

To a solution of 4- (2-ethoxy-2-oxoethylene) cyclohexanecarboxylic acid intermediate A4(3.2g, 14mmol) in ethanol (150mL) was added 10% wt palladium on charcoal (0.4 g). Ammonium formate (2.4g, 37mmol) was then added at 30 ℃. The mixture was stirred at 50 ℃ for 1 hour. It was then cooled to room temperature and the catalyst was removed by filtration through celite. The filtrate was concentrated to give a residue which was partitioned between ethyl acetate (100mL) and 1M aqueous hydrochloric acid (30 mL). The organic phase was separated, washed three times with water (100mL), over anhydrous Na₂SO₄₍s₎Drying, filtration and concentration gave the title compound as a yellow oil (3.1g, 96% yield) which was used directly in the next reaction without further purification. LC-MS (ESI): r_T＝0.266min，C₁₁H₁₈O₄Calculated mass of 214.1, M/z found value 213.0[ M-H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.02(s,1H),4.04(q,J＝7.2Hz,2H),2.46-2.42(m,0.3H),2.20-2.15(m,2H),2.10(tt,J＝12.0,3.6Hz,0.7H),1.91-1.81(m,2H),1.73-1.70(m,2H),1.66-1.60(m,1H),1.54-1.46(m,1H),1.35-1.22(m,2H),1.17(t,J＝7.2Hz,3H),0.98(tq,J＝12.0,3.2Hz,1H)。

Acid 5

Intermediate a 5: 3-Methanesulfonyl-3-aza-bicyclo [3.2.1] octane-8-carboxylic acid methyl ester

To 3-azabicyclo [3.2.1] at 0 deg.C]To a solution of octane-8-carboxylic acid methyl ester hydrochloride (600mg, 2.93mmol) in dichloromethane (10mL) were added triethylamine (1.18g, 11.7mmol) and methanesulfonyl chloride (500mg, 4.39 mmol). After stirring overnight at room temperature, the mixture was quenched with water (40mL) andextracted twice with dichloromethane (30 mL). The combined organic layers were washed twice with brine (50mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a white solid (700mg, 97% yield). LC-MS (ESI): for MS R_T＝1.37min，C₁₀H₁₇NO₄Calculated mass of S247.1, found value of M/z 248.4[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ3.67(s,1.6H),3.61(s,1.4H),3.31(d,J＝2.4Hz,1H),3.21(d,J＝4.0Hz,0.4H),3.18(d,J＝3.2Hz,0.6H),3.04(s,0.6H),3.01(s,0.4H),2.92(s,0.5H),2.89(s,0.5H),2.84(s,1.4H),2.81(s,1.6H),2.70(t,J＝4.0Hz,0.6H),2.62(s,0.4H),2.56(br s,1H),2.47(br s,1H),1.74-1.50(m,4H)。

Acid 5: 3- (methylsulfonyl) -3-azabicyclo [3.2.1] octane-8-carboxylic acid

To 3-methanesulfonyl-3-aza-bicyclo [3.2.1] at room temperature]To a solution of intermediate A5(440mg, 1.76mmol) in tetrahydrofuran (3mL), methanol (1mL) and water (1mL) was added lithium hydroxide hydrate (150mg, 3.57 mmol). After stirring overnight, the mixture was concentrated under reduced pressure to give a residue which was diluted in water (6mL) and extracted with ethyl acetate (6 mL). The remaining aqueous layer was adjusted to pH 1-2 with 1M aqueous hydrochloric acid and extracted three times with ethyl acetate (20 mL). The combined latter organic layers were concentrated under reduced pressure to give the title compound as a white solid (400mg, 98% yield).¹H NMR(400MHz,DMSO-d₆)δ12.33(s,1H),3.32(d,J＝4.0Hz,0.6H),3.30(d,J＝3.2Hz,0.4H),3.20(d,J＝3.2Hz,0.4H),3.17(d,J＝3.6Hz,0.6H),3.08(s,0.6H),3.05(s,0.4H),2.90(s,0.5H),2.87(s,0.5H),2.83(s,1.5H),2.80(s,1.5H),2.62(t,J＝4.8Hz,0.5H),2.54(br s,1H),2.51-2.50(m,0.5H),2.43(br s,1H),1.72-1.64(m,2H),1.58-1.48(m,2H)。

Similarly using a similar procedure, the following acids were prepared:

acid 6: 8-methanesulfonyl-8-aza-bicyclo [3.2.1] octane-3-carboxylic acid

LC-MS(ESI)：R_T＝0.29min，C₉H₁₅NO₄Calculated mass of S233.1, found value of M/z 233.8[ M + H [)]⁺。¹HNMR(300MHz,CDCl₃)δ4.31(s,2H),2.94(s,3H),2.82-2.71(m,1H),2.13-2.09(m,2H),2.02-1.92(m,4H),1.79-1.72(m,2H)。

Acid 7: (methylsulfonyl) proline

¹H NMR(300MHz,DMSO-d₆)δ12.70(br s,1H),4.23-4.19(m,1H),3.37-3.35(m,1H),3.32-3.29(m,1H),2.95(s,3H),2.26-2.19(m,1H),1.95-1.81(m,3H)

Acid 8

Intermediate a 6: 2- (methoxycarbonyl) piperidine-4-carboxylic acid

To a solution of 2- (methoxycarbonyl) isonicotinic acid (4.20g, 23.2mmol) in methanol (500mL) at room temperature under a nitrogen atmosphere was added 10% wt palladium on charcoal (420 mg). After replacing the internal nitrogen atmosphere with hydrogen, the mixture was stirred under hydrogen atmosphere (50psi) at 40 ℃ overnight. After cooling to room temperature and releasing the internal pressure to normal pressure, the flask was evacuated and charged with a nitrogen atmosphere three times. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title compound as a grey solid (4.30g, 99% yield). LC-MS (ESI): r_T＝0.31min，C₈H₁₃NO₄Calculated mass of 187.1, M/z found value 185.9[ M-H [)]^-。¹H NMR(400MHz,D₂O)δ4.13(dd,J＝12.4,2.8Hz,1H),3.87(s,3H),3.63-3.60(m,1H),3.16-3.09(m,1H),2.64-2.56(m,2H),2.20-2.17(m,1H),1.83-1.72(m,2H)。

Acid 8: 1- (tert-Butoxycarbonyl) -2- (methoxycarbonyl) piperidine-4-carboxylic acid

To a solution of 2- (methoxycarbonyl) piperidine-4-carboxylic acid intermediate a6(4.30g, 23.0mmol) in 1, 4-dioxane (60mL) was added water (60mL), sodium bicarbonate (5.80g, 69.0mmol) and di-tert-butyl dicarbonate (10.0g, 46.0mmol) at room temperature. After stirring overnight at room temperature, the reaction mixture was partitioned between ethyl acetate (50mL) and saturated aqueous sodium bicarbonate (100mL). The aqueous layer was extracted three times with ethyl acetate (100mL), and then 0.5N aqueous hydrochloric acid was added dropwise to adjust the pH to 4-5. The aqueous layer was concentrated under reduced pressure to give a residue which was purified by C18 (acetonitrile: 5% to 50% water, wavelength: 205nm) to give the title compound as a colourless oil (5.24g, 79% yield). LC-MS (ESI): r_T＝1.610min，C₁₃H₂₁NO₆Calculated mass of 287.1, found value of M/z 286.1[ M-H [)]^-。¹H NMR(400MHz,CDCl₃)δ4.63-4.56(m,1H),3.87-3.80(m,1H),3.69(s,3H),3.37-3.28(m,1H),2.73-2.69(m,1H),2.54-2.45(m,1H),2.09-2.03(m,2H),1.82-1.71(m,1H),1.43(s,9H)。

Acid 9

Intermediate a 7: pyridine-3, 4-dicarboxylic acid dimethyl ester

To a solution of pyridine-3, 4-dicarboxylic acid (7.00g, 41.9mmol) and 4-dimethylaminopyridine (80mg, 0.65mmol) in methanol (230mL) was added thionyl chloride (24.9g, 210mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 30 minutes. The reaction temperature was then raised to reflux and stirred continuously overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was redissolved in water (200 mL). The prepared solution is adjusted to pH 8-9 with saturated aqueous sodium bicarbonate solution at 0 ℃. The aqueous layer was then extracted three times with ethyl acetate (150 mL). The combined organic layers were washed with brine (200mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (5.26g, 64% yield). LC-MS (ESI): r_T＝1.27min，C₉H₉NO₄Calculated mass of 195.1, found M/z value of 196.4[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.02(d,J＝0.8Hz,1H),8.91(d,J＝5.2Hz,1H),7.70(d,J＝5.2,0.8Hz,1H),3.87(s,6H)。

Intermediate A8: 3-methyl pyridine-3, 4-dicarboxylate

To a suspension of pyridine-3, 4-dicarboxylic acid dimethyl ester intermediate A7(5.26g, 27.0mmol) in water (50mL) at 0 deg.CA solution of sodium hydroxide (1.08g, 27.0mmol) in water (16mL) was added. The mixture was stirred at room temperature overnight, during which time the mixture became homogeneous. The unconsumed diester is removed by extraction with chloroform and the remaining aqueous layer is acidified to a pH of about 1 with concentrated hydrochloric acid. The resulting solution was evaporated to dryness at 30 ℃ under reduced pressure. The resulting residue was extracted with hot tetrahydrofuran to give the crude monoester which was recrystallized from methanol (1.0g of the crude monoester in 3mL methanol, from 80 ℃ to room temperature) to give the title compound as a grey solid (2.0g, 34% yield). LC-MS (ESI): r_T＝0.25min，C₈H₇NO₄Calculated mass of 181.0, found value of M/z 182.3[ M + H ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ8.94(s,1H),8.86(d,J＝4.8Hz,1H),7.68(d,J＝4.8Hz,1H),3.85(s,3H)。

Intermediate a 9: cis-piperidine-3, 4-dicarboxylic acid 3-methyl ester hydrochloride

To a solution of pyridine-3, 4-dicarboxylic acid 3-methyl ester intermediate A8(1.04g, 4.79mmol) in methanol (30mL) was added platinum (IV) oxide (0.12g, 0.53mmol) and 7M hydrochloric acid (1.0mL, 7.0mmol) in methanol solution. The mixture was stirred under an atmosphere of hydrogen (50psi) at room temperature for 24 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (1.26g,>100% yield). LC-MS (ESI): r_T＝0.25min，C₈H₁₃NO₄Calculated mass of 187.1, found M/z value of 188.5[ M + H ]]⁺。¹H NMR(400MHz,D₂O)δ3.80(s,3H),3.75-3.62(m,1H),3.57-3.46(m,1H),3.42-3.39(m,1H),3.34-3.22(m,2.7H),3.18-3.11(m,0.3H),2.27-2.16(m,1.8H),1.98-1.91(m,0.2H)。

Acid 9: cis-piperidine-1, 3, 4-tricarboxylic acid 1-tert-butyl ester 3-methyl ester

To a solution of cis-piperidine-3, 4-dicarboxylic acid 3-methyl ester hydrochloride intermediate a9(1.26g, 5.65mmol) in water (19mL) was added a solution of sodium carbonate (1.50g, 14.1mmol) in water (5mL) at 0 ℃, followed by di-tert-butyl dicarbonate (2.46g, 11.3mmol) in 1, 4-dioxane (6 mL). The mixture was stirred at room temperature for 20 hours. It was diluted with water (20mL) and extracted twice with ethyl acetate (20 mL). Separating the aqueous layer inThe solution was acidified to pH 1-2 with 2M citric acid and extracted three times with ethyl acetate (40 mL). The combined organic layers were washed with water (50mL), brine (50mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (1.37g, 85% yield). LC-MS (ESI): r_T＝1.49min，C₁₃H₂₁NO₆Calculated mass of 287.1, M/z found value 233.5[ M + H-55 ]]⁺。¹H NMR(300MHz,CDCl₃)δ4.13-4.07(m,1H),3.70-3.63(m,4H),3.45(dd,J＝13.8,3.3Hz,1H),3.22-3.13(m,1H),2.96-2.79(m,2H),2.21-2.08(m,1H),1.94-1.80(m,1H),1.46(s,1.4H),1.44(s,7.6H)。

Acid 10

Intermediate a 10: cis-tetrahydrofuran-2, 5-dicarboxylic acid

To a solution of furan-2, 5-dicarboxylic acid (8.0g, 51.3mmol) in acetic acid (150mL) was added 10% wt palladium on charcoal (1.0g) at room temperature under a nitrogen atmosphere. After stirring overnight at 140 ℃ under a hydrogen atmosphere (5MPa), the mixture was cooled to room temperature and the catalyst was filtered off. The filtrate was concentrated under reduced pressure to give the title compound as a green solid (7.1g, 87% yield). LC-MS (ESI): r_T＝0.30min，C₆H₈O₅Calculated mass of 160.0, found value of M/z 161.1[ M + H ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ12.85(br s,2H),4.47(s,2H),2.26-2.16(m,2H),2.02-1.90(m,2H)。

Intermediate a 11: cis-3, 8-dioxabicyclo [3.2.1] octane-2, 4-dione

A solution of cis-tetrahydrofuran-2, 5-dicarboxylic acid intermediate A10(8.67g, 54.2mmol) in trifluoroacetic anhydride (60mL) was stirred at 45 ℃ overnight and then at 55 ℃ for 2 days. After cooling to room temperature, the mixture was concentrated under reduced pressure to give the title compound (8.8g,>100% yield).¹H NMR(300MHz,DMSO-d₆)δ5.18(s,2H),2.27-2.14(m,4H)。

Intermediate a 12: cis-5- (methoxycarbonyl) tetrahydrofuran-2-carboxylic acid

To cis-3, 8-dioxabicyclo [3.2.1] at 0 deg.C]To a solution of octane-2, 4-dione intermediate A11(8.8g, 54.2mmol) in methanol (170mL) was added triethylamine (7.12g, 70.5 mmol). The mixture was stirred at room temperature for 20 hours. It was then concentrated to dryness under reduced pressure. The residue was dissolved in water (40mL), adjusted to pH 1-2 with 2M aqueous hydrochloric acid, and extracted three times with ethyl acetate (300 mL). The combined organic layers were washed twice with water (200mL), twice with brine (200mL), and over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (6.19g, 66% yield). LC-MS (ESI): r_T＝0.27min，C₇H₁₀O₅Calculated mass of (3) 174.1, found value of M/z 175.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ11.61(br s,1H),4.53-4.50(m,1H),4.43-4.40(m,1H),3.64(s,3H),2.22-2.11(m,2H),2.03-1.94(m,2H)。

Intermediate a 13: cis-2-benzyl 5-methyltetrahydrofuran-2, 5-dicarboxylate

To a solution of cis-5- (methoxycarbonyl) tetrahydrofuran-2-carboxylic acid intermediate a12(5.0g, 28.7mmol) in N, N-dimethylformamide (50mL) was added potassium carbonate (15.8g, 114mmol) and (bromomethyl) benzene (9.8g, 57.3mmol) at room temperature. After stirring overnight at 30 ℃, the mixture was poured into water (200mL) and extracted twice with ethyl acetate (200 mL). The combined organic layers were washed twice with water (200mL) and then twice with brine (200mL) over Na₂SO_4(s)Dried, filtered and concentrated. The residue was purified by C18 column (acetonitrile: water ═ 60%) to give the title compound as a colourless oil (5g, 66% yield). LC-MS (ESI): r_T＝1.54min，C₁₄H₁₆O₅Calculated mass of 264.1, M/z found value 265.1[ M + H]⁺。¹H NMR(300MHz,CDCl₃)δ7.37-7.35(m,5H),5.25-5.15(m,2H),4.66-4.59(m,2H),3.70(s,3H),2.32-2.17(m,4H)。

Acid 10: cis-5- (methoxycarbonyl) tetrahydrofuran-2-carboxylic acid

To cis-2-benzyl 5-methyltetrahydrofuran-2, 5-dicarboxylate intermediate A13(5.0g, 18.9mmol) in methyl at room temperature under nitrogenTo a solution in alcohol (60mL) was added 10% by weight of palladium on charcoal (500 mg). After stirring under hydrogen balloon pressure at 25 ℃ overnight, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a colourless oil (3.2g, 97% yield). LC-MS (ESI): r_T＝0.24min，C₇H₁₀O₅Calculated mass of (3) 174.1, found value of M/z 175.1[ M + H ]]⁺。¹HNMR(300MHz,DMSO-d₆)δ12.56(br s,1H),4.51(t,J＝6.3Hz,1H),4.41(t,J＝6.3Hz,1H),3.64(s,3H),2.17-1.91(m,4H)。

Acid 11

Intermediate a 14: 3-methylene-cyclobutanecarboxylic acid

To a solution of 3-methylene-cyclobutanecarbonitrile (11.2g, 120mmol) in ethanol (30mL) and water (30mL) was added potassium hydroxide (33.7g, 602 mmol). The mixture was stirred at 105 ℃ overnight. After cooling, it was concentrated. The aqueous residue was neutralized with concentrated hydrochloric acid and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed twice with brine (20mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (13.0g, 96% yield).¹H NMR(400MHz,DMSO-d₆)δ12.21(s,1H),4.79-4.76(m,2H),3.10-3.01(m,1H),2.85-2.82(m,4H)。

Intermediate a 15: 3-methylene-cyclobutanecarboxylic acid tert-butyl ester

To a solution of 3-methylene-cyclobutanecarboxylic acid intermediate A14(13.0g, 116mmol) in tetrahydrofuran (150mL) was added di-tert-butyl dicarbonate (33.0g, 151mmol) and 4-dimethylaminopyridine (2.83g, 23.2 mmol). After stirring overnight at room temperature, the mixture was diluted with ethyl acetate (200mL), washed with water (50mL), brine (50mL), and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (100% petroleum ether) to give the title compound (9.4g, 48% yield) as a colorless oil.¹H NMR(400MHz,DMSO-d₆)δ4.79-4.77(m,2H),3.07-2.99(m,1H),2.88-2.77(m,4H),1.40(s,9H)。

Intermediate a 16: 3-hydroxymethyl-cyclobutanecarboxylic acid tert-butyl ester

A solution of 3-methylene-cyclobutanecarboxylic acid tert-butyl ester intermediate A15(2.0g, 11.9mmol) in tetrahydrofuran (20mL) was cooled to-20 ℃.10M borane-methyl sulfide complex (0.36mL, 3.57mmol) in dimethyl sulfide was then added slowly under a nitrogen atmosphere. After stirring at room temperature for 4 hours, the mixture was cooled to-20 ℃ to-10 ℃. Methanol (2mL) and 30% aqueous hydrogen peroxide (400mg, 11.9mmol) were added sequentially. After stirring for 15 minutes, 3M aqueous sodium hydroxide (1.59mL, 4.76mmol) was added. The resulting mixture was stirred at-20 ℃ to-10 ℃ for 2 hours. Saturated aqueous sodium sulfite (20mL) was added. The mixture was diluted with water (20mL) and then extracted three times with ethyl acetate (30 mL). The combined organic layers were washed with brine (30mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound (1.53g, 69% yield) as a colorless oil.¹H NMR(300MHz,DMSO-d₆)δ3.38(d,J＝6.6Hz,0.8H),3.28(d,J＝6.0Hz,1.2H),2.99-2.81(m,1H),2.34-2.24(m,1H),2.15-2.04(m,2H),1.94-1.77(m,2H),1.40(s,3.6H),1.38(s,5.4H)。

Intermediate a 17: cyclobutane-1, 3-dicarboxylic acid

To a hot concentrated nitric acid (5mL) containing one drop of fuming nitric acid was added dropwise a solution of 3-hydroxymethyl-cyclobutanecarboxylic acid tert-butyl ester intermediate A16(1.0g, 5.38mmol) in 2M aqueous nitric acid (1.0 mL). The mixture was heated to 120 ℃ and stirred for 3 hours until the solution became almost colorless and the evolution of gas ceased. The completed reaction mixture was cooled to room temperature. Most of the excess nitric acid was removed under reduced pressure and traces of nitric acid were destroyed by addition of formic acid (2 mL). The resulting solution was concentrated to give the title compound as a yellow oil (800mg, crude) which was used in the next step without further purification. LC-MS (ESI): r_T＝0.28min，C₆H₈O₄Calculated mass of 144.0, found M/z value of 145.0[ M + H [)]⁺。

Intermediate a 18: cyclobutane-1, 3-dicarboxylic acid dimethyl ester

To a solution of cyclobutane-1, 3-dicarboxylic acid intermediate a17(560mg, 3.9mmol) in methanol (10mL) was added a drop of concentrated sulfuric acid. The mixture was heated to 75 ℃ and stirred overnight. It was then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50mL) and washed with saturated aqueous sodium bicarbonate (20mL) and then brine (20 mL). The remaining organic layer was passed over Na₂SO₄(s) dried, filtered and concentrated to give the title compound as a colourless oil (600mg, 90% yield).¹H NMR(300MHz,CDCl₃)δ3.71(s,6H),3.28-3.17(m,2H),2.53(t,J＝7.8Hz,4H)。

Acid 11: cyclobutane-1, 3-dicarboxylic acid monomethyl ester

To a solution of cyclobutane-1, 3-dicarboxylic acid dimethyl ester intermediate A18(600mg, 3.49mmol) in methanol (15mL) and water (1.5mL) was added sodium hydroxide (142mg, 3.55 mmol). The mixture was stirred at room temperature overnight. It was then concentrated under reduced pressure and the residue was dissolved in water (15 mL). The resulting solution was extracted with diethyl ether (15 mL). The aqueous layer was acidified to pH about 2 with 2M aqueous hydrochloric acid and then extracted three times with ethyl acetate (20 mL). The combined organic layers were passed over Na₂SO₄(s) dried and concentrated to give the title compound as a colourless oil (478mg, 87% yield). LC-MS (ESI): r_T＝0.26min，C₇H₁₀O₄Calculated mass of 158.1, found value of M/z 157.4[ M-H [)]^-。¹H NMR(300MHz,DMSO-d₆)δ12.19(br s,1H),3.62(s,3H),3.16-3.00(m,2H),2.37(t,J＝7.8Hz,4H)。

Acid 12

Intermediate a 19: trans-methyl 2- (2- (tert-butoxy) -2-oxoethyl) cyclopropane-1-carboxylate

To a solution of diisopropylamine (7.80g, 77.4mmol) in dry tetrahydrofuran (40mL) at-78 deg.C under a nitrogen atmosphere was added n-butyllithium (31mL, 77.4mmol, 2M in hexanes). Stirring at-78 deg.C for 1 hrThereafter, tert-butyl acetate (10.0g, 86.0mmol) was added. The reaction mixture was stirred for an additional 1 hour, then a solution of 4-bromobut-2-enoate (14.3g, 60.2mmol) in anhydrous tetrahydrofuran (20mL) was added to the reaction mixture at-78 ℃. The resulting mixture was allowed to warm to room temperature and stirred overnight. It was then quenched with saturated aqueous ammonium chloride (100mL) and extracted twice with ethyl acetate (500 mL). The combined organic layers were washed three times with brine (400mL) and anhydrous Na₂SO_4(s)Drying and concentration gave the title compound as a brown oil (12.8g, 100% yield).¹H NMR(400MHz,CDCl₃)δ3.67(s,3H),2.24-2.21(m,2H),1.70-1.60(m,1H),1.45-1.44(m,10H),1.27-1.23(m,1H),0.87-0.75(m,1H)。

Acid 12: trans-2- (2- (tert-butoxy) -2-oxoethyl) cyclopropane-1-carboxylic acid

To a solution of trans-methyl 2- (2- (tert-butoxy) -2-oxoethyl) cyclopropane-1-carboxylate intermediate a19(5.00g, 23.3mmol) in tetrahydrofuran/methanol/water (60mL/30 mL) was added lithium hydroxide hydrate (980mg, 23.3 mmol). The reaction mixture was stirred at room temperature for 2 hours. It was then concentrated to remove most of the solvent at room temperature under reduced pressure. The aqueous residue was diluted with water (60mL) and the pH adjusted to 3 with aqueous hydrochloric acid (1M). The resulting mixture was extracted three times with ethyl acetate (200mL) over anhydrous Na₂SO_4(s)Drying and concentration gave the title compound as a colourless oil (3.30g, 70% yield).¹H NMR(400MHz,DMSO-d₆)δ12.14(br s,1H),2.42-2.38(m,1H),2.34-2.28(m,1H),2.25-2.15(m,1H),1.78-1.74(m,1H),1.40(s,9H),1.01-0.96(m,1H),0.78-0.73(m,1H)。

Acid 13: 4- (methoxycarbonyl) cycloheptanecarboxylic acid

Intermediate a 20: 2- (3-oxo-3-phenylpropyl) cyclopentanone

To a suspension of 3- (dimethylamino) -1-phenylpropan-1-one hydrochloride (5.00g, 23.4mmol) in dioxane (50mL) was added 4- (cyclopent-1-en-1-ol-1 at room temperature-yl) morpholine (3.58g, 23.4 mmol). The mixture was heated to 110 ℃ and stirred under a nitrogen atmosphere overnight. It was then cooled and concentrated. The residue was dissolved in ethyl acetate (100mL) and washed with 1N aqueous hydrochloric acid (50 mL). The aqueous layer was extracted three times with ethyl acetate (100 mL). The combined organic layers were washed with brine (100mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give the title compound (2.3g, 46% yield) as a yellow solid. LC-MS (ESI): r_T＝1.36min，C₁₄H₁₆O₂Calculated mass of 216.1, M/z found value 217.1[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ7.98(d,J＝7.5Hz,2H),7.57(t,J＝7.5Hz,1H),7.47(d,J＝7.5Hz,2H),3.22-3.05(m,2H),2.38-1.99(m,6H),1.88-1.73(m,2H),1.63-1.53(m,1H)。

Intermediate a 21: mixtures of 4-phenylcyclohept-3-enecarboxylic acid and 4-phenylcyclohept-4-enecarboxylic acid

To a solution of 2- (3-oxo-3-phenylpropyl) cyclopentanone intermediate a20(1.00g, 4.63mmol) in acetic acid (8mL) was added concentrated hydrochloric acid (2mL) at room temperature. The mixture was heated to 110 ℃ and stirred for 4 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was dissolved in water (30mL) and extracted with diethyl ether (30 mL). The separated ether layer was extracted with 6N aqueous sodium hydroxide (10 mL). The separated aqueous layer was acidified to pH about 1 with concentrated hydrochloric acid and then extracted twice with diethyl ether (30 mL). The combined organic layers were passed over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a mixture of the title compound as a yellow oil (750mg, 75% yield). LC-MS (ESI): r_T＝1.24min，C₁₄H₁₆O₂Calculated mass of 216.1, found value of M/z 215.3[ M-H [)]^-。¹H NMR(400MHz,DMSO-d₆)δ12.12(br s,1H),7.31-7.28(m,4H),7.25-7.20(m,1H),6.08-6.02(m,1H),2.68-2.54(m,2H),2.46-2.33(m,2H),2.27-2.20(m,0.5H),2.11-1.78(m,3H),1.61-1.42(m,1.5H)。

Intermediate a 22: mixtures of methyl 4-phenylcyclohept-3-enecarboxylate and methyl 4-phenylcyclohept-4-enecarboxylate

To a solution of the mixture of 4-phenylcyclohept-3-enecarboxylic acid and 4-phenylcyclohept-4-enecarboxylic acid intermediate A21(750mg, 3.47mmol) in dry methanol (10mL) was added a drop of concentrated sulfuric acid. The mixture was heated to 70 ℃ and stirred overnight. After cooling, the mixture was concentrated and the residue was dissolved in ethyl acetate (50 mL). The resulting solution was washed with saturated aqueous sodium bicarbonate (30mL) and brine (30mL) over Na₂SO₄(s) drying and filtering. The filtrate was concentrated to give a mixture of the title compound as a yellow oil (740mg, 93% yield). LC-MS (ESI): r_T＝1.83min，C₁₅H₁₈O₂Calculated mass of 230.1, found value of M/z 231.3[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.29-7.15(m,5H),6.05(t,J＝6.0Hz,0.5H),6.00(t,J＝6.4Hz,0.5H),3.66(s,1.5H),3.65(s,1.5H),2.74-2.38(m,4.5H),2.30-1.84(m,3H),1.72-1.49(m,1.5H)。

Intermediate a 23: methyl 4-phenylcycloheptane formate

To a solution of mixture of methyl 4-phenylcyclohept-3-enecarboxylate and methyl 4-phenylcyclohept-4-enecarboxylate intermediate A22(1.64g, 7.13mmol) in methanol (50mL) was added 10% wt palladium on charcoal (160 mg). The resulting reaction mixture was then stirred under a hydrogen atmosphere at 30 ℃ overnight. The catalyst was then filtered. The filtrate was concentrated to give the title compound as a yellow oil (1.6g, 97% yield).¹H NMR(400MHz,CD₃OD)δ7.25-7.09(m,5H),3.66(s,3H),2.74-2.63(m,2H),2.09-1.46(m,10H)。

Acid 13: 4- (methoxycarbonyl) cycloheptanecarboxylic acid

To a solution of sodium periodate (26.6g, 124mmol) in acetonitrile (13mL) and water (26mL) was added a solution of methyl 4-phenylcycloheptanecarboxylate intermediate A23(1.6g, 6.90mmol) in carbon tetrachloride (13mL) and ruthenium trichloride (29mg, 0.14 mmol). After stirring overnight at room temperature, the mixture was filtered and the filtrate was adjusted to pH 8-9 using saturated aqueous sodium bicarbonate. The resulting solution was washed with dichloromethane (20mL), acidified to pH 2-3 with 1N aqueous hydrochloric acid, and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed with brine (30mL) and Na₂SO₄(s) drying and filtering. The filtrate was concentrated to give the title compound as a yellow oil (1.2g, 87% yield). LC-MS (ESI): r_T0.29min (MS peak), C₁₀H₁₆O₄Calculated mass of 200.1, found value of M/z 199.1[ M-H [)]^-。¹H NMR(300MHz,CD₃OD)δ3.66(s,3H),2.59-2.47(m,2H),2.07-1.44(m,10H)。

Acid 36: 4- (N-methylsulfamoyl) cyclohexanecarboxylic acid

Intermediate 24: benzyl 4-hydroxycyclohexane-1-carboxylate

To a solution of 4-hydroxycyclohexanecarboxylic acid (24.8g, 172mmol) in N, N-dimethylformamide (125mL) was added potassium carbonate (25.0g, 184mmol) and benzyl bromide (28.0g, 163mmol) at room temperature. After stirring overnight under a nitrogen atmosphere, the mixture was poured into water (200mL) and extracted twice with ethyl acetate (150 mL). The combined organic layers were washed with brine (100mL) and Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound as a colourless oil (36.0g, 89% yield). LC-MS (ESI): r_T＝1.50min，C₁₄H₁₈O₃Calculated mass of 234.1, M/z found value 235.3[ M + H [ ]]⁺。

Intermediate 25: benzyl 4- ((methylsulfonyl) oxy) cyclohexanecarboxylate

To a solution of benzyl 4-hydroxycyclohexanecarboxylate intermediate 24(27.0g, 115mmol) and N-ethyl-N-isopropylpropan-2-amine (22.3g, 173mmol) in dichloromethane (300mL) at 0 deg.C was slowly added methanesulfonyl chloride (14.5g, 127 mmol). After stirring at room temperature for 1 hour, the mixture was diluted in dichloromethane (500mL), washed with water (100mL), brine (100mL), and Na₂SO_4(s)Drying, filtration and concentration gave the title compound (36.5g, crude) as a pale yellow solid.¹H NMR(400MHz,DMSO-d₆)δ7.40-7.31(m,5H),5.11(s,1H),5.09(s,1H),4.88-4.78(m,0.4H),4.64-4.53(m,0.6H),3.17(s,3H),2.57-2.52(m,0.4H),2.45-2.37(m,0.6H),2.11-2.03(m,1H),2.00-1.92(m,1H),1.88-1.80(m,1H),1.75-1.69(m,3H),1.60-1.47(m,2H)。

Intermediate 26: benzyl 4- (acetylthio) cyclohexanecarboxylate

To a solution of benzyl 4- ((methylsulfonyl) oxy) cyclohexanecarboxylate intermediate 25(36.5g, crude, ca. 115mmol) in N, N-dimethylformamide (350mL) was added potassium ethanethiol (15.8g, 139 mmol). The mixture was stirred at 80 ℃ for 5 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted in water (500 mL). The resulting mixture was extracted three times with ethyl acetate (200 mL). The combined organic layers were washed with water (100mL), brine (100mL) and Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound (26.0g, 77% yield) as a brown oil.¹H NMR(400MHz,DMSO-d₆)δ7.40-7.30(m,5H),5.10(s,1.4H),5.09(s,0.6H),3.71-3.65(m,0.8H),3.30-3.23(m,0.2H),2.58-2.52(m,1H),2.30(s,2H),2.29(s,1H),1.97-1.88(m,1H),1.84-1.72(m,3H),1.69-1.57(m,3H),1.50-1.37(m,1H)。

Intermediate 27: benzyl 4- (N-methylsulfamoyl) cyclohexanecarboxylate

To a solution of benzyl 4- (acetylthio) cyclohexanecarboxylate intermediate 26(2.00g, 6.85mmol) in acetonitrile (20mL) at 0 deg.C was added 2M aqueous hydrochloride solution (1 mL). 1-Chloropyrrolidine-2, 5-dione (3.66g, 27.4mmol) was then added. After stirring at 0 ℃ for 1 hour under a nitrogen atmosphere, the mixture was diluted in ether (100mL), washed with water (30mL), brine (30mL), and then Na₂SO_4(s)Dried, filtered and concentrated to give a residue, which is dissolved in tetrahydrofuran (10mL) and cooled to 0 ℃.2M methylamine in tetrahydrofuran (17mL, 34.3mmol) was then added. After stirring at 0 ℃ for 1 hour, the mixture was diluted in water (50mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with water (20mL), 0.5M aqueous hydrochloride (20mL), brine (20mL), and Na₂SO_4(s)Drying, filtering and concentrating to obtainThe residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the title compound (2.00g, 94% yield) as a white solid.¹H NMR(300MHz,DMSO-d₆)δ7.43-7.29(m,5H),6.91-6.81(m,1H),5.13(s,1H),5.19(s,1H),3.13-2.96(m,1H),2.77-2.70(m,0.5H),2.57-2.53(m,3H),2.44-2.32(m,0.5H),2.18-2.05(m,3H),1.92-1.79(m,1H),1.65-1.34(m,4H)。

Acid 36: 4- (N-methylsulfamoyl) cyclohexanecarboxylic acid

To a solution of benzyl 4- (N-methylsulfamoyl) cyclohexanecarboxylate intermediate 27(2.45g, 7.88mmol) in methanol (50mL) was added 10% wt palladium on charcoal (245 mg). The reaction mixture was stirred under an atmosphere of hydrogen (50psi) at room temperature overnight. The completed reaction mixture was filtered and the filter cake was washed with methanol (20 mL). The filtrate was concentrated to give the title compound as a pale yellow solid (1.50g, 86% yield).¹H NMR(300MHz,DMSO-d₆)δ6.89-6.77(m,1H),3.04-2.89(m,1H),2.57-2.55(m,3H),2.20-1.79(m,4H),1.62-1.28(m,4H)。

Acid 37: 4- (pyrrolidin-1-ylsulfonyl) cyclohexane-1-carboxylic acid

Intermediate 28: benzyl 4- (pyrrolidin-1-ylsulfonyl) cyclohexanecarboxylate

To a solution of benzyl 4- (acetylthio) cyclohexanecarboxylate intermediate 26(2.70g, 9.25mmol) in acetonitrile (40mL) was added 2M aqueous hydrochloride solution (1.4mL, 2.78mmol), 1-chloro-pyrrolidine-2, 5-dione (4.90g, 37.0mmol) at 0 ℃. After stirring at 0 ℃ for 1 hour, the reaction mixture was poured into water (200mL) and extracted twice with ethyl acetate (100 mL). The combined organic layers were washed with water (100mL), brine (100mL) and Na₂SO_4(s)Dried, filtered and concentrated to give the crude product (3.37g), which was used in the next step without further purification. To a solution of the crude product (1.70g) in tetrahydrofuran (20mL) was added pyrrolidine (1.60g, 23.2mmol) at 0 ℃. After stirring at 0 ℃ for 1 hour, the solvent was removed to give a residue which was washed with waterPurification by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1 to 3:1) gave the title compound (1.60g, 99% yield) as a yellow solid. LC-MS (ESI): r_T＝1.89min，C₁₈H₂₅NO₄Calculated mass of S351.2, M/z found value 352.4[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ7.42-7.31(m,5H),5.17(s,0.9H),5.13(s,1.1H),3.42-3.35(m,4H),3.03-2.90(m,1H),2.75-2.67(m,0.4H),2.41-2.33(m,1.4H),2.25-2.17(m,2.2H),2.07-2.00(m,1H),1.96-1.88(m,4H),1.85-1.71(m,1H),1.67-1.47(m,3H)。

Acid 37: 4- (pyrrolidin-1-ylsulfonyl) cyclohexane-1-carboxylic acid to a solution of benzyl 4- (pyrrolidin-1-ylsulfonyl) cyclohexanecarboxylate intermediate 28(1.60g, 4.56mmol) in methanol (40mL) was added 5% wt palladium on charcoal (160 mg). After stirring overnight at 25 ℃ under an atmosphere of hydrogen (50psi), the reaction mixture was filtered through celite. The filtrate was concentrated to give the title compound as a yellow solid (1.40g, crude) which was used in the next step without further purification.¹H NMR(300MHz,DMSO-d₆)δ12.12(br s,1H),3.33-3.11(m,6H),2.60-2.54(m,0.4H),2.28-2.14(m,0.6H),2.10-1.95(m,3H),1.89-1.80(m,4H),1.60-1.34(m,4H)。

Acid 38: 3- (N-methylacetamido) cyclopentanecarboxylic acid

Intermediate 29: benzyl 3-oxocyclopentane carboxylate

To a solution of 3-oxocyclopentanecarboxylic acid (5.00g, 39.1mmol) in N, N-dimethylformamide (50mL) was added potassium carbonate (16.2g, 117mmol) and benzyl bromide (13.4g, 78.2 mmol). After stirring at room temperature overnight, the mixture was poured into water (200mL) and extracted twice with ethyl acetate (200 mL). The combined organic layers were washed with water (200mL) and brine (200mL) and washed with Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1 to 8:1) to give the title compound as a colorless oil (8.00g, 94% yield).¹H NMR(300MHz,CDCl₃)δ7.43-7.33(m,5H),5.18(s,2H),3.25-3.14(m,1H),2.61-2.10(m,6H)。

Intermediate 30: benzyl 3- ((tert-butoxycarbonyl) (methyl) amino) cyclopentane-carboxylate

To a solution of benzyl 3-oxocyclopentane carboxylate EO 8495-514.2 (4.20g, 19.3mmol) in 1, 2-dichloroethane (50mL) was added methylamine hydrochloride (1.90g, 28.6mmol) and N, N-diisopropylethylamine (3.70g, 28.7 mmol). The mixture was stirred at room temperature for 1 hour, then sodium cyanoborohydride (3.00g, 47.8mmol) was added. After the reaction mixture was stirred at room temperature overnight, N-diisopropylethylamine (7.40g, 57.4mmol) and di-tert-butyl dicarbonate (10.5g, 48.2mmol) were added. After stirring at room temperature for 3 hours, the mixture was diluted with dichloromethane (100mL) and washed twice with water (100mL) and with brine (100mL), Na₂SO_4(s)Dried and filtered. The filtrate was concentrated and purified by C18 column (acetonitrile: water 70% to 75%) to give the title compound as a yellow oil (1.70g, 22% yield). LC-MS (ESI): r_T＝1.52min，C₁₉H₂₇NO₄Calculated mass of (3) < 333.2 >, found value of M/z < 334.3 > [ M + H >]⁺。¹H NMR(300MHz,CDCl₃)δ7.40-7.30(m,5H),5.13(s,2H),2.96-2.77(m,1H),2.73(s,3H),2.20-2.03(m,2H),1.95-1.67(m,5H),1.45(s,9H)。

Intermediate 31: benzyl 3- (N-methylacetamido) cyclopentanecarboxylate

To a solution of benzyl 3- ((tert-butoxycarbonyl) methylamino) cyclopentanecarboxylate intermediate 30(1.70g, 5.04mmol) in dichloromethane (15mL) was added trifluoroacetic acid (15 mL). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to remove volatiles. The residue was dissolved in dichloromethane (20mL) and triethylamine (1.27g, 12.6mmol) and acetic anhydride (771mg, 7.56mmol) were added. After stirring at room temperature for 2 hours, the mixture was diluted with dichloromethane (30mL) and washed with water (30mL) and brine (30mL) over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated and purified by C18 column (acetonitrile: water 55% to 60%) to give the title compound as a colourless oil (1.07g, 76% yield). LC-MS (ESI): r_T＝1.49min，C₁₆H₂₁NO₃Calculated mass of 275.2, M/z found value 276.4[ M + H ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ7.51-7.30(m,5H),5.11(s,2H),4.91-4.82(m,0.5H),4.33-4.22(m,0.5H),3.04-2.86(m,1H),2.79(s,1.5H),2.65(s,1.5H),2.03-1.52(m,9H)。

Acid 38: 3- (N-methylacetamido) cyclopentanecarboxylic acid

To a solution of benzyl 3- (N-methylacetamido) cyclopentanecarboxylate intermediate 31(1.07g, 3.89mmol) in methanol (10mL) was added 10% wt palladium on charcoal (107 mg). After stirring overnight at room temperature under a hydrogen atmosphere, the mixture was filtered. The filtrate was concentrated to give the title compound as a white solid (710mg, 99% yield).¹H NMR(300MHz,DMSO-d₆)δ12.13(s,1H),4.91-4.78(m,0.5H),4.32-4.17(m,0.5H),2.87-2.67(m,4H),2.03-1.50(m,9H)。

Acid 39: (cis) -4-methyltetrahydrofuran-2-carboxylic acid

Intermediate 32: methyl 4-methylfuran-2-carboxylate

To a solution of methyl 4-bromofuran-2-carboxylate (2.00g, 9.75mmol) in 1, 4-dioxane (50mL) was added a solution of 2,4, 6-trimethyl-1, 3,5,2,4, 6-trioxatriborane (1.84g, 14.6mmol) and potassium carbonate (4.04g, 29.3mmol) in water (10mL) at room temperature under a nitrogen atmosphere. The mixture was degassed with nitrogen for 10 min, then bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) -palladium (II) dichloride (690mg, 0.975mmol) was added at room temperature. After stirring overnight at 100 ℃ under a nitrogen atmosphere, the mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The separated organic layer was washed three times with water (60mL) and Na₂SO_4(s)Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 8:1) to give the title compound as a yellow oil (760mg, 56% yield).¹HNMR(400MHz,DMSO-d₆)δ7.72(s,1H),7.18(s,1H),3.80(s,3H),2.03(s,3H)。

Intermediate 33: (cis) -methyl-4-methyltetrahydrofuran-2-carboxylate

To a solution of methyl 4-methylfuran-2-carboxylate 32(760mg, 5.42mmol) in propan-2-ol (50mL) was added 5% wt ruthenium charcoal (100mg) at room temperature under a nitrogen atmosphere. After replacing the inert nitrogen atmosphere with hydrogen, the mixture was stirred at 100 ℃ overnight under a hydrogen atmosphere using a balloon. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (780mg, 99% yield).¹H NMR(300MHz,DMSO-d₆)δ4.43-4.38(m,1H),3.92-3.87(m,1H),3.64(s,3H),3.33-3.28(m,1H),2.45-2.19(m,2H),1.52-1.42(m,1H),0.97(d,J＝6.6Hz,3H)。

Acid 39: (cis) -4-methyltetrahydrofuran-2-carboxylic acid

To a solution of (cis) -methyl 4-methyltetrahydrofuran-2-carboxylate 33(780mg, 5.42mmol) in tetrahydrofuran (20mL) was added a solution of lithium hydroxide monohydrate (2.27g, 54.2mmol) in water (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with ethyl acetate (100mL) and acidified to pH 1 with concentrated aqueous hcl (about 20 mL). The aqueous phase was separated and extracted three times with ethyl acetate (20 mL). The combined organic layers were passed over anhydrous Na₂SO_4(s)Dried, filtered and concentrated to give the title compound as a yellow oil (300mg, 43% yield).¹H NMR(300MHz,DMSO-d₆)δ12.28(s,1H),4.29(t,J＝7.8Hz,1H),3.88(t,J＝7.2Hz,1H),3.30(t,J＝8.1Hz,1H),2.43-2.36(m,1H),2.26-2.16(m,1H),1.50-1.41(m,1H),0.97(d,J＝6.6Hz,3H)。

Acid 40: 4- ((tert-butoxycarbonyl) amino) cycloheptanecarboxylic acid

Intermediate 34: methyl 4- ((tert-butoxycarbonyl) amino) cycloheptane carboxylate

To a solution of 4- (methoxycarbonyl) cycloheptanecarboxylic acid EO8495 — 393.7(6.10g, 30.5mmol) in tert-butanol (300mL) was added triethylamine (9.20g, 91.4mmol) and diphenylphosphoryl azide (9.10g,33.5 mmol). The mixture was heated to 105 ℃ and stirred at 105 ℃ for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated, and a saturated aqueous sodium bicarbonate solution (300mL) was added to the residue, and extracted three times with ethyl acetate (200 mL). The combined organic layers were passed over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound (6.20g, 75% yield) as a yellow oil. LC-MS (ESI): r_T＝2.220min，C₁₄H₂₅NO₄Calculated mass of 271.2, found M/z value of 216.1[ M + H-56 [)]⁺And 172.1[ M + H-Boc]⁺。

Intermediate 35: benzyl 4- ((tert-butoxycarbonyl) amino) cycloheptane carboxylate

To a solution of methyl 4- ((tert-butoxycarbonyl) amino) cycloheptanecarboxylate 34(6.20g, 22.8mmol) in methanol (40mL) was added a solution of lithium hydroxide monohydrate (1.90g, 45.6mmol) in water (10mL) at 0 ℃. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure to remove volatiles and water (30mL) was added and extracted three times with ethyl acetate (30 mL). The aqueous layer was acidified to pH 2-3 with saturated citric acid (20mL) and extracted three times with ethyl acetate (30 mL). The latter organic layer was washed with brine (30mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated to give a residue, which was dissolved in N, N-dimethylformamide (50mL), followed by addition of potassium carbonate (8.00g, 58.0mmol) and benzyl bromide (6.70g, 39.0mmol) at 0 ℃. After stirring at room temperature overnight, water (500mL) was added to the mixture and extracted four times with ethyl acetate (50 mL). The combined organic layers were passed over Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:1 to 30:1 to 20:1) to give the title compound as a pale yellow oil (3.50g, 53% yield). LC-MS (ESI): r_T＝2.516min，C₂₀H₂₉NO₄Has a calculated mass of 347.2, M/z found value of 292.1[ M + H-56 [ ]]⁺,248.1[M+H-100]⁺。¹H NMR(300MHz,CDCl₃)δ7.48-7.30(m,5H),5.14(s,2H),4.64-4.30(m,1H),3.77-3.49(m,1H),2.69-2.43(m,1H),2.20-1.54(m,8H),1.45(s,9H),1.40-1.20(m,2H)。

Acid 40: 4- ((tert-butoxycarbonyl) amino) cycloheptanecarboxylic acid

To a solution of benzyl 4- ((tert-butoxycarbonyl) amino) cycloheptanecarboxylate 35(3.50g, 10.0mmol) in methanol (50mL) was added 10% wt palladium on charcoal (350mg), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. After filtration, the filtrate was concentrated to give the title compound as a pale yellow oil (2.58g, 100% yield). LC-MS (ESI): r_T＝1.67min，C₁₃H₂₃NO₄Calculated mass 257.2, M/z found 202.4[ M + H-56 ]]⁺。¹H NMR(300MHz,CDCl₃)δ4.74-4.30(m,1H),3.76-3.52(m,1H),2.74-2.39(m,1H),2.13-1.60(m,8H),1.49(s,9H),1.41-1.28(m,2H)。

Acid 41: 3- ((tert-butoxycarbonyl) amino) bicyclo [1.1.1] pentane-1-carboxylic acid

Intermediate 36: methyl 3- ((tert-butoxycarbonyl) amino) bicyclo [1.1.1] pentane-1-carboxylate

To 3- (methoxycarbonyl) bicyclo [1.1.1] at room temperature]To a solution of pentane-1-carboxylic acid (1.00g, 5.90mmol) in t-butanol (10mL) was added diphenylphosphorylazide (1.60g, 5.90mmol) and triethylamine (596mg, 5.90 mmol). After stirring at 105 ℃ for 24 hours under a nitrogen atmosphere and then cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with ethyl acetate (20 mL). The mixture was washed three times with saturated aqueous ammonium chloride (20mL), saturated aqueous sodium bicarbonate (20mL) and brine (20mL) and then over Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound as a white solid (0.91g, 76% yield). LC-MS (ESI): r_T＝1.844min，C₁₂H₁₉NO₄Calculated mass of 241.1, M/z found value 242.2[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ4.96(br s,1H),3.70(s,3H),2.30(s,6H),1.46(s,9H)。

Acid 41: 3- ((tert-butoxycarbonyl) amino) bicyclo [1.1.1] pentane-1-carboxylic acid

To methyl 3- ((tert-butoxycarbonyl) amino) bicyclo [1.1.1]To a solution of intermediate 36 pentane-1-carboxylate (850mg, 3.52mmol) in tetrahydrofuran (10mL), methanol (3mL) and water (3mL) was added lithium hydroxide monohydrate (296mg, 7.04 mmol). After stirring at room temperature overnight, the mixture was poured into water (30mL) and the pH was adjusted to 3-4 with 1M aqueous hydrochloride solution (8 mL). The obtained aqueous solution was extracted three times with ethyl acetate (20 mL). The combined organic layers were passed over Na₂SO_4(s)Dried, filtered and concentrated to give the title product as a white solid (720mg, 90% yield). LC-MS (ESI): r_T＝0.661min，C₁₁H₁₇NO₄Calculated mass of (8) (227.1), found value of M/z 226.0[ M-H]^-。¹H NMR(300MHz,DMSO-d₆)δ12.35(s,1H),7.58(s,1H),2.10(s,6H),1.37(s,9H)。

Acid 42: (cis) -5- (ethoxycarbonyl) tetrahydrofuran-3-carboxylic acid

To a solution of 5- (ethoxycarbonyl) furan-3-carboxylic acid (7.00g, 38mmol) in isopropanol (50mL) was added 5% wt ruthenium charcoal (1.40g) at room temperature and the mixture was stirred under a hydrogen atmosphere (5.0MPa) at 100 ℃ overnight. After cooling to room temperature, the suspension was filtered and the filtrate was concentrated in vacuo to give the desired product as a colourless oil (7.10g, crude). LC-MS (ESI): r_T＝0.710min，C₈H₁₂O₅Calculated mass of 188.1, M/z found value 187.1[ M-H]^-。¹H NMR(300MHz,CDCl₃)δ9.15(br s,1H),4.55-4.50(m,1H),4.25-4.14(m,4H),3.25-3.15(m,1H),2.59-2.40(m,2H),1.29(t,J＝7.2Hz,3H)。

Acid 43:1, 4-dioxaspiro [4.5]]Decane-7-carboxylic acid

Intermediate 37: ethyl 1, 4-dioxaspiro [4.5] decane-7-carboxylate

To a solution of ethyl 3-oxocyclohexanecarboxylate (5.00g, 29.4mmol) in toluene (15mL) was added ethane-1, 2-diol (6.38g, 103mmol) and 4-methylbenzenesulfonic acid hydrate (67mg, 0.353mmol) at room temperature. After stirring at 25 ℃ for 20 h, the reaction mixture was concentrated under reduced pressure and the residue was redissolved in ethyl acetate (50mL) and water (60 mL). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (150 mL). The combined organic layers were washed twice with saturated aqueous sodium carbonate (100mL), brine (50mL), and Na₂SO_4(s)Drying, filtration and concentration under reduced pressure gave the title compound as a colourless oil (5.50g, 87% yield).

¹H NMR(300MHz,CDCl₃)δ4.15-4.08(m,2H),3.94(s,4H),2.62-2.53(m,1H),2.04-1.34(m,8H),1.26-1.21(m,3H)。

Acid 43: 1, 4-dioxaspiro [4.5] decane-7-carboxylic acid

To ethyl 1, 4-dioxaspiro [4.5] spiro at room temperature]To a solution of decane-7-carboxylate intermediate 37(2.00g, 9.35mmol) in tetrahydrofuran (15mL) and methanol (5mL) was added a solution of lithium hydroxide monohydrate (1.18g, 28.1mmol) in water (5 mL). After stirring at room temperature under a nitrogen atmosphere overnight, the reaction mixture was concentrated under reduced pressure, acidified with 2M aqueous hydrochloric acid until pH 3-4, and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed twice with brine (10mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 8:1 to 3:1) to give the title compound as a white solid (1.70g, 98% yield).¹HNMR(300MHz,DMSO-d₆)δ12.12(s,1H),3.85-3.83(m,4H),2.41-2.33(m,1H),1.86-1.21(m,8H)。

Acid 44: (cis) -4- (((tert-butyldiphenylsilyl) oxy) methyl) tetrahydrofuran-2-carboxylic acid

Intermediate 38: (cis) -Ethyl 4- (hydroxymethyl) tetrahydrofuran-2-carboxylate

To a solution of (cis) -5- (ethoxycarbonyl) tetrahydrofuran-3-carboxylic acid 42(4.50g, 24.0mmol) in tetrahydrofuran (150mL) at 0 deg.C was added 10M borane-methyl sulfide complex in tetrahydrofuran (2.9mL, 28.8 mmol). After stirring at room temperature under a nitrogen atmosphere for 4 hours, the mixture was quenched with methanol (30mL) and concentrated in vacuo to give a residue which was chromatographed on silica gel (dichloromethane: methanol 100:1) to give the desired product as a colourless oil (3.77g, 90% yield). LC-MS (ESI): r_T＝1.115min，C₈H₁₄O₄Calculated mass of (3) 174.1, found value of M/z 175.1[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ4.47-4.42(m,1H),4.24-4.12(m,2H),4.03-3.98(m,1H),3.87-3.83(m,1H),3.66-3.57(m,2H),2.58-2.37(m,2H),1.84-1.76(m,1H),1.29(t,J＝6.9Hz,3H)。

Intermediate 39: (cis) -Ethyl 4- (((tert-butyldiphenylsilyl) oxy) methyl) -tetrahydrofuran-2-carboxylate

To a solution of (cis) -ethyl 4- (hydroxymethyl) tetrahydrofuran-2-carboxylate 38(3.77g, 21.7mmol), imidazole (2.95g, 43.4mmol), and 4-dimethylaminopyridine (53mg, 0.434mmol) in dichloromethane (100mL) was added tert-butylchlorobenzylsilane (8.95g, 32.6 mmol). After stirring at room temperature under a nitrogen atmosphere overnight, the mixture was concentrated in vacuo to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the desired product as a yellow oil (3.28g, 37% yield). LC-MS (ESI): r_T＝2.901min，C₂₄H₃₂O₄Calculated mass of Si 412.2, found value of M/z 430.2[ M + NH ]₄]⁺。¹H NMR(400MHz,CDCl₃)δ7.73-7.65(m,4H),7.47-7.38(m,6H),4.46(t,J＝7.8Hz,1H),4.20(q,J＝7.2Hz,2H),4.07-4.02(m,1H),3.87(t,J＝7.8Hz,1H),3.65(d,J＝6.0Hz,2H),2.62-2.53(m,1H),2.43-2.33(m,1H),1.85-1.75(m,1H),1.28(t,J＝7.2Hz,3H),1.06(s,9H)。

Acid 44: (cis) -4- (((tert-butyldiphenylsilyl) oxy) methyl) tetrahydrofuran-2-carboxylic acid

To a solution of (cis) -ethyl 4- (((tert-butyldiphenylsilyl) oxy) methyl) tetrahydrofuran-2-carboxylate intermediate 39(3.28g, 7.96mmol) in tetrahydrofuran (40mL) and water (5mL) at 0 deg.C was added a solution of lithium hydroxide monohydrate (504mg, 12.0mmol) in water (5 mL). After stirring at 0 ℃ for 2h, the mixture was poured into water (20mL) and the pH was adjusted to 5-6 with 2M aqueous hydrochloride solution (6 mL). The obtained aqueous solution was extracted three times with ethyl acetate (30 mL). The combined organic layers were concentrated to give the desired product as a yellow oil (2.75g, 90% yield).¹H NMR(300MHz,CDCl₃)δ7.66-7.63(m,4H),7.48-7.37(m,6H),4.52-4.47(m,1H),4.15-4.03(m,1H),3.92-3.87(m,1H),3.69-3.56(m,2H),2.63-2.55(m,1H),2.51-2.41(m,1H),1.92-1.83(m,1H),1.06(s,9H)。

Acid 45: 4- (N, N-dimethylsulfamoyl) cyclohexanecarboxylic acid

Intermediate 40: benzyl 4- (chlorosulfonyl) cyclohexanecarboxylate

To a solution of benzyl 4- (acetylthio) cyclohexanecarboxylate intermediate 26(1.70g, 5.82mmol) in acetonitrile (30mL) at 0 deg.C under a nitrogen atmosphere was added 2M aqueous hydrochloride solution (1mL) and 1-chloropyrrolidine-2, 5-dione (3.10g, 23.3 mmol). After stirring at room temperature for 1 hour, the mixture was concentrated at room temperature under reduced pressure to give a residue, which was diluted with water (50mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed twice with brine (50mL) and Na₂SO_4(s)Dried, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to give the title compound (2.80g, according to¹Purity of H NMR 65%, 66% yield).¹H NMR(400MHz,CDCl₃)δ7.40-7.33(m,5H),5.17(s,2H),3.56-3.48(m,1H),2.43-2.38(m,2H),2.29-2.24(m,2H),2.04-1.93(m,2H),1.69-1.57(m,3H)。

Intermediate 41: benzyl 4- (N, N-dimethylsulfamoyl) cyclohexanecarboxylate

To a solution of benzyl 4- (chlorosulfonyl) cyclohexanecarboxylate intermediate 40(1.40g, 65% purity, 2.88mmol) in dry tetrahydrofuran (20mL) at 0 ℃ under a nitrogen atmosphere was added 2M dimethylamine in tetrahydrofuran (16mL, 32 mmol). After stirring overnight at room temperature, the mixture was quenched with water (50mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the title compound (810mg, 77% yield) as a white solid.¹H NMR(400MHz,CDCl₃)δ7.36-7.34(m,5H),5.16(s,0.9H),5.11(s,1.1H),3.02-2.95(m,1H),2.91(s,3.5H),2.87(s,2.5H),2.39-2.32(m,1.5H),2.19-2.17(m,2.5H),2.00-1.96(m,1H),1.81-1.71(m,1H),1.67-1.60(m,1H),1.55-1.43(m,2H)。

Acid 45: 4- (N, N-dimethylsulfamoyl) cyclohexanecarboxylic acid

To a solution of benzyl 4- (N, N-dimethylsulfamoyl) cyclohexanecarboxylate intermediate 41(810mg, 2.49mmol) in methanol (20mL) was added 10% wt palladium on charcoal (81 mg). After stirring overnight at room temperature under a balloon of hydrogen atmosphere, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound as a white solid (500mg, 85% yield).¹HNMR(400MHz,CDCl₃)δ3.04-2.96(m,1H),2.93-2.92(m,6H),2.37-2.31(m,1.5H),2.22-2.19(m,2.5H),2.02-1.98(m,1H),1.87-1.76(m,1H),1.68-1.47(m,3H)。

Acid 46: 4- (N-Isopropylsulfamoyl) cyclohexanecarboxylic acid

Intermediate 42: benzyl 4- (N-isopropylsulfamoyl) cyclohexanecarboxylate

To benzyl 4- (Acetylthio) cyclohexanecarboxylate intermediate 26(700mg, 2.40mmol) in acetonitrile (12mL) at 0 deg.C under a nitrogen atmosphereTo the solution were added 2M aqueous hydrochloride (0.4mL) and 1-chloropyrrolidine-2, 5-dione (1.28g, 9.60 mmol). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give a residue at room temperature. It was diluted with water (10mL) and then extracted three times with ethyl acetate (10 mL). The combined organic layers were washed twice with brine (10mL) and Na₂SO_4(s)Dried, filtered and concentrated under reduced pressure to give a residue which is diluted in dry tetrahydrofuran (20mL) and then 2M isopropylamine (709mg, 12.0mmol) in tetrahydrofuran (6mL) is added to the resulting solution and stirred at 0 ℃ for 4 h. The mixture was concentrated under reduced pressure, quenched with water (10mL), and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1 to 2:1) to give the title compound as a white solid (630mg, 77% yield).¹H NMR(300MHz,CDCl₃)δ7.42-7.33(m,5H),5.16(s,0.7H),5.13(s,1.3H),3.88-3.73(m,1H),3.67-3.57(m,1H),2.91-2.78(m,1H),2.76-2.69(m,0.3H),2.42-2.18(m,4H),2.11-2.06(m,0.7H),1.84-1.70(m,0.7H),1.66-1.45(m,3.3H),1.26-1.21(m,6H)。

Acid 46: 4- (N-Isopropylsulfamoyl) cyclohexanecarboxylic acid

To a solution of benzyl 4- (N-isopropylsulfamoyl) cyclohexanecarboxylate (630mg, 1.86mmol) in methanol (20mL) was added 10% wt palladium on charcoal (70 mg). After stirring overnight at room temperature under a balloon of hydrogen atmosphere, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound as a white solid (440mg, 95% yield).¹H NMR(400MHz,CDCl₃)δ4.10-3.99(m,1H),3.67-3.57(m,1H),2.91-2.79(m,1H),2.73-2.70(m,0.3H),2.37-2.19(m,4H),2.11-2.06(m,0.7H),1.84-1.73(m,0.7H),1.64-1.44(m,3.3H),1.25-1.22(m,6H)。

Acid 47: (cis) -4- ((tert-butoxycarbonyl) amino) tetrahydrofuran-2-carboxylic acid

Intermediate 43: ethyl 4- ((tert-butoxycarbonyl) amino) furan-2-carboxylate

To a solution of 5- (ethoxycarbonyl) furan-3-carboxylic acid (4.00g, 21.7mmol) in t-butanol (100mL) was added triethylamine (2.40g, 23.8mmol) and diphenylphosphoryl azide (7.00g, 25.5 mmol). After stirring at 100 ℃ for 24 h under a nitrogen atmosphere, it was cooled to room temperature and concentrated under reduced pressure to give a residue, which was suspended in ethyl acetate (50mL) and saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (50mL) and brine (50mL) over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give the desired product as a pale yellow solid (4.00g, 73% yield). LC-MS (ESI): r_T＝2.179min，C₁₂H₁₇NO₅Calculated mass of 255.11, M/z found 200.1[ M + H-56 ]]⁺。¹H NMR(300MHz,CDCl₃)δ7.88(br s,1H),7.03(s,1H),6.35(br s,1H),4.36(q,J＝7.2Hz,2H),1.52(s,9H),1.38(t,J＝7.2Hz,3H)。

Intermediate 44: (cis) -Ethyl 4- ((tert-butoxycarbonyl) amino) tetrahydrofuran-2-carboxylate

To a solution of ethyl 4- ((tert-butoxycarbonyl) amino) furan-2-carboxylate intermediate 43(4.00g, 15.7mmol) in isopropanol (80mL) was added 5% wt ruthenium/charcoal (200 mg). After stirring overnight at 100 ℃ under hydrogen atmosphere (3Mpa), the reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with isopropanol (200mL) and methanol (100 mL). The filtrate was concentrated to give the desired product as a black solid (4.00g, 98.5% yield). LC-MS (ESI): r_T＝2.001min，C₁₂H₂₁NO₅Calculated mass of 259.14, M/z found 160.1[ M + H-100 ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ6.97(br s,1H),4.41(t,J＝7.2Hz,1H),4.11(q,J＝7.2Hz,2H),4.03-3.94(m,1H),3.87(t,J＝6.9Hz,1H),3.54(t,J＝6.9Hz,1H),2.47-2.40(m,1H),1.91-1.82(m,1H),1.37(s,9H),1.20(t,J＝6.9Hz,3H)。

Acid 47: (cis) -4- ((tert-butoxycarbonyl) amino) tetrahydrofuran-2-carboxylic acid

To a solution of (cis) -ethyl 4- ((tert-butoxycarbonyl) amino) tetrahydrofuran-2-carboxylate intermediate 44(4.00g, 15.4mmol) in ethanol (40mL) was added lithium hydroxide monohydrate (970mg, 23.1mmol) in water (10 mL). After stirring at room temperature for 2 hours, the solution was poured into water (100mL) and acidified to pH 5-6 by addition of proton-type cation exchange resin (Amberlyst 15 ion exchange resin, 3 g). The resin was then filtered and washed three times with acetonitrile (100 mL). The filtrate was concentrated to give the desired product (3.60g, crude) as a yellow solid.¹H NMR(400MHz,DMSO-d₆)δ7.06-7.04(m,1H),4.28-4.24(m,1H),4.02-3.97(m,1H),3.84-3.80(m,1H),3.53-3.49(m,1H),2.42-2.35(m,1H),1.81-1.75(m,1H),1.37(s,9H)。

Acid 48: (cis) -4- (methylcarbamoyl) tetrahydrofuran-2-carboxylic acid

Intermediate 45: (cis) -Ethyl 4- (methylcarbamoyl) tetrahydrofuran-2-carboxylate

To a solution of (cis) -5- (ethoxycarbonyl) tetrahydrofuran-3-carboxylic acid (2.50g, 13.3mmol) and triethylamine (2.01g, 20.0mmol) in dichloromethane (60mL) at-20 deg.C under a nitrogen atmosphere was added ethyl chloroformate (1.87g, 17.3 mmol). After stirring for 10 min at-20 ℃, 2M methylamine in tetrahydrofuran (10mL, 20.0mmol) was added at-20 ℃ and the mixture was stirred at room temperature for 3 h. It was then concentrated to give a residue which was purified by silica gel column chromatography (dichloromethane: methanol ═ 50:1) to give the title compound as a yellow oil (1.70g, 66% yield). LC-MS (ESI): r_T＝0.716min，C₉H₁₅NO₄Calculated mass 201.1, found value of M/z 202.1[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ6.23(br s,1H),4.50-4.45(m,1H),4.23(q,J＝6.9Hz,2H),4.12-4.00(m,2H),3.04-2.94(m,1H),2.80(s,1.5H),2.78(s,1.5H),2.60-2.49(m,1H),2.35-2.27(m,1H),1.29(t,J＝7.2Hz,3H)。

Acid 48: (cis) -4- (methylcarbamoyl) tetrahydrofuran-2-carboxylic acid

To a solution of (cis) -ethyl 4- (methylcarbamoyl) tetrahydrofuran-2-carboxylate intermediate 45(1.07g, 5.32mmol) in tetrahydrofuran (20mL) and water (5mL) was added lithium hydroxide monohydrate (300mg, 7.14mmol) at room temperature. After stirring at room temperature under a nitrogen atmosphere for 2 hours, the mixture was concentrated to give a residue, which was diluted with water (10 mL). The pH of the aqueous solution was adjusted to 5-6 with 2M aqueous hydrochloride (4mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were concentrated to give the desired product as a white solid (660mg, crude). LC-MS (ESI): r_T＝0.273min，C₇H₁₁NO₄Calculated mass of 173.1, found value of M/z 174.1[ M + H ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ7.99-7.95(m,1H),4.36-4.31(m,1H),3.97-3.90(m,1H),3.71-3.64(m,1H),2.95-2.89(m,1H),2.57(s,1.5H),2.55(s,1.5H),2.41-2.31(m,1H),2.11-2.01(m,1H)。

Acid 49: 6- (tert-Butoxycarbonyl) tetrahydro-2H-pyran-3-carboxylic acid

Intermediate 46: ethyl 2-hydroxypent-4-enoate

To a solution of ethyl 2-oxoacetate (50.0g, 490mmol), allyltrimethylsilane (100g, 882mmol) in dichloromethane (1L) was added dropwise boron trifluoride etherate (104g, 735mmol) at 0 ℃. After stirring at room temperature for 2 hours, saturated aqueous sodium bicarbonate (1L) was added, and the organic layer was separated and purified over Na₂SO_4(s)Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title product as a yellow oil (41.0g, 58% yield).¹H NMR(400MHz,CDCl₃)δ5.85-5.76(m,1H),5.18-5.13(m,2H),4.28-4.21(m,3H),2.91(d,J＝6.0Hz,1H),2.62-2.55(m,1H),2.48-2.41(m,1H),1.35-1.24(m,3H)。

Intermediate 47: ethyl 2- ((2- (ethoxycarbonyl) allyl) oxy) pent-4-enoic acid ester

To a solution of ethyl 2-hydroxypent-4-enoate intermediate 46(41.0g, 285mmol) in N, N-dimethylformamide (500mL) at 0 deg.C was added 60% wt sodium hydride in mineral oil (13.7g, 342 mmol). Ethyl 2- (bromomethyl) acrylate (55.0g, 285mmol) was then added dropwise. After stirring overnight at room temperature, water (500mL) was added and the organic layer was separated over Na₂SO_4(s)Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 5:1) to give the title product as a white oil (16.0g, 22% yield).¹H NMR(400MHz,CDCl₃)δ6.31(d,J＝1.2Hz,1H),5.94(d,J＝1.6Hz,1H),5.88-5.78(m,1H),5.16-5.08(m,2H),4.39(d,J＝13.6Hz,1H),4.22(q,J＝7.2Hz,4H),4.14(d,J＝14.0Hz,1H),4.01(t,J＝6.4Hz,1H),2.56-2.52(m,2H),1.32-1.27(m,6H)。

Intermediate 48: diethyl 3, 6-dihydro-2H-pyran-2, 5-dicarboxylate

To a solution of ethyl 2- ((2- (ethoxycarbonyl) allyl) oxy) pent-4-enoate intermediate 47(15.0g, 58.6mmol) in dichloromethane (6L) was added grubbs ii catalyst (4.90g, 5.86mmol) at room temperature. After stirring overnight at room temperature, water (3L) was added and the organic layer was separated over Na₂SO_4(s)Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title product as a white oil (8.9g, 66% yield).¹H NMR(400MHz,CDCl₃)δ7.05-7.03(m,1H),4.64(dd,J＝16.8,1.6Hz,1H),4.37(dd,J＝16.8,2.4Hz,1H),4.29-4.15(m,5H),2.56-2.54(m,2H),1.33-1.26(m,6H)。

Intermediate 49: lithium 5- (ethoxycarbonyl) -3, 6-dihydro-2H-pyran-2-carboxylate

To a solution of diethyl 3, 6-dihydro-2H-pyran-2, 5-dicarboxylate intermediate 48(8.90g, 39.0mmol) in tetrahydrofuran (160mL) was added a solution of lithium hydroxide hydrate (1.50g, 35.1mmol) in water (40 mL). The reaction mixture was stirred at room temperature for 2 hours. After addition of water (200mL) and ethyl acetate (200mL), the aqueous phase was separated and reducedConcentration under pressure gave the title product as a white solid (6.4g, 80% yield), which was used in the next step without further purification. LC-MS (ESI): r_T＝0.323min，C₉H₁₁LiO₅Calculated mass of 206.1, M/z found value 199.1[ M-Li ]]^-。

Intermediate 50: 2-benzyl-5-ethyl-3, 6-dihydro-2H-pyran-2, 5-dicarboxylic acid ester

To a solution of lithium 5- (ethoxycarbonyl) -3, 6-dihydro-2H-pyran-2-carboxylate intermediate 49(6.40g, 31.0mmol) in N, N-dimethylformamide (100mL) was added benzyl bromide (15.9g, 93.0 mmol). After stirring at 25 ℃ overnight, the mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the product which was further purified by C18 column (acetonitrile: water ═ 10% to 95%) to give the title compound as a white solid (6.4g, 71% yield).¹H NMR(400MHz,CDCl₃)δ7.36(br s,5H),7.02(s,1H),5.23(s,2H),4.64(dd,J＝16.4,1.2Hz,1H),4.36(dd,J＝16.8,2.4Hz,1H),4.23-4.18(m,3H),2.56-2.55(m,2H),1.29(t,J＝6.8Hz,3H)。

Intermediate 51: 5- (ethoxycarbonyl) tetrahydro-2H-pyran-2-carboxylic acid

To a solution of 2-benzyl 5-ethyl 3, 6-dihydro-2H-pyran-2, 5-dicarboxylate intermediate 50(6.40g, 22.1mmol) in tetrahydrofuran (200mL) was added 10% wt palladium on charcoal (1.30 g). The reaction mixture was stirred at room temperature under a hydrogen atmosphere overnight. The completed reaction mixture was filtered and the filtrate was concentrated to give the title compound as a white oil (4.40g, 98% yield). LC-MS (ESI): r_T＝0.313min，C₉H₁₄O₅Calculated mass of 202.1, found value of M/z 201.1[ M-H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.68(br s,1H),4.40(dd,J＝11.2,2.4Hz,0.7H),4.31(d,J＝8.8Hz,0.3H),4.23-4.13(m,2.7H),3.99(d,J＝9.2Hz,0.3H),3.79(dd,J＝11.6,3.2Hz,0.8H),3.56(t,J＝11.2Hz,0.2H),2.64(t,J＝11.6Hz,0.3H),2.55(t,J＝4.0Hz,0.7H),2.35-2.14(m,1.5H),1.98-1.96(m,1H),1.88-1.82(m,1H),1.78-1.64(m,0.5H),1.27(t,J＝6.8Hz,3H)。

Intermediate 52: 2-tert-butyl 5-ethyltetrahydro-2H-pyran-2, 5-dicarboxylate

To a solution of intermediate 51(2.80g, 13.9mmol) of 5- (ethoxycarbonyl) tetrahydro-2H-pyran-2-carboxylic acid, di-tert-butyl dicarbonate (5.99g, 27.8mmol) in tert-butanol (20mL) was added 4-dimethylaminopyridine (169mg, 1.39mmol) at room temperature. After stirring overnight at 40 ℃, the mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give the title product as a yellow oil (3.10g, 86% yield).¹H NMR(400MHz,CDCl₃)δ4.31(dd,J＝11.6,5.6Hz,1H),4.18-4.12(m,2H),4.01(dd,J＝7.6,3.6Hz,0.8H),3.82-3.76(m,1H),3.50(t,J＝11.6Hz,0.2H),2.63(t,J＝11.6Hz,0.3H),2.52(t,J＝3.6Hz,0.7H),2.22-2.18(m,0.4H),2.07-2.05(m,0.6H),2.03-1.95(m,1H),1.85-1.83(m,1H),1.75-1.71(m,0.4H),1.64-1.58(m,0.6H),1.48(s,9H),1.27(t,J＝7.2Hz,3H)。

Acid 49: 6- (tert-Butoxycarbonyl) tetrahydro-2H-pyran-3-carboxylic acid

To a solution of 2-tert-butyl 5-ethyltetrahydro-2H-pyran-2, 5-dicarboxylate intermediate 52(4.00g, 15.5mmol) in methanol (80mL) and water (20mL) was added barium hydroxide octahydrate (2.40g, 7.75 mmol). After stirring at 25 ℃ overnight, the mixture was concentrated under reduced pressure to give a residue, and water (50mL) and ethyl acetate (200mL) were added. Macroporous resin (amberlyst)15 iron exchange resin (ca. 200g) was added to the separated aqueous phase and extracted three times with ethyl acetate (200 mL). Subjecting the separated organic layer to Na₂SO_4(s)Dried, filtered and concentrated under reduced pressure to give a residue which was used in the next step without further purification. LC-MS (ESI): r_T＝0.29min，C₁₁H₁₈O₅Calculated mass of 230.1, M/z found value 229.2[ M-H]^-。¹H NMR(300MHz,DMSO-d₆)δ12.41(br s,1H),4.08--3.97(m,2H)，3.84--3.79(m,0.3H),3.68--3.60(m,0.7H),2.50--2.41(m,1H),2.04--1.99(m,1H),1.91--1.83(m,1H),1.78--1.72(m,2H),1.41(s,9H)。

Acid 50: 5-oxo-1- (2-trimethylsilyl-ethoxymethyl) -pyrrolidine-3-carboxylic acid

Intermediate 53: methyl 5-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) pyrrolidine-3-carboxylate

To a solution of methyl 5-oxopyrrolidine-3-carboxylate (1.0g, 7.0mmol) in N, N-dimethylformamide (20mL) at 0 deg.C was added 60% wt sodium hydride in mineral oil (336mg, 8.4 mmol). After stirring for 30 minutes at 0 deg.C, (2- (chloromethoxy) ethyl) trimethylsilane (1.40g, 8.4mmol) was added slowly and the mixture was stirred at 0 deg.C under a nitrogen atmosphere for 3 hours. It was then poured into ice water (50mL) and extracted three times with ethyl acetate (30 mL). The combined organic layers were washed twice with brine (10mL) and Na₂SO_4(s)Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the title compound (786mg, 41% yield) as a colourless oil.¹H NMR(300MHz,CDCl₃)δ4.73(s,2H),3.76(s,3H),3.72-3.69(m,2H),3.50(t,J＝9.0Hz,2H),3.30-3.21(m,1H),2.82-2.64(m,2H),0.92(t,J＝8.4Hz,2H),0.01(s,9H)。

Acid 50: 5-oxo-1- (2-trimethylsilyl-ethoxymethyl) -pyrrolidine-3-carboxylic acid

To a solution of methyl 5-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) pyrrolidine-3-carboxylate intermediate 53(500mg, 1.83mmol) in methanol (1mL), tetrahydrofuran (3mL) and water (1mL) was added lithium hydroxide monohydrate (154mg, 3.66mmol) under a nitrogen atmosphere. After stirring at room temperature for 1 hour, the mixture was concentrated to give a residue, which was diluted with water (10mL), acidified to pH 5-6 with saturated aqueous citric acid solution, and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed twice with brine (10mL) and Na₂SO_4(s)Drying, filtration and concentration under reduced pressure gave the title compound as a colourless oil (470mg, 99% yield).¹H NMR(300MHz,CDCl₃)δ4.75(s,2H),3.79-3.73(m,2H),3.52(t,J＝8.4Hz,2H),3.36-3.25(m,1H),2.85-2.75(m,2H),0.93(t,J＝8.1Hz,2H),0.01(s,9H)。

Acid 51: 4- (N- (2-ethoxy-2-oxoethyl) sulfamoyl) cyclohexanecarboxylic acid

Intermediate 54: benzyl 4- (N- (2-ethoxy-2-oxoethyl) sulfamoyl) -cyclohexanecarboxylate

To a solution of benzyl 4- (acetylthio) cyclohexanecarboxylate (2.92g, 10.0mmol) in acetonitrile (30mL) at 0 deg.C were added 2M aqueous hydrochloride solution (1.25mL, 2.5mmol) and 1-chloropyrrolidine-2, 5-dione (5.30g, 40.0 mmol). After stirring at 0 ℃ for 1 hour, the mixture was quenched with water (100mL) and extracted twice with ether (100 mL). The combined organic layers were passed over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure at 30 ℃ to give a residue, which was dissolved in dry dichloromethane (20 mL). To the above solution were added ethyl 2-amino acetate hydrochloride (4.20g, 30.0mmol) and triethylamine (5.05g, 50.0 mmol). After stirring at 25 ℃ for 1 hour, the mixture was concentrated and diluted with dichloromethane (150 mL). The resulting solution was washed with 1M aqueous hydrochloride (100mL) and brine (100mL) over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1 to 2:1) to give the title compound as a pale yellow oil (1.40g, 88% yield). LC-MS (ESI): r_T＝1.64min，C₁₈H₂₅NO₆Calculated mass of S383.1, found value of M/z 384.4[ M + H]⁺。¹H NMR(300MHz,CDCl₃)δ7.42-7.31(m,5H),5.15(d,J＝12.3Hz,2H),4.71-4.62(m,1H),4.25(q,J＝7.2Hz,2H),3.91(dd,J＝13.5,5.7Hz,2H),3.00-2.87(m,1H),2.75-2.69(m,0.5H),2.41-2.31(m,2.5H),2.23-2.16(m,1H),2.13-2.08(m,1H),1.84-1.67(m,2H),1.56-1.49(m,2H),1.33-1.27(m,3H)。

Acid 51: 4- (N- (2-ethoxy-2-oxoethyl) sulfamoyl) cyclohexanecarboxylic acid

To benzyl 4- (N- (2-ethoxy-2-oxoethyl) sulfamoyl) cyclohexanecarboxylate intermediate 54 (1)40g, 3.65mmol) in methanol (20mL) was added 10% wt palladium on charcoal (300 mg). After stirring overnight at 25 ℃ under a balloon atmosphere of hydrogen, the mixture was filtered and the filtrate was concentrated to give the title compound as a white solid (1.00g, 94% yield).¹H NMR(300MHz,CDCl₃)δ4.91-4.78(m,1H),4.27-4.24(m,2H),3.94(s,2H),3.01-2.90(m,1H),2.72-2.70(m,0.5H),2.38-2.33(m,2H),2.25-2.11(m,2H),1.84-1.48(m,.3.5H),1.33-1.28(m,3H)。

Acid 52: (R) -4- ((3- (methoxycarbonyl) pyrrolidin-1-yl) sulfonyl) -cyclohexanecarboxylic acid

Intermediate 55: (R) -methyl 1- ((4- ((benzyloxy) carbonyl) cyclohexyl) sulfonyl) -pyrrolidine-3-carboxylic acid ester

To a solution of benzyl 4- (chlorosulfonyl) cyclohexanecarboxylate (2.2g, 6.94mmol) and triethylamine (2.10g, 20.8mmol) in dichloromethane (30mL) at 0 deg.C was added (R) -methylpyrrolidine-3-carboxylate hydrochloride (1.50g, 9.03 mmol). After stirring at room temperature for 16 h, the mixture was washed twice with water (30mL), then with brine (30mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 8:1 to 3:1) to give the title compound (2.30g, 82% yield) as a colorless oil.¹H NMR(300MHz,CDCl₃)δ7.42-7.28(m,5H),5.16(s,1H),5.11(s,1H),3.72(s,3H),3.69-3.62(m,1H),3.59-3.40(m,3H),3.17-3.05(m,1H),3.02-2.89(m,1H),2.73-2.65(m,0.5H),2.42-2.29(m,1.5H),2.27-2.11(m,4H),2.08-1.94(m,1H),1.84-1.71(m,1H),1.60-1.42(m,3H)。

Acid 52: (R) -4- ((3- (methoxycarbonyl) pyrrolidin-1-yl) sulfonyl) -cyclohexanecarboxylic acid

To a solution of (R) -methyl 1- ((4- ((benzyloxy) carbonyl) cyclohexyl) sulfonyl) pyrrolidine-3-carboxylate intermediate 55(2.30g, 5.62mmol) in methanol (80mL) was added 10% wt palladium on charcoal (595mg, 0.562mmol) at room temperature. After stirring overnight at room temperature under a hydrogen atmosphere (1atm)The mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the title compound as a white solid (1.79g, 99% yield).¹H NMR(300MHz,CDCl₃)δ3.73(s,3H),3.71-3.66(m,1H),3.62-3.43(m,3H),3.19-3.08(m,1H),3.05-2.90(m,1H),2.75-2.67(m,0.5H),2.40-2.28(m,1.5H),2.27-2.15(m,4H),2.10-1.98(m,1H),1.90-1.74(m,1H),1.71-1.44(m,3H)。

Acid 53: 3- ((tert-butyldiphenylsilyl) oxy) cyclobutanecarboxylic acid

Intermediate 56: methyl 3- ((tert-butyldiphenylsilyl) oxy) cyclobutanecarboxylate

Tert-butylchlorodiphenylsilane (8.66g, 31.5mmol) was slowly added to a solution of methyl 3-hydroxycyclobutanecarboxylate (3.90g, 30.0mmol) and 1H-imidazole (2.45g, 36.0mmol) in tetrahydrofuran (50mL) at 0 deg.C. After stirring at room temperature for 16 h, the mixture was washed with saturated aqueous sodium bicarbonate (150mL), then brine (150mL), over Na₂SO_4(s)Drying, filtration and concentration gave the title compound as a colourless oil (10.5g, 95% yield). LC-MS (ESI): r_T＝1.87min，C₂₂H₂₈O₃Calculated mass of Si 368.2, found value of M/z 369.4[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ7.67-7.65(m,4H),7.44-7.28(m,6H),4.15-4.10(m,1H),3.68(s,3H),2.37-2.34(m,5H),1.04(s,9H)。

Acid 53: 3- ((tert-butyldiphenylsilyl) oxy) cyclobutanecarboxylic acid

To a solution of methyl 3- ((tert-butyldiphenylsilyl) oxy) cyclobutanecarboxylate intermediate 56(3.50g, 9.50mmol) in tetrahydrofuran (12mL), methanol (4mL) and water (4mL) was added lithium hydroxide monohydrate (798mg, 19.0mmol) at 0 ℃ under a nitrogen atmosphere. After stirring at room temperature for 4 hours, the mixture was diluted with water (150mL), concentrated at room temperature under reduced pressure, acidified with 1M aqueous hydrochloric acid (20mL), and extracted with ethyl acetate (150 mL). The organic layer was washed with brine (150mL) andNa₂SO_4(s)dried and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound as a colorless oil (3.10g, 87% yield), which was used without further purification.¹H NMR(300MHz,CDCl₃)δ7.68-7.66(m,4H),7.45-7.37(m,6H),4.16-4.13(m,1H),2.44-2.37(m,5H),1.05(s,9H)。

Acid 54: 4- (N- (2- ((tert-butyldimethylsilyl) oxy) ethyl) methylsulfonamido) -cyclohexanecarboxylic acid

Intermediate 54 a: benzyl 4- ((2-hydroxyethyl) amino) cyclohexanecarboxylate

To a solution of benzyl 4-oxocyclohexanecarboxylate (4.80g, 20.7mmol) and 2-aminoethanol (12.6g, 210mmol) in methanol (40mL) at 0 deg.C under a nitrogen atmosphere was added sodium cyanoborohydride (2.60g, 41.4 mmol). After stirring overnight at room temperature, the mixture was concentrated under reduced pressure to give a residue which was dissolved in dichloromethane (50mL), washed twice with water (20mL) and then twice with brine (20mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (5.40g, 93% yield).¹H NMR(400MHz,DMSO-d₆)δ7.38-7.31(m,5H),5.11-5.08(m,2H),4.69-4.62(m,0.5H),4.45-4.31(m,0.5H),3.50-3.46(m,1H),3.44-3.40(m,2H),2.62-2.53(m,2H),2.39-2.26(m,1H),2.11-1.82(m,4H),1.66-1.49(m,2H),1.45-1.31(m,2H),1.06-0.96(m,1H)。

Intermediate 54 b: benzyl 4- ((2- ((tert-butyldimethylsilyl) oxy) ethyl) amino) -cyclohexanecarboxylate

To a solution of benzyl 4- ((2-hydroxyethyl) amino) benzylcarboxylate intermediate 54a (5.40g, 19.5mmol) in dichloromethane (50mL) at 0 ℃ under a nitrogen atmosphere was added N, N-diisopropylethylamine (3.80g, 29.3mmol) and tert-butyldimethylsilyl chloride (3.60g, 23.4 mmol). After stirring at room temperature for 24 hours, the mixture was concentrated under reduced pressure to give a residue, which was dissolved in dichloromethane (50 mL). The solution was washed twice with water (20mL),then washed twice with brine (20mL) over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (6.27g, 70% yield).¹H NMR(400MHz,DMSO-d₆)δ7.35-7.31(m,5H),5.27(br s,0.3H),5.10-5.07(m,1.7H),3.65-3.58(m,1.5H),3.50-3.44(m,1.5H),2.64-2.55(m,2H),2.45-2.24(m,1H),2.11-1.83(m,4H),1.57-1.24(m,3.5H),1.08-0.84(m,1.5H),0.86(s,9H),0.03(s,6H)。

Intermediate 54 c: benzyl 4- (N- (2- (tert-butyldimethylsilyl) ethyl) -methylsulfonylamino) cyclohexanecarboxylate

To a solution of benzyl 4- ((2- ((tert-butyldimethylsilyl) oxy) ethyl) amino) cyclohexanecarboxylate intermediate 54b (6.27g, 16.0mmol) in tetrahydrofuran (50mL) at 0 ℃ under a nitrogen atmosphere was added triethylamine (4.85g, 48.0mmol) and methanesulfonyl chloride (2.21g, 19.0 mmol). After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound (3.80g, 51% yield) as a yellow oil.¹H NMR(400MHz,DMSO-d₆)δ7.37-7.32(m,5H),5.13(s,.0.8H),5.08(s,1.2H),3.66-3.48(m,3H),3.17-3.12(m,1H),3.05-3.00(m,0.5H),2.93(s,3H),2.74-2.69(m,0.5H),2.40-2.30(m,0.7H),2.13-2.08(m,1H),1.99-1.94(m,1.3H),1.83-1.72(m,1.5H),1.62-1.42(m,4.5H),0.87(s,9H),0.05-0.04(m,6H)。

Acid 54: 4- (N- (2- ((tert-butyldimethylsilyl) oxy) ethyl) methylsulfonamido) -cyclohexanecarboxylic acid

To a solution of benzyl 4- (N- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -methylsulfonamido) cyclohexanecarboxylate intermediate 54c (1.35g, 2.87mmol) in methanol (20mL) was added 10% wt palladium on charcoal (200 mg). After stirring overnight at room temperature under a balloon of hydrogen atmosphere, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound as a white solid (900mg, 82% yield).¹H NMR(400MHz,CDCl₃)δ3.75-3.70(m,2H),3.63-3.57(m,1H),3.25-3.18(m,1.5H),2.89-2.88(s,3H),2.65-2.62(m,0.5H),2.29-2.09(m,3H),1.90-1.88(m,1H),1.72-1.52(m,5H),0.91-0.88(m,9H),0.07(s,6H)。

Acid 55: 4- (N- (2-methoxyethyl) sulfamoyl) cyclohexanecarboxylic acid

Intermediate 55 a: benzyl 4- (N- (2-ethoxyethyl) sulfamoyl) cyclohexanecarboxylate

To a solution of benzyl 4- (acetylthio) cyclohexanecarboxylate intermediate 26(1.0g, 3.42mmol) in acetonitrile (25mL) at 0 deg.C were added 2M aqueous hydrochloride solution (0.5mL, 1.0mmol) and 1-chloropyrrolidine-2, 5-dione (1.83g, 13.7 mmol). After stirring at 0 ℃ for 1 hour, the mixture was quenched with water (50mL), concentrated and extracted twice with ether (50 mL). The combined organic layers were passed over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure at 30 ℃ to give a residue, which was dissolved in anhydrous dichloromethane (35 mL). To the above solution was added 2-methoxyethylamine (1.54g, 20.6 mmol). After stirring overnight at room temperature, the resulting solution was washed with 1M aqueous hydrochloride (30mL) and brine (30mL) over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate) ═ 10:1 to 5:1) to give the title compound (1.35g, 92% yield) as a light yellow oil. LC-MS (ESI): r_T＝1.262min，C₁₇H₂₅NO₅Calculated mass of S355.2, found M/z 356.1[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ7.42-7.33(m,5H),5.16-5.13(m,2H),4.59-4.48(m,1H),3.51-3.46(m,2H),3.37(s,3H),3.32-3.23(m,2H),2.98-2.85(m,1H),2.72(br s,0.4H),2.39-2.18(m,3.6H),2.08-2.04(m,1H),1.83-1.74(m,1H),1.63-1.43(m,3H)。

Acid 55: 4- (N- (2-methoxyethyl) sulfamoyl) cyclohexanecarboxylic acid

To a solution of benzyl 4- (N- (2-methoxyethyl) sulfamoyl) cyclohexanecarboxylate intermediate 55a (1.35g, 3.79mmol) in methanol (50mL) was added 10% wt palladium on charcoal (300 mg). After stirring overnight at 25 ℃ under a hydrogen atmosphere in a balloon, the mixture was filtered and the filtrate was concentrated to giveTo the title compound as a white solid (970mg, 97% yield).¹H NMR(300MHz,CDCl₃)δ4.74-4.68(m,0.5H),4.65-4.61(m,0.5H),3.53-3.49(m,2H),3.38(s,3H),3.34-3.30(m,2H),3.00-2.87(m,1H),2.72(br s,0.5H),2.39-2.07(m,4.5H),1.85-1.73(m,1H),1.65-1.47(m,3H)。

Acid 56: 4- (N- (3- (tert-butoxy) -2, 2-dimethyl-3-oxopropyl) sulfamoyl) -cyclohexanecarboxylic acid

Intermediate 56 a: benzyl 4- (N- (3- (tert-butoxy) -2, 2-dimethyl-3-oxopropyl) sulfamoyl) cyclohexanecarboxylate

To a solution of tert-butyl 3-amino-2, 2-dimethylpropionate hydrochloride (710mg, 3.40mmol) in dichloromethane (15mL) was added triethylamine (1.70g, 17.0mmol) at 0 ℃. After stirring at 0 ℃ for 20 minutes, a solution of benzyl 4- (chlorosulfonyl) cyclohexanecarboxylate (1.06g, 3.40mmol) in dichloromethane (15mL) was added. The resulting mixture was stirred at room temperature overnight. Thereafter, it was concentrated under reduced pressure to give a residue, which was dissolved in ethyl acetate (10mL), washed twice with water (8mL), twice with brine (8mL), and washed with Na₂SO_4(s)Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 15:1 to 8:1) to give the desired compound as a yellow oil (700mg, 46% yield).¹H NMR(300MHz,CDCl₃)δ7.36(br s,5H),5.17(s,0.7H),5.13(s,1.3H),4.91-4.80(m,1H),4.18-4.09(m,0.7H),3.11-3.07(m,2H),2.95-2.83(m,1H),2.76-2.68(m,0.3H),2.42-2.28(m,2H),2.26-2.17(m,2H),2.09-2.01(m,1.4H),1.89-1.71(m,0.6H),1.46(s,9H),1.39-1.24(m,2H),1.21(s,6H)。

Acid 56: 4- (N- (3- (tert-butoxy) -2, 2-dimethyl-3-oxopropyl) sulfamoyl) -cyclohexanecarboxylic acid

To a solution of benzyl 4- (N- (3- (tert-butoxy) -2, 2-dimethyl-3-oxopropyl) sulfamoyl) cyclohexanecarboxylate intermediate 56a (700mg, 1.54mmol) in methanol (20mL) was added 10% wt palladium on charcoal (240 m/L)g) In that respect The reaction mixture was stirred under a hydrogen atmosphere balloon at 50 ℃ overnight. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give the compound as a white solid (640mg, 80% purity, 91% yield).¹H NMR(400MHz,DMSO-d₆)δ6.98-6.93(m,1H),3.04-3.00(m,2H),2.96-2.89(m,1H),2.55-2.54(m,0.3H),2.20-2.14(m,0.7H),2.09-2.04(m,2H),2.00-1.97(m,1.4H),1.87-1.84(m,0.6H),1.59-1.45(m,2H),1.39(s,9H),1.36-1.24(m,2H),1.05(s,6H)。

Acids 57R and 57S: 5- (ethoxycarbonyl) tetrahydro-2H-pyran-2-carboxylic acid

Intermediates 57R- A and 57S- A: 2-benzyl-5-ethyl-3, 6-dihydro-2H-pyran-2, 5-dicarboxylic acid ester

The racemic mixture (3.36g, 11.6mmol) was separated by chiral preparative HPLC (column: chiralpakff 5 μm 20 × 250 mm; mobile phase: Hex: EtOH ═ 60:40, at 10 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compounds 57R- A (1.37g, 41% yield) and 57S- A (1.34g, 40% yield).

Acid 57R: 5- (ethoxycarbonyl) tetrahydro-2H-pyran-2-carboxylic acid

To A solution of 2-benzyl 5-ethyl 3, 6-dihydro-2H-pyran-2, 5-dicarboxylate 57R-A (610mg, 2.10mmol) in tetrahydrofuran (30mL) was added 10% wt palladium on charcoal (180 mg). The reaction mixture was stirred at room temperature under a balloon of hydrogen atmosphere overnight. The reaction mixture was then filtered and concentrated to give the title compound as a white solid (456mg, crude). LC-MS (ESI): no R_T，C₉H₁₄O₅Calculated mass of 202.1, found value of M/z 203.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.69(br s,1H),4.13-4.02(m,3H),3.88(dd,J＝11.6,2.8Hz,0.6H),3.67(dd,J＝11.6,3.6Hz,1H),3.45-3.40(m,0.4H),2.59-2.53(m,1H),2.06-2.01(m,0.2H),1.99-1.92(m,0.8H),1.88-1.82(m,3H),1.21-1.16(m,3H)。

Acid 57S: 5- (ethoxycarbonyl) tetrahydro-2H-pyran-2-carboxylic acid

Acid 57S was prepared from intermediate 57S-A similarly to acid 57R, LC-ms (esi): no R_T，C₉H₁₄O₅Calculated mass of 202.1, found value of M/z 203.1[ M + H ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ12.72(br s,1H),4.15-4.03(m,3.6H),3.88(dd,J＝8.1,1.8Hz,0.3H),3.67(dd,J＝8.7,2.4Hz,0.7H),3.43(t,J＝8.1Hz,0.4H),2.59-2.54(m,1H),2.05-2.00(m,0.3H),1.91-1.88(m,1H),1.80-1.44(m,2.7H),1.21-1.16(m,3H)。

Acid 58: (trans) -1- (tert-Butoxycarbonyl) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -piperidine-4-carboxylic acid

Intermediate 58 a: tert-butyl 4- (((tert-butyldimethylsilyl) oxy) methyl) piperidine-1-carboxylate

To a solution of tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate (20.0g, 93.0mmol) in dichloromethane (200mL) was added tert-butylchlorodimethylsilane (20.9g, 139mmol), imidazole (12.7g, 186mmol) and 4-dimethylaminopyridine (227mg, 1.86 mmol). After stirring overnight at room temperature under a nitrogen atmosphere, the mixture was quenched with water (50mL) and extracted twice with dichloromethane (100 mL). The combined organic layers were washed twice with brine (250mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give the title compound (22.5g, 74% yield) as a colorless oil. LC-MS (ESI): r_T＝2.521min，C₁₇H₃₅NO₃S_iCalculated mass of 329.2, M/z found 274.2[ M + H-56 ]]⁺。¹H NMR(400MHz,CDCl₃)δ4.13-4.08(m,2H),3.42(d,J＝6.4Hz,2H),2.69-2.64(m,2H),1.68-1.64(m,2H),1.62-1.53(m,1H),1.44(s,9H),1.13-1.03(m,2H),0.87(s,7H),0.85(s,2H),0.02(s,5H),0.01(s,1H)。

Intermediate 58 b: (trans) -tert-butyl 4- (((tert-butyldimethylsilyl) oxy) methyl) -2-formylpiperidine-1-carboxylate

To a solution of tert-butyl 4- (((tert-butyl-butyldimethylsilyl) oxy) methyl) piperidine-1-carboxylate intermediate 58a (15.0g, 45.6mmol) in anhydrous tetrahydrofuran (150mL) was added tetramethylethylenediamine (75.6g, 68.0 mmol). After stirring at-78 ℃ for 1 hour, 1.3M sec-butyllithium in tetrahydrofuran (52.5mL, 68.0mmol) was added at-78 ℃ under a nitrogen atmosphere. After stirring for 1 hour, a solution of N, N-dimethylformamide (5.25mL, 68.0mmol) in dry tetrahydrofuran (20mL) was added at-78 ℃. The resulting mixture was stirred at-78 ℃ for 2 hours. It was then warmed to room temperature and quenched with saturated aqueous ammonium chloride (100mL) and extracted twice with ethyl acetate (200 mL). The combined organic layers were washed three times with brine (400mL) over anhydrous Na₂SO_4(s)Drying and concentration gave the crude compound which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 30:1) to give the title compound as a colourless oil (7.47g, 40% yield). LC-MS (ESI): r_T＝2.294min，C₁₈H₃₅NO₄S_iCalculated mass 357.2, found M/z 302.2[ M + H-56 ]]⁺。¹HNMR(300MHz,CDCl₃)δ9.62-9.59(m,0.8H),9.45-9.43(m,0.2H),4.89-4.84(m,0.4H),4.67-4.63(m,0.3H),4.23-4.04(m,1H),3.87-3.62(m,0.3H),3.48-3.41(m,2H),2.91-2.69(m,1H),2.32-2.24(m,0.8H),1.89-1.82(m,0.2H),1.71-1.64(m,2H),1.49(s,3H),1.46(s,6H),1.36-1.24(m,1H),1.17-1.05(m,1H),0.89-0.88(m,9H),0.04(s,6H)。

Intermediate 58 c: (trans) -tert-butyl 4- (((tert-butyldimethylsilyl) oxy) methyl) -2- (hydroxymethyl) piperidine-1-carboxylate

To a solution of (trans) -tert-butyl 4- (((tert-butyldimethylsilyl) oxy) methyl) -2-formylpiperidine-1-carboxylic acid based intermediate 58b (7.47g, 21.0mmol) in anhydrous tetrahydrofuran (100mL) was added sodium borohydride (2.38g, 63.0 mmol). After stirring overnight at room temperature under a nitrogen atmosphere, the reaction mixture was quenched with water (50mL) and extracted three times with ethyl acetate (100 mL). The combined organic layers were washed three times with brine (200mL) over anhydrous Na₂SO_4(s)Drying and concentrating to give a residue which is purified by silica gel column chromatography (stone)Oily ether ethyl acetate 3:1) to give the title compound as a colourless oil (6.49g, 86% yield).¹H NMR(400MHz,DMSO-d₆)δ4.64-4.60(m,1H),4.03-3.98(m,1H),3.87-3.77(m,1H),3.43-3.38(m,2H),3.35-3.32(m,1H),2.81-2.64(m,1H),1.78-1.67(m,2H),1.62-1.52(m,1H),1.36(s,9H),1.07-0.99(m,1H),0.99-0.89(m,1H),0.84(s,9H),0.00(s,6H)。

Intermediate 58 d: (trans) -tert-butyl 4- (((tert-butyldimethylsilyl) oxy) methyl) -2- (((tert-butyldiphenylsilyl) oxy) methyl) piperidine-1-carboxylate

To a solution of (trans) -tert-butyl 4- (((tert-butyldimethylsilyl) oxy) methyl) -2- (hydroxymethyl) piperidine-1-carboxylate intermediate 58c (6.49g, 18.0mmol) in dichloromethane (200mL) was added tert-butylchlorodiphenylsilane (7.46g, 27.0mmol), imidazole (2.46g, 36.0mmol), and 4-dimethylaminopyridine (44mg, 0.36 mmol). After stirring overnight at room temperature under a nitrogen atmosphere, the reaction mixture was quenched with water (100mL) and extracted twice with dichloromethane (50 mL). The combined organic layers were washed twice with brine (150mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 30:1) to give the title compound (9.39g, 87% yield) as a colorless oil. LC-MS (ESI): r_T＝5.380min，C₃₄H₅₅NO₄Si₂Calculated mass of 597.4, M/z found value 498.3[ M + H-Boc [, Boc [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.68-7.65(m,2H),7.61-7.59(m,3H),7.45-7.35(m,5H),4.35-4.21(m,1H),3.88-3.79(m,1H),3.70-3.51(m,3H),3.43-3.39(m,1H),2.69-2.57(m,1H),2.03-2.00(m,0.5H),1.89-1.86(m,0.5H),1.68(br s,1H),1.57-1.54(m,1H),1.35(s,3H),1.29(s,6H),1.13-1.07(m,2H),0.96(s,6H),0.93(s,3H),0.83(s,9H),0.00(s,6H)。

Intermediate 58 e: (trans) -tert-butyl 2- (((tert-butyldiphenylsilyl) oxy) methyl) -4- (hydroxymethyl) piperidine-1-carboxylate

To (trans) -tert-butyl 4- (((tert-butyldimethylsilyl) oxy) methyl) -2- (((tert-butyldiphenylsilyl) oxy) methyl) To a solution of piperidine-1-carboxylate intermediate 58d (9.39g, 15.7mmol) in ethanol (80mL) was added pyridinium 4-toluenesulfonate (1.15g, 4.00 mmol). After stirring at 50 ℃ under a nitrogen atmosphere overnight, the mixture was cooled to room temperature and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound (5.40g, 71% yield) as a colorless oil. LC-MS (ESI): r_T＝2.173min，C₂₈H₄₁NO₄Calculated mass of Si 483.3, found in M/z value 384.3[ M + H []⁺。¹H NMR(400MHz,CDCl₃)δ7.66(br s,4H),7.43-7.37(m,6H),4.59-4.56(m,0.5H),4.37-4.36(m,0.5H),4.15-4.07(m,0.5H),3.96-3.90(m,0.5H),3.72-3.61(m,2H),3.48-3.35(m,2H),2.71-2.60(m,1H),2.05-1.97(m,0.5H),1.86-1.84(m,0.5H),1.74-1.64(m,1H),1.60-1.52(m,1H),1.42(s,9H),1.37-1.17(m,2H),1.05(s,9H)。

Acid 58: (trans) -1- (tert-Butoxycarbonyl) -2- (((tert-butyldiphenylsilyl) oxy) -methyl) piperidine-4-carboxylic acid

To a solution of (trans) -tert-butyl 2- (((tert-butyldiphenylsilyl) oxy) methyl) -4- (hydroxymethyl) piperidine-1-carboxylate intermediate 58e (4.00g, 8.30mmol) in dichloromethane (30mL) was added dess-martin periodinane (10.4g, 24.8mmol) and after stirring overnight at room temperature under a nitrogen atmosphere, the solution was quenched with saturated sodium sulfite (250mL) and extracted three times with dichloromethane (100 mL). The combined organic layers were washed twice with brine (150mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by C18 column (acetonitrile: water 50% to 95%) to give the title compound as a pale yellow oil (3.07g, 75% yield). LC-MS (ESI): r_T＝2.428min，C₂₈H₃₉NO₅Calculated mass of Si 497.3, found value of M/z 398.2[ M + H-Boc [. ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.25(s,1H),7.63-7.61(m,4H),7.48-7.41(m,6H),4.41-4.29(m,1H),3.93-3.83(m,1H),3.74-3.62(m,2H),3.32(s,1H),2.78-2.63(m,1H),2.16-2.00(m,1H),1.83-1.76(m,1H),1.55-1.46(1,1H),1.33(s,9H),1.28-1.19(m,1H),0.99(s,9H)。

Acid 59: (trans) -4- ((tert-butyldimethylsilyl) oxy) cyclohexanecarboxylic acid

Intermediate 59 a: (trans) -methyl 4- ((tert-butyldimethylsilyl) oxy) -cyclohexanecarboxylate

To a mixture of (trans) -methyl 4-hydroxycyclohexanecarboxylate (865mg, 6.00mmol) and imidazole (1.02g, 15.0mmol) in N, N-dimethylformamide (5mL) at 0 deg.C under a nitrogen atmosphere was added tert-butylchlorodimethylsilane (1.09g, 7.20 mmol). The reaction mixture was stirred at room temperature overnight, then poured into water (30mL) and extracted three times with ethyl acetate (30 mL). The combined organic layers were washed with water (30mL) and Na₂SO_4(s)Drying and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 100:1 to 20:1) to give the title compound as a colourless oil (1.34g, 86% yield).¹H NMR(400MHz,CD₃OD)δ3.58-3.51(m,4H),2.24-2.17(m,1H),1.91-1.81(m,4H),1.45-1.36(m,2H),1.29-1.20(m,2H),0.82(s,9H),0.01(s,6H)。

Acid 59: (trans) -4- ((tert-butyldimethylsilyl) oxy) cyclohexanecarboxylic acid

To (trans) -methyl 4- ((tert-butyldimethylsilyl) oxy) cyclohexanecarboxylic acid ester under a nitrogen atmosphere

To a solution of intermediate 59a (681mg, 2.50mmol) in methanol (6mL) and water (1.5mL) was added lithium hydroxide monohydrate (210mg, 5.00 mmol). After stirring overnight at room temperature, the solvent was removed and the residue was diluted with water (10mL), acidified to pH 2 with 1M aqueous hydrochloride solution and filtered. The solid was washed with water (10mL) and dried in vacuo to give the title compound as a white solid (510mg, 79% yield).¹H NMR(300MHz,CD₃OD)δ3.64-3.59(m,1H),2.24-2.19(m,1H),2.03-1.86(m,4H),1.50-1.27(m,4H),0.90-0.89(m,9H),0.08-0.01(m,6H)。

Acid 60: 1, 4-dioxaspiro [4.5] decane-8-carboxylic acid

Intermediate 60 a: ethyl 1, 4-dioxaspiro [4.5] decane-8-carboxylate

To a solution of ethyl 4-oxocyclohexanecarboxylate (5.00g, 29.4mmol) in toluene (20mL) at room temperature under a nitrogen atmosphere was added p-toluenesulfonic acid (1.50g, 8.80mmol) and ethane-1, 2-diol (6.00g, 103 mmol). After stirring at room temperature overnight, the mixture was concentrated under reduced pressure to give a residue, which was dissolved in diethyl ether (20 mL). The solution was washed twice with water (30mL) and then twice with saturated aqueous sodium bicarbonate (20mL) over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (5.50g, 99% yield).¹HNMR(400MHz,DMSO-d₆)δ4.10(q,J＝9.6Hz,2H),3.92(s,4H),2.34-2.30(m,1H),1.95-1.89(m,2H),1.85-1.74(m,4H),1.58-1.50(m,2H),1.23(t,J＝9.6Hz,3H)。

Acid 60: 1, 4-dioxaspiro [4.5] decane-8-carboxylic acid

To ethyl 1, 4-dioxaspiro [4.5]]To a solution of decane-8-carboxylate intermediate 60a (5.60g, 26.1mmol) in tetrahydrofuran (56mL), methanol (28mL) and water (28mL) was added lithium hydroxide monohydrate (3.29g, 78.3 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated at room temperature under reduced pressure. The resulting residue was acidified to pH 3-4 with 0.5M aqueous hydrochloride and extracted twice with dichloromethane (200 mL). The combined organic layers were washed with brine (100mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (4.10g, 84% yield).¹H NMR(300MHz,CDCl₃)δ3.94(s,3.4H),3.77-3.74(m,0.6H),2.42-2.33(m,1H),2.00-1.94(m,2H),1.87-1.77(m,4H),1.61-1.51(m,2H)。

Acid 61: 4- (azetidin-1-ylsulfonyl) cyclohexanecarboxylic acid

Intermediate 61 a: benzyl 4- (azetidin-1-ylsulfonyl) cyclohexanecarboxylate

To a solution of benzyl 4- (acetylthio) cyclohexanecarboxylate (300mg, 1.03mmol) in acetonitrile (10mL) at 0 deg.C under a nitrogen atmosphere was added 2M aqueous hydrochloride solution (0.2mL) and 1-chloropyrrolidine-2, 5-dione (550mg, 4.12 mmol). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure to give a residue. It was diluted in water (50mL) and extracted three times with ether (30 mL). The combined organic layers were washed twice with brine (10mL) and Na₂SO_4(s)Dried, filtered and concentrated under reduced pressure to give a residue. The residue was diluted with dry tetrahydrofuran (10mL) and dichloromethane (5mL), and then azetidine hydrochloride (480mg, 5.15mmol) and triethylamine (1.21g, 12.0mmol) were added to the resulting solution and stirred at room temperature for 4 hours. The mixture was concentrated, quenched with water (50mL), and acidified to pH about 2 with 1M aqueous hydrochloride solution, then extracted three times with ethyl acetate (50 mL). The combined organic layers were passed over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (230mg, 58% yield).¹H NMR(400MHz,CDCl₃)δ7.38-7.32(m,5H),5.16(s,1H),5.11(s,1H),3.99-3.90(m,4H),2.81-2.78(m,1H),2.31-2.20(m,5H),2.04-1.99(m,1H),1.73-1.55(m,5H)。

Acid 61: 4- (azetidin-1-ylsulfonyl) cyclohexanecarboxylic acid

To a solution of benzyl 4- (azetidin-1-ylsulfonyl) cyclohexanecarboxylate intermediate 61a (230mg, 0.682mmol) in methanol (5mL) was added 10% wt palladium on charcoal (35 mg). After stirring overnight at room temperature under a hydrogen atmosphere, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound as a white solid (160mg, 95% yield).¹H NMR(400MHz,CDCl₃)δ4.00-3.95(m,4H),2.84-2.72(m,1H),2.34-2.18(m,6H),2.07-2.03(m,1H),1.78-1.75(m,1H),1.61-1.43(m,3H)。

Acid 62: 3- ((tert-butoxycarbonyl) amino) -2, 2-dimethylcyclobutanecarboxylic acid

Intermediate 62 a: methyl 2, 2-dimethyl-3-oxocyclobutanecarboxylate

In N₂To a mixture of 1-chloro-N, N, 2-trimethylprop-1-en-1-amine (45mL, 0.340mol) and methyl acrylate (384mL, 0.425mol) was added bis (((trifluoromethyl) under an atmosphere

Sulfonyl) oxy) zinc (30.6g, 0.084 mol). After stirring at room temperature for 30 minutes, the mixture was stirred at 35 ℃ for another 6 hours, then quenched with water (400mL) and extracted three times with dichloromethane (300 mL). The combined organic layers were washed with brine (100mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (petroleum: ethyl acetate ═ 15:1 to 5:1) to give the title compound as a yellow oil (24g, 46% yield).¹HNMR(300MHz,CDCl₃)δ3.76(s,3H),3.59-3.51(m,1H),3.15-3.06(m,1H),2.99-2.93(m,1H),1.32(s,3H),1.12(s,3H)。

Intermediate 62 b: (Z) -3- (hydroxyimino) -2, 2-dimethylcyclobutanecarboxylic acid

In N₂To a solution of methyl 2, 2-dimethyl-3-oxocyclobutanecarboxylate intermediate 62a (10.0g, 64.1mmol) in methanol (200mL) under an atmosphere was added hydroxylamine hydrochloride (8.80g, 128.2mmol) and sodium bicarbonate (14.7g, 175 mmol). After stirring at room temperature overnight, the mixture was filtered and concentrated under pressure to give the title compound as a colourless oil (10.6g, 97% yield).¹H NMR(300MHz,CDCl₃)δ3.78(s,0.5H),3.74(s,2.5H),3.35-3.24(m,1H),3.20-3.01(m,1H),2.96-2.82(m,1H),1.56-1.53(m,0.8H),1.45-1.41(m,2.2H),1.32-1.29(m,0.8H),1.23-1.20(m,2.2H)。

Intermediate 62 c: methyl 3-amino-2, 2-dimethylcyclobutanecarboxylic acid ester

To a solution of (Z) -3- (hydroxyimino) -2, 2-dimethylcyclobutanecarboxylic acid intermediate 62b (8.60g, 50.3mmol) in methanol (100mL) under a nitrogen atmosphere were added raney nickel (1.0g) and ammonium hydroxide (3 mL). After stirring overnight at room temperature under a hydrogen atmosphere, the mixture was filtered and concentrated to give the title compound as a colorless oilMaterial (6.0g, 77% yield).¹H NMR(300MHz,CDCl₃)δ3.70(s,0.5H),3.66(s,2.5H),3.42-2.84(m,1H),2.66-2.45(m,1.3H),2.24(br s,0.7H),1.90(br s,1H),1.19(s,1.8H),1.14(s,1.2H),1.00(s,1H),0.88(s,2H)。

Intermediate 62 d: methyl 3- ((tert-butoxycarbonyl) amino) -2, 2-dimethylcyclobutanecarboxylate

In N₂To a solution of methyl 3-amino-2, 2-dimethylcyclobutanecarboxylate intermediate 62c (6.00g, 38.2mmol) in dichloromethane (100mL) under atmosphere was added di-tert-butyl dicarbonate (16.5g, 76.4mmol) and N, N-dimethylpyridin-4-amine (466mg, 3.82 mmol). After stirring at room temperature overnight, the mixture was concentrated to give a residue, which was washed with a mixed solvent (petroleum: ethyl acetate 10:1, 50mL) and then twice with petroleum (50mL) to give the title compound as a white solid (5.0g, 51% yield).¹H NMR(400MHz,CDCl₃)δ4.64(br s,1H),3.88-3.78(m,1H),3.67(s,3H),2.59-2.53(m,1H),2.37-2.27(m,1H),2.08-1.97(m,1H),1.43(s,9H),1.28(s,3H),0.89(s,3H)。

Acid 62: 3- ((tert-butoxycarbonyl) amino) -2, 2-dimethylcyclobutanecarboxylic acid

To methyl 3- ((tert-butoxycarbonyl) amino) -2, 2-dimethylcyclobutanecarboxylate at room temperature

To a solution of intermediate 62d (2.50g, 9.70mmol) in tetrahydrofuran (40mL) was added a solution of lithium hydroxide monohydrate (817mg, 19.4mmol) in water (10 mL). After stirring overnight at room temperature under a nitrogen atmosphere, the mixture was concentrated and diluted with ethyl acetate (50mL) and acidified to pH about 5 with 2M aqueous hydrochloride solution (5 mL). The resulting solid was then collected by filtration and washed with water (50mL) and dried to give the title compound as a white solid (2.20g, 93% yield).¹HNMR(400MHz,DMSO-d₆)δ11.96(s,1H),6.97-6.94(m,1H),3.65-3.56(m,1H),2.45-2.42(m,1H),2.08-1.99(m,2H),1.38(s,9H),1.16(s,3H),0.82(s,3H)。

Acid 63: 4- (N- (3-methoxy-3-oxopropyl) sulfamoyl) cyclohexanecarboxylic acid

Intermediate 63 a: benzyl 4- (N- (3-methoxy-3-oxopropyl) sulfamoyl) -cyclohexanecarboxylate

To a solution of benzyl 4- (acetylthio) cyclohexanecarboxylate intermediate 26(3.00g, 10.3mmol) in acetonitrile (45mL) at 0 deg.C was added 2M aqueous hydrochloride solution (1.5mL, 3.00 mmol). 1-Chloropyrrolidine-2, 5-dione (5.35g, 40.1mmol) was then added. After stirring at 0 ℃ for 1 hour under a nitrogen atmosphere, the mixture was diluted in ether (100mL), washed with water (30mL), brine (30mL), and then Na₂SO_4(s)Dried, filtered and concentrated to give a residue a. To a solution of methyl 3-aminopropionate hydrochloride in dichloromethane (40mL) at 0 deg.C were added triethylamine (5.19g, 51.4mmol) and residue A (dissolved in 20mL dichloromethane). The mixture was stirred under nitrogen overnight. Dichloromethane (200mL) was added to the mixture and washed with water (50mL), 0.5M aqueous hydrochloride (50mL), brine (50mL), Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1 to 3:1) to give the title compound (2.40g, 57% yield) as a yellow oil. LC-MS (ESI): r_T＝1.60min，C₁₈H₂₅NO₆Calculated mass of S383.1, found value of M/z 384.4[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ7.39-7.27(m,5H),5.15(s,1H),5.12(s,1H),4.84-4.81(m,0.5H),4.77-4.74(m,0.5H),3.71(s,3H),3.39-3.31(m,2H),2.94-2.84(m,1H),2.64-2.58(m,2H),2.39-2.02(m,4H),1.79-1.69(m,1H),1.63-1.44(m,3H)。

Acid 63: 4- (N- (3-methoxy-3-oxopropyl) sulfamoyl) cyclohexanecarboxylic acid

To a solution of benzyl 4- (N- (3-methoxy-3-oxopropyl) sulfamoyl) -cyclohexanecarboxylate intermediate 63a (2.40g, 6.26mmol) in methanol (25mL) was added 10% wt palladium on charcoal (400 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon) overnight. The completed reaction mixture was filtered and the filter cake was washed with methanol (20 mL). The filtrate was concentrated to give the title compound acid 63 (1) as a pale white solid.60g, 87% yield).¹H NMR(300MHz,DMSO-d₆)δ7.10(s,1H),3.60(s,3H),3.21-3.12(m,4H),3.05-2.89(m,1H),2.59-2.52(m,1H),2.18-1.84(m,4H),1.59-1.33(m,4H)。

Part II: preparation of aryl aldehydes (P1)

Aldehyde 1, Al 1: 2-chloro-4-fluoro-benzaldehyde

Aldehyde 2, Al 2: 2-chloro-3-fluoro-benzaldehyde

Aldehyde 3, Al 3: 4-chloro-2-fluorobenzaldehyde

Aldehyde 4, Al 4: 2-bromo-4-fluorobenzaldehyde

Aldehyde 5, Al 5: 4-chloro-3-fluorobenzaldehyde

Aldehyde 6, Al 6: 2-chloro-3, 4-difluorobenzaldehyde

Aldehyde 7, Al 7: 2-chlorobenzaldehyde

Aldehyde 8, Al 8: 2-bromobenzaldehyde

Aldehyde 9, Al 9: 2-bromo-3-fluorobenzaldehyde

Aldehyde 10, Al 10: 3, 4-difluoro-2-methylbenzaldehyde

Aldehyde 11, Al 11: 2-bromo-3, 4-difluoro-benzaldehyde

Aldehyde 12, Al 12: 2-methyl-4-difluoro-benzaldehyde

Aldehyde 13: al 13: 2-methyl-3-difluoro-benzaldehyde

Intermediate B1: 2-chloro-3, 4-difluorobenzoic acid

Adding N in tetrahydrofuran (45mL)¹,N¹,N²,N²-a solution of tetramethylethane-1, 2-diamine (3.7g, 69.6mmol) was cooled to-70 ℃ under a nitrogen atmosphere, then a solution of 1.3M sec-butyllithium in hexane ((60mL, 75.9mmol) was added dropwise, followed by a solution of 3, 4-difluorobenzoic acid (5.0g, 31.6mmol) in tetrahydrofuran (20mL) over 10 minutes the resulting mixture was stirred at-70 ℃ for 1 hour, and then a solution of 1,1,1,2,2, 2-hexachloroethane (26g, 110.8mmol) in THF (45mL) was added dropwise the mixture continued stirring at-70 ℃ for 2 hours the mixture was warmed to-10 ℃, quenched with water (125mL), diethyl ether (60mL) was added, and then the two phases were separated the aqueous layer was acidified to pH 1 using concentrated aqueous hydrochloric acid and extracted twice with diethyl ether (125mL) the combined organic extracts were concentrated in vacuo to give a yellow solid, the solid is treated with acetic acidThe ethyl ester (30mL) was recrystallized to provide the title compound as a yellow solid (2.7g, 45% yield).¹H NMR(400MHz,DMSO-d₆)δ13.69(br s,1H),7.75-7.71(m,1H),7.55-7.48(m,1H)。

Intermediate B2: 2-chloro-3, 4-difluoro-N-methoxy-N-methyl-benzamide

To a solution of 2-chloro-3, 4-difluorobenzoic acid intermediate B1(1.0g, 5.2mmol) in N, N-dimethylformamide (10mL) was added 1-hydroxybenzotriazole (1.1g, 7.8mmol), N-diisopropylethylamine (4.6mL, 26mmol), and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.5g, 7.8mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 minutes. O, N-dimethyl-hydroxylamine hydrochloride (0.5g, 5.2mmol) was added and stirring continued at room temperature overnight. After quenching with water (20mL), the mixture was extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with water (20mL), brine (20mL) and Na₂SO₄(solid) was dried, filtered and concentrated to leave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 4:1 to 2:1) to give the title compound (1.06g, 87% yield) as a yellow solid.¹H NMR(400MHz,DMSO-d₆)δ7.60-7.53(m,1H),7.42-7.38(m,1H),3.80-3.45(m,3H),3.39-3.06(m,3H)。

Aldehyde 6: 2-chloro-3, 4-difluorobenzaldehyde

To a solution of 2-chloro-3, 4-difluoro-N-methoxy-N-methyl-benzamide intermediate B2(500mg, 2.13mmol) in tetrahydrofuran (8mL) at-78 ℃ under a nitrogen atmosphere was added dropwise 1M diisobutylaluminum hydride in toluene (2.8mL, 2.8 mmol). After the addition, the mixture was stirred at-78 ℃ for 1 hour. It was then quenched with water (15mL) and extracted three times with ethyl acetate (25 mL). The combined organic layers were washed with 1M aqueous hydrochloric acid (10mL) and Na₂SO_4(s)Dried, filtered and evaporated under reduced pressure to leave a yellow residue which is purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give the title compound (200mg, 53% yield) as a yellow solid.¹H NMR(400MHz,DMSO-d₆)δ10.23(s,1H),7.80-7.76(m,1H),7.69-7.62(m,1H)。

Intermediate B3: 2-bromo-3, 4-difluoro-N-methoxy-N-methylbenzamide

To a solution of 2-bromo-3, 4-difluorobenzoic acid (2.50g, 10.6mmol) in N, N-dimethylformamide (25mL) was added 1-hydroxybenzotriazole (2.15g, 15.9mmol), N-diisopropylethylamine (6.84g, 53.0mmol) and N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide hydrochloride (3.05g, 15.9mmol) at room temperature under a nitrogen atmosphere. The mixture was stirred for 10 min and N, O-dimethylhydroxylamine hydrochloride (1.04g, 10.6mmol) was added. After stirring overnight at room temperature, the mixture was poured into water (80mL) and extracted twice with ethyl acetate (75 mL). The separated organic layer was washed twice with water (100mL), twice with brine (50mL) and Na₂SO_4(s)Drying, filtration, concentration and purification by silica gel column chromatography (petroleum ether: ethyl acetate 10:1 to 5:1) gave the title compound as a yellow solid (1.9g, 66% yield).¹HNMR(300MHz,CDCl₃)δ7.26-7.17(m,1H),7.14-7.09(m,1H),3.93-3.16(m,6H)。

Aldehyde 12: 2-bromo-3, 4-difluorobenzaldehyde

To a solution of 2-bromo-3, 4-difluoro-N-methoxy-N-methyl-benzamide intermediate B3(1.90g, 6.81mmol) in tetrahydrofuran (30mL) was added dropwise 1.5M diisobutylaluminum hydride (5.90mL, 8.85mmol) in toluene at-78 ℃ under a nitrogen atmosphere. After stirring at-78 ℃ for 1 hour, the mixture was quenched with water (40mL) and extracted three times with ethyl acetate (75 mL). The separated organic layer was washed twice with 2M aqueous hydrochloride (30mL), water (40mL), brine (20mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1 to 5:1) to give the title compound (1.0g, 67% yield) as a yellow solid.¹H NMR(300MHz,DMSO-d₆)δ10.12(s,1H),7.81-7.65(m,2H)。

Part III: preparation of carboxamide (P2)

Carboxamide 1, Ca 1: thiazole-2-carboxamide hydrochloride

Carboxamide 2, Ca 2:2, 4, 6-trifluorobenzamide

To a solution of 2,4, 6-trifluorobenzonitrile (2.00g, 12.7mmol) in toluene (50mL) was added 2M trimethylaluminum (7.00mL, 14.0mmol) and ammonium chloride (0.76g, 14.0mmol) in toluene at room temperature. After stirring overnight at 120 ℃, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was dissolved in a mixed solvent of methanol/dichloromethane (10/1, 50 mL). To the resulting mixture was added silica gel (100-200 mesh, 3g) and stirred at room temperature for another 1 hour. It was then filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by recrystallization from petroleum ether/ethyl acetate (5/1, 20mL) to give the title compound as a white solid (1.00g, 45% yield). LC-MS (ESI): r_T＝0.88min，C₇H₅F₃N₂Calculated mass of (3) 174.0, found value of M/z 175.0[ M + H [)]⁺。¹H NMR(300MHz,DMSO-d₆)δ9.04(br s,3H),7.55(t,J＝9.6Hz,2H)。

Carboxamide 3, Ca 3: 3, 5-difluoropicolinamide hydrochloride

To a stirred suspension of ammonium chloride (1.89g, 35.7mmol) in toluene (100mL) at 0 deg.C under a nitrogen atmosphere was added dropwise 2M trimethylaluminum (21mL, 42.8mmol) in toluene. The resulting mixture was then allowed to warm to room temperature and stirring was continued for 30 minutes. A solution of 3, 5-difluoropyridinecarbonitrile (5.00g, 35.7mmol) in toluene (50mL) was added, followed by stirring the reaction mixture at 80 ℃ overnight. After cooling to room temperature, the mixture was poured into a slurry of silica gel in dichloromethane (50 mL). After stirring for 10 minutes, the slurry was filtered and washed with methanol. The filtrate was concentrated in vacuo to give the title compound as a white solid (1.90g, 34% yield). LC-MS (ESI): r_T＝0.357min，C₆H₆ClF₂N₃Calculated mass of (3) 193.0, found value of M/z 157.9[ M + H-HCl ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.77(br s,2H),9.60(br s,2H),8.79(d,J＝1.6Hz,1H),8.41-8.35(m,1H)。

Carboxamide 4, Ca 4: 4-methylthiazole-2-carboximidamide hydrochloride

To the solution was added 4-methylthiazole-2-carbonitrile (3.90g, 31.5mmol)To a solution in methanol (30mL) was added 1M aqueous sodium methoxide (44mL, 44.0 mmol). After stirring at room temperature for 30 minutes, ammonium chloride (2.50g, 47.2mmol) was added to the mixture and stirring was continued at room temperature for 48 hours. The reaction mixture was then filtered and washed with methanol (50 mL). The filtrate was concentrated to give a residue which was purified by silica gel column chromatography (dichloromethane: methanol ═ 5:1) to give a crude product which was further purified by C18 column (acetonitrile: water ═ 2% to 40%) to give the title compound as a white solid (3.00g, 54% yield). LC-MS (ESI): r_T＝0.409min，C₅H₈ClN₃Calculated mass of S177.0M/z found value 142.0[ M + H-HCl ]]⁺。¹H NMR(300MHz,CD₃OD)δ7.78(d,J＝0.9Hz,1H),2.57(s,3H)。

Part IV: preparation of sulfonyl chlorides

Sulfonyl chloride 1: 2- (trimethylsilyl) ethyl 4- (chlorosulfonyl) -1-methylcyclohexane-1-carboxylate

Intermediate 1 a: 2- (trimethylsilyl) ethyl 4-oxocyclohexanecarboxylate

To a solution of (10.0g, 70.3mmol) in tetrahydrofuran (250mL) was added 2- (trimethylsilyl) ethanol (11.0g, 93.0mmol), N1- ((ethylimino) methylene) -N3, N3-dimethylpropane-1, 3-diamine hydrochloride (20.0g, 104mmol), and N, N-dimethylpyridin-4-amine (15.5g, 127mmol) at room temperature. After stirring overnight, the mixture was concentrated to give a residue, which was diluted with water (50mL) and extracted twice with ethyl acetate (150 mL). The combined organic layers were washed with 2M aqueous hydrochloride (150mL), brine (150mL) and Na₂SO_4(s)Drying, filtration and concentration gave the desired product as a pale yellow oil (14.1g, 90% purity, 74% yield).¹H NMR(300MHz,CDCl₃)δ4.25-4.19(m,2H),2.79-2.68(m,1H),2.56-2.45(m,2H),2.41-2.31(m,2H),2.27-2.17(m,2H),2.08-1.97(m,2H),1.05-0.98(m,2H),0.07(s,9H)。

Intermediate 1 b: 2- (trimethylsilyl) ethyl 1, 4-dioxaspiro [4.5] decane-8-carboxylate

To a solution of 2- (trimethylsilyl) ethyl 4-oxocyclohexanecarboxylate 1a (14.1g, 90% purity, 52.4mmol) in toluene (180mL) was added ethane-1, 2-diol (13.0g, 209mmol) and p-toluenesulfonic acid monohydrate (390mg, 2.05mmol) at room temperature, which was then refluxed overnight under azeotropic removal. The mixture was cooled to room temperature, diluted with ethyl acetate (200mL), washed twice with water (200mL), washed with brine (200mL), and Na₂SO_4(s)Drying, filtration and concentration gave the desired product as a pale yellow oil (11g, 90% purity, 66% yield).¹H NMR(300MHz,CDCl₃)δ4.21-4.12(m,2H),3.95(s,4H),2.37-2.26(m,1H),2.00-1.90(m,2H),1.86-1.72(m,4H),1.63-1.48(m,2H),1.02-0.94(m,2H),0.53(s,9H)。

Intermediate 1 c: 2- (trimethylsilyl) ethyl 8-methyl-1, 4-dioxaspiro [4.5] decane-8-carboxylate

To 2- (trimethylsilyl) ethyl 1, 4-dioxaspiro [4.5] at-78 deg.C]To a solution of decane-8-carboxylate 1b (4.0g, 90% purity, 12.6mmol) in tetrahydrofuran (60mL) was added 2M lithium diisopropylamide in tetrahydrofuran (13mL, 26.0 mmol). After stirring at-78 ℃ for 2h, iodomethane (3.8g, 26.8mmol) was added. The mixture was then warmed to room temperature and stirred for 1 hour. The mixture was poured into water (60mL) and extracted twice with ethyl acetate (60 mL). The combined organic layers were washed with brine (60mL) and Na₂SO_4(s)Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give the desired product (3.1g, purity 90%, 74% yield) as a pale yellow oil.¹HNMR(300MHz,CDCl₃)δ4.20-4.17(m,2H),3.94(s,4H),2.19-2.08(m,2H),1.68-1.64(m,4H),1.57-1.44(m,2H),1.19(s,3H),1.02-0.97(m,2H),0.05(s,9H)。

Intermediate 1 d: 2- (trimethylsilyl) ethyl 1-methyl-4-oxocyclohexanecarboxylate

To 2- (trimethylsilyl) ethyl 8-methyl-1, 4-dioxaspiro [4.5]]Decane-8-carboxylic acid ester 1c (4.20g, 90% purity, 12.6mmol)) To a solution in acetone (50mL) and water (50mL) was added pyridinium p-toluenesulfonate (6.30g, 25.1mmol), and the reaction was heated at 65 ℃ overnight. To the mixture was added water (80mL), and the mixture was extracted twice with ethyl acetate (80 mL). The combined organic layers were washed with 2M aqueous hydrochloride (60mL), saturated aqueous sodium carbonate (40mL), brine (60mL), and Na₂SO_4(s)Drying, filtration and concentration gave the desired product as a colorless oil (3.5g, 90% purity, 98% yield).¹H NMR(300MHz,CDCl₃)δ4.28-4.22(m,2H),2.52-2.27(m,6H),1.75-1.62(m,2H),1.30(s,3H),1.06-1.00(m,2H),0.06(s,9H)。

Intermediate 1 e: 2- (trimethylsilyl) ethyl 4-hydroxy-1-methylcyclohexane-carboxylate

To a solution of 2- (trimethylsilyl) ethyl 1-methyl-4-oxocyclohexanecarboxylate 1d (2.50g, 90% purity, 8.78mmol) in tetrahydrofuran (30mL) and water (3mL) was added sodium borohydride (0.996g, 26.3mmol) at 0 ℃. After stirring at room temperature for 2 hours, the reaction was concentrated to give a residue, to which water (50mL) was added and extracted twice with ethyl acetate (50 mL). The combined organic layers were washed with 1M aqueous hydrochloride (50mL) and brine (50mL) over Na₂SO_4(s)Drying, filtration and concentration gave the desired product as a pale yellow oil (2.30g, 90% purity, 91% yield).¹H NMR(300MHz,CDCl₃)δ4.22-4.16(m,2H),3.87-3.80(m,0.3H),3.65-3.56(m,0.7H),2.27-2.19(m,2H),1.92-1.80(m,2H),1.75-1.45(m,2H),1.45-1.21(m,2H),1.15(s,3H),1.05-0.98(m,2H),0.06(s,9H)。

Intermediate 1 f: 2- (trimethylsilyl) ethyl 1-methyl-4- (tosyloxy) cyclohexane-carboxylate

To a solution of 2- (trimethylsilyl) ethyl 4-hydroxy-1-methylcyclohexanecarboxylate 1e (2.30g, 90% purity, 8.01mmol) in dichloromethane (30mL) was added 4-methylbenzene-1-sulfonyl chloride (1.83g, 9.60mmol), N-dimethylpyridin-4-amine (1.52g, 12.4mmol) at room temperature. After stirring overnight, the mixture was diluted with dichloromethane (80mL), washed with water (50mL), 2M aqueous hydrochloride (50mL), brine (50mL), and Na₂SO_4(s)Drying, filtering andand (5) concentrating. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give the desired product (3.20g, purity 90%, 87% yield) as a pale yellow oil.¹H NMR(300MHz,CDCl₃)δ7.79(d,J＝8.1Hz,2H),7.34(d,J＝8.1Hz,2H),4.67-4.61(m,0.2H),4.50-4.38(m,0.8H),4.19-4.14(m,2H),2.46(s,3H),2.24-2.19(m,2H),1.94-1.73(m,2H),1.65-1.51(m,2H),1.25-1.12(m,2H),1.12(s,3H),1.01-0.95(m,2H),0.06(s,9H)。

Intermediate 1 g: 2- (trimethylsilyl) ethyl 4- (acetylthio) -1-methylcyclohexanecarboxylate

To a solution of 2- (trimethylsilyl) ethyl 1-methyl-4- (tosyloxy) cyclohexanecarboxylate 1f (3.20g, 90% purity, 6.98mmol) in N, N-dimethylformamide (20mL) was added potassium ethyl mercaptide (3.20g, 28.0mmol) at room temperature, and the reaction was heated at 85 ℃ for 3 hours. After cooling to room temperature, the mixture was poured into water (100mL) and extracted twice with ethyl acetate (60 mL). The combined extracts were washed with water (100mL), brine (50mL), and Na₂SO_4(s)Drying, filtration and concentration gave the desired product as a brown oil (2.40g, 90% purity, 98% yield).¹H NMR(300MHz,CDCl₃)δ4.23-4.16(m,2H),3.61-3.48(m,1H),2.19(s,3H),2.15-2.01(m,4H),1.96-1.83(m,4H),1.27(s,3H),1.04-0.97(m,2H),0.07(s,9H)。

Sulfonyl chloride 1: 2- (trimethylsilyl) ethyl 4- (chlorosulfonyl) -1-methylcyclohexanecarboxylate

To a solution of 1g (1.30g, 90% purity, 3.70mmol) of 2- (trimethylsilyl) ethyl 4- (acetylthio) -1-methylcyclohexanecarboxylate in acetonitrile (15mL) at 0 deg.C was added 1M aqueous hydrochloride solution (0.5mL) and 1-chloropyrrolidine-2, 5-dione (1.60g, 12.0 mmol). After stirring at 0 ℃ for 1 hour, the mixture was diluted with ethyl acetate (100mL), washed with brine (50mL), and taken over Na₂SO_4(s)Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the desired product as a light brown oil (800mg, purity 90%, 57% yield).¹H NMR(300MHz,CDCl₃)δ4.28-4.08(m,2H),3.96-3.80(m,0.3H),3.63-3.47(m,0.7H),2.53-2.24(m,3H),2.14-2.06(m,2H),2.01-1.78(m,3H),1.28-1.24(m,3H),1.03-0.96(m,2H),0.07(s,9H)。

Sulfonyl chloride 2: tert-butyl 3- (chlorosulfonyl) -2, 2-dimethylpropionate

Intermediate 2 a: 1-tert-butyl 3-methyl 2, 2-dimethylmalonate

To a suspension of 60% wt sodium hydride (1.56g, 39.0mmol) in mineral oil in tetrahydrofuran (40mL) was added dropwise methyl tert-butyl malonate (3.50g, 20.0mmol) at 0 ℃. After stirring at this temperature for 30 minutes, methyl iodide (5.54g, 39.0mmol) was added dropwise and stirring continued at room temperature for another 5 hours. The mixture was then quenched with water (30mL) and extracted twice with ethyl acetate (50 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a brown oil (3.80g, 94% yield).¹H NMR(300MHz,CDCl₃)δ3.72(s,3H),1.44(s,9H),1.40(s,6H)。

Intermediate 2 b: tert-butyl 3-hydroxy-2, 2-dimethylpropionate

To a solution of 1-tert-butyl 3-methyl 2, 2-dimethylmalonate 2a (5.00g, 24.7mmol) in tetrahydrofuran (30mL) was added dropwise 1.5M diisobutylaluminum hydride (41.3mL, 61.9mmol) in toluene at-78 ℃ under a nitrogen atmosphere. After stirring at this temperature under a nitrogen atmosphere for 2 hours and at room temperature overnight, the mixture was quenched with water (50mL) and extracted three times with ethyl acetate (100 mL). The combined organic layers were washed three times with water (200mL) and brine (100mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a white oil (2.00g, 47% yield).¹H NMR(300MHz,CDCl₃)δ3.52(d,J＝5.4Hz,2H),2.58(br s,1H),1.47(s,9H),1.16(s,6H)。

Intermediate 2 c: tert-butyl 2, 2-dimethyl-3- (tosyloxy) propionate

At 0 ℃ to tert-butylTo a solution of 3-hydroxy-2, 2-dimethylpropionate 2b (2.00g, 11.5mmol) in pyridine (8mL) and dichloromethane (20mL) was added tosyl chloride (5.49g, 28.7 mmol). After stirring overnight at room temperature under a nitrogen atmosphere, the mixture was concentrated and dissolved in ethyl acetate (40mL) and water (40mL), then 0.5M aqueous hydrochloride solution (24mL) was added and separated. The aqueous layer was extracted twice with ethyl acetate (40 mL). The combined organic layers were washed with 0.5M aqueous hydrochloride (20mL) and brine (20mL) over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give the title compound (1.80g, 48% yield) as a white solid.¹H NMR(300MHz,CDCl₃)δ7.79(d,J＝8.1Hz,2H),7.35(d,J＝8.1Hz,2H),3.98(s,2H),2.46(s,3H),1.40(s,9H),1.14(s,6H)。

Intermediate 2 d: tert-butyl 3- (acetylthio) -2, 2-dimethylpropionate

To a solution of tert-butyl 2, 2-dimethyl-3- (tosyloxy) propionate 2c (1.80g, 5.49mmol) in N, N-dimethylformamide (30mL) was added potassium thioacetate (1.25g, 11.0mmol) at room temperature. After stirring at 100 ℃ for 4 hours under a nitrogen atmosphere, the reaction mixture was cooled to room temperature, taken up in water (100mL) and extracted three times with ethyl acetate (100 mL). The combined organic layers were washed with brine (80mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (1.2g, 96% yield).¹H NMR(300MHz,CDCl₃)δ3.11(s,2H),2.33(s,3H),1.43(s,9H),1.18(s,6H)。

Sulfonyl chloride 2: tert-butyl 3- (chlorosulfonyl) -2, 2-dimethylpropionate

To a solution of tert-butyl 3- (acetylthio) -2, 2-dimethylpropionate EO 8495-522.5 (1.20g, 5.57mmol) in acetonitrile (28mL) at 0 deg.C were added 2M aqueous hydrochloride solution (1mL) and 1-chloropyrrolidine-2, 5-dione (2.97g, 22.3 mmol). After stirring at this temperature under a nitrogen atmosphere for 2 hours, the mixture was quenched with water (30mL) and extracted three times with ethyl acetate (80 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄(solid) driedDried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 40:1) to give the title compound as a white oil (250mg, 18% yield).¹H NMR(300MHz,CDCl₃)δ4.14(s,2H),1.48(s,9H),1.43(s,6H)。

Sulfonyl chloride 3: tert-butyl 3- (chlorosulfonyl) azetidine-1-carboxylate

Intermediate 3 a: tert-butyl 3- (tosyloxy) azetidine-1-carboxylate

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate EO8495 — 681.1(2.00g, 11.5mmol) and pyridine (2.73g, 34.5mmol) in dry dichloromethane (20mL) was added a solution of tosyl chloride (4.41g, 23.1mmol) in dry dichloromethane (10mL) at 0 ℃ under a nitrogen atmosphere. The mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for 48 hours. It was concentrated under reduced pressure to leave a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 8:1) to give the title compound as a colorless oil (3.75g, 99% yield). LC-MS (ESI): r_T＝2.364min，C₁₅H₂₁NO₅Calculated mass of S327.1, found value of M/z 349.9[ M + Na [)]⁺。¹H NMR(300MHz,CDCl₃)δ7.79(d,J＝8.1Hz,2H),7.38(d,J＝8.1Hz,2H),5.06-4.96(m,1H),4.14-4.08(m,2H),3.95-3.92(m,2H),2.47(s,3H),1.42(s,9H)。

Intermediate 3 b: tert-butyl 3- (acetylthio) azetidine-1-carboxylate

To a solution of tert-butyl 3- (tosyloxy) azetidine-1-carboxylate EO8495 — 681.2(3.25g, 9.93mmol) in N, N-dimethylformamide (30mL) was added potassium thioacetate (2.27g, 19.9 mmol). After stirring overnight at 100 ℃, the mixture was cooled to room temperature, poured into water (90mL), and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed three times with water (30mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated to give the title compound as a brown oilMaterial (2.24g, 97% yield). LC-MS (ESI): r_T＝1.703min，C₁₀H₁₇NO₃Calculated mass of S231.1, found value of M/z 176.0[ M + H-56]⁺。¹H NMR(300MHz,CDCl₃)δ4.41-4.37(m,2H),4.22-4.12(m,1H),3.93-3.77(m,2H),2.35(s,3H),1.45(s,9H)。

Sulfonyl chloride 3: tert-butyl 3- (chlorosulfonyl) azetidine-1-carboxylate

To a solution of tert-butyl 3- (acetylthio) azetidine-1-carboxylate EO8495 — 681.3(2.24g, 9.69mmol) in acetonitrile (20mL) was added 2M aqueous hydrochloride solution (0.8mL) and N-chlorosuccinimide (5.17g, 38.7mmol) at 0 ℃. After stirring at 0 ℃ for 1 hour, the mixture was quenched with water (60mL) and extracted three times with ether (30 mL). The combined organic layers were passed over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 8:1) to give the title compound (910mg, 37% yield) as a yellow solid. LC-MS (ESI): r_T＝1.895min，C₈H₁₄ClNO₄Calculated mass of S255.0, found value of M/z 199.9[ M + H-56]⁺。¹H NMR(300MHz,CDCl₃)δ4.59-4.47(m,1H),4.43-4.31(m,4H),1.47(s,9H)。

Sulfonyl chloride 4: 1-cyclopropyl-1H-pyrazole-4-sulfonyl chloride

Intermediate 4 a: 1-cyclopropyl-4-iodo-1H-pyrazoles

To a solution of 4-iodo-1H-pyrazole (7.00g, 36.0mmol) in 1, 4-dioxane (30mL) under a nitrogen atmosphere was added cyclopropylboronic acid (6.20g, 72.0mmol), copper acetate monohydrate (9.40g, 47.0mmol), 4-dimethylaminopyridine (108mg, 43.0mmol), and pyridine (3.50g, 43.0 mmol). After stirring overnight at 110 ℃, the reaction mixture was cooled to room temperature and diluted with water (50mL) and extracted three times with ethyl acetate (60 mL). The combined organic layers were washed with brine (40mL) and Na₂SO₄(solid) dried and filtered. Concentrating the filtrate under reduced pressure to obtain crude productThe product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to give the title compound as a pale yellow oil (1.80g, 21% yield).¹H NMR(400MHz,CDCl₃)δ7.49(s,1H),7.47(s,1H),3.62-3.57(m,1H),1.13-1.08(m,2H),1.05-0.99(m,2H)。

Intermediate 4 b: 4- (benzylthio) -1-cyclopropyl-1H-pyrazoles

To a solution of 1-cyclopropyl-4-iodo-1H-pyrazole intermediate 4a (500mg, 2.13mmol) in 1, 4-dioxane (10mL) under a nitrogen atmosphere were added benzylthiol (527mg, 4.30mmol), N-diisopropylethylamine (554g, 4.30mmol), tris (dibenzylideneacetone) dipalladium (20mg, 0.020mmol), and 9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (23mg, 0.040 mmol). After stirring overnight at 110 ℃, the reaction mixture was cooled to room temperature and diluted with water (20mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give the title compound as a colorless oil (330mg, 67% yield). LC-MS (ESI): r_T＝2.358min，C₁₃H₁₄N₂Calculated mass of S230.1, found value of M/z 230.9[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ7.32-7.17(m,4H),7.13-7.07(m,3H),3.78(s,2H),3.57-3.46(m,1H),1.07-0.92(m,4H)。

Sulfonyl chloride 4: 1-cyclopropyl-1H-pyrazole-4-sulfonyl chloride

To a solution of 4- (benzylthio) -1-cyclopropyl-1H-pyrazole EO8495 — 729.3(330mg, 1.43mmol) in acetonitrile (6mL) at 0 ℃ under a nitrogen atmosphere was added acetic acid (0.7mL), water (0.5mL) and 1, 3-dichloro-5, 5-dimethylhydantoin (570mg, 2.87 mmol). After stirring at 0 ℃ for 2h, the reaction mixture was diluted with water (10mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (320mg, crude) as a colorless oil. LC-MS (ESI): r_T＝1.457min，C₆H₇ClN₂O₂Calculated mass of S206.0, found value of M/z 206.9[ M + H [ ]]⁺。

Sulfonyl chloride 5: (trans) -tert-butyl 3- (chlorosulfonyl) cyclobutanecarboxylic acid ester

Intermediate 5 a: (cis) -tert-butyl 3-hydroxycyclobutanecarboxylate

A1L three-necked flask was charged with nitrogen and a solution of 3-oxocyclobutanecarboxylic acid ester (21.5g, 126.316mmol) in MeOH (52mL, 0.791g/mL, 1283.684mmol) and THF (160mL, 0.886g/mL, 1965.969mmol) was added dropwise over 20 minutes under a nitrogen atmosphere to a suspension of sodium borohydride (2.389g, 63.158mmol) in THF (108mL, 0.886g/mL, 1327.029mmol) at 0 deg.C. [ Warning! Reaction with outgassing!][ monitoring the temperature of the internal reaction system to not exceed 20 ℃.]The reaction mixture was stirred at 0 ℃ for 2h, TLC ((3:1 ═ HEX: EA) showed consumption of starting material the mixture was concentrated under reduced pressure to give a residue to which was added a saturated Na2CO3 solution (200mL) and extracted with EA (300mL X3) the combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated to give the crude product (21.5g, 98.83% yield) which was used in the next step without further purification.¹H NMR(300MHz,CDCl₃)δ4.73-4.69(m,1H),4.16-4.14(m,1H),2.64-2.40(m,3H),2.27-2.06(m,2H),1.44(s,9H)。

Intermediate 5 b: (cis) -tert-butyl 3- (tosyloxy) cyclobutanecarboxylic acid ester

4-methyl-benzenesulfonyl chloride (93g, 488mmol) was slowly added to a solution of (cis) -tert-butyl 3-hydroxycyclobutanecarboxylate 5a (42g, 244mmol) in pyridine (150mL) and dichloromethane (400mL) at 0 ℃. After stirring at room temperature for 16 hours, the mixture was diluted with water (200mL, 0 ℃) and stirred at room temperature for 0.5 hours. The aqueous phase was extracted with dichloromethane (200mL x 2), the organic layers were combined and washed with 0.5N HCl (200mL), brine (100mL), Na₂SO_4(s)Drying, filtration and concentration gave the title compound as a white solid (79.6g, 92% yield).¹H NMR(300MHz,CDCl₃)δ7.80(d,J＝8.1Hz,2H),7.35(d,J＝7.5Hz,2H),4.74-4.69(m,1H),2.56-2.30(m,8H),1.42(s,9H)。

Intermediate 5 c: (trans) -tert-butyl 3- (acetylthio) cyclobutanecarboxylic acid ester

A1L three-necked flask was charged with nitrogen under a nitrogen atmosphere, and to a solution of (cis) -tert-butyl 3- (tosyloxy) cyclobutanecarboxylate 5b (41.36g, 126.71mmol) in DMF (400mL, 0.944g/mL, 5165.903mmol) at room temperature was added potassium thioacetate (24.8g, 217.145 mmol). The reaction was stirred at 100 ℃ overnight (12 hours) under a nitrogen atmosphere. TLC (10:1 ═ PE: EA) showed consumption of all starting material. Most of the solvent was evaporated under reduced pressure and the residue was redissolved in EA (1L), washed with water (200mL), saturated aqueous NaCl (100mL X10), dried over Na2SO4, evaporated to remove the solvent to give a residue which was subjected to flash column (PE: EA ═ 100:1 to 50:1) to give the title compound as a yellow oil (22.5g, 77.094% yield).¹H NMR(300MHz,CDCl₃)δ4.16-4.06(m,1H),3.19-3.11(m,1H),2.79-2.70(m,2H),2.29-2.20(m,5H),1.46(s,9H)。

Sulfonyl chloride 5: (trans) -tert-butyl 3- (chlorosulfonyl) cyclobutanecarboxylic acid ester

To a solution of (trans) -tert-butyl 3- (acetylthio) cyclobutanecarboxylate 5c (25g, 109mmol) and 2M aqueous hydrochloride (13mL, 27mmol) in acetonitrile (400mL) at 0 deg.C was slowly added 1-chloropyrrolidine-2, 5-dione (58g, 435 mmol). After stirring at 0 ℃ for 30 min, the reaction mixture was concentrated in vacuo to remove acetonitrile (25 ℃ bath). And the residue was partitioned between ethyl acetate (800mL) and saturated aqueous sodium bicarbonate (400 mL). The separated organic layer was washed with saturated aqueous sodium thiosulfate (400mL), then brine (400mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 150:1) to give the title compound (19g, 71% yield) as a white solid.¹H NMR(400MHz,CDCl₃)δ4.49-4.41(m,1H),3.29-3.21(m,1H),2.93-2.86(m,2H),2.80-2.73(m,2H),1.47(s,9H)。

Sulfonyl chloride 6: 1, 4-dioxaspiro [4.5] decan-2-ylmethanesulfonyl chloride

Intermediate 6 a: 1, 4-dioxaspiro [4.5] decan-2-ylmethanol

To a solution of glycerol (18.2g, 0.2mol) and cyclohexanone (13.0g, 0.13mol) in toluene (13mL) was added 4-toluenesulfonic acid (1.30g, 7.80mmol) at room temperature. After stirring at 105 ℃ for 16 h, the reaction mixture was cooled to room temperature. The mixture was concentrated under reduced pressure to give a residue, which was diluted with water (150mL) and ethyl acetate (100 mL). The aqueous layer was extracted twice with ethyl acetate (100 mL). The combined organic layers were washed with brine (250mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound as a yellow oil (21.4g, 95% yield), which was used without further purification.¹H NMR(300MHz,DMSO-d₆)δ4.02-3.87(m,2H),3.64-3.55(m,1H),3.45-3.26(m,2H),1.97-1.20(m,10H)。

Intermediate 6 b: 1, 4-dioxaspiro [4.5] decan-2-ylmethyl 4-methylbenzenesulfonate

4-Methylbenzene-1-sulfonyl chloride (44.0g, 231mmol) was slowly added to 1, 4-dioxaspiro [4.5] at 0 deg.C]Decan-2-ylmethanol intermediate 6a (10.0g, 58mmol) in pyridine (10mL) and dichloromethane (100 mL). After stirring at room temperature for 16 hours, the mixture was diluted with water (100mL) and stirred at room temperature for 30 minutes. The aqueous layer was extracted twice with dichloromethane (100mL), and the combined organic layers were washed with 0.5N aqueous hydrochloride (200mL) and brine (100mL) over Na₂SO_4(s)Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 30:1) to give the title compound as a white solid (15.0g, 79% yield).¹H NMR(300MHz,CDCl₃)δ7.87-7.76(m,2H),7.42-7.36(m,2H),4.34-4.24(m,1H),4.09-3.92(m,3H),3.83-3.72(m,1H),2.47(s,3H),1.59-1.55(m,10H)。

Intermediate 6 c: s- (1, 4-dioxaspiro [4.5] decan-2-ylmethyl) ethanethiol ester

To 1, 4-dioxaspiro [4.5] at room temperature]To a solution of decan-2-ylmethyl 4-methylbenzenesulfonate intermediate 6b (15.0g, 45.9mmol) in N, N-dimethylformamide (150mL) was added potassium thioacetate (21g, 183 mmol). After stirring at 100 ℃ for 16 hours, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, added with 5% aqueous sodium chloride (500mL) and extracted twice with ethyl acetate (150 mL). The combined organic layers were passed over Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 30:1) to give the title compound as a yellow oil (9g, 86% yield).¹H NMR(300MHz,CDCl₃)δ4.25-4.22(m,1H),4.10-4.06(m,1H),3.68-3.62(m,1H),3.11-3.10(m,2H),2.36(s,3H),1.64-1.58(m,10H)。

Sulfonyl chloride 6: 1, 4-dioxaspiro [4.5] decan-2-ylmethanesulfonyl chloride

To S- (1, 4-dioxaspiro [4.5] at 0 deg.C]Decan-2-ylmethyl) ethanethiol ester intermediate 6c (920mg, 4mmol) and a solution of 2N hydrochloride in water (0.5mL, 1.00mmol) in acetonitrile (30mL) was slowly added 1-chloropyrrolidine-2, 5-dione (1.07g, 8.00 mmol). After stirring at 0 ℃ for 30 min, the reaction mixture was concentrated in vacuo to remove acetonitrile (25 ℃ bath). And the residue was partitioned between ethyl acetate (50mL) and saturated aqueous sodium bicarbonate (50 mL). The combined organic layers were washed with saturated aqueous sodium thiosulfate (50mL), then brine (50mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound (380mg, 40% yield) as a yellow oil.¹H NMR(300MHz,CDCl₃)δ4.76-4.68(m,0.2H),4.67-4.58(m,0.4H),4.46-4.37(m,0.4H),4.25-4.31(m,3H),3.60-3.48(m,0.3H),3.39-3.33(m,0.7H),1.70-1.51(m,8H),1.47-1.32(m,2H)。

Sulfonyl chloride 7: tert-butyl 3- (chlorosulfonyl) cyclopentane carboxylate

Intermediate 7 a: tert-butyl 3-oxocyclopentane carboxylate

To a solution of 3-oxocyclopentanecarboxylic acid (5.00g, 39.1mmol) and tert-butyl dicarbonate (17.0g, 78.0mmol) in tert-butanol (100mL) was added 4-dimethylaminopyridine (1.40g, 11.5 mmol). After stirring at room temperature overnight, the mixture was concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1 to 10:1) to give the title compound (4.60g, 64% yield) as a yellow oil.¹H NMR(300MHz,CDCl₃)δ3.09-2.99(m,1H),2.54-2.07(m,6H),1.47(s,9H)。

Intermediate 7 b: tert-butyl 3-hydroxycyclopentanecarboxylic acid ester

Sodium borohydride (946mg, 25.0mmol) was slowly added to a solution of tert-butyl 3-oxocyclopentanecarboxylate intermediate 7a (4.60g, 25.0mmol) in methanol (50mL) at 0 deg.C. After stirring at 10 ℃ for 1 hour, the mixture was diluted with water (50mL), concentrated and extracted twice with ethyl acetate (80 mL). The combined organic layers were passed over Na₂SO_4(s)Dried, filtered and concentrated to give the crude product as a colourless oil (4.50g, crude), which was used in the next step without further purification.¹H NMR(300MHz,CDCl₃)δ4.45(br s,0.2H),4.30(br s,0.8H),3.01-2.76(m,2H),2.09-1.68(m,6H),1.46-1.45(m,9H)。

Intermediate 7 c: tert-butyl 3- (tosyloxy) cyclopentane carboxylate

4-methyl-benzenesulfonyl chloride (5.50g, 29mmol) was slowly added to a solution of tert-butyl 3-hydroxycyclopentanecarboxylate intermediate 7b (4.50g, 24mmol), 4-dimethylaminopyridine (30mg, 0.24mmol) and triethylamine (4.9g, 48mmol) in dichloromethane (45mL) at 0 ℃. After stirring at room temperature for 16 h, the mixture was washed with saturated aqueous sodium bicarbonate (30mL), then brine (30mL), over Na₂SO_4(s)Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1 to 10:1) to give the title compound (5.60g, 68% yield) as a colorless oil.¹H NMR(300MHz,CDCl₃)δ7.79(d,J＝7.8Hz,2H),7.34(d,J＝7.8Hz,2H),5.02(s,0.2H),4.96-4.89(m,0.8H),2.95-2.77(m,0.2H),2.69-2.59(m,0.8H),2.46(s,3H),2.21-1.76(m,6H),1.43(s,9H)。

Intermediate 7 d: tert-butyl 3- (acetylthio) cyclopentanecarboxylic acid ester

To a solution of tert-butyl 3- (tosyloxy) cyclopentanecarboxylate intermediate 7c (4.60g, 13.5mmol) in N, N-dimethylformamide (50mL) was added potassium thioacetate (6.20g, 54.1mmol) at room temperature. After stirring at 80 ℃ for 16 h, the reaction mixture was cooled to room temperature, quenched with 5% aqueous sodium chloride (50mL), and extracted twice with ethyl acetate (100 mL). The combined organic layers were passed over Na₂SO_4(s)Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:1 to 30:1) to give the title compound as a brown oil (3.50g, 87% yield).¹H NMR(300MHz,CDCl₃)δ3.92-3.78(m,0.8H),3.72-3.67(m,0.2H),2.88-2.73(m,1H),2.42-2.13(m,5H),2.07-1.80(m,3H),1.62-1.53(m,1H),1.45(s,9H)。

Sulfonyl chloride 7: tert-butyl 3- (chlorosulfonyl) cyclopentane carboxylate

To a solution of tert-butyl 3- (acetylthio) cyclopentanecarboxylate intermediate 7d (3.00g, 12mmol) and 2N aqueous hydrochloride (1.8mL, 3.6mmol) in acetonitrile (80mL) was added 1-chloropyrrolidine-2, 5-dione (6.60g, 49mmol) at 0 deg.C. After stirring at 0 ℃ for 1 hour, the mixture was added into water (30mL), concentrated under reduced pressure, and extracted twice with ethyl acetate (50 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1 to 10:1) to give the title compound as a white solid (2.9g, 88% yield).¹H NMR(300MHz,CDCl₃)δ4.32-4.22(m,0.8H),4.18-4.07(m,0.2H),3.08-2.98(m,0.8H),2.91-2.79(m,0.2H),2.57-2.46(m,2H),2.38-1.90(m,4H),1.46(s,9H)。

Sulfonyl chloride 8: tert-butyl 4- (chlorosulfonyl) cyclohexanecarboxylate

Intermediate 8 a: tert-butyl 4-hydroxycyclohexanecarboxylic acid ester

Sodium borohydride (611mg, 16.0mmol) was slowly added to a solution of tert-butyl 4-oxocyclohexanecarboxylate EO 8495-830.1 (3.20g, 16.0mmol) in methanol (30mL) at 0 ℃. After stirring at 10 ℃ for 1 hour, the mixture was added into water (50mL), concentrated under reduced pressure and extracted twice with ethyl acetate (40 mL). The combined organic layers were passed over Na₂SO_4(s)Dried, filtered and concentrated to give the crude product as a colourless oil (3.20g, crude) which was used in the next step without further purification.¹H NMR(300MHz,CDCl₃)δ3.91-3.85(m,0.4H),3.65-3.57(m,0.6H),2.30-2.27(m,0.4H),2.18-2.10(m,0.6H),2.04-1.89(m,3H),1.66-1.60(m,3H),1.53-1.35(m,10H),1.30-1.21(m,2H)。

Intermediate 8 b: tert-butyl 4- (tosyloxy) cyclohexanecarboxylate

4-methyl-benzenesulfonyl chloride (3.7g, 19mmol) was slowly added to a solution of tert-butyl 4-hydroxycyclohexanecarboxylate intermediate 8a (3.2g, 16mmol), 4-dimethylaminopyridine (20mg, 0.16mmol) and triethylamine (3.2g, 32mmol) in dichloromethane (30mL) at 0 ℃. After stirring at room temperature for 16 h, the mixture was washed with saturated aqueous sodium bicarbonate (15mL), then brine (15mL), over Na₂SO_4(s)Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1 to 10:1) to give the title compound (4.0g, 72% yield) as a colorless oil.¹HNMR(300MHz,CDCl₃)δ7.80(d,J＝8.1Hz,2H),7.34(d,J＝8.1Hz,2H),4.70(br s,0.3H),4.41(br s,0.7H),2.46(s,3H),2.25-2.13(m,1H),1.98-1.79(m,4H),1.71-1.42(m,13H)。

Intermediate 8 c: tert-butyl 4- (acetylthio) cyclohexanecarboxylate

To a solution of tert-butyl 4- (tosyloxy) cyclohexanecarboxylate intermediate 8b (3.00g, 8.50mmol) in N, N-dimethylformamide (30mL) was added potassium thioacetate (3.90g, 33.8mmol) at room temperature. After stirring at 80 ℃ for 16 hours, the reaction was carried outThe mixture was cooled to room temperature, quenched with 5% aqueous sodium chloride (50mL), and extracted twice with ethyl acetate (100 mL). The combined organic layers were passed over Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:1 to 30:1) to give the title compound as a brown oil (1.9g, 65% yield).¹H NMR(300MHz,CDCl₃)δ3.75(s,1H),2.30-2.29(m,3.7H),2.21-2.14(m,0.3H),2.01-1.94(m,0.7H),1.81-1.72(m,6.7H),1.56-1.52(m,0.3H),1.43(s,9H),1.38-1.33(m,0.3H)。

Sulfonyl chloride 8: tert-butyl 4- (chlorosulfonyl) cyclohexanecarboxylate

To a solution of tert-butyl 4- (acetylthio) cyclohexanecarboxylate intermediate 8c (1.4g, 5.4mmol) and 2M aqueous hydrochloride (0.8mL, 1.6mmol) in acetonitrile (50mL) was added 1-chloropyrrolidine-2, 5-dione (2.9g, 21.7mmol) at 0 deg.C. After stirring at 0 ℃ for 1 hour, the mixture was diluted with water (20mL), concentrated under reduced pressure, and extracted twice with ethyl acetate (40 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1 to 10:1) to give the title compound as a white solid (1.2g, 78% yield).¹H NMR(300MHz,CDCl₃)δ3.59-3.49(m,1H),2.62-2.49(m,1H),2.39-2.22(m,4H),2.09-1.95(m,2H),1.86-1.63(m,1H),1.57-1.54(m,1H),1.48-1.45(m,9H)。

Sulfonyl chloride 9: 2- (trimethylsilyl) ethyl 3- (chlorosulfonyl) -1-methylcyclobutanecarboxylate

Intermediate 9 a: 1-methyl-3-oxocyclobutanecarboxylic acid

To a solution of ethyl 1-methyl-3-oxocyclobutanecarboxylate EO8495 — 670.1(4.00g, 25.6mmol) in methanol (50mL) and water (10mL) was added lithium hydroxide monohydrate (2.15g, 51.2 mmol). After stirring overnight at room temperature, the mixture was acidified with 2M aqueous hydrochloride solutionTo a pH of about 2, then concentrated under reduced pressure to give a residue, which was dissolved in water (50mL) and extracted three times with ethyl acetate (30 mL). The combined organic layers were passed over Na₂SO_4(s)Drying and concentration gave the title compound as a yellow oil (4.10g, 90% purity, 100% yield).¹H NMR(400MHz,CDCl₃)δ3.67-3.62(m,2H),2.99-2.93(m,2H),1.62(s,3H)。

Intermediate 9 b: 2- (trimethylsilyl) ethyl 1-methyl-3-oxocyclobutanecarboxylate

To a solution of 1-methyl-3-oxocyclobutanecarboxylic acid intermediate 9a (4.10g, 90% pure, 28.8mmol) and 2- (trimethylsilyl) ethanol (3.75g, 31.7mmol), N-dimethylpyridin-4-amine (3.50g, 28.6mmol) in tetrahydrofuran (100mL) under nitrogen was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (8.30g, 43.2 mmol). After stirring at room temperature overnight, the mixture was quenched with water (50mL), then concentrated under reduced pressure to remove volatiles and extracted three times with ethyl acetate (80 mL). The combined organic layers were washed with 2M aqueous hydrochloride (100mL) and Na₂SO_4(s)Drying and concentration gave the title compound as a yellow oil (5.10g, 80% purity, 100% yield).¹H NMR(400MHz,CDCl₃)δ4.21-4.17(m,2H),3.54-3.49(m,2H),2.85-2.80(m,2H),1.52(s,3H),0.99-0.95(m,2H),0.07(s,9H)。

Intermediate 9 c: 2- (trimethylsilyl) ethyl 3-hydroxy-1-methylcyclobutane-carboxylic acid ester

To a solution of 2- (trimethylsilyl) ethyl 1-methyl-3-oxocyclobutanecarboxylate intermediate 9b (5.10g, 80% purity, 17.9mmol) in tetrahydrofuran (100mL) and water (10mL) was added sodium tetrahydroborate (2.70g, 71.5mmol) dropwise at room temperature. After stirring at room temperature overnight, the mixture was quenched with water (20mL) and then concentrated under reduced pressure to give a residue. The residue was taken up in water (50mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were passed over Na₂SO_4(s)Drying and concentration gave the title compound as a yellow oil (3.80g, 90% purity, 100% yield).¹H NMR(400MHz,CDCl₃)δ4.38-4.22(m,1H),4.16-4.10(m,2H),3.71-3.67(m,1H),2.80-2.71(m,1H),2.32-2.21(m,2H),1.85-1.77(m,1H),1.35(s,1.5H),1.30(s,1.5H),0.97-0.89(m,2H),0.07(s,9H)。

Intermediate 9 d: 2- (trimethylsilyl) ethyl 1-methyl-3- (tosyloxy) cyclobutene-carboxylate

To a solution of 2- (trimethylsilyl) ethyl 3-hydroxy-1-methylcyclobutanecarboxylate intermediate 9c (3.70g, 90% purity, 14.5mmol) and N, N-dimethylpyridin-4-amine (2.90g, 23.7mmol) in dichloromethane (100mL) under nitrogen was added 4-methylbenzene-1-sulfonyl chloride (3.3g, 17.3 mmol). After stirring at room temperature overnight, the reaction solution was washed with water (40mL) and Na₂SO_4(s)Dried and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 8:1) to give the title compound (3.10g, purity 95%, 48% yield) as a pale yellow oil.

¹H NMR(400MHz,CDCl₃)δ7.74(d,J＝8.4Hz,2H),7.30(d,J＝8.0Hz,2H),4.87-4.83(m,1H),4.14-4.10(m,1H),2.72-2.66(m,0.8H),2.56-2.52(m,1.2H),2.42(s,3H),2.17-2.11(m,1.2H),2.08-2.03(m,0.8H),1.33(s,1H),1.28(s,2H),0.95-0.91(m,2H),0.01(s,9H)。

Intermediate 9 e: 2- (trimethylsilyl) ethyl 3- (acetylthio) -1-methylcyclobutanecarboxylate

To a solution of 2- (trimethylsilyl) ethyl 1-methyl-3- (tosyloxy) cyclobutanecarboxylate intermediate 9d (3.10g, 95% purity 7.26mmol) in N, N-dimethylformamide (70mL) was added potassium thioacetate (3.00g, 26.3mmol) at room temperature. After stirring at 100 ℃ for 6 hours, the reaction mixture was cooled and poured into water (200mL) and extracted three times with ethyl acetate (80 mL). The combined organic layers were washed three times with water (100mL) and Na₂SO_4(s)Drying and concentration gave the title compound as a yellow oil (2.30g, 90% purity, 99% yield).¹H NMR(400MHz,CDCl₃)δ4.27-4.21(m,2H),4.19-4.08(m,1H),3.06-3.00(m,1H),2.59-2.50(m,1H),2.41-2.36(m,1H),2.32(s,3H),2.04-1.99(m,1H),1.50(s,1.2H),1.44(s,1.8H),1.08-1.01(m,2H),0.07(s,9H)。

Sulfonyl chloride 9: 2- (trimethylsilyl) ethyl 3- (chlorosulfonyl) -1-methylcyclobutanecarboxylate

To a solution of 2- (trimethylsilyl) ethyl 3- (acetylthio) -1-methylcyclobutanecarboxylate intermediate 9e (1.10g, 90% purity 7.52mmol) in acetonitrile (50mL) at 0 deg.C was added 2M aqueous hydrochloride solution (0.2mL) and 1-chloropyrrolidine-2, 5-dione (1.35g, 10.1 mmol). After stirring at 0 ℃ for 1 hour, the resulting mixture was concentrated under reduced pressure, and the resulting crude product was poured into water (30mL) and extracted three times with ethyl acetate (30 mL). The combined organic layers were washed three times with water (20mL) and Na₂SO_4(s)Drying and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound (820mg, purity 95%, 73% yield) as a pale yellow oil.¹H NMR(400MHz,CDCl₃)δ4.48-4.33(m,1H),4.26-4.19(m,2H),3.16-3.10(m,0.8H),2.97-2.91(m,1.2H),2.63-2.57(m,1.2H),2.41-2.36(m,0.8H),1.48(s,3H),1.04-0.99(m,2H),0.07(s,9H)。

Sulfonyl chloride 10: 3- ((tert-butyldiphenylsilyl) oxy) cyclobutane-1-sulfonyl chloride

Intermediate 10 a: N-methoxy-N-methyl-3-oxocyclobutanecarboxamide

To a solution of 3-oxocyclobutanecarboxylic acid (11.4g, 100mmol) and 1-hydroxybenzotriazole (17.9g, 150mmol) in dichloromethane (200mL) at 0 deg.C was added N-methoxymethylaminohydrochloride (9.70g, 105mmol), N' - (ethylcarbonylimino) -N, N-dimethylpropan-1, 3-diamine hydrochloride (28.8g, 150mmol) and triethylamine (30.1g, 300 mmol). After stirring at room temperature for 16 hours, the mixture was diluted in water (200mL) and stirred at room temperature for 0.5 hours. The organic layer was separated and the aqueous phase was extracted twice with dichloromethane (200 mL). The combined organic layers were washed with brine (200mL) and Na₂SO_4(s)Dried, filtered and concentrated to give a residue which is purified by silica gel column chromatography (petroleum ether: ethyl acetate 30:1) to give the title yellow oilThe title compound (13.9g, 88% yield). LC-MS (ESI): r_T＝1.02min，C₇H₁₁NO₃Calculated mass of 157.1, M/z found 158.0[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ3.73(s,3H),3.63-3.55(m,1H),3.51-3.44(m,2H),3.26-3.17(m,5H)。

Intermediate 10 b: 3-hydroxy-N-methoxy-N-methylcyclobutanecarboxamide

Sodium borohydride (3.30g, 88.0mmol) was slowly added to a solution of N-methoxy-N-methyl-3-oxocyclobutanecarboxamide intermediate 10a (13.9g, 31.6mmol) in tetrahydrofuran (90mL) and methanol (30mL) at 0 ℃. After stirring at 0 ℃ for 2 hours, the mixture was diluted with water (200mL) and extracted with ethyl acetate (300 mL). The separated organic layer was dried, filtered and concentrated to give the crude title compound as a yellow oil (7.20g, 51% yield), which was used in the next step without further purification.¹H NMR(400MHz,CDCl₃)δ4.23-4.12(m,1H),3.65(s,3H),3.17(s,3H),3.06-2.95(m,1H),2.59-2.50(m,2H),2.24-2.15(m,2H)。

Intermediate 10 c: 3- ((tert-butyldiphenylsilyl) oxy) -N-methoxy-N-methylcyclobutanecarboxamide Tert-butyldiphenylchlorosilane (18.5g, 67.5mmol) was slowly added to a solution of 3-hydroxy-N-methoxy-N-methylcyclobutanecarboxamide intermediate 10b (7.20g, 45.0mmol) and imidazole (6.10g, 90.0mmol) in dichloromethane (100mL) at 0 deg.C. After stirring at room temperature for 16 h, the mixture was washed with saturated aqueous sodium bicarbonate (200mL) and then brine (200mL) over Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the title compound as a yellow oil (15.0g, 85% yield).¹H NMR(400MHz,CDCl₃)δ7.68-7.62(m,4H),7.43-7.33(m,6H),4.19-4.10(m,1H),3.60-3.57(m,3H),3.18-3.12(m,3H),2.76-2.72(m,1H),2.37-2.29(m,4H),1.03-1.00(m,9H)。

Intermediate 10 d: 1- (3- ((tert-butyldiphenylsilyl) oxy) cyclobutyl) ethanone

1M Methylmagnesium Bromide in tetrahydrofuran (53mL, 105mmol) at 0 deg.CThe solution was slowly added to a solution of 3- ((tert-butyldiphenylsilyl) oxy) -N-methoxy-N-methylcyclobutanecarboxamide intermediate 10c (14.0g, 35.2mmol) in tetrahydrofuran (100 mL). After stirring at room temperature for 2 hours, the mixture was diluted with water (150mL) and extracted with ethyl acetate (150 mL). The separated organic layer was washed with brine (150mL) and Na₂SO_4(s)Drying, filtration and concentration gave the title compound as a white solid (12.0g, 97% yield), which was used in the next step without further purification. LC-MS (ESI): r_T＝2.09min，C₂₂H₂₈O₂Calculated mass of Si 352.2, found value of M/z 353.4[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.66-7.60(m,4H),7.45-7.35(m,6H),4.18-4.10(m,1H),2.56-2.47(m,1H),2.35-2.31(m,2H),2.29-2.17(m,2H),2.04(s,3H),1.03(s,9H)。

Intermediate 10 e: 3- ((tert-butyldiphenylsilyl) oxy) cyclobutyl acetate

To a solution of 1- (3- ((tert-butyldiphenylsilyl) oxy) cyclobutyl) ethanone intermediate 10d (7.06g, 20.0mmol) and 3-chloroperoxybenzoic acid (10.3g, 60.0mmol) in dichloromethane (100mL) at 0 deg.C was added sodium bicarbonate (5.04g, 60.0 mmol). After stirring at room temperature for 16 hours, the mixture was diluted in water (200mL) and stirred at room temperature for 0.5 hours. The organic layer was separated and the aqueous phase was extracted twice with dichloromethane (100 mL). The combined organic layers were washed with brine (200mL) and Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 30:1) to give the title compound as a yellow oil (6.00g, 81% yield).¹H NMR(400MHz,CDCl₃)δ7.65-7.62(m,4H),7.43-7.34(m,6H),4.46-4.35(m,1H),3.96-3.87(m,1H),2.69-2.59(m,2H),2.20-2.10(m,2H),2.03(s,3H),1.00(s,9H)。

Intermediate 10 f: 3- ((tert-butyldiphenylsilyl) oxy) cyclobutanol

To 3- ((tert-butyldiphenylsilyl) oxy) cyclobutyl acetate intermediate 10e (6.00g, 16.3mmol) in tetrahydrofuran (30mL), methanol (30mL) and water (3mL) at 0 ℃ under a nitrogen atmosphere0mL) was added lithium hydroxide monohydrate (1.37g, 32.5 mmol). After stirring at room temperature for 2 hours, the mixture was concentrated at room temperature under reduced pressure to remove volatiles, and extracted with ethyl acetate (200 mL). The separated organic layer was washed with water (150mL) and brine (150mL) and washed with Na₂SO_4(s)Drying, filtration and concentration gave the title compound as a colourless oil (4.00g, 75% yield), which was used in the next step without further purification.¹H NMR(400MHz,CDCl₃)δ7.66-7.63(m,4H),7.40-7.37(m,6H),3.87-3.78(m,1H),3.77-3.67(m,1H),2.64-2.56(m,2H),2.07-1.97(m,2H),1.04(s,9H)。

10g of intermediate: 3- ((tert-butyldiphenylsilyl) oxy) cyclobutyl 4-methylbenzenesulfonate

4-methyl-benzenesulfonyl chloride (4.40g, 22.9mmol) was slowly added to a solution of 3- ((tert-butyldiphenylsilyl) oxy) cyclobutanol intermediate 10f (4.00g, 11.5mmol) in pyridine (2.70g, 34.5mmol) and dichloromethane (100mL) at 0 ℃. After stirring at room temperature for 16 hours, the mixture was diluted in water (100mL) and stirred at room temperature for 0.5 hours. The organic layer was separated and the aqueous phase was extracted twice with dichloromethane (100 mL). The combined organic layers were washed with 0.5M aqueous hydrochloride (200mL), brine (100mL) and Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give the title compound as a yellow oil (5.10g, 92% yield).¹H NMR(400MHz,CDCl₃)δ7.77-7.69(m,2H),7.61-7.44(m,4H),7.35-7.27(m,8H),4.25-4.16(m,1H),3.82-3.72(m,1H),2.53-2.37(m,5H),2.29-2.19(m,2H),1.01-0.96(m,9H)。

Intermediate 10 h: s- (3- ((tert-butyldiphenylsilyl) oxy) cyclobutyl) ethanethiol ester

To a solution of 10g (2.40g, 5.00mmol) of the 3- ((tert-butyldiphenylsilyl) oxy) cyclobutyl 4-methylbenzenesulfonate intermediate in N, N-dimethylformamide (50mL) was added potassium thioacetate (2.30g, 20.0mmol) at room temperature. After stirring at 100 ℃ for 16 h, the reaction mixture was cooled to room temperature and concentrated to give a residue which was chlorinated with 5% wtAqueous sodium solution (200mL) was diluted and extracted twice with ethyl acetate (100 mL). The combined organic layers were passed over Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give the title compound as a yellow oil (1.60g, 81% yield).¹H NMR(400MHz,CDCl₃)δ7.63-7.61(m,4H),7.44-7.35(m,8H),4.51-4.45(m,1H),3.92-3.86(m,1H),2.67-2.59(m,2H),2.26(s,3H),2.23-2.14(m,2H),1.04(s,9H)。

Sulfonyl chloride 10: 3- ((tert-butyldiphenylsilyl) oxy) cyclobutane-1-sulfonyl chloride

To a solution of S- (3- ((tert-butyldiphenylsilyl) oxy) cyclobutyl) ethanethiol ester intermediate 10h (1.60g, 4.20mmol) and 2M aqueous hydrochloride (0.5mL, 1.00mmol) in acetonitrile (20mL) at 0 deg.C was slowly added N-chlorosuccinimide (1.70g, 12.5 mmol). After stirring at 0 ℃ for 30 min, the reaction mixture was concentrated in vacuo at 25 ℃ to give a residue which was partitioned between ethyl acetate (50mL) and saturated aqueous sodium bicarbonate (50 mL). The separated organic layer was washed with saturated aqueous sodium thiosulfate (50mL), then brine (50mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound (1.20g, 70% yield) as a colourless oil.¹H NMR(400MHz,CDCl₃)δ7.62-7.57(m,4H),7.49-7.27(m,6H),4.69-4.61(m,1H),4.39-4.29(m,1H),2.87-2.75(m,2H),2.67-2.56(m,2H),1.06(s,6H),1.04(s,3H)。

Sulfonyl chloride 11: ethyl 4- (chlorosulfonyl) cyclohexanecarboxylate

Intermediate 11 a: ethyl 4-hydroxycyclohexanecarboxylate

To a solution of ethyl 4-oxocyclohexanecarboxylate (30.0g, 176mmol) in tetrahydrofuran (200mL) and methanol (70mL) was added sodium borohydride (3.40g, 88.0mmol) at 0 ℃. The mixture was then brought to 0 deg.CStirred for 1 hour. Thereafter, it was quenched with water (150mL) and extracted twice with ethyl acetate (250 mL). The combined organic layers were washed with brine (100mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (29.5g, 98% yield).¹H NMR(300MHz,CDCl₃)δ4.14-4.05(m,2H),3.89-3.81(m,0.3H),3.65-3.52(m,0.7H),2.39-2.31(m,0.3H),2.25-2.15(m,0.7H),2.02-1.90(m,4H),1.69-1.60(m,1.7H),1.54-1.40(m,1.3H),1.31-1.19(m,4H)。

Intermediate 11 b: ethyl 4- (tosyloxy) cyclohexanecarboxylate

To a solution of ethyl 4-hydroxycyclohexanecarboxylate intermediate 11a (30.0g, 174mmol) in dichloromethane (500mL) was added N, N-lutidine-4-amine (2.12g, 17.4mmol), triethylamine (20.0g, 192mmol) and 4-methylbenzene-1-sulfonyl chloride (36.0g, 192mmol) at room temperature. After stirring overnight at room temperature under a nitrogen atmosphere, the mixture was washed twice with 0.5M aqueous hydrochloride solution (300mL) and with brine (500mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a brown oil (55.0g, 96% yield).¹H NMR(300MHz,CDCl₃)δ7.79(d,J＝8.1Hz,2H),7.33(d,J＝8.4Hz,2H),4.74-4.68(m,0.3H),4.46-4.37(m,0.7H),4.15-4.06(m,2H),2.45(s,3H),2.35-2.20(m,1H),2.04-1.82(m,4.2H),1.74-1.68(m,0.8H),1.55-1.46(m,3H),1.28-1.20(m,3H)。

Intermediate 11 c: ethyl 4- (acetylthio) cyclohexanecarboxylate

To a solution of ethyl 4- (tosyloxy) cyclohexanecarboxylate intermediate 11b (10.0g, 31.0mmol) in N, N-dimethylformamide (35mL) was added potassium ethanethiol (7.00g, 61.0mmol) at room temperature. After stirring at 110 ℃ for 8 hours under a nitrogen atmosphere, the mixture was cooled to room temperature, poured into water (300mL), and extracted twice with ethyl acetate (150 mL). The combined organic layers were washed with brine (100mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a brown oil (5.00g, 71% yield).¹H NMR(300MHz,CDCl₃)δ4.16-4.10(m,2H),3.80-3.73(m,1H),2.43-2.36(m,1H),2.31-2.25(m,4H),1.81-1.77(m,5H),1.61-1.59(m,2H),1.27-1.22(m,3H)。

Sulfonyl chloride 11: ethyl 4- (chlorosulfonyl) cyclohexanecarboxylate

To a solution of ethyl 4- (acetylthio) cyclohexanecarboxylate intermediate 11c (5.00g, 21.7mmol) in acetonitrile (50mL) and water (1mL) was added 2M aqueous hydrochloride solution (3.5mL, 7.0mmol) and 1-chloropyrrolidine-2, 5-dione (11.6g, 86.9mmol) at 0 ℃. After stirring at 0 ℃ for 2 hours under a nitrogen atmosphere, the mixture was quenched with water (50mL) and extracted twice with ethyl acetate (50 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (5.00g, 91% yield).¹H NMR(400MHz,CDCl₃)δ4.19(d,J＝7.2Hz,2H),3.59-3.49(m,1H),2.69-2.67(m,0.7H),2.54-2.51(m,0.3H),2.41-2.37(m,2H),2.31-2.27(m,2H),2.07-1.97(m,2H),1.69-1.62(m,2H),1.30-1.26(t,J＝7.2Hz,3H)。

Sulfonyl chloride 12: tert-Butylchlorosulfonyl carbamate

To a solution of thioisocyano chloride (1.14g, 7.80mmol) in toluene (2mL) at 0 deg.C was added a solution of 2-methylpropan-2-ol (0.59g, 7.80mmol) in toluene (2 mL). After stirring at 0 ℃ for 1 hour, the mixture was diluted with petroleum ether (5mL) and filtered. The obtained solid was dried to give the title compound as a white solid (810mg, 48% yield).¹H NMR(400MHz,DMSO-d₆)δ13.49(s,1H),1.62-1.25(m,9H)。

Sulfonyl chloride 13: trans-methyl-4- ((chlorosulfonyl) methyl) cyclohexane-1-carboxylate

Intermediate 13 a: trans-methyl-4- (hydroxymethyl) cyclohexane-1-carboxylate

To a solution of trans-4- (methoxycarbonyl) cyclohexane-1-carboxylic acid (5.0g, 26.9mmol) in THF (50mL) at-78 deg.C was added borane-tetrahydrofuran complex (34.9mL, 1M, 34.9mmol), after which the mixture was slowly warmed to room temperature and stirred at room temperature for 4 h. The mixture was quenched with MeOH (25mL) and stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo to give trans-methyl-4- (hydroxymethyl) cyclohexane-1-carboxylate (6g, crude) as a colorless oil, which was used in the next step without further purification.¹H NMR(400MHz,CDCl₃)δ3.66(s,3H),3.64-3.46(m,2H),2.35-2.20(m,1H),2.13-1.97(m,2H),1.93-1.79(m,1H),1.60-1.33(m,4H),1.05-0.86(m,2H)。

Intermediate 13 b: trans-methyl-4- ((tosyloxy) methyl) cyclohexane-1-carboxylate

To a solution of trans-methyl-4- (hydroxymethyl) cyclohexane-1-carboxylate intermediate 13a (6g, 34.8mmol) and 4-methylbenzenesulfonyl chloride (6.6g, 34.8mmol) in DCM (60mL) at 0 deg.C was added pyridine (2.806mL, 0.982g/mL, 34.8 mmol). After stirring at room temperature for 16 h, the mixture was washed with saturated aqueous sodium bicarbonate (15mL), then brine (15mL), over Na₂SO_4(s)Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 10:1) to give the title compound (4.5g, 39.5% yield) as a colorless oil.¹H NMR(400MHz,CDCl₃)δ7.78(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),3.83(d,J＝8.0Hz,2H),3.85(s,3H),2.45(s,3H),2.25-2.16(m,1H),2.02-1.94(m,2H),1.83-1.75(m,2H),1.69-1.61(m,1H),1.47-1.36(m,2H),1.04-0.91(m,2H)。

Intermediate 13 c: trans-methyl-4- ((acetylthio) methyl) cyclohexane-1-carboxylate

To a solution of trans-methyl-4- ((tosyloxy) methyl) cyclohexane-1-carboxylate intermediate 13b (4.5g, 13.8mmol) in N, N-dimethylformamide (45mL) was added potassium thioacetate (3.10g, 27.6mmol) at room temperature. After stirring at 80 ℃ for 16 h, the reaction mixture was cooled to room temperature, quenched with 5% aqueous sodium chloride (50mL), and extracted twice with ethyl acetate (100 mL). The combined organic layers were passed over Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (hexanes: EtOAc ═ 20:1) to give the title compound as a brown oil (2.5g, 78% yield).¹H NMR(400MHz,CDCl₃)δ3.66(s,3H),2.80(d,J＝8.0Hz,2H),2.34(s,3H),2.26-2.19(m,1H),2.04-1.94(m,2H),1.94-1.84(m,2H),1.51-1.34(m,3H),1.02-0.96(m,2H)。

Sulfonyl chloride 13: trans-methyl-4- ((chlorosulfonyl) methyl) cyclohexane-1-carboxylate

To a solution of trans-methyl-4- ((acetylthio) methyl) cyclohexane-1-carboxylate intermediate 13c (2.5g, 10.8mmol) and 2M aqueous hydrochloride salt (8.1mL, 16.2mmol) in acetonitrile (25mL) was added 1-chloropyrrolidine-2, 5-dione (5.8g, 43.4mmol) at 0 ℃. After stirring at 0 ℃ for 1 hour, the mixture was diluted with water (20mL) and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with saturated NaHCO₃(100mL) washed over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1 to 10:1) to give the title compound as a colourless oil (1.5g, 54% yield).¹H NMR(400MHz,CDCl₃)δ3.68(s,3H),3.63(d,J＝6.2Hz,2H),2.30-2.22(m,1H),2.15-2.03(m,4H),1.55-1.47(m,2H),1.29-1.13(m,3H)。

Sulfonyl chloride 14: (trans) -methyl 4- ((chlorosulfonyl) methyl) cyclohexane-carboxylate

Intermediate 14 a: (trans) -methyl 4- ((tosyloxy) methyl) cyclohexanecarboxylate

To a solution of (1r,4r) -methyl 4- (hydroxymethyl) cyclohexanecarboxylate (5.00g, 29.0mmol) in dichloromethane (80mL) at room temperature were added N, N-dimethylpyridin-4-amine (355mg, 2.91mmol), triethylamine (3.23g, 31.9mmol) and p-toluenesulfonyl chloride (6.0g, 31.5 mmol). After stirring overnight at room temperature under a nitrogen atmosphere, the mixture was washed twice with 0.5M aqueous hydrochloride solution (80mL) and with water (80mL), viaNa₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (8.0g, 85% purity according to NMR, 72% yield) as a white solid.¹HNMR(400MHz,CDCl₃)δ7.78(d,J＝8.0Hz,2H),7.35(d,J＝8.4Hz,2H),3.83(d,J＝6.4Hz,2H),3.65(s,3H),2.46(s,3H),2.04-1.77(m,5H),1.49-1.34(m,3H),1.04-0.92(m,2H)。

Intermediate 14 b: (trans) -methyl 4- ((acetylthio) methyl) cyclohexanecarboxylate

To a solution of (1r,4r) -methyl 4- ((tosyloxy) methyl) cyclohexanecarboxylate intermediate 14a (8.00g, 85% purity, 20.8mmol) in N, N-dimethylformamide (50mL) was added potassium thioacetate (5.00g, 43.8mmol) at room temperature. After stirring at 100 ℃ for 4 hours under a nitrogen atmosphere, the mixture was cooled and taken up in water (200mL) and extracted twice with ethyl acetate (80 mL). The combined organic layers were washed with brine (80mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a brown oil (5.40g, 96% yield).¹H NMR(400MHz,CDCl₃)δ3.60(s,1.2H),3.59(s,1.8H),2.73(d,J＝6.8Hz,2H),2.27(s,3H),1.99-1.91(m,5H),1.44-1.32(m,5H)。

Sulfonyl chloride 14: (trans) -methyl 4- ((chlorosulfonyl) methyl) cyclohexane-carboxylate

To a solution of (1r,4r) -methyl 4- ((acetylthio) methyl) cyclohexanecarboxylate intermediate 14b (2.0g, 85% purity, 7.38mmol) in acetonitrile (50mL) at 0 ℃ were added 2M aqueous hydrochloride solution (1.5mL) and 1-chloropyrrolidine-2, 5-dione (4.6g, 34.4 mmol). After stirring at this temperature under a nitrogen atmosphere for 2 hours, the mixture was quenched with water (30mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.10g, purity according to NMR 90%, 53% yield) as a yellow solid.¹H NMR(400MHz,CDCl₃)δ3.68(s,3H),3.64(d,J＝6.0Hz,2H),2.30-2.18(m,2H),2.14-2.05(m,4H),1.57-1.47(m,2H),1.25-1.16(m,2H)。

Sulfonyl chloride 15: methyl 4- ((chlorosulfonyl) methyl) -4-methylcyclohexanecarboxylate

Intermediate 15 a: 8-methyl-1, 4-dioxaspiro [4.5] decane-8-carboxylic acid ester

Ethyl 1, 4-dioxaspiro [4.5] at-78 ℃ under a nitrogen atmosphere]A solution of decane-8-carboxylic acid ester (3.00g, 95% purity, 13.3mmol) in dry tetrahydrofuran (30mL) was added dropwise 2.0M lithium diisopropylamide (8.0mL, 16.0mmol) in tetrahydrofuran. After the addition, the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (1.3mL, 20.9mmol) was added dropwise at-78 ℃. After stirring at-78 ℃ for 1 hour and then at room temperature for another 1 hour, the reaction was quenched with saturated aqueous ammonium chloride (30mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give the title compound (2.40g, purity 95%, 75% yield) as a pale yellow oil. LC-MS (ESI): r_T＝1.61min，C₁₂H₂₀O₄Calculated mass of 228.1, M/z found value 229.0[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ4.14(q,J＝7.2Hz,2H),3.94(s,4H),2.16-2.11(m,2H),1.69-1.60(m,3.6H),1.59-1.57(m,0.4H),1.54-1.47(m,2H),1.25(t,J＝7.2Hz,3H),1.19(s,3H)。

Intermediate 15 b: (8-methyl-1, 4-dioxaspiro [4.5] decan-8-yl) methanol

To ethyl 8-methyl-1, 4-dioxaspiro [4.5] at 0 deg.C]To a solution of decane-8-carboxylate intermediate 15a (2.40g, 95% purity, 9.99mmol) in dry tetrahydrofuran (12mL) was slowly added lithium aluminum hydride (379mg, 9.99 mmol). The mixture was then stirred at 0 ℃ for 2 hours. The reaction was quenched with water (0.38mL) and 15% aqueous sodium hydroxide (0.38 mL). The resulting suspension was filtered through celite and washed with tetrahydrofuran (10mL) and ethyl acetate (10 mL). The filtrate was concentrated to give the title compound as a white solid (2.00g, 90% purity, 97)% yield).¹H NMR(400MHz,DMSO-d₆)δ4.47(t,J＝5.2Hz,1H),3.82(s,4H),3.13(d,J＝5.2Hz,2H),1.52-1.41(m,6H),1.24-1.19(m,2H),0.83(s,3H)。

Intermediate 15 c: 8- ((benzyloxy) methyl) -8-methyl-1, 4-dioxaspiro [4.5] decane

To (8-methyl-1, 4-dioxaspiro [4.5] at 0 DEG C]Decan-8-yl) methanol intermediate 15b (2.00g, 90% pure, 9.67mmol) to a solution in dry tetrahydrofuran (15mL) was slowly added sodium hydride (60% in mineral oil, 464mg, 11.6 mmol). After addition, the suspension was stirred at 0 ℃ for 20 minutes. After benzyl bromide (1.7mL, 14.3mmol) was added dropwise, the mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (30mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed with brine (30mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel chromatography (petroleum ether: ethyl acetate ═ 30:1 to 20:1) to give the title compound (2.20g, purity 95%, 78% yield) as a white solid. LC-MS (ESI): r_T＝1.54min，C₁₇H₂₄O₃Calculated mass of 276.2, found M/z value 277.0[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.36-7.28(m,5H),4.52(s,2H),3.93(s,4H),3.21(s,2H),1.69-1.60(m,4H),1.58-1.55(m,2H),1.45-1.40(m,2H),1.00(s,3H)。

Intermediate 15 d: 4- ((benzyloxy) methyl) -4-methylcyclohexanone

Reacting 8- ((benzyloxy) methyl) -8-methyl-1, 4-dioxaspiro [4.5]]A solution of decane intermediate 15c (2.20g, 95% purity, 7.56mmol) in dichloromethane (20mL) and trifluoroacetic acid (20mL) was stirred at 30 ℃ overnight. The mixture was concentrated under reduced pressure to remove volatiles. The residue obtained was dissolved in dichloromethane (50mL) and washed twice with saturated aqueous sodium bicarbonate (50mL) and with brine (50mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give the title compound (1.75g, purity 95%, 95% yield) as a colorless oil. LC-MS (ESI): r_T＝1.27min，C₁₅H₂₀O₂Calculated mass of 232.1, found value of M/z 233.0[ M + H [)]⁺。¹HNMR(400MHz,CDCl₃)δ7.38-7.27(m,5H),4.54(s,2H),3.31(s,2H),2.41-2.28(m,4H),1.85-1.81(m,2H),1.71-1.65(m,2H),1.14(s,3H)。

Intermediate 15 e: ((4- (methoxymethylene) -1-methylcyclohexyl) methoxy) -methyl) benzene

To a suspension of (methoxymethyl) triphenylphosphonium chloride EO 8495-1093.5 (3.80g, 11.1mmol) in dry tetrahydrofuran (20mL) at 0 deg.C was slowly added potassium tert-butoxide (1.25g, 11.1mmol) to keep the internal temperature below 5 deg.C. After the addition, the mixture was stirred at 0 ℃ for 30 minutes. A solution of 4- ((benzyloxy) methyl) -4-methylcyclohexanone intermediate 15d (1.70g, 95% pure, 6.95mmol) in dry tetrahydrofuran (5mL) was added. The mixture was then warmed to room temperature and stirred at room temperature overnight. The mixture was quenched with water (30mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:1 to 30:1) to give the title compound (1.70g, purity 95%, 89% yield) as a pale yellow oil.¹H NMR(400MHz,CDCl₃)δ7.36-7.28(m,5H),5.75(s,1H),4.51(s,2H),3.53(s,3H),3.20(s,2H),2.33-2.27(m,1H),2.10-1.96(m,2H),1.93-1.87(m,1H),1.47-1.30(m,4H),1.00(s,3H)。

Intermediate 15 f: 4- ((benzyloxy) methyl) -4-methylcyclohexanecarboxaldehyde

To (((4- (methoxymethylene) -1-methylcyclohexyl) methoxy) methyl) at 0 deg.C

To a solution of benzene intermediate 15e (1.70g, 95% purity, 6.20mmol) in tetrahydrofuran (12mL) was slowly added 6M aqueous hydrochloride solution (3.1mL, 18.6 mmol). After stirring at room temperature for 2 hours, the reaction mixture was quenched with brine (30mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were passed over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give the title compound as a pale yellow oil (1.60g, 90% purity, 94% yield).¹H NMR(400MHz,CDCl₃)δ9.65(d,J＝1.2Hz,0.6H),9.63(d,J＝0.8Hz,0.4H),7.37-7.27(m,5H),4.51(s,1.2H),4.49(s,0.8H),3.22(s,0.8H),3.15(s,1.2H),2.27-2.13(m,1H),1.83-1.72(m,2H),1.67-1.61(m,1H),1.59-1.37(m,4H),1.24-1.17(m,1H),0.99(s,1.2H),0.93(s,1.8H)。

Intermediate 15 g: 4- ((benzyloxy) methyl) -4-methylcyclohexanecarboxylic acid

To a solution of 4- ((benzyloxy) methyl) -4-methylcyclohexanecarboxaldehyde intermediate 15f (1.60g, 90% pure, 5.85mmol) in acetone (45mL) and water (9mL) was added potassium permanganate (2.30g, 14.6mmol) at 0 ℃. After stirring at 0 ℃ to room temperature for 1 hour, solid sodium bisulfite (3.10g, 29.8mmol) was added, and the mixture was diluted with acetone (50mL) and water (50 mL). The resulting suspension was stirred at room temperature for 15 minutes and filtered through celite. The filtrate was concentrated at room temperature under reduced pressure to remove acetone. The resulting aqueous solution was acidified to a pH of about 3 with solid citric acid and extracted twice with ethyl acetate (50 mL). The combined organic layers were passed over Na₂SO_4(s)Drying and concentration gave the title compound as a yellow oil (1.5g, 70% purity, 68% yield).¹H NMR(400MHz,DMSO-d₆)δ12.06(s,1H),7.37-7.26(m,5H),4.47(s,0.8H),4.46(s,1.2H),3.23(s,0.8H),3.11(s,1.2H),2.20-2.05(m,1H),1.71-1.56(m,3H),1.53-1.43(m,2H),1.39-1.25(m,2H),1.13-1.05(m,1H),0.90(s,1.2H),0.89(s,1.8H)。

Intermediate 15 h: methyl 4- ((benzyloxy) methyl) -4-methylcyclohexanecarboxylate

To a solution of 15g (1.50g, 70% purity, 4.00mmol) of 4- ((benzyloxy) methyl) -4-methylcyclohexanecarboxylic acid intermediate in dry methanol (40mL) was added 2 drops of concentrated sulfuric acid. After stirring at 75 ℃ overnight, the mixture was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 30:1) to give the title compound as a pale yellow oil (1.00g, 95% purity, 86% yield). LC-MS (ESI): r_T＝1.35min，C₁₇H₂₄O₃Calculated mass of 276.2, M/z found value 294.0[ M + NH ]₄]⁺。¹H NMR(400MHz,CDCl₃)δ7.36-7.27(m,5H),4.51(s,2H),3.67(s,1.8H),3.66(s,1.2H),3.29(s,0.8H),3.13(s,1.2H),2.32-2.18(m,1H),1.81-1.52(m,4.8H),1.48-1.45(m,1.2H),1.39-1.32(m,1.2H),1.19-1.11(m,0.8H),0.97(s,1.2H),0.96(s,1.8H)。

Intermediate 15 i: methyl 4- (hydroxymethyl) -4-methylcyclohexanecarboxylate

To a solution of methyl 4- ((benzyloxy) methyl) -4-methylcyclohexanecarboxylate intermediate 15h (1.00g, 95% purity, 3.44mmol) in methanol (30mL) was added 10% palladium on charcoal (250 mg). After stirring at 30 ℃ under a hydrogen atmosphere (50psi) overnight, the mixture was filtered and the filtrate was concentrated to give the title compound as a colorless oil (670mg, 95% purity, 99% yield).¹H NMR(400MHz,CDCl₃)δ3.68(s,1.8H),3.67(s,1.2H),3.48(s,0.8H),3.31(s,1.2H),2.35-2.18(m,1H),1.85-1.73(m,2H),1.69-1.58(m,2H),1.45-1.42(m,1H),1.32-1.24(m,2H),1.20-1.13(m,1H),0.94(s,1.8H),0.93(s,1.2H)。

Intermediate 15 j: methyl 4-methyl-4- (((methylsulfonyl) oxy) methyl) -cyclohexanecarboxylate

To a solution of methyl 4- (hydroxymethyl) -4-methylcyclohexanecarboxylate intermediate 15i (670mg, 95% purity, 3.42mmol) in dichloromethane (5mL) was added N, N-diisopropylethylamine (650mg, 5.03mmol) and methanesulfonyl chloride (500mg, 4.37mmol) at room temperature. After stirring overnight at 30 ℃ under a nitrogen atmosphere, the mixture was concentrated and diluted with water (10mL) and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated to give the title compound as a brown oil (1.07g, 80% purity, 95% yield).¹H NMR(400MHz,CDCl₃)δ4.06(s,0.8H),3.89(s,1.2H),3.69(s,1.4H),3.68(s,1.6H),3.02(s,3H),2.36-2.20(m,1H),1.87-1.80(m,1.8H),1.69-1.63(m,3H),1.52-1.49(m,1.2H),1.37-1.23(m,2H),1.02(s,1.8H),1.01(s,1.2H)。

Intermediate 15 k: methyl 4- ((acetylthio) methyl) -4-methylcyclohexanecarboxylate

To methyl 4-methyl-4- (((methylsulfonyl) oxy) methyl) cyclohexane

Formate intermediate 15j (1.07g, 80% purity, 3.24mmol) in N, N-dimethyl

Formamide (10mL)To the solution in (1.20g, 10.5mmol) was added potassium thioacetate. After stirring at 80 ℃ for 5 hours under a nitrogen atmosphere, the mixture was poured into water (40mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed with brine (50mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:1 to 20:1) to give the title compound (340mg, purity 90%, 39% yield) as a brown oil.¹HNMR(400MHz,CDCl₃)δ3.67(s,1.6H),3.66(s,1.4H),2.99(s,1H),2.86(s,1H),2.35(s,1.6H),2.34(s,1.4H),2.28-2.19(m,1H),1.81-1.58(m,5.6H),1.49-1.46(m,1.1H),1.26-1.19(m,1.3H),0.94(s,1.4H),0.89(s,1.6H)。

Sulfonyl chloride 15: methyl 4- ((chlorosulfonyl) methyl) -4-methylcyclohexanecarboxylate

To a solution of methyl 4- ((acetylthio) methyl) -4-methylcyclohexanecarboxylate intermediate 15k (340mg, 90% purity, 1.25mmol) in acetonitrile (5mL) was added 2M aqueous hydrochloride solution (0.2mL) and N-chlorosuccinimide (0.68g, 4.99mmol) at 0 ℃. After stirring at 0 ℃ for 2 hours, the mixture was diluted with water (20mL) and extracted twice with ethyl acetate (20 mL). The combined organic layers were concentrated and purified by silica gel chromatography (petroleum ether: ethyl acetate: 30:1 to 10:1) to give the title compound as a yellow oil (280mg, 90% purity, 75% yield).¹H NMR(400MHz,CDCl₃)δ3.91(s,1H),3.78(s,1H),3.69(s,1.6H),3.68(s,1.4H),2.38-2.25(m,1H),1.90-1.48(m,8H),1.32(s,1.6H),1.31(s,1.4H)。

Sulfonyl chloride 16: methyl 3- ((chlorosulfonyl) methyl) bicyclo [1.1.1] pentane-1-carboxylate

Intermediate 16 a: methyl 3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylate

3- (methoxycarbonyl) bicyclo [1.1.1] n-60 ℃ under a nitrogen atmosphere]To a solution of pentane-1-carboxylic acid (5.00g, 29.4mmol) in tetrahydrofuran (80mL) was added 10M borane-dimethyl sulfide complex (5mL, 50.0mmol)). After stirring at room temperature for 2 hours under a nitrogen atmosphere, the mixture was concentrated under reduced pressure to give a residue, which was dissolved in dichloromethane (20mL) and washed twice with saturated aqueous sodium bicarbonate solution (20 mL). The combined aqueous layers were extracted twice with dichloromethane (60 mL). The combined organic layers were passed over Na₂SO_4(s)Dried, filtered and concentrated under reduced pressure to give the title compound (4.00g, according to¹Purity of H NMR 90%, 78% yield).¹H NMR(400MHz,CDCl₃)δ3.68(s,3H),3.63(s,2H),2.00(s,6H)。

Intermediate 16 b: methyl 3- ((tosyloxy) methyl) bicyclo [1.1.1] pentane-1-carboxylate

To methyl 4- (hydroxymethyl) bicyclo [1.1.1] at room temperature]To a solution of pentane-2-carboxylate intermediate 16a (1.00g, 90% purity, 5.77mmol) in dichloromethane (10mL) was added 4-methylbenzene-1-sulfonyl chloride (1.20g, 6.30mmol) and N, N-dimethylpyridin-4-amine (1.40g, 11.5 mmol). After stirring at room temperature for 3 hours, the mixture was concentrated under reduced pressure to give a residue, which was diluted in water (10mL), acidified to pH about 7 with 1M aqueous hydrochloride solution (2mL) and extracted twice with ethyl acetate (50 mL). The combined organic layers were washed twice with water (20mL) and brine (20mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1 to 2:1) to give the title compound (1.70g, according to the formula: b) as a white solid¹Purity of H NMR 90%, 86% yield).¹H NMR(400MHz,CDCl₃)δ7.78(d,J＝8.4Hz,2H),7.35(d,J＝8.0Hz,2H),4.03(s,2H),3.66(s,3H),2.46(s,3H),1.97(s,6H)。

Intermediate 16 c: methyl 3- ((acetylthio) methyl) bicyclo [1.1.1] pentane-1-carboxylate

To methyl 4- (hydroxymethyl) bicyclo [1.1.1] at room temperature]To a solution of pentane-2-carboxylate intermediate 16b (1.70g, 90% purity, 4.93mmol) in N, N-dimethylformamide (5mL) was added potassium thioacetate (1.20g, 10.5 mmol). After stirring at 100 ℃ for 2 hours, the mixture was dissolved in ethyl acetate (40mL) and washed twice with saturated sodium bicarbonate (60 mL). Will be provided withThe combined aqueous layers were extracted twice with ethyl acetate (80 mL). The combined organic layers were washed twice with water (30mL) and brine (30mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.10g, according to¹Purity of H NMR 90%, 94% yield).¹H NMR(400MHz,CDCl₃)δ3.66(s,3H),3.03(s,2H),2.35(s,3H),1.96(s,6H)。

Sulfonyl chloride 16: methyl 3- ((chlorosulfonyl) methyl) bicyclo [1.1.1] pentane-1-carboxylate

To methyl 3- ((acetylthio) methyl) bicyclo [1.1.1]To a solution of pentane-1-carboxylate intermediate 16c (1.10g, 90% purity, 4.62mmol) in acetonitrile (5mL) was added 2M aqueous hydrochloride solution (0.5mL, 1.00mmol) and 1-chloropyrrolidine-2, 5-dione (2.46g, 18.4 mmol). After stirring at 0 ℃ for 1 hour, the mixture was concentrated to give a residue, which was diluted with dilute water (10mL) and extracted twice with ethyl acetate (40 mL). The combined organic layers were washed twice with water (15mL) and brine (15mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound (1.10g, according to the formula¹Purity of H NMR 90%, 90% yield).¹H NMR(400MHz,CDCl₃)δ3.93(s,2H),3.70(s,3H),2.31(s,6H)。

Sulfonyl chloride 17: 1- (3-hydroxy-3-methylbutyl) -1H-pyrazole-4-sulfonyl chloride

Intermediate 17 a: methyl 3- (4-iodo-1H-pyrazol-1-yl) propionate

To a solution of methyl 4-iodo-1H-pyrazole (3.00g, 15.5mmol) in acetonitrile (45mL) at 0 deg.C was added 1, 8-diazabicyclo [ 5.4.0%]Undecen-7-ene (1.17g, 7.73mmol) followed by the addition of methyl acrylate (2.65g, 30.9 mmol). After stirring at room temperature for 2 hours, the reaction mixture was quenched with 1M aqueous hydrochloride (30mL) and extracted twice with ethyl acetate (30 mL).The combined organic layers were washed twice with water (20mL) and brine (20mL) over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a brown solid (1.00g, 77% yield).¹H NMR(400MHz,CDCl₃)δ7.50(s,2H),4.42(t,J＝6.4Hz,2H),3.69(s,3H),2.88(t,J＝6.4Hz,2H)。

Intermediate 17 b: methyl 3- (4- (benzylthio) -1H-pyrazol-1-yl) propionate

To a solution of methyl 3- (4-iodo-1H-pyrazol-1-yl) propionate intermediate 17a (3.30g, 11.8mmol) and phenyl-methanethiol (2.20g, 17.7mmol) in 1, 4-dioxane (50mL) was added N, N-diisopropylethylamine (2.30g, 17.8mmol) under a nitrogen atmosphere, followed by 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (102mg, 0.177mmol) and tris (dibenzylideneacetone) dipalladium (162mg, 0.177mmol) under a nitrogen atmosphere. After stirring at 80 ℃ for 6 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to give the title compound as a brown oil (1.60g, 50% yield). LC-MS (ESI): r _T＝2.275min，C₁₄H₁₆N₂O₂Calculated mass of S276.1, found value of M/z 277.1[ M + H]⁺。

Intermediate 17 c: 4- (4- (benzylthio) -1H-pyrazol-1-yl) -2-methylbutan-2-ol

To a solution of methyl 3- (4- (benzylthio) -1H-pyrazol-1-yl) propanoate intermediate 17b (500mg, 1.80mmol) in tetrahydrofuran (20mL) was added 3M methylmagnesium bromide in tetrahydrofuran (3mL, 9.00mmol) at 0 ℃. After stirring at 0 ℃ for 1 hour, the reaction mixture was quenched with 1M aqueous hydrochloride (20mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed twice with brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by C18 column (acetonitrile: water 40% to 60%) to give the title compound as a colourless oil (200mg, 40% yield). LC-MS (ESI): r_T＝2.089min，C₁₅H₂₀N₂Calculated mass of OS 276.1, M/z found value 277.1[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ7.32(s,1H),7.25-7.20(m,2H),7.17-7.10(m,4H),4.18(t,J＝7.2Hz,2H),3.76(s,2H),2.26(br s,1H),1.96(t,J＝7.2Hz,2H),1.24(s,6H)。

Sulfonyl chloride 17: 1- (3-hydroxy-3-methylbutyl) -1H-pyrazole-4-sulfonyl chloride

To a solution of 4- (4- (benzylthio) -1H-pyrazol-1-yl) -2-methylbutan-2-ol intermediate 17c (200mg, 0.722mmol) in acetonitrile (10mL) and water (0.2mL) was added acetic acid (0.2mL) and 1, 3-dichloro-5, 5-dimethylhydantoin (284mg, 1.44mmol) at 0 ℃ under a nitrogen atmosphere. After stirring at 0 ℃ for 1 hour, the mixture was diluted with water (20mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed twice with brine (20mL) and Na₂SO_4(s)Drying, filtration and concentration under reduced pressure gave the title compound as a colourless oil (200mg, 50% purity, 55% yield). LC-MS (ESI): r_T＝2.038min，C₈H₁₃ClN₂O₃Calculated mass of S252.0, found value of M/z 252.9[ M + H [ ]]⁺。

Sulfonyl chloride 18: 2- (2- (2-methoxyethoxy) ethoxy) ethanesulfonyl chloride

Intermediate 18 a: 2- (2- (2-methoxyethoxy) ethoxy) ethyl 4-methylbenzenesulfonate

To a solution of 2- (2- (2-methoxyethoxy) ethoxy) ethanol (5.00g, 30.5mmol) in dichloromethane (70mL) was added N, N-dimethylpyridin-4-amine (366mg, 3.00mmol), triethylamine (3.30g, 32.7mmol) and 4-methylbenzene-1-sulfonyl chloride (6.30g, 33.1mmol) at room temperature. After stirring overnight at room temperature under a nitrogen atmosphere, the mixture was washed three times with 1M aqueous hydrochloride (50mL) and brine (80mL) over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a white oil (8.30g, 86% yield).¹H NMR(300MHz,CDCl₃)δ7.82-7.79(m,2H),7.36-7.34(m,2H),4.17(s,2H),3.69-3.54(m,10H),3.38(s,3H),2.46(s,3H)。

Intermediate 18 b: s- (2- (2- (2-methoxyethoxy) ethoxy) ethyl) ethanethiol ester

To a solution of 2- (2- (2-methoxyethoxy) ethoxy) ethyl 4-methylbenzenesulfonate intermediate 18a (1.50g, 4.71mmol) in N, N-dimethylformamide (25mL) at room temperature was added potassium ethanethiolate (1.08g, 9.47 mmol). After stirring at 100 ℃ for 5 hours under a nitrogen atmosphere, it was cooled to room temperature, poured into water (100mL), and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with brine (80mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.10g, according to¹Purity of H NMR 90%, 95% yield).¹H NMR(300MHz,CDCl₃)δ3.62-3.54(m,10H),3.37(s,3H),3.08(br s,2H),2.32(s,3H)。

Sulfonyl chloride 18: 2- (2- (2-methoxyethoxy) ethoxy) ethanesulfonyl chloride

To a solution of S- (2- (2- (2-methoxyethoxy) ethoxy) ethyl) ethanethiol ester intermediate 18b (873mg, 90% purity, 3.54mmol) in acetonitrile (10mL) at 0 deg.C was added 2M aqueous hydrochloride solution (0.5mL and 1-chloropyrrolidine-2, 5-dione (1.89g, 14.2mmol), after stirring at this temperature under a nitrogen atmosphere for 2 hours, the mixture was quenched with water (30mL) and extracted twice with ethyl acetate (30 mL). the combined organic layers were washed with brine (50mL), washed with Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (900mg, according to¹Purity by H NMR 94%, 97% yield).¹H NMR(400MHz,CDCl₃)δ4.15-4.09(m,2H),4.02-3.99(m,2H),3.73-3.71(m,2H),3.67-3.64(m,4H),3.57-3.55(m,2H),3.38(d,J＝1.2Hz,3H)。

Sulfonyl chloride 19: 2,5,8, 11-Tetraoxatridecane-13-sulfonyl chloride

Intermediate 19 a: 2,5,8, 11-Tetraoxatridec-13-yl 4-methylbenzenesulfonate

Under nitrogen gasTo a solution of 2,5,8, 11-tetraoxatridec-13-ol (1.50g, 7.21mmol), triethylamine (2.18g, 21.6mmol), and N, N-lutidine-4-amine (88mg, 0.720mmol) in dichloromethane (30mL) under an atmosphere was added 4-methylbenzene-1-sulfonyl chloride (1.37g, 7.19 mmol). After stirring overnight at room temperature, the reaction mixture was washed three times with water (30mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (1.80g, 86% yield).¹H NMR(300MHz,CDCl₃)δ7.82-7.79(m,2H),7.36-7.27(m,2H),4.16(s,2H),3.70-3.56(m,14H),3.38(s,3H),2.45(s,3H)。

Intermediate 19 b: s-2,5,8, 11-Tetraoxatridec-13-ylethylthiol ester

To a solution of 2,5,8, 11-tetraoxatridec-13-yl 4-methylbenzenesulfonate intermediate 19a (1.00g, 2.76mmol) in N, N-dimethylformamide (20mL) was added potassium thioacetate (670mg, 5.88mmol) at room temperature. After stirring at 100 ℃ for 4 hours, the reaction mixture was cooled to room temperature, poured into water (20mL), and extracted three times with ethyl acetate (40 mL). The combined organic layers were washed three times with water (20mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated to give the title compound as a colorless oil (800mg, 95% yield).¹H NMR(300MHz,CDCl₃)δ3.67-3.55(m,14H),3.39-3.67(m,3H),3.12-3.06(m,2H),2.34-2.32(sm,3H)。

Sulfonyl chloride 19: 2,5,8, 11-Tetraoxatridecane-13-sulfonyl chloride

To a solution of S-2,5,8, 11-tetraoxatridec-13-ylethylthiol intermediate 19b (600mg, 2.26mmol) in acetonitrile (8mL) at 0 deg.C was added 2M aqueous hydrochloride solution (0.35mL) and 1-chloropyrrolidine-2, 5-dione (1.10g, 8.24 mmol). After stirring at 0 ℃ for 2h, the mixture was concentrated under reduced pressure to give a residue, which was diluted with water (30mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed three times with water (20mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated to give the title compound as a colorless oil (400mg, 64% yield).¹H NMR(300MHz,CDCl₃)δ4.07-3.87(m,4H),3.63-3.41(m,12H),3.35(s,3H)。

Sulfonyl chloride 20: 2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecane-12-sulfonyl chloride

Intermediate 20 a: 12-chloro-2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecane

To a solution of 2- (2- (2-chloroethoxy) ethoxy) ethanol (5.04g, 29.9mmol) in tetrahydrofuran (45mL) at 0 deg.C were added 1H-imidazole (2.55g, 37.5mmol) and tert-butylchlorodiphenylsilane (9.06g, 33.0 mmol). After stirring at room temperature overnight, water (20mL) was added to the mixture, and extracted three times with ethyl acetate (20 mL). The combined organic layers were passed over Na₂SO_4(s)Dried, filtered and concentrated to give the crude product as a colourless oil (13g, crude) which was used in the next step without further purification. LC-MS (ESI): r_T＝2.180min，C₂₂H₃₁ClO₃Calculated mass of Si 406.2, found value of M/z 424.1[ M + NH ]₄]⁺。

Intermediate 20 b: 12-chloro-2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecane

To a solution of 12-chloro-2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecane intermediate 20a (12g, 29.5mmol) in N, N-dimethylformamide (50mL) was added potassium ethanethiolate (6.74g, 59.1mmol) at room temperature. After stirring at 80 ℃ overnight, the mixture was cooled to room temperature, poured into water (200mL) and extracted twice with ethyl acetate (200mL), and the combined organic layers were washed with brine (100mL) and Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 40:1 to 20:1) to give the title compound as a yellow oil (7.50g, 56% yield).¹H NMR(400MHz,CDCl₃)δ7.70-7.67(m,4H),7.42-7.36(m,6H),3.81(t,J＝5.2Hz,2H),3.64-3.58(m,8H),3.08(t,J＝6.4Hz,2H),2.32(s,3H),1.05(s,9H)。

Sulfonyl chloride 20: 2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecane-12-sulfonyl chloride

To a solution of 12-chloro-2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecane intermediate 20b (2.23g, 5.00mmol) in acetonitrile (20mL) was added 2N aqueous hydrochloride solution (0.75mL, 1.5mmol) and N-chlorosuccinimide (2.67g, 20.0mmol) at 0 ℃. After stirring at 0 ℃ for 1 hour, the mixture was quenched with water (50mL) and extracted twice with dichloromethane (50mL), and the combined organic layers were washed with brine (50mL) and Na₂SO_4(s)Dried, filtered and concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 30:1 to 20:1) to give the title compound (0.50g, 20% yield) as a yellow oil.¹H NMR(300MHz,CDCl₃)δ7.67-7.63(m,4H),7.39-7.25(m,6H),4.09-4.03(m,2H),3.91-3.85(m,2H),3.81-3.77(m,2H),3.65-3.58(m,6H),1.04(s,9H)。

Sulfonyl chloride 21: (trans) -tert-butyl 3- (4- (chlorosulfonyl) -1H-pyrazol-1-yl) cyclobutanecarboxylic acid ester

Intermediate 21 a: tert-butyl 3-oxocyclobutanecarboxylic acid ester

To a solution of 3-oxocyclobutanecarboxylic acid (8.0g, 70mmol) and di-tert-butyl dicarbonate (31.0g, 140mmol) in tert-butanol (150mL) at 0 deg.C under a nitrogen atmosphere was added 4-dimethylaminopyridine (3.4g, 28 mmol). After stirring at room temperature overnight, the mixture was quenched with water (80mL), then concentrated under reduced pressure to remove volatiles and extracted three times with ethyl acetate (200 mL). The combined organic layers were washed with 2M aqueous hydrochloride (100mL) and Na₂SO_4(s)Drying and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound as a pale yellow oil (10g, 70% yield).¹H NMR(300MHz,CDCl₃)δ3.34-2.96(m,5H),1.40(s,9H)。

Intermediate 21 b: (cis) -tert-butyl 3-hydroxycyclobutanecarboxylate

Under a nitrogen atmosphere, tert-butyl 3-oxocyclobutanecarboxylate intermediate 21a (10g, 46.7mmol) was addedTo a solution in tetrahydrofuran (60mL) and methanol (20mL) was added sodium borohydride (900mg, 23.0mmol) dropwise. After stirring at 0 ℃ for 2h, the mixture was quenched with water (20mL) and extracted three times with ethyl acetate (100 mL). The combined organic layers were passed over Na₂SO_4(s)Drying and concentration gave the title compound as a yellow oil (7g, 70% yield).¹H NMR(300MHz,DMSO-d₆)δ5.22-5.14(m,1H),4.04-3.92(m,1H),2.55-2.31(m,3H),2.08-1.88(m,2H),1.43(s,9H)。

Intermediate 21 c: (cis) -tert-butyl 3- ((methylsulfonyl) oxy) cyclobutanecarboxylic acid ester

To a solution of (cis) -tert-butyl 3-hydroxycyclobutanecarboxylate intermediate 21b (5.0g, 23mmol) in dichloromethane (30mL) under a nitrogen atmosphere was added methanesulfonyl chloride (5.3g, 46mmol) and triethylamine (7.0g, 69 mmol). After stirring overnight at room temperature, the reaction mixture was washed with water (40mL) and Na₂SO_4(s)Dried and concentrated under reduced pressure to give the title compound as a white solid (7g, 85% yield).¹H NMR(300MHz,CDCl₃)δ4.89-4.80(m,1H),2.95(s,3H),2.67-2.41(m,5H),1.39(s,9H)。

Intermediate 21 d: (trans) -tert-butyl 3- (4-iodo-1H-pyrazol-1-yl) cyclobutanecarboxylic acid ester

To a solution of (cis) -tert-butyl 3- ((methylsulfonyl) oxy) cyclobutanecarboxylate intermediate 21c (3.5g, 14mmol) in N, N-dimethylformamide (30mL) was added 4-iodo-1H-pyrazole (2.7g, 14mmol) and potassium carbonate (3.9g, 28mmol) at room temperature. After stirring overnight at 100 ℃, the reaction mixture was cooled to room temperature, poured into water (100mL), and extracted three times with ethyl acetate (80 mL). The combined organic layers were washed three times with brine (80mL) and Na₂SO_4(s)Drying and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give the title compound as a white solid (2.8g, 60% yield).¹H NMR(300MHz,CDCl₃)δ7.53(s,1H),7.44(s,1H),5.04-4.86(m,1H),3.09-2.94(m,1H),2.87-2.60(m,4H),1.49-1.38(m,9H)。

Intermediate 21 e: (trans) -tert-butyl 3- (4- (benzylthio) -1H-pyrazol-1-yl) cyclobutanecarboxylic acid ester

A solution of (trans) -tert-butyl 3- (4-iodo-1H-pyrazol-1-yl) cyclobutanecarboxylate intermediate 21d (2.80g, 7.24mmol) in dioxane (20mL) was treated with phenylmethylthiol (1.80g, 14.5mmol) and N, N-diisopropylethylamine (2.80g, 21.7mmol) in that order under a nitrogen atmosphere. And tris (dibenzylideneacetone) dipalladium (67mg, 0.073mmol) and 9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene (42mg, 0.073mmol) were added to the reaction mixture under a nitrogen atmosphere. After heating to 110 ℃ overnight, the reaction mixture was cooled to room temperature, diluted with water (20mL) and extracted twice with ethyl acetate (20 mL). The combined extracts were washed with brine (40mL) and Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the desired compound (1.7g, purity 90%, 61% yield) as a white solid.¹H NMR(300MHz,CDCl₃)δ7.40-7.29(m,5H),7.17-7.07(m,2H),4.93-4.80(m,1H),3.78(s,2H),3.11-2.96(m,1H),2.80-2.57(m,4H),1.49(s,9H)。

Sulfonyl chloride 21: (trans) -tert-butyl 3- (4- (chlorosulfonyl) -1H-pyrazol-1-yl) cyclobutanecarboxylic acid ester

To a solution of (trans) -tert-butyl 3- (4- (benzylthio) -1H-pyrazol-1-yl) cyclobutanecarboxylate intermediate 21e (1.5g, 3.919mmol) in acetonitrile (20mL) at 0 ℃ was added acetic acid (5mL) and water (3 mL). 1, 3-dichloro-5, 5-dimethylhydantoin (1.5g, 7.613mmol) was then added in portions over 10 minutes. After stirring at 0 ℃ for 2h, the reaction mixture was quenched with water (20mL), concentrated under reduced pressure to remove volatiles, and extracted with ethyl acetate (30 mL). The organic phase was washed with brine (20mL) and Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by C18 column (acetonitrile: water 60% to 80%) to give the desired compound as a white solid (800mg, 57% yield).¹H NMR(300MHz,CDCl₃)δ8.05(s,1H),8.02(s,1H),5.10-5.00(m,1H),3.21-3.05(m,1H),2.91-2.69(m,4H),1.49(s,9H)。

Sulfonyl chloride 22: (trans) -Ethyl 2- (4- (chlorosulfonyl) cyclohexyl) acetate

Intermediate 22 a: ethyl 2- (4-hydroxycyclohexyl) acetate

Sodium tetrahydroborate (2.10g, 55.5mmol) was slowly added to a solution of ethyl 2- (4-oxocyclohexyl) acetate (5.00g, 26.6mmol) in ethanol (50mL) at 0 ℃ under a nitrogen atmosphere. After stirring at 0 ℃ for 2h under a nitrogen atmosphere, the reaction was quenched at 0 ℃ with saturated aqueous ammonium chloride (150mL), then concentrated at room temperature under reduced pressure to give a residue, which was dissolved in water (100mL) and extracted three times with ethyl acetate (150 mL). The combined organic layers were washed with brine (100mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound intermediate 22a (4.80g, according to¹Purity by H NMR 95%, 92% yield).¹H NMR(300MHz,CDCl₃)δ4.15-4.07(m,2H),4.00-3.92(m,0.3H),3.59-3.48(m,0.7H),2.24-2.08(m,2H),1.98-1.40(m,7H),1.35-0.96(m,6H)。

Intermediate 22 b: ethyl 2- (4- (tosyloxy) cyclohexyl) acetate

To a solution of ethyl 2- (4-hydroxycyclohexyl) acetate intermediate 22a (4.80g, 95% purity, 24.5mmol) in dichloromethane (100mL) was added triethylamine (3.80g, 37.6mmol), dimethylaminopyridine (153mg, 1.30mmol) and p-toluenesulfonyl chloride (5.20g, 27.3mmol) at 0 ℃. The resulting mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with ethyl acetate (100mL) and washed twice with 20% wt aqueous citric acid (55mL), with water (50mL) and brine (50mL), and filtered. The filtrate was concentrated under reduced pressure to give the title compound intermediate 22b (4.70g, according to¹Purity by H NMR 95%, 53% yield).¹H NMR(300MHz,CDCl₃)δ7.78(d,J＝8.1Hz,2H),7.32(d,J＝7.8Hz,2H),4.72(br s,0.1H),4.41-4.31(m,0.9H),4.09(q,J＝7.2Hz,2H),2.43(s,3H),2.20-2.12(m,2H),1.98-1.85(m,2H),1.82-1.69(m,3H),1.56-1.43(m,2H),1.24-1.20(m,3H),1.06-0.82(m,2H)。

Intermediate 22 c: ethyl 2- (4- (acetylthio) cyclohexyl) acetate

To a solution of ethyl 2- (4- (tosyloxy) cyclohexyl) acetate intermediate 22b (1.70g, 95% purity, 4.74mmol) in N, N-dimethylformamide (17mL) was added potassium thioacetate (1.09g, 9.54mmol) at room temperature. After stirring at 100 ℃ for 2 hours, the mixture was cooled to room temperature, water (50mL) was added to the mixture and extracted three times with ethyl acetate (50mL), the combined organic layers were washed twice with water (50mL), washed with brine (50mL), and over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 100:1 to 50:1) to give the title compound intermediate 22c as a brown oil (650mg, 95% purity, 53% yield).¹HNMR(300MHz,CDCl₃)δ4.12(q,J＝7.2Hz,2H),3.91-3.86(m,1H),2.31-2.30(m,3H),2.22(d,J＝7.2Hz,2H),1.93-1.73(m,5H),1.70-1.61(m,2H),1.30-1.19(m,5H)。

Sulfonyl chloride 22: (trans) -Ethyl 2- (4- (chlorosulfonyl) cyclohexyl) acetate

To a solution of 1-chloropyrrolidine-2, 5-dione (1.35g, 10.1mmol) in acetonitrile (13mL) at 0 deg.C were added aqueous 2N hydrochloride (0.4mL, 0.8mmol) and ethyl 2- (4- (acetylthio) cyclohexyl) acetate intermediate 22c (0.65g, 2.5 mmol). After stirring at 0 ℃ for 30 min, the reaction mixture was quenched with water (10mL) and concentrated under reduced pressure to give a residue, which was dissolved in ethyl acetate (50mL) and washed twice with water (30mL), washed with brine (30mL), over Na₂SO_4(s)Drying and filtering. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound (600mg, according to the formula: 1) as a colorless oil¹H NMR purity 95%, 84% yield).¹HNMR(300MHz,CDCl₃)δ4.13(q,J＝7.2Hz,2H),3.69-3.61(m,1H),2.36-2.31(m,2H),2.24-2.08(m,5H),1.81-1.63(m,4H),1.25(t,J＝7.2Hz,3H)。

Sulfonyl chloride 23: tert-butyl 2- (3- (chlorosulfonyl) cyclobutyl) acetate

Intermediate 23 a: 3- (2-diazaoetyl) cyclobutanone

To a solution of 3-oxocyclobutanecarboxylic acid (4.00g, 35.1mmol) in ethyl acetate (55mL) at 0 deg.C was added thionyl chloride (5.1mL, 70.1mmol) and the mixture was stirred at 60 deg.C under a nitrogen atmosphere for 4 hours. After cooling to room temperature, the reaction was concentrated and azeotroped with toluene to give a white solid, which was dissolved in tetrahydrofuran (33mL) and acetonitrile (33 mL). To this was added a 2.0M solution of trimethylsilyldiazomethine (26.3mL, 52.6mmol) in hexane (in tetrahydrofuran (33mL) and acetonitrile (33 mL)) at 0 ℃. After stirring overnight at room temperature under a nitrogen atmosphere, the mixture was quenched with acetic acid (5mL) and water (20mL) at 0 ℃. It was then concentrated to give a residue which was diluted with saturated aqueous sodium bicarbonate (100 mL). The resulting mixture was extracted three times with ethyl acetate (100 mL). The combined organic layers were washed with brine (100mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (100% dichloromethane, then petroleum ether: ethyl acetate ═ 1:1) to give the title compound (4.00g, according to¹Purity of H NMR 90%, 74% yield).¹H NMR(300MHz,CDCl₃)δ5.38(s,1H),3.51-3.38(m,2H),3.30-3.12(m,3H)。

Intermediate 23 b: 2- (3-Oxetanyl) acetic acid

A solution of 3- (2-diazeacetyl) cyclobutanone intermediate 23a (4.00g, 90% pure, 26.1mmol) in tetrahydrofuran (40mL) and water (4mL) was added dropwise to a solution of silver trifluoroacetate (288mg, 1.30mmol) and triethylamine (7.91g, 78.2mmol) in tetrahydrofuran (70mL) and water (7mL) at room temperature for about 20 minutes. After stirring overnight at room temperature, the mixture was concentrated to give a residue which was diluted with water (50mL), acidified to pH 1-2 with 1M aqueous hydrochloride solution and extracted three times with ethyl acetate (80 mL). The combined organic layers were washed with brine (80mL) and Na₂SO₄(solid) driedDried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (3.20g, according to¹Purity by H NMR 80%, 77% yield).¹H NMR(300MHz,CDCl₃)δ3.46-3.20(m,4H),2.88-2.75(m,2H),2.70-2.68(m,1H)。

Intermediate 23 c: tert-butyl 2- (3-oxocyclobutyl) acetate

To a solution of 2- (3-oxocyclobutyl) acetic acid intermediate 23b (3.20g, 80% purity, 20.0mmol) and di-tert-butyl dicarbonate (6.54g, 30.0mmol) in tert-butanol (70mL) was added N, N-dimethylpyridin-4-amine (733mg, 5.99mmol) at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated to give a residue, which was dissolved in ethyl acetate (150 mL). The organic phase was washed with water (80mL), 0.2M aqueous hydrochloride (80mL), water (80mL) and brine (80mL) and washed with Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 40:1 to 20:1) to give the title compound (750mg, according to formula i) as a colorless oil¹Purity of H NMR 90%, 18% yield).¹H NMR(300MHz,CDCl₃)δ3.27-3.17(m,2H),2.84-2.69(m,3H),2.54-2.52(m,2H),1.41(s,9H)。

Intermediate 23 d: tert-butyl 2- (3-hydroxycyclobutyl) acetate

To a solution of tert-butyl 2- (3-oxocyclobutyl) acetate intermediate 23c (730mg, 90% purity, 3.57mmol) in methanol (2mL) and tetrahydrofuran (11mL) was added sodium borohydride (68mg, 1.78mmol) at 0 ℃. After stirring at room temperature for 3 hours, the mixture was quenched slowly with water (10mL) and then with saturated aqueous sodium carbonate (3 mL). It was then concentrated to give a residue, which was extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (730mg, according to¹Purity by H NMR 85%, 89% yield).¹H NMR(300MHz,CDCl₃)δ4.41-4.36(m,0.1H),4.16-4.06(m,0.9H),2.54-2.45(m,2H),2.34-2.22(m,3H),2.09-1.99(m,2H),1.41(s,9H)。

Intermediate 23 e: tert-butyl 2- (3- (tosyloxy) cyclobutyl) acetate

To a solution of tert-butyl 2- (3-hydroxycyclobutyl) acetate intermediate 23d (730mg, 85% purity, 3.33mmol) in dichloromethane (14mL) at 0 deg.C was added pyridine (2.5mL) and 4-methylbenzene-1-sulfonyl chloride (1.59g, 8.33 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in ethyl acetate (30mL) and washed with 0.5M aqueous hydrochloric acid (50 mL). The aqueous phase was extracted twice with ethyl acetate (30 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (30mL), brine (30mL), and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1 to 10:1) to give the title compound (1.20g, according to the formula: 1) as a colorless oil¹Purity of H NMR 90%, 95% yield). LC-MS (ESI): r_T＝1.76min，C₁₇H₂₄O₅Calculated mass of S340.1, found value of M/z 358.5[ M + H [ ]₂O]⁺。¹H NMR(300MHz,CDCl₃)δ7.77(d,J＝7.8Hz,2H),7.33(d,J＝8.1Hz,2H),4.96-4.87(m,0.2H),4.70-4.61(m,0.8H),2.47-2.36(m,5.3H),2.31-2.29(m,2H),2.19-2.04(m,1H),1.89-1.79(m,1.7H),1.39(s,9H)。

Intermediate 23 f: tert-butyl 2- (3- (acetylthio) cyclobutyl) acetate

To a solution of tert-butyl 2- (3- (tosyloxy) cyclobutyl) acetate intermediate 23e (1.20g, 90% purity, 3.17mmol) in N, N-dimethylformamide (12mL) at room temperature was added potassium thioacetate (724mg, 6.34 mmol). After stirring at 100 ℃ for 6 hours, the reaction mixture was cooled to room temperature, diluted with water (30mL), and extracted three times with ethyl acetate (30 mL). The combined organic layers were washed with water (40mL) and brine (40mL) and washed with Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 100:1 to 50:1) to give the title compound (680mg, according to the formula: 1) as a brown oil¹Purity of H NMR 90%, 79% yield). LC-MS (ESI)：R_T＝1.74min，C₁₂H₂₀O₃Calculated mass of S244.1, found value of M/z 262.3[ M + H [)₂O]⁺。¹H NMR(300MHz,CDCl₃)δ4.11-4.00(m,0.9H),3.98-3.88(m,0.1H),2.84-2.70(m,0.9H),2.67-2.48(m,0.7H),2.43-2.40(m,1.6H),2.33-2.15(m,6.8H),1.45-1.42(m,9H)。

Sulfonyl chloride 23: tert-butyl 2- (3- (chlorosulfonyl) cyclobutyl) acetate

To a solution of tert-butyl 2- (3- (acetylthio) cyclobutyl) acetate intermediate 23f (680mg, 90% purity, 2.51mmol) in acetonitrile (14mL) at 0 deg.C was added 2M aqueous hydrochloride solution (0.4mL, 0.80mmol) and 1-chloropyrrolidine-2, 5-dione (1.34g, 10.0 mmol). After stirring at 0 ℃ for 1 hour, the reaction mixture was quenched with water (30mL) and extracted three times with ethyl acetate (30 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 40:1 to 20:1) to give the title compound (600mg, according to the formula: 1) as an oil¹Purity of H NMR 90%, 80% yield).¹H NMR(400MHz,CDCl₃)δ4.41-4.27(m,1H),2.99-2.85(m,2.5H),2.73-2.65(m,0.5H),2.46-2.43(m,2H),2.41-2.32(m,2H),1.44(s,9H)。

Sulfonyl chloride 24: tert-butyl 3- ((chlorosulfonyl) methyl) cyclobutanecarboxylic acid ester

Intermediate 24 a: tert-butyl 3- ((tosyloxy) methyl) cyclobutanecarboxylic acid ester

To a solution of tert-butyl 3- (hydroxymethyl) cyclobutanecarboxylate (3.50g, 18.8mmol) in pyridine (10mL) and dichloromethane (50mL) at 0 deg.C was slowly added 4-methyl-benzenesulfonyl chloride (7.20g, 37.6 mmol). After stirring at room temperature for 16 hours, the mixture was diluted with water (150mL) and stirring was continued at room temperature for 0.5 hour. The resulting mixture was extracted twice with dichloromethane (150 mL). The combined organic layers were washed with 0.5N aqueous hydrochloride (200mL), brine(150mL) washed over Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 30:1) to give the title compound as a white solid (3.60g, 56% yield).¹H NMR(300MHz,CDCl₃)δ7.81-7.78(m,2H),7.38-7.27(m,2H),4.04-3.96(m,3H),2.99-2.84(m,1H),2.70-2.49(m,1H),2.46(s,3H),2.35-2.19(m,2H),2.02-1.84(m,2H),1.44(s,9H)。

Intermediate 24 b: tert-butyl 3- ((acetylthio) methyl) cyclobutanecarboxylic acid ester

To a solution of tert-butyl 3- ((tosyloxy) methyl) cyclobutanecarboxylate intermediate 24a (1.10g, 3.20mmol) in N, N-dimethylformamide (20mL) was added potassium thioacetate (1.50g, 12.9mmol) at room temperature. After stirring at 100 ℃ for 16 h, the reaction mixture was cooled to room temperature and concentrated to give a residue, which was diluted with 5% aqueous sodium chloride (200mL) and extracted twice with ethyl acetate (100 mL). The combined organic layers were passed over Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 30:1) to give the title compound as a red-yellow oil (450mg, 62% yield).¹H NMR(300MHz,CDCl₃)δ3.02-2.92(m,2.2H),2.88-2.78(m,0.8H),2.57-2.50(m,0.5H),2.42-2.27(m,5.5H),2.02-1.84(m,2H),1.93-1.83(m,2H),1.44(s,9)。

Sulfonyl chloride 24: tert-butyl 3- ((chlorosulfonyl) methyl) cyclobutanecarboxylic acid ester

To a solution of tert-butyl 3- ((acetylthio) methyl) cyclobutanecarboxylate intermediate 24b (450mg, 1.85mmol) in 2M aqueous hydrochloride (0.25mL) and acetonitrile (10mL) was slowly added 1-chloropyrrolidine-2, 5-dione (984mg, 7.30mmol) at 0 ℃. After stirring at 0 ℃ for 30 minutes, the reaction mixture was concentrated in vacuo at 25 ℃ to remove acetonitrile. The residue obtained was partitioned between ethyl acetate (50mL) and saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated and washed with saturated aqueous sodium thiosulfate (50mL), then brine (50mL), over Na₂SO_4(s)Dried and filtered. Concentrating the filtrate to obtain a residue, and subjecting the residue to distillationPurification by silica gel column chromatography (petroleum ether: ethyl acetate ═ 30:1) gave the title compound (380mg, 80% yield) as a colourless oil.¹H NMR(300MHz,CDCl₃)δ3.86-3.79(m,2H),3.29-3.20(m,0.5H),3.10-2.94(m,1.5H),2.65-2.51(m,2H),2.29-2.12(m,2H),1.47(s,9)。

Sulfonyl chloride 25: 3- (2- ((tert-butyldiphenylsilyl) oxy) ethoxy) propane-1-sulfonyl chloride

Intermediate 25 a: 2- (2- ((tert-butyldiphenylsilyl) oxy) ethoxy) ethanol

To a solution of 2,2' -oxydiethanol (5.00g, 47.2mmol) in dichloromethane (100mL) at 0 deg.C was added 1H-imidazole (6.42g, 94.2mmol) and tert-butylchlorodiphenylsilane (14.2g, 51.8 mmol). After stirring overnight at room temperature, the mixture was quenched with water (100mL) and extracted three times with dichloromethane (100 mL). The combined organic layers were washed with brine (100mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 6:1 to 3:1) to give the title compound (6.51g, 95% purity, 38% yield) as a colourless oil. LC-MS (ESI): r_T＝1.85min，C₂₀H₂₈O₃Calculated mass of Si 344.2, found value of M/z 362.4[ M + H ]₂O]⁺。¹H NMR(300MHz,CDCl₃)δ7.72-7.67(m,4H),7.46-7.35(m,6H),3.84-3.79(m,2H),3.73-3.67(m,2H),3.64-3.56(m,4H),2.22(s,1H),1.06-1.05(m,9H)。

Intermediate 25 b: 2- (2- ((tert-butyldiphenylsilyl) oxy) ethoxy) ethyl 4-methylbenzenesulfonate

To a solution of 2- (2- ((tert-butyldiphenylsilyl) oxy) ethoxy) ethanol intermediate 25a (6.51g, 95% purity, 18.0mmol) in dichloromethane (35mL) was added pyridine (14mL) and 4-methylbenzene-1-sulfonyl chloride (8.56g, 44.9mmol) at 0 ℃. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure to give a residue, which wasDissolved in ethyl acetate (100mL), washed with 0.5M aqueous hydrochloric acid (50mL), and extracted twice with ethyl acetate (80 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50mL), brine (50mL), and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1 to 10:1) to give the title compound (7.61g, according to the formula: 1) as a colorless oil¹Purity of H NMR 90%, 77% yield).¹H NMR(300MHz,CDCl₃)δ7.81-7.75(m,2H),7.68-7.63(m,4H),7.45-7.35(m,6H),7.31-7.27(m,2H),4.16-4.12(m,2H),3.76-3.72(m,2H),3.70-3.66(m,2H),3.55-3.51(m,2H),2.42(s,3H),1.04(s,9H)。

Intermediate 25 c: s- (2- (2- ((tert-butyldiphenylsilyl) oxy) ethoxy) ethyl) ethanethiol ester

To a solution of 2- (2- ((tert-butyldiphenylsilyl) oxy) ethoxy) ethyl 4-methylbenzenesulfonate intermediate 25b (7.61g, 90% pure, 13.7mmol) in N, N-dimethylformamide (60mL) was added potassium thioacetate (3.14g, 27.5mmol) at room temperature. After stirring overnight at 100 ℃, the reaction mixture was cooled to room temperature, diluted with water (150mL) and extracted three times with ethyl acetate (100 mL). The combined organic layers were washed twice with water (100mL), washed with brine (100mL), and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 40:1 to 30:1) to give the title compound as a brown oil (5.73g, 90% purity, 93% yield). LC-MS (ESI): r_T＝2.13min，C₂₂H₃₀O₃Calculated mass of SSi 402.2, M/z found value 420.5[ M + H₂O]⁺。¹H NMR(400MHz,CDCl₃)δ7.70-7.68(m,4H),7.45-7.36(m,6H),3.81-3.78(m,2H),3.63-3.57(m,4H),3.09-3.06(m,2H),2.33(s,3H),1.06(s,9H)。

Sulfonyl chloride 25: 3- (2- ((tert-butyldiphenylsilyl) oxy) ethoxy) propane-1-sulfonyl chloride

Intermediate to S- (2- (2- ((tert-butyldiphenylsilyl) oxy) ethoxy) ethyl) ethanethiol ester at 0 DEG CTo a solution of 25c (1.00g, 90% purity, 2.24mmol) in acetonitrile (15mL) was added 2M aqueous hydrochloride solution (0.4mL) and 1-chloropyrrolidine-2, 5-dione (1.19g, 8.94 mmol). After stirring at 0 ℃ for 1 hour, the reaction mixture was quenched with water (30mL) and extracted three times with ethyl acetate (30 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1 to 10:1) to give the title compound (350mg, according to the formula: 1) as a colorless oil¹Purity by H NMR 85%, 31% yield).¹HNMR(300MHz,CDCl₃)δ7.75-7.68(m,4H),7.47-7.37(m,6H),4.10-4.06(m,2H),3.90-3.82(m,4H),3.66-3.63(m,2H),1.09-1.07(m,9H)。

The assembly of a dihydropyrimidine of general formula I in combination with an acid of general formula II, an aryl aldehyde (P1) and a formamidine (P2) by two consecutive reaction steps (one method selected from scheme 1 and scheme 2, respectively) is shown in table 1:

ketoesters having the general formula II:

ketone ester 1: methyl 3- (1-methyl-2-oxopiperidin-4-yl) -3-oxopropanoate

LC-MS(ESI)：R_T＝1.040min，C₁₀H₁₅NO₄Calculated mass 213.1, M/z found 213.9[ M + H [ ]]⁺；¹HNMR(300MHz,CDCl₃)δ3.84-3.74(m,3H),3.66-3.55(m,2H),3.42-3.33(m,2H),3.13-3.07(m,1H),3.03-2.94(m,3H),2.59-2.45(m,2H),2.22-2.17(m,1H),1.92-1.83(m,1H)。

Ketone ester 2: methyl 3- (1-acetylpiperidin-4-yl) -3-oxopropanoate

LC-MS(ESI)：R_T＝1.148min，C₁₁H₁₇NO₄Calculated mass of (8) ((227.1), found value of M/z 228.1[ M + H)]⁺。

Ketoester 3: methyl 3-oxo-3- (2-oxopiperidin-4-yl) propanoate

LC-MS(ESI)：R_T＝0.52min，C₉H₁₃NO₄Calculated mass of (3) 199.1, found value of M/z 200.0[ M + H ]]⁺。¹HNMR(400MHz,DMSO-d₆)δ7.51(s,1H),3.78(d,J＝16.8Hz,1H),3.71(d,J＝16.8Hz,1H),3.63(s,3H),3.17-3.16(m,1H),3.13-3.09(m,2H),3.08-2.98(m,1H),2.32-2.26(m,1H),2.05-1.97(m,1H),1.67-1.57(m,1H)。

Ketone ester 4: tert-butyl 4- (3-methoxy-3-oxopropanoyl) piperidine-1-carboxylate

LC-MS(ESI)：R_T＝2.484min，C₁₄H₂₃NO₅Calculated mass of 285.2, M/z found 230.0[ M + H-t-Bu]⁺。¹H NMR(300MHz,CDCl₃)δ4.96(s,0.2H),4.10-4.06(m,2H),3.71(s,3H),3.49(s,1.8H),3.77(t,J＝16Hz,2H),2.60(tt,J＝11.3,3.83Hz,1H),1.84-1.80(m,2H),1.58-1.46(m,2H),1.44(s,9H)。

Ketoester 5: methyl 3- (1- ((1-methoxy-2-methyl-1-oxopropan-2-yl) sulfonyl) piperidin-4-yl) -3-oxopropanoate

LC-MS(ESI)：R_T＝1.42min，C₁₄H₂₃NO₇Calculated mass of S349.1, found value of M/z 350.5[ M + H [)]⁺。

Ketoester 6: 4- (2-ethoxycarbonyl-acetyl) -piperidine-1-carboxylic acid tert-butyl ester

¹H NMR(300MHz,CDCl₃)δ12.17(s,0.2H),4.99(s,0.2H),4.26-4.03(m,4H),3.50(s,1.6H),2.87-2.72(m,2H),2.68-2.58(m,1H),1.94-1.76(m,2H),1.63-1.49(m,2H),1.46(s,9H),1.28(t,J＝10.5Hz,3H)。

Ketoester 7: methyl 3- (trans-4- ((tert-butoxycarbonyl) amino) cyclohexyl) -3-oxopropanoate

¹H NMR(300MHz,CDCl₃)δ4.47-4.31(m,1H),3.73(s,3H),3.49(s,2H),3.44-3.29(m,1H),2.40(t,J＝12.3Hz,1H),2.09(d,J＝11.1Hz,2H),1.96(d,J＝13.5Hz,2H),1.65-1.47(m,1H),1.43(s,9H),1.11(q,J＝13.5Hz,2H)。

Ketoester 8: methyl 3- (cis-4- ((tert-butoxycarbonyl) amino) cyclohexyl) -3-oxopropanoate

¹H NMR(400MHz,CDCl3)δ4.71-4.37(m,1H),3.71(s,3H),3.67-3.59(m,1H),3.48(s,2H),1.75-1.60(m,8H),1.41(s,9H)

Ketoester 9: trans-methyl 4- (3-methoxy-3-oxopropanoyl) cyclohexanecarboxylate

¹H NMR(400MHz,DMSO-d₆)δ3.66-3.53(m,8H),2.45-2.40(m,1H),2.33-2.24(m,1H),1.95-1.87(m,4H),1.35-1.18(m,4H)。

Ketone ester 38: trans-methyl 4- (3-ethoxy-3-oxopropanoyl) cyclohexane-carboxylate

¹H NMR(300MHz,CDCl₃)δ4.20(q,J＝7.2Hz,2H),3.68(s,3H),3.49(s,2H),2.54-2.43(m,1H),2.34-2.23(m,1H),2.14-1.95(m,5H),1.49-1.37(m,3H),1.28(t,J＝7.2Hz,3H)。

Ketone ester 10: cis-methyl 3- (3-methoxy-3-oxopropanoyl) cyclohexanecarboxylate

LC-MS(ESI)：R_T＝1.67min，C₁₂H₁₈O₅Calculated mass of 242.1, found value of M/z 242.9[ M + H ]]⁺。¹HNMR(400MHz,CDCl₃)δ12.04(s,0.1H),4.98(s,0.1H),3.72(s,2.7H),3.71(s,0.3H),3.68(s,0.4H),3.66(s,2.6H),3.51(s,0.2H),3.50(s,1.4H),2.84-2.78(m,0.1H),2.75-2.72(m,0.1H),2.54-2.46(m,0.8H),2.38-2.26(m,1H),2.21-2.10(m,1H),2.03-1.87(m,2.7H),1.83-1.75(m,0.3H),1.54-1.43(m,1H),1.39-1.24(m,3H)。

Ketone ester 11: methyl 3- (4- (2-ethoxy-2-oxoethyl) cyclohexyl) -3-oxopropanoate

¹H NMR(400MHz,DMSO-d₆)δ4.07-4.01(m,2H),3.72-3.65(m,2H),3.63-3.50(m,3H),2.63-2.60(m,0.3H),2.39(tt,J＝12.0,3.2Hz,0.6H),2.21-2.16(m,2H),1.91-1.82(m,2H),1.74(dd,J＝13.2,3.2Hz,2H),1.67-1.46(m,2H),1.30-1.22(m,2H),1.19-1.15(m,3H),0.99(tq,J＝13.2,3.2Hz,1H)。

Ketone ester 12: tert-butyl 3- (3-methoxy-3-oxopropanoyl) piperidine-1-carboxylate

LC-MS(ESI)：R_T＝1.58min，C₁₄H₂₃NO₅Calculated mass 285.2, M/z found 286.1[ M + H [ ]]⁺。¹HNMR(300MHz,CDCl₃)δ5.00-4.96(m,0.2H),4.12-3.77(m,2H),3.70(s,3H),3.52-3.51(m,1.3H),3.43(s,0.3H),3.19-3.02(m,1H),2.95-2.85(m,1H),2.64-2.58(m,1H),1.97-1.88(m,1H),1.69-1.42(m,12H)。

Ketone ester 13: tert-butyl 4-fluoro-4- (3-methoxy-3-oxopropanoyl) piperidine-1-carboxylate

¹H NMR(400MHz,CDCl₃)δ12.10(d,J＝2.4Hz,0.15H),5.39(d,J＝2.8Hz,0.15H),4.04(br s,2H),3.75(d,J＝6.0Hz,3H),3.67(d,J＝4.4Hz,1.7H),3.04(br s,2H),1.99-1.82(m,4H),1.45(d,J＝3.2Hz,9H)。

Ketone ester 14: methyl 3- (3- (methylsulfonyl) -3-azabicyclo [3.2.1] oct-8-yl) -3-oxopropanoate

LC-MS(ESI)：R_T＝1.32min，C₁₂H₁₉NO₅Calculated mass of S289.1, found value of M/z 290.4[ M + H]⁺。¹HNMR(300MHz,CDCl₃)δ3.75-3.74(m,3H),3.63(dd,J＝11.1,3.0Hz,1H),3.53(d,J＝11.1Hz,2H),3.38(dd,J＝10.8,3.3Hz,1H),3.18(d,J＝10.8Hz,1H),2.85(d,J＝11.1Hz,1H),2.76(d,J＝11.1Hz,3H),2.66(s,1H),2.61(s,2H),1.83(s,2H),1.71(m,2H)。

Ketone ester 15: 3- (8-methanesulfonyl-8-aza-bicyclo [3.2.1] oct-3-yl) -3-oxo-propionic acid methyl ester

LC-MS(ESI)：R_T＝1.26min，C₁₂H₁₉NO₅Calculated mass of S289.1, found value of M/z 290.4[ M + H]⁺。¹HNMR(300MHz,CDCl₃)δ4.35(s,2H),3.75(s,3H),3.50(s,2H),2.94(s,3H),

Ketoester 16: (1R,5S,6R) -tert-butyl 6- (3-ethoxy-3-oxopropanoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate

LC-MS(ESI)：R_T＝1.38min，C₁₅H₂₃NO₅Calculated mass 297.2, M/z found 242.1[ M-56+ H]⁺。¹HNMR(300MHz,CDCl₃)δ4.21(q,J＝7.2Hz,2H),3.70-3.62(m,2H),3.57(s,2H),3.45-3.41(m,2H),2.18(s,2H),1.92(s,1H),1.45(s,9H),1.29(t,J＝7.2Hz,3H)。

Ketone ester 17: 1-tert-butyl 2-methyl 4- (3-methoxy-3-oxopropanoyl) piperidine-1, 2-dicarboxylate

LC-MS(ESI)：R_T＝2.537min，C₁₆H₂₅NO₇Calculated mass of 343.2, M/z found value 342.1[ M-H [ ]]^-。¹HNMR(400MHz,CDCl₃)δ5.06-5.02(m,0.5H),4.87-4.83(m,0.5H),4.18-4.12(m,0.5H),4.06-4.02(m,0.5H),3.75-3.71(m,7H),3.55-3.48(m,2H),3.03-2.96(m,0.5H),2.91-2.85(m,0.5H),2.51-2.41(m,1H),1.94-1.72(m,2H),1.47(s,4H),1.44(s,9H)。

Ketone ester 18: cis-4- (2-methoxycarbonyl-acetyl) -piperidine-1, 3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester

LC-MS(ESI)：R_T＝1.59min，C₁₆H₂₅NO₇Calculated mass of 343.2, M/z found 244.0[ M + H-100 ]]⁺。¹H NMR(400MHz,CDCl₃)δ4.19(dd,J＝13.6,5.6Hz,1H),3.79-3.62(m,7H),3.58(s,2H),3.45(dd,J＝13.6,2.8Hz,1H),3.17-3.12(m,1H),2.99(q,J＝4.4Hz,1H),2.92-2.87(m,1H),2.12-2.05(m,1H),1.94-1.85(m,1H),1.44(s,9H)。

Ketone ester 19: ethyl 3-cyclohexyl-3-oxopropanoate

¹H NMR(300MHz,CDCl₃)δ12.15(br s,0.2H),4.96(br s,0.2H),4.19(q,J＝7.2Hz,2H),3.48(s,1.6H),2.50-2.42(m,1H),1.91-1.66(m,5H),1.42-1.17(m,8H)。

Ketone ester 20: methyl 3-oxo-3- (tetrahydro-2H-pyran-3-yl) propanoate

LC-MS(ESI)：R_T＝1.15min，C₉H₁₄O₄Calculated mass of 186.1, found value of 187.5[ M + H ] M/z]⁺。¹HNMR(300MHz,CDCl₃)δ12.02(s,0.2H),4.99(s,0.2H),4.04-3.94(m,1H),3.91-3.78(m,1H),3.72(s,2.4H),3.71(s,0.6H),3.55-3.35(m,3.6H),2.81-2.72(m,0.8H),2.48-2.38(m,0.2H),2.04-1.91(m,1H),1.76-1.62(m,3H)。

Ketone ester 21: methyl 3-oxo-3- (tetrahydro-2H-pyran-2-yl) propanoate

LC-MS(ESI)：R_T＝1.764min，C₉H₁₄O₄Calculated mass of 186.1, found value of 187.0[ M + H ] M/z]⁺。¹HNMR(300MHz,CDCl₃)δ4.01(dd,J＝11.4,2.1Hz,1H),3.84(dd,J＝10.8,2.1Hz,1H),3.71(s,3H),3.65(s,0.2H),3.59(d,J＝6.3Hz,1.6H),3.52(s,0.2H),3.49-3.41(m,1H),1.91-1.88(m,2H),1.59-1.36(m,4H)。

Ketone ester 22: 3-oxo-3- (tetrahydro-pyran-4-yl) -propionic acid methyl ester

¹H NMR(300MHz,CDCl₃)δ12.06(s,0.1H),4.98(s,0.1H),4.01-3.97(m,2H),3.71(s,3H),3.50(s,1.8H),3.41(td,J＝11.4,2.4Hz,2H),2.74-2.64(m,0.8H),2.40-2.30(m,0.2H),1.80-1.67(m,4H)。

Ketone ester 23: 3- (3-tert-Butoxycarbonylamino-cyclopentyl) -3-oxo-propionic acid methyl ester

LC-MS(ESI)：R_T＝1.52min，C₁₄H₂₃NO₅Calculated mass of 285.2, M/z found value 286.2[ M + H ]]⁺。¹HNMR(400MHz,CDCl₃)δ4.85(br s,0.8H),4.54(br s,0.2H),4.10-3.96(m,1H),3.71(s,3H),3.50(s,1.5H),3.47(s,0.5H),3.17-3.04(m,1H),2.17-2.08(m,1H),1.96-1.80(m,3H),1.72-1.63(m,1H),1.58-1.50(m,1H),1.44(s,9H)。

Ketone ester 24: (9H-fluoren-9-yl) methyl 3- (3-methoxy-3-oxopropanoyl) pyrrolidine-1-carboxylate

LC-MS(ESI)：R_T＝1.67min，C₂₃H₂₃NO₅Calculated mass 393.2, found value of M/z 394.5[ M + H ]]⁺。¹HNMR(300MHz,CDCl₃)δ12.13(d,J＝5.7Hz,0.2H),7.78(d,J＝7.5Hz,2H),7.62(d,J＝7.2Hz,2H),7.42(t,J＝7.2Hz,2H),7.33(t,J＝7.2Hz,2H),5.09(s,0.2H),4.48-4.35(m,2H),4.28-4.24(m,1H),3.78-2.95(m,10H),2.24-2.15(m,2H)。

Ketone ester 25: tert-butyl 3- (3-methoxy-3-oxopropanoyl) pyrrolidine-1-carboxylate

LC-MS(ESI)：R_T＝2.053min，C₃H₂₁NO₅Calculated mass of 271.1, found value of M/z 294.1[ M + Na ]]⁺。¹H NMR(300MHz,CDCl₃)δ12.06(s,0.2H),5.03(s,0.2H),3.73(s,3H),3.61-3.47(m,4.4H),3.38-3.25(m,2H),2.90(br s,0.2H),2.14-2.00(m,2H),1.44(s,9H)。

Ketone ester 26: methyl 3- (1- (methylsulfonyl) pyrrolidin-2-yl) -3-oxopropanoate

¹H NMR(400MHz,CDCl₃)δ12.01(s,0.2H),5.32(s,0.2H),4.45(dd,J＝8.4,4.8Hz,0.8H),4.33(dd,J＝7.6,3.6Hz,0.2H),3.75(s,3H),3.74(s,0.2H),3.70(s,0.6H),3.65(s,0.6H),3.63(s,0.1H),3.61(s,0.2H),3.53-3.43(m,2H),2.93(s,2.5H),2.88(s,0.5H),2.27-2.12(m,2H),2.02-1.95(m,2H)。

Ketone ester 27: methyl 3-oxo-3- (tetrahydrofuran-2-yl) propanoate

¹H NMR(400MHz,DMSO-d₆)δ4.37-4.32(m,1H),3.79(t,J＝8.4Hz,2H),3.68-3.62(m,5H),2.16-2.05(m,1H),1.92-1.76(m,3H)。

Ketone ester 29: cis-methyl 5- (3-methoxy-3-oxopropanoyl) tetrahydrofuran-2-carboxylate

¹H NMR(300MHz,CDCl₃)δ11.89(s,0.15H),5.69(s,0.15H),4.61(dd,J＝7.2,4.2Hz,1H),4.53(t,J＝7.2Hz,1H),4.00-3.76(m,1.7H),3.73(s,6H),2.30-2.02(m,4H)。

Ketone ester 30: methyl 3-oxo-3- (tetrahydrofuran-3-yl) propanoate

¹H NMR(300MHz,CDCl₃)δ3.95-3.93(m,2H),3.91-3.78(m,2H),3.75(s,3H),3.54(s,2H),3.38-3.33(m,1H),2.17-2.10(m,2H)。

Ketone ester 31: methyl 3-oxo-3- (5-oxopyrrolidin-2-yl) propanoate

¹H NMR(300MHz,CDCl₃)δ11.85(br s,0.2H),8.15(br s,0.4H),7.34(s,0.4H),7.17(s,0.2H),5.19(s,0.2H),4.39(t,J＝6.9Hz,0.6H),4.21-4.14(m,0.4H),3.73(s,3H),3.57(d,J＝3.6Hz,1H),3.38(s,0.6H),2.54-2.36(m,2H),2.26-2.10(m,0.9H),1.91(s,0.1H),1.47-1.42(m,0.4H),1.32(s,0.2H),1.11(s,0.2H)。

Ketone ester 28: methyl 3- (3-methoxy-3-oxopropanoyl) cyclopentanecarboxylate

¹H NMR(400MHz,DMSO-d₆)δ3.69-3.65(m,1H),3.63(s,1.4H),3.60-3.59(m,5.6H),3.15-3.03(m,0.4H),2.92-2.78(m,1.6H),2.19-2.07(m,1H),1.97-1.69(m,5H)。

Ketone ester 34: trans-methyl 3- (3- ((tert-butoxycarbonyl) amino) cyclobutyl) -3-oxopropanoate

¹H NMR(400MHz,CDCl₃)δ4.71(br s,1H),4.19-4.02(m,1H),3.72(s,3H),3.45(s,2H),3.35-3.25(m,1H),2.68-2.51(m,2H),2.22-2.07(m,2H),1.43(s,9H)。

Ketone ester 36: trans-Ethyl 3- (2- (2- (tert-butoxy) -2-oxoethyl) cyclopropyl) -3-oxopropanoate

¹H NMR(300MHz,CDCl₃)δ4.22-4.15(m,2H),3.56-3.54(m,2H),2.06-2.02(m,2H),1.94-1.89(m,1H),1.73-1.64(m,1H),1.43-1.42(m,9H),1.29-1.21(m,4H),0.93-0.86(m,1H)。

Ketone ester 32: tert-butyl 3- (3-methoxy-3-oxopropanoyl) azetidine-1-carboxylate

LC-MS(ESI)：R_T＝1.44min，C₁₂H₁₉NO₅Calculated mass of 257.1, M/z found 258.2[ M + H ]]⁺。¹HNMR(400MHz,CDCl₃)δ12.11(s,0.2H),5.09(s,0.2H),4.13-4.03(m,4H),3.75(s,3H),3.65-3.57(m,1H),3.49(s,1.6H),1.43(s,9H)。

Ketoester 37: methyl 4- (3-methoxy-3-oxopropanoyl) cycloheptane carboxylate

LC-MS(ESI)：R_T＝1.28min，C₁₃H₂₀O₅Calculated mass of 256.1, M/z found value 257.1[ M + H ]]⁺。¹HNMR(300MHz,DMSO-d₆)δ3.66(s,2H),3.60(s,3H),3.56(s,3H),2.70-2.61(m,1H),2.50-2.43(m,1H),1.96-1.33(m,10H)。

Ketone ester 39: 3- (2-Methoxycarbonyl-acetyl) -cyclobutanecarboxylic acid methyl ester

¹H NMR(400MHz,CDCl₃)δ12.07(s,0.05H),11.97(s,0.05H),5.02(s,0.05H),5.00(s,0.05H),3.74-3.68(m,6H),3.52-3.48(m,0.5H),3.44-3.43(m,1.8H),3.35-3.03(m,1.5H),2.58-2.38(m,4H)。

Ketone ester 40: methyl 3- (4- (N-methylsulfamoyl) cyclohexyl) -3-oxopropanoate

¹H NMR(300MHz,DMSO-d₆)δ6.93-6.82(m,1H),3.69(s,2H),3.65(s,0.4H),3.62(s,2.4H),3.53(s,0.2H),3.08-2.94(m,1H),2.77-2.70(m,0.5H),2.57-2.54(m,3H),2.47-2.41(m,0.5H),2.13-1.94(m,3H),1.85-1.76(m,1H),1.63-1.26(m,4H)。

Ketone ester 41: methyl 3-oxo-3- (4- (pyrrolidin-1-ylsulfonyl) cyclohexyl) propionate

¹H NMR(300MHz,DMSO-d₆)δ3.68(s,2H),3.64-3.60(m,3H),3.31-3.19(m,6H),2.08-1.95(m,4H),1.88-1.81(m,4H),1.54-1.40(m,2H),1.35-1.21(m,2H)。

Ketone ester 42: methyl 3- (3- (N-methylacetamido) cyclopentyl) -3-oxopropanoate

LC-MS(ESI)：R_T＝1.17min，C₁₂H₁₉NO₄Calculated mass of 241.1, M/z found value 242.3[ M + H [ ]]⁺。¹HNMR(300MHz,CDCl₃)δ5.12-5.00(m,0.5H),4.30-4.18(m,0.5H),3.75(s,3H),3.52-3.51(m,2H),3.25-3.03(m,1H),2.89-2.80(m,3H),2.14-1.53(m,9H)。

Ketoester 43: (cis) -methyl 3- (4-methyltetrahydrofuran-2-yl) -3-oxopropanoate using as crude ketoester 44: tert-butyl (cis) -5- (3-methoxy-3-oxopropanoyl) hexahydro-cyclopenta [ c]Pyrrole-2 (1H) -carboxylate, LC-ms (esi): r_T＝1.54min，C₁₆H₂₅NO₅Calculated mass of 311.2, found value of M/z 256.2[ M + H-56 ]]⁺。¹HNMR(400MHz,CDCl₃)δ12.04(s,0.1H),5.01(s,0.1H),3.73(s,2.7H),3.72(s,0.3H),3.48(s,1.8H),3.47-3.43(m,2H),3.28-3.07(m,3H),2.77-2.71(m,0.2H),2.69-2.58(m,1.8H),2.21-2.04(m,2H),1.68-1.56(m,2H),1.44(s,9H)。

Ketone ester 45: methyl 3- (4- ((tert-butoxycarbonyl) amino) cycloheptyl) -3-oxopropanoate, LC-ms (esi): c₁₆H₂₇NO₅Calculated mass of 313.2, found value of M/z 336.2[ M + Na ]]⁺。¹H NMR(300MHz,CDCl₃)δ4.59-4.41(m,1H),3.74(s,3H),3.70-3.53(m,1H),3.50(s,2H),2.78-2.62(m,1H),2.17-1.49(m,9H),1.44(s,9H),1.43-1.23(m,1H)。

Ketoester 46: methyl 3- (3- ((tert-butoxycarbonyl) amino) bicyclo [1.1.1]Pent-1-yl) -3-oxopropanoate, LC-ms (esi): r_T＝1.753min，C₁₄H₂₁NO₅Calculated mass of 283.1, M/z found value 227.9[ M + H-56 ]]⁺。¹H NMR(400MHz,CDCl₃)δ11.78(s,0.2H),4.99(s,0.2H),4.96(br s,1H),3.73(s,3H),3.49(s,1.6H),2.30(s,4.5H),.2.21(s,1.5H),1.45(s,9H)。

Ketone ester 47: ethyl (cis) -4- (3-methoxy-3-oxopropanoyl) tetrahydrofuran-2-carboxylate,¹H NMR(400MHz,CDCl₃)δ12.09(s,0.1H),12.05(s,0.1H),5.08(s,0.1H),5.07(s,0.1H),4.63-4.49(m,1H),4.27-4.19(m,2.4H),4.16-4.14(m,0.6H),4.11-4.06(m,0.5H),4.01-3.92(m,0.2H),3.75(s,3H),3.65-3.64(m,0.3H),3.53(s,1.6H),3.49-3.40(m,0.8H),3.11-3.01(m,0.1H),2.96-2.88(m,0.1H),2.59-2.37(m,1.4H),2.30-2.20(m,0.6H),1.31-1.24(m,3H)。

ketone ester 48: methyl 3- (oxetan-3-yl) -3-oxopropanoate,¹H NMR(300MHz,CDCl₃)12.13(s,0.2H),5.06(s,0.2H),4.81-4.76(m,2.6H),4.15-4.05(m,0.5H),3.95-3.92(m,0.5H),3.90-3.76(m,1H),3.73(s,1.5H),3.72(s,1.5H),3.71-3.63(m,0.7H),3.47(s,1H),3.22-3.15(m,0.3H)。

ketone ester 49: methyl 3-oxo-3- (1, 4-dioxaspiro [4.5] dec-7-yl) propionate

¹H NMR(300MHz,CDCl₃)δ12.06(s,0.1H),4.99(s,0.1H),3.96(s,4H),3.74(s,3H),3.52(s,1.8H),2.82-2.74(m,1H),1.94-1.65(m,5.2H),1.56-1.26(m,2.8H)。

Ketone ester 50: (cis) -methyl 3- (4- (((tert-butyldiphenylsilyl) oxy) methyl) -tetrahydrofuran-2-yl) -3-oxopropanoate, LC-MS (ESI): r_T＝2.808min，C₂₅H₃₂O₅Calculated mass of Si 440.2, found value of M/z 458.2[ M + NH ]₄]⁺。¹H NMR(300MHz,CDCl₃)δ7.69-7.61(m,4H),7.46-7.38(m,6H),4.43-4.37(m,1H),4.04-3.99(m,1H),3.81-3.72(m,4H),3.66-3.49(m,4H),2.63-2.53(m,1H),2.34-2.25(m,1H),1.79-1.70(m,1H),1.06(s,9H)。

Ketone ester 52: methyl 3- (4- (N-isopropylsulfamoyl) cyclohexyl) -3-oxopropanoate,¹H NMR(300MHz,CDCl₃)δ12.29(s,0.1H),12.08(s,0.1H),5.09(s,0.1H),5.00(s,0.1H),4.19-4.09(m,1H),3.79(s,0.4H),3.75(s,2.6H),3.69-3.56(m,1H),3.53(s,1.3H),3.44(s,0.3H),3.17-3.09(m,0.2H),2.97-2.73(m,1.2H),2.54-2.46(m,0.6H),2.34-2.23(m,1.7H),2.18-1.95(m,2.3H),1.87-1.75(m,0.6H),1.67-1.54(m,1.9H),1.48-1.36(m,1.5H),1.29-1.23(m,6H)。

ketone ester 53: methyl 3- (3-methoxy-3-oxopropanoyl) bicyclo [1.1.1]The pentane-1-formic ester is obtained by reacting pentane-1-formic ester,¹H NMR(400MHz,CDCl₃)δ7.11(s,0.3H),4.99(s,0.3H),3.74(s,3H),3.70(s,3H),3.50(s,1.4H),2.33(s,4H),2.25(s,2H)。

ketone ester 54: (cis) -Ethyl 3- (4- ((tert-Butoxycarbonyl) amino) tetrahydrofuran-2-yl) -3-oxopropanoate，LC-MS(ESI)：R_T＝2.019min，C₁₄H₂₃NO₆301.1, found value of m/z 202.1. [ M + H-100 ]]⁺。¹HNMR(300MHz,CDCl3)δ12.08(s,0.2H),5.33(s,0.2H),4.99(br s,1H),4.57-4.52(m,0.2H),4.47-4.42(m,0.8H),4.25-4.21(m,2H),3.98-3.93(m,1H),3.82-3.71(m,1.6H),3.57-3.52(m,1H),2.55-2.44(m,1H),2.18-2.05(m,1H),1.44(s,9H),1.32-1.28(m,3H)。

Ketone ester 55: (cis) -methyl 3- (4- (methylcarbamoyl) tetrahydrofuran-2-yl) -3-oxopropanoate, LC-MS (ESI): r_T0.961min and 1.236min, C₁₀H₁₅NO₅Calculated mass of 229.1, M/z found 230.1[ M + H ]]⁺。

Ketone ester 56: tert-butyl 5- (3-ethoxy-3-oxopropanoyl) tetrahydro-2H-pyran-2-carboxylate,¹H NMR(300MHz,CD₃OD)δ4.30-4.19(m,3H),4.15-4.02(m,1H),3.92-3.79(m,1H),3.52-3.44(m,1H),2.91-2.81(m,0.4H),2.76-2.69(m,0.6H),2.50-2.42(m,0.3H),2.24-2.16(m,0.5H),2.11-2.01(m,1.2H),1.91-1.78(m,2H),1.71-1.54(m,1H),1.48(s,9H),1.27(t,J＝7.2Hz,3H)。

ketoester 57: methyl 3-oxo-3- (5-oxo-1- ((2-trimethylsilyl) ethoxy) methyl) pyrrolidin-3-yl) propionate,¹H NMR(300MHz,CDCl₃)δ4.71(s,2H),3.76(s,3.5H),3.72-3.46(m,6.5H),2.71-2.65(m,2H),0.92(t,J＝8.4Hz,2H),0.01(s,9H)。

ketone ester 58: methyl 3- (4- (N- (2-ethoxy-2-oxoethyl) sulfamoyl) cyclohexyl) -3-oxopropanoate,¹H NMR(300MHz,CDCl₃)δ4.86-4.73(m,1H),4.28-4.09(m,2H),3.96-3.92(m,2H),3.77(s,3H),3.53(s,2H),3.01-2.87(m,1H),2.78-2.73(m,0.4H),2.58-2.47(m,0.6H),2.40-2.25(m,2H),2.15-2.06(m,1H),1.92-1.77(m,1H),1.71-1.57(m,2H),1.50-1.40(m,1H),1.33-1.27(m,3H)。

ketoester 59: (R) -methyl 1- ((4- (3-methoxy-3-oxopropanoyl) cyclohexyl) -sulfonyl) pyrrolidine-3-carboxylate,¹H NMR(300MHz,CDCl₃)δ12.27(s,0.1H),12.06(s,0.1H),5.08(s,0.1H),4.98(s,0.1H),3.74(s,3H),3.73(m,3H),3.70-3.63(m,1H),3.60-3.44(m,4.6H),3.18-3.08(m,1H),3.04-2.90(m,1H),2.77-2.69(m,0.5H),2.56-2.43(m,0.5H),2.32-2.16(m,4H),2.15-2.06(m,1H),2.04-1.94(m,1H),1.91-1.77(m,1H),1.71-1.55(m,2H),1.50-1.36(m,1H)。

ketone ester 60: methyl 3- (3- ((tert-butyldiphenylsilyl) oxy) cyclobutyl) -3-oxopropanoate, LC-ms (esi): r_T＝1.94min，C₂₄H₃₀O₄Calculated mass of Si 410.2, found value of M/z 411.5[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ7.66-7.61(m,4H),7.47-7.37(m,6H),4.21-4.11(m,1H),3.73(s,3H),3.41(s,2H),2.75-2.62(m,1H),2.39-2.21(m,4H),1.04(s,9H)。

Ketone ester 61: methyl 4- (3-ethoxy-3-oxopropanoyl) cycloheptane carboxylate,¹H NMR(300MHz,CDCl₃)δ12.14(s,0.1H),4.96(s,0.1H),4.19(q,J＝6.9Hz,2H),3.67(s,3H),3.48(s,1.8H),2.75-2.61(m,1H),2.59-2.45(m,1H),2.12-1.80(m,5.4H),1.75-1.53(m,4H),1.49-1.37(m,0.6H),1.28(t,J＝6.9Hz,3H)。

ketone ester 62: methyl 3- (4- (N- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -methylsulfonylamino) cyclohexyl) -3-oxopropionate,¹H NMR(400MHz,CDCl₃)δ3.75-3.72(m,5H),3.52-3.50(m,2H),3.27-3.17(m,2H),2.89(s,3H),2.27-2.20(m,0.7H),2.06-1.92(m,3.3H),1.69-1.63(m,4.5H),1.55-1.45(m,1.5H),0.91(s,9H),0.08(s,6H)。

ketone ester 63: methyl 3- (4- (N- (2-methoxyethyl) sulfamoyl) cyclohexyl) -3-oxopropanoate,¹H NMR(300MHz,CDCl₃)δ4.55(br s,1H),3.75(s,3H),3.52-3.50(m,4H),3.38(s,3H),3.31-3.30(m,2H),2.99-2.84(m,1H),2.75(br s,0.4H),2.56-2.48(m,0.6H),2.33-2.24(m,2H),2.15-2.02(m,2H),1.87-1.57(m,3H),1.49-1.38(m,1H)。

ketone ester 64: tert-butyl 3- (4- (3-methoxy-3-oxopropanoyl) -cyclohexanesulfonamido) -2, 2-dimethylpropionate,¹H NMR(300MHz,CDCl₃)δ4.94-4.86(m,1H),3.77(s,1.5H),3.75(s,1.5H),3.53(s,1.4H),3.41(s,0.6H),3.10(d,J＝6.3Hz,2H),2.97-2.88(m,1H),2.56-2.46(m,1H),2.36-2.23(m,2H),2.19-1.97(m,2H),1.88-1.79(m,0.4H),1.70-1.53(m,2H),1.46(s,9H),1.31-1.25(m,0.6H),1.21(s,6H)。

ketoester 65R: ethyl 6- (3-ethoxy-3-oxopropanoyl) tetrahydro-2H-pyran-3-carboxylate, LC-ms (esi): r_T＝2.151min，C₁₃H₂₀O₆Calculated mass of 272.1, found value of M/z 273.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ4.47-3.83(m,6H),3.75-3.54(m,2H),3.49-3.28(m,1H),2.76-2.57(m,1H),2.26-1.99(m,1H),1.93-1.65(m,2H),1.62-1.37(m,1H),1.32-1.04(m,6H)。

Ketoester 65S: ethyl 6- (3-ethoxy-3-oxopropanoyl) tetrahydro-2H-pyran-3-carboxylate, LC-ms (esi): r_T＝1.962min，C₁₃H₂₀O₆Calculated mass of 272.1, found value of M/z 290.2[ M + NH ]₄]⁺。¹H NMR(300MHz,CDCl₃)δ4.50-4.38(m,1H),4.28-4.10(m,4.3H),3.94-3.82(m,1H),3.70-4.46(m,2.7H),2.64-2.51(m,1H),2.32-2.20(m,1H),2.10-2.03(m,0.4H),1.87-1.68(m,2.2H),1.56-1.46(m,0.4H),1.31-1.24(m,6H)。

Ketone ester 66: (trans) -tert-butyl 2- (((tert-butyldiphenylsilyl) oxy) methyl) -4- (3-ethoxy-3-oxopropanoyl) piperidine-1-carboxylate, LC-MS (ESI): r_T＝2.574min，C₃₂H₄₅NO₆Calculated mass of Si 567.3, found value of M/z 468.3[ M + H-Boc [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.15-12.12(m,0.1H),7.63(t,J＝5.6Hz,4H),7.48-7.42(m,6H),5.09-5.03(m,0.2H),4.50-4.29(m,1H),4.17-4.12(m,1H),4.07-4.04(m,2H),3.97-3.86(m,1H),3.73-3.63(m,3.7H),2.82-2.66(m,2H),2.08-2.02(m,0.5H),1.97-1.91(m,0.5H),1.87-1.69(m,1H),1.62-1.49(m,1H),1.39(s,4H),1.33(s,5H),1.27-1.14(m,3H),0.99(s,9H)。

Ketone ester 67: (trans) -methyl 3- (4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -3-oxopropanoate,¹H NMR(300MHz,CD₃OD)δ3.70(s,3H),3.65-3.57(m,1H),3.34-3.29(m,2H),2.51-2.44(m,1H),2.00-1.86(m,4H),1.45-1.27(m,4H),0.90(s,9H),0.08(s,6H)。

ketoester 68: tert-butyl 4- (3-methoxy-3-oxopropanoyl) azepane-1-carboxylate,¹H NMR(400MHz,CDCl₃)δ12.06(s,0.1H),4.96(s,0.1H),3.72(s,3H),3.61-3.38(m,4H),3.34-3.11(m,1.8H),2.60-2.55(m,1H),2.18-1.85(m,3H),1.74-1.51(m,3H),1.44(s,9H)。

ketone ester 69: methyl 3-oxo-3- (1, 4-dioxaspiro [4.5]]Decan-8-yl) propanoate ester,¹H NMR(400MHz,CDCl₃)δ3.95-3.91(m,4H),3.73(s,3H),3.50(s,2H),2.52-2.45(m,1H),1.92-1.87(m,2H),1.82-1.77(m,2H),1.74-1.63(m,2H),1.59-1.53(m,2H)。

ketone ester 70: methyl 3- (4- (azetidin-1-ylsulfonyl) cyclohexyl) -3-oxopropanoate

¹H NMR(400MHz,CDCl₃)δ12.27(s,0.1H),12.06(s,0.1H),5.07(s,0.1H),4.97(s,0.1H),4.00-3.95(m,4H),3.75(s,2H),3.74(s,1H),3.52(s,0.7H),3.50(s,0.7H),2.91-2.70(m,1.5H),2.53-2.44(m,0.5H),2.30-2.21(m,4H),2.11-2.07(m,1H),2.02-1.92(m,1H),1.83-1.73(m,2H),1.64-1.51(m,2H),1.46-1.33(m,1H)。

Ketone ester (b): 71: ethyl 3- (3- ((tert-butoxycarbonyl) amino) -2, 2-dimethylcyclobutyl) -3-oxopropanoate, LC-ms (esi): r_T＝1.662min，C₁₆H₂₇NO₅Calculated mass of 313.2, found M/z 258.0[ M-tBu + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ7.70(s,0.3H),7.10(s,0.7H),4.59(br s,0.5H),4.24-4.15(m,2H),3.86-3.83(m,0.5H),3.38-3.27(m,2H),2.89-2.83(m,0.6H),2.21-2.04(m,1.4H),1.69(brs,1H),1.43-1.38(m,9H),1.30-1.25(m,6H),0.91-0.86(s,3H)。

Ketoester 72: methyl 3- (4- (N- (3-methoxy-3-oxopropyl) sulfamoyl) cyclohexyl) -3-oxopropanoate,¹H NMR(300MHz,CDCl₃)δ12.07(s,0.2H),4.99(s,0.2H),4.91-4.79(m,1H),3.74(s,3H),3.72(s,3H),3.52(s,1.6H),3.40-2.31(m,2H),2.98-2.81(m,1H),2.78-2.71(m,0.4H),2.65-2.60(m,1.6H),2.57-2.46(m,0.5H),2.34-1.94(m,3.5H),1.37-1.36(m,4H)。

dihydropyrimidines having the general formula I:

compound 1: methyl 4- (2-chloro-4-fluorophenyl) -6- (1-methyl-2-oxopiperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 1(600mg, 1.29mmol) was further separated by chiral preparative HPLC (first separation conditions: column: Chiralpak IB 5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 90:10, at 15 mL/min; temperature: 30 ℃; wavelength: 214nm followed by second separation conditions: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 50:50, at 10 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomer compound 1A (10.6mg, 1.8% yield), compound 1C (77.2mg, 13% yield), compound 1B (71.8mg, 12% yield), and compound 1D (117mg, 20% yield).

Compound 1A: LC-MS (ESI): r_T＝3.863min，C₂₁H₂₀ClFN₄O₃Calculated mass of S462.1, M/z found value 462.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝9.256min)。¹H NMR(400MHz,DMSO-d6)δ9.62(d,J＝3.6Hz,0.9H),9.30(s,0.1H),8.02-7.99(m,1.9H),7.94(d,J＝3.2Hz,0.1H),7.42(dd,J＝8.8,2.4Hz,1H),7.39-7.36(m,1H),7.22(td,J＝8.4,2.8Hz,1H),6.03(s,0.1H),5.93(d,J＝4.0Hz,0.9H),4.32-4.22(m,0.1H),4.12-4.04(m,0.9H),3.53(s,2.7H),3.51(s,0.3H),3.32-3.26(m,2H),2.87(s,3H),2.66-2.60(m,1H),2.40-2.32(m,1H),2.06-1.96(m,1H),1.91-1.81(m,1H)。

Compound 1B: LC-MS (ESI): r_T＝3.846min，C₂₁H₂₀ClFN₄O₃Calculated mass of S462.1, M/z found value 462.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝10.048min)。¹H NMR(400MHz,DMSO-d₆)δ9.59(d,J＝3.6Hz,0.9H),9.26(s,0.1H),8.02-8.00(m,1.9H),7.93(d,J＝3.2Hz,0.1H),7.43(dd,J＝8.8,2.4Hz,1H),7.40-7.37(m,1H),7.22(td,J＝8.4,2.4Hz,1H),6.01(s,0.1H),5.93(d,J＝3.6Hz,0.9H),4.30-4.25(m,0.1H),4.12-4.01(m,0.9H),3.52(s,2.7H),3.51(s,0.3H),3.39-3.36(m,2H),2.87(s,3H),2.47-2.40(m,1H),2.22(dd,J＝16.8,4.0Hz,1H),2.17-2.06(m,1H),2.00-1.94(m,1H)。

Compound 2: methyl 6- (1-acetylpiperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 2(190mg, 0.400mmol) was further separated by chiral preparative HPLC (column: Chiralpak OD-H5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm), followed by preparative HPLC (column: xbridge C185 μm19 ℃; mobile phase a: water (0.1% hydrochloric acid), mobile phase B: acetonitrile, flow rate: 20mL/min, gradient: 30% -50% (% B)) to give the stereoisomer compound 2A (19.6mg, 16% yield) and compound 2B (19.4mg, 15.4% yield) as yellow solids.

Compound 2B: LC-MS (ESI): r_T＝4.331min，C₂₂H₂₂ClFN₄O₃Calculated mass of S476.1, M/z found value 477.1[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak OD-H5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 80:20 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, 100% ee, R_T＝7.351min)。¹H NMR(400MHz,CD₃OD)δ8.32(d,J＝2.8Hz,1H),8.27(d,J＝3.2Hz,1H),7.58-7.55(m,1H),7.40(dd,J＝8.0,2.4Hz,1H),7.22(td,J＝8.4,2.8Hz,1H),6.33(s,1H),4.74(d,J＝13.2Hz,1H),4.21-4.14(m,2H),3.69(s,3H),3.31-3.24(m,1H),2.83-2.74(m,1H),2.23(s,1.5H),2.21(s,1.5H),2.15-1.85(m,4H)。

Compound 3: methyl 4- (2-chloro-4-fluorophenyl) -6- (2-oxopiperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydro-pyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 3(250mg, 0.56mmol) was further separated by chiral preparative HPLC (separation conditions: first separation (column: Chiralpak ID5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 70:30, at 12 mL/min; temperature: 30 ℃; wavelength: 214nm), followed by second separation: method a (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 50:50, at 8 mL/min; temperature: 30 ℃; wavelength: 214nm) and method B (column: Chiralpak IF5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.3, at 10 mL/min; temperature: 30 ℃; wavelength: 214nm)) to give the stereoisomeric compound 3A (20.5mg, 8% yield), compound 3B (41.1mg, 3.1%, compound 3 (3.3 mg, and compound (3.9 mg, 3 mg), 11% yield).

Compound 3A: LC-MS (ESI): r_T＝3.647min，C₂₀H₁₈ClFN₄O₃Calculated mass of S448.1, M/z found value 448.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝10.135min)。¹H NMR(400MHz,CDCl₃)δ7.84(d,J＝3.2Hz,1H),7.51(d,J＝2.8Hz,1H),7.50-7.49(m,1H),7.28-7.27(m,1H),7.16-7.13(m,1H),6.96(td,J＝8.0,2.4Hz,1H),6.07(d,J＝2.8Hz,1H),5.81(br s,1H),4.37-4.32(m,1H),3.62(s,3H),3.51-3.48(m,0.4H),3.43-3.39(m,1.6H),3.00-2.93(m,1H),2.65-2.59(m,1H),2.14-2.07(m,1H),1.96-1.91(m,1H)。

Compound 3C: LC-MS (ESI): r_T＝3.643min，C₂₀H₁₈ClFN₄O₃Calculated mass of S448.1, M/z found value 448.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝10.646min)。¹H NMR(400MHz,CDCl₃)δ7.83(d,J＝3.2Hz,1H),7.52(d,J＝2.8Hz,1H),7.46(br s,1H),7.29-7.27(m,1H),7.16(dd,J＝8.4,2.8Hz,1H),6.95(td,J＝8.4,2.4Hz,1H),6.11(d,J＝2.8Hz,1H),5.80(br s,1H),4.31-4.29(m,1H),3.61(s,3H),3.53-3.50(m,2H),2.87-2.80(m,1H),2.46-2.40(m,1H),2.29-2.24(m,1H),2.13-2.09(m,1H)。

Compound 4: methyl 4- (2-chloro-3-fluorophenyl) -6- (1-methyl-2-oxopiperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 4(0.51g, 1.1mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 20 mL/min; temperature: 30 ℃; wavelength: 230nm and column: Chiralpak IB 5 μm 20: 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomers compound 4A (107mg, 83% yield), compound 4B (54mg, 42% yield), compound 4C (58mg, 45% yield) and compound 4D (109mg, 85% yield).

Compound 4B: LC-MS (ESI): r_T＝3.975min，C₂₁H₂₀ClFN₄O₃Calculated mass of S462.1, M/z found value 462.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IB 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; chiral HPLC (column: Chiralpak IB 5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA: 90:10: 0.2; temperature: 30 ℃; wavelength: 230 nm; chiral HPLC_T＝11.927min)。¹H NMR(400MHz,DMSO-d₆)δ9.66(br s,0.9H),9.32(br s,0.1H),8.03-8.00(m,1.9H),7.94(d,J＝3.6Hz,0.1H),7.42-7.32(m,2H),7.25-7.21(m,0.9H),7.18-7.14(m,0.1H),6.09(s,0.1H),5.98(s,0.9H),4.33-4.23(m,0.1H),4.14-4.04(m,0.9H),3.53(s,2.7H),3.51(s,0.3H),3.32-3.28(m,2H),2.87(s,3H),2.66-2.60(m,1H),2.39-2.34(m,1),2.07-1.97(m,1H),1.90-1.81(m,1H)。

Compound 8: methyl 4- (2-chloro-3-fluorophenyl) -6- (1- ((1-methoxy-2-methyl-1-oxoprop-2-yl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝4.436min，C₂₅H₂₈ClFN₄O₆S₂Calculated mass of 598.1, found value of M/z 598.9[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; temperature: R-_T6.361min and 10.935 min).¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝3.6Hz,0.8H),9.39(s,0.2H),8.00(s,1.8H),7.93(d,J＝2.8Hz,0.2H),7.40-7.31(m,2H),7.22-7.15(m,1H),6.06(s,0.2H),5.97(d,J＝3.6Hz,0.8H),4.08-3.98(m,0.2H),3.80-3.74(m,5.8H),3.53(s,3H),3.06-2.98(m,2H),2.08-2.00(m,1H),1.87-1.85(m,2H),1.72-1.61(m,7H)。

Compound 37: methyl 4- (2-chloro-3-fluorophenyl) -6- (3- (methylsulfonyl) -3-azabicyclo [3.2.1] oct-8-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 37(30mg, 0.060mmol) was further separated by chiral preparative HPLC (column: Chiralpak IF5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 50:50, at 8 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomers compound 37A (3.1mg, 10% yield) and compound 37B (3.0mg, 10% yield) as yellow solids.

Compound 37B: LC-MS (ESI): r_T＝3.099min，C₂₃H₂₄ClFN₄O₄S₂Calculated mass of 538.1, M/z found value 538.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝14.052min)。¹H NMR(400MHz,CDCl₃)δ8.35(s,0.2H),7.84(d,J＝3.2Hz,0.7H),7.82(d,J＝3.2Hz,0.3H),7.52(d,J＝3.2Hz,1.5H),7.46(d,J＝2.8Hz,0.3H),7.24-7.20(m,0.8H),7.18-7.15(m,0.2H),7.11-7.08(m,1.8H),7.05-7.00(m,0.2H),6.28(s,0.3H),6.14(d,J＝2.8Hz,0.7H),3.86(s,0.2H),3.74-3.65(m,2.8H),3.60(s,2.1H),3.59(s,0.9H),3.18-3.12(m,1H),3.08-3.04(m,1H),2.82(s,3H),2.68(br s,0.7H),2.63-2.61(m,0.6H),2.55(br s,0.7H),2.14-2.01(m,2.5H),1.87-1.77(m,1.5H)。

Compound 38: 4- (2-chloro-4-fluoro-phenyl) -6- (8-methanesulfonyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (mixture of 2 stereoisomers)

Compound 38(100mg, 0.186mmol) was further separated by chiral preparative HPLC (column: Chiralpak IA5 μm20 × 250mm, mobile phase: Hex: EtOH ═ 85:15, at 20mL/min, temperature: 30 ℃, wavelength: 230nm) to give the stereoisomer compound 38A (19.7mg, 20% yield) and compound 38B (19.4mg, 19% yield).

Compound 38B: LC-MS (ESI): r_T＝3.995min，C₂₃H₂₄ClFN₄O₄S₂Calculated mass of 538.1, M/z found value 538.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝14.787min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.6Hz,0.8H),9.05(s,0.2H),8.00-7.98(m,1.8H),7.93(d,J＝2.8Hz,0.2H),7.44-7.40(m,1H),7.34-7.28(m,1H),7.23-7.16(m,1H),6.01(s,0.2H),5.92(d,J＝3.6Hz,0.8H),4.49-4.40(m,0.2H),4.27-4.15(m,2.8H),3.54(s,3H),2.99(s,3H),2.20-1.94(m,4H),1.85-1.66(m,3.2H),1.52-1.49(m,0.8H)。

Compound 39: 4- (2-chloro-3-fluoro-phenyl) -6- (8-methanesulfonyl-8-aza-bicyclo [3.2.1] oct-3-yl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (mixture of 2 stereoisomers)

Compound 39(74mg, 0.137mmol) was further separated by chiral preparative HPLC (column: Chiralpak IA5 μm20 × 250mm, mobile phase: Hex: IPA: DEA ═ 90:10:0.3 at 20mL/min, temperature: 30 ℃, wavelength: 230nm) to give the stereoisomers compound 39A (15.8mg, 21% yield) and compound 39B (18.4mg, 25% yield).

Compound 39B: LC-MS (ESI): r_T＝3.899min，C₂₃H₂₄ClFN₄O₄S₂Calculated mass of 538.1, M/z found value 538.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: IPA: DEA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝17.400min)；¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝3.6Hz,0.8H),9.12(s,0.2H),8.00-7.94(m,2H),7.40-7.29(m,2H),7.19-7.13(m,1H),6.06(s,0.2H),5.97(d,J＝3.2Hz,0.8H),4.50-4.41(m,0.2H),4.27-4.21(m,2.8H),3.54(s,3H),3.00(s,3H),2.21-1.95(m,4H),1.87-1.67(m,3.2H),1.53-1.50(m,0.8H)。

Compound 47: ethyl 4- (2-chloro-4-fluorophenyl) -6-cyclohexyl-2- (thiazol-2-yl) -1, 4-dihydro-pyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 47(150mg, 0.33mmol) was further separated by chiral preparative HPLC (column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: IPA: DEA ═ 98:2:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomer compound 47A (31.4mg, 21% yield) and compound 47B (32.1mg, 21% yield) as yellow solids.

Compound 47A: LC-MS (ESI): r_T＝4.304min，C₂₂H₂₃ClFN₃O₂Calculated mass of S447.1, m/zFound value 448.1[ M + H]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: IPA: DEA: 95:5:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝5.332min)。¹H NMR(400MHz,DMSO-d₆)δ9.40(d,J＝2.8Hz,0.5H),8.79(s,0.5H),7.99-7.94(m,2H),7.44-7.41(m,1H),7.36-7.32(m,1H),7.24-7.19(m,1H),6.02(s,0.5H),5.90(d,J＝3.2Hz,0.5H),3.99-3.92(m,2H),3.87-3.81(m,0.5H),3.61(br s,0.5H),1.82-1.56(m,7H),1.33-1.23(m,3H),1.09-1.03(m,3H)。

Compound 48: methyl 4- (2-chloro-4-fluorophenyl) -6- (tetrahydro-2H-pyran-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 48(300mg, 0.690mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE5 μm20 × 250mm, mobile phase: Hex: EtOH ═ 85:15, at 11mL/min, temperature: 30 ℃, wavelength: 214nm) to give the stereoisomers compound 48A (7.7mg, 3% yield), compound 48B (10.4mg, 3% yield), compound 48C (87.5mg, 29% yield) and compound 48D (88mg, 29% yield) as yellow solids.

Compound 48A: LC-MS (ESI): r_T＝4.273min，C₂₀H₁₉ClFN₃O₃Calculated mass of S435.1, found value of M/z 435.9[ M + H [ ]]⁺. Chiral HPLC (Chiralpak IC5 μm4.6 × 250mm, mobile phase: Hex: EtOH: DEA: 90:10:0.2 at 1.0mL/min, temperature: 30 ℃, wavelength: 230nm, R_T＝7.397min)；¹H NMR(400MHz,DMSO-d₆)δ9.87(s,0.4H),9.48(d,J＝3.6Hz,0.6H),8.00-7.98(m,1.5H),7.93(d,J＝3.6Hz,0.5H),7.45-7.40(m,1.4H),7.35-7.31(m,0.6H),7.22-7.14(m,1H),6.02(s,0.4H),5.91(d,J＝3.6Hz,0.6H),4.17(dd,J＝11.6,8.0Hz,0.5H),3.94-3.79(m,3H),3.68-3.59(m,1H),3.53(s,1.8H),3.50(s,1.2H),3.36-3.34(m,0.5H),1.99-1.86(m,1.5H),1.73-1.53(m,2.5H)。

Compound 48D: LC-MS (ESI): r_T＝4.124min，C₂₀H₁₉ClFN₃O₃Calculated mass of S435.1, found value of M/z 435.9[ M + H [ ]]⁺. Chiral HPLC (Chiralpak IE5 μm4.6 x 250mm,mobile phase: hex EtOH 80:20 at 1.0mL/min, temperature: 30 ℃, wavelength: 230nm, R_T＝9.849min)；¹H NMR(400MHz,DMSO-d₆)δ9.77(s,0.4H),9.50(d,J＝3.6Hz,0.6H),8.01-7.98(m,1.5H),7.92(d,J＝3.2Hz,0.5H),7.44-7.40(m,1H),7.38-7.33(m,1H),7.24-7.19(m,1H),6.04(s,0.4H),5.91(d,J＝3.6Hz,0.6H),4.03(dd,J＝10.0,3.6Hz,0.4H),3.92-3.72(m,3H),3.64-3.56(m,1H),3.53(s,1.8H),3.49(s,1.2H),3.37-3.34(m,0.6H),2.09-1.61(m,4H)。

Compound 49: methyl 4- (2-chloro-4-fluorophenyl) -6- (tetrahydro-2H-pyran-2-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 49(450mg, 1.03mmol) was further separated by chiral preparative HPLC (column: Chiralpak IF5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 15 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the stereoisomers compound 49A (100mg, 22% yield, mixture of the two stereoisomers) and compound 49B (41.0mg, 10% yield), compound 49C (54.0mg, 12% yield).

Compound 49C: LC-MS (ESI): r_T＝4.296min，C₂₀H₁₉ClFN₃O₃Calculated mass of S435.1, found value of M/z 435.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝8.252min)。¹H NMR(400MHz,DMSO-d₆)δ8.91(s,1H),8.00(d,J＝3.2Hz,1H),7.96(d,J＝3.2Hz,1H),7.43(dd,J＝8.8,3.2Hz,1H),7.32(dd,J＝8.8,6.2Hz,1H),7.23-7.18(m,1H),6.06(s,1H),5.15(d,J＝8.0Hz,1H),4.13(d,J＝10.0Hz,1H),3.63-3.57(m,1H),3.53(s,3H),2.01-1.99(m,1H),1.94-1.88(m,1H),1.70-1.56(m,4H)。

Compound 51: methyl 4- (2-chloro-4-fluorophenyl) -6- (tetrahydro-2H-pyran-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 51(150mg, 0.35mmol) was further separated by chiral preparative HPLC (column: Chiralpak IE5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomer compound 51A (45.6mg, 30% yield) and compound 51B (59.7mg, 40% yield) as yellow solids.

Compound 51B: LC-MS (ESI): r_T＝3.957min，C₂₀H₁₉ClFN₃O₃Calculated mass of S435.1, found value of M/z 435.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝9.116min)。¹H NMR(400MHz,DMSO-d₆)δ9.48(d,J＝3.6Hz,0.8H),8.95(s,0.2H),8.00(s,1.8H),7.94(d,J＝3.6Hz,0.2H),7.45-7.41(m,1H),7.37-7.32(m,1H),7.23-7.17(m,1H),6.02(s,0.2H),5.92(d,J＝3.2Hz,0.8H),4.13-4.06(m,0.2H),4.02-3.82(m,2.8H),3.53(s,2.1H),3.52(s,0.9H),3.39(q,J＝10.4Hz,2H),2.10-2.00(m,1H),1.98-1.87(m,1H),1.72(d,J＝11.2Hz,0.2H),1.63-1.57(m,1H),1.42(d,J＝13.2Hz,0.8H)。

Compound 50: 4- (2-chloro-3-fluoro-phenyl) -6- (tetrahydro-pyran-4-yl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (mixture of 2 stereoisomers)

Compound 50(150mg, 0.35mmol) was further separated by chiral preparative HPLC (column: Chiralpak IE5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomers compound 50A (54.8mg, 37% yield) and compound 50B (52.1mg, 35% yield) as yellow solids.

Compound 50B: LC-MS (ESI): r_T＝3.715min，C₂₀H₁₉ClFN₃O₃Calculated mass of S435.1, found value of M/z 435.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝9.537min)。¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝3.6Hz,0.8H),9.00(s,0.2H),8.01(s,1.7H),7.94(d,J＝3.2Hz,0.3H),7.40-7.29(m,2H),7.21-7.16(m,1H),6.07(s,0.3H),5.97(d,J＝3.6Hz,0.7H),4.14-4.08(m,0.2H),4.01-3.84(m,2.8H),3.52(s,3H),3.46-3.37(m,2H),2.10-2.00(m,1H),1.98-1.88(m,1H),1.72(d,J＝13.2Hz,0.2H),1.59(t,J＝13.4Hz,1H),1.41(d,J＝15.6Hz,0.8H)。

Compound 69: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (methylsulfonyl) pyrrolidin-2-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 69 was further purified by preparative HPLC (column: Gilson X-bridge C18(5 μm 19X 150 mm); mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min gradient: 40% -70% (% B)) to give two mixtures compound 69X (60mg, 6% yield, mixture of 2 stereoisomers) and compound 69Y (60mg, 6% yield, mixture of 2 stereoisomers) as a yellow solid.

Compound 69Y (60mg, 0.12mmol) was further separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.3 at 12 mL/min; temperature: 30 ℃ C; wavelength: 214nm) to give the stereoisomer compound 69C (11.0mg, 18% yield) and compound 69D (9.6mg, 16% yield) as yellow solids.

Compound 69C: LC-MS (ESI): r_T＝3.901min，C₂₀H₂₀ClFN₄O₄S₂Calculated mass of 498.1, M/z found value 498.9[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 1 ℃; temperature: 30 ℃; wavelength: 230 nm; time: R;)_T＝8.394min)；¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝3.6Hz,0.3H),8.89(s,0.6H),7.99(dd,J＝20.4,2.8Hz,2H),7.58(t,J＝6.4Hz,0.3H),7.51(dd,J＝8.2,6.6Hz,0.7H),7.43(dd,J＝8.8,2.4Hz,1H),7.10(td,J＝8.4,2.0Hz,1H),6.00(s,0.7H),5.87(d,J＝3.6Hz,0.3H),5.75-5.72(m,0.3H),5.44(t,J＝7.2Hz,0.7H),3.62-3.50(m,5H),3.12(s,2H),2.95(s,1H),2.67-2.60(m,1H),2.30-2.25(m,0.2H),2.19-2.10(m,0.3H),2.00-1.77(m,2.5H)。

Compound 70: methyl 4- (2-chloro-4-fluorophenyl) -6- (tetrahydrofuran-2-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 70(300mg, 0.71mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 80:20 at 10 ml/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomer compound 70C (25mg, 8.3% yield), compound 70D (26mg, 8.6% yield) and a mixture of compound 70A and compound 70B (120 mg). The mixture (120mg) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak ID5 μm20 × 250 mm; mobile phase: Hex: IPA: 80:20 at 12 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the stereoisomer compound 70A (14mg, 4.6% yield) and compound 70B (20mg, 6.6% yield).

Compound 70D: LC-MS (ESI): r_T＝3.558min，C₁₉H₁₇ClFN₃O₃Calculated mass of S421.1, M/z found mass 421.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: IPA 80:20 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝11.261min)。¹H NMR(400MHz,DMSO-d₆)δ8.97(s,1H),8.01(d,J＝2.8Hz,1H),7.96(d,J＝2.8Hz,1H),7.43(dd,J＝8.8,2.4Hz,1H),7.35-7.32(m,1H),7.20(td,J＝8.4,2.0Hz,1H),6.06(s,1H),5.40(t,J＝7.2Hz,1H),4.12-4.09(m,1H),3.95-3.91(m,1H),3.53(s,3H),2.61-2.55(m,1H),2.02-1.88(m,3H)。

Compound 74: methyl 4- (2-chloro-3-fluorophenyl) -6- (tetrahydrofuran-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 74(300mg, 0.710mmol) was further separated by chiral preparative HPLC (first separation conditions (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.3 at 8 mL/min; temperature: 30 ℃; wavelength: 230nm) followed by second separation conditions: method a (column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.2 at 12 mL/min; temperature: 30 ℃; wavelength: 214nm) and method B (column: Chiralpak ie5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.3 at 12 mL/min; temperature: 30 ℃; wavelength: 214nm)) to give the stereoisomeric compound 74A as a yellow solid (27mg, compound B) at 9mg, compound B at 9% yield (74mg, 9mg, compound B) at 9% yield, 9mg, compound C (74mg, 26% yield, 26% and method B (74mg, 8% yield).

Compound 74A: LC-MS (ESI): r_T＝3.603min，C₁₉H₁₇ClFN₃O₃Calculated mass of S421.1, M/z found value 422.1[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 1 ℃; wavelength: 230 nm; time: R;)_T＝8.120min)。¹H NMR(400MHz,DMSO-d₆)δ9.67(d,J＝3.6Hz,0.6H),8.89(s,0.4H),8.01-7.99(m,1.6H),7.95-7.94(m,0.4H),7.40-7.30(m,2H),7.24-7.20(m,1H),6.08(s,0.4H),5.96(d,J＝3.6Hz,0.6H),4.70-4.65(m,0.4H),4.41-4.33(m,0.6H),4.17-4.13(m,0.5H),4.07-4.04(m,0.5H),3.96-3.90(m,1.3H),3.87-3.82(m,0.7H),3.74-3.68(m,0.3H),3.66-3.62(m,0.7H),3.53-3.51(m,3H)2.37-2.29(m,1H),2.14-2.05(m,1H)。

Compound 74C: LC-MS (ESI): r_T＝3.600min，C₁₉H₁₇ClFN₃O₃Calculated mass of S421.1, M/z found value 422.1[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 1 ℃; wavelength: 230 nm; time: R;)_T＝10.731min)。¹H NMR(400MHz,DMSO-d₆)δ9.67(s,0.6H),8.88(s,0.4H),8.01(s,1.8H),7.95(s,0.2H),7.41-7.32(m,2H),7.25-7.22(m,1H),6.08(s,0.4H),5.96(s,0.6H),4.71-4.65(m,0.3H),4.42-4.33(m,0.6H),4.16-3.81(m,2.7H),3.73-3.57(m,1.4H),3.53(s,3H),2.35-2.30(m,1H),2.14-2.04(m,1H)。

Compound 74D: LC-MS (ESI): r_T＝3.704min，C₁₉H₁₇ClFN₃O₃Calculated mass of S421.1, M/z found value 421.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 1 ℃; wavelength: 230 nm; time: R;)_T＝14.190min)。¹H NMR(400MHz,DMSO-d₆)δ9.63(s,0.6H),8.98(s,0.4H),8.01(s,1.8H),7.95(s,0.2H),7.38-7.15(m,3H),6.08(s,0.4H),6.00(s,0.6H),4.67-4.61(m,0.3H),4.39-4.20(m,1H),4.07-4.03(m,1H),3.95-3.66(m,2.7H),3.53(s,3H),2.22-2.16(m,1H),1.98-1.90(m,1H)。

Compound 75: methyl 4- (2-chloro-3-fluorophenyl) -6- (5-oxopyrrolidin-2-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 75(400mg, 0.920mmol) was further separated by chiral preparative HPLC (column: ChiralpakIB, Hex: EtOH ═ 85: 15; 13 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the product, which was then purified by C18 (acetonitrile: water ═ 5% to 100%) to give the stereoisomer compound 75A (66mg, 17% yield), compound 75B (20mg, 5% yield), compound 75C (130mg, 33% yield) and compound 75D (25mg, 6% yield) as a yellow solid.

Compound 75A: LC-MS (ESI): r_T＝1.842min，C₁₉H₁₆ClFN₄O₃Calculated mass of S434.1, found value of M/z 435.1[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IB 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝8.614min)。¹H NMR(400MHz,CDCl₃)δ8.56(s,0.2H),7.81(d,J＝2.8Hz,0.8H),7.71(d,J＝2.8Hz,0.3H),7.49(s,0.7H),7.46(d,J＝3.2Hz,1H),7.42(d,J＝2.8Hz,0.2H),7.24-7.17(m,0.9H),7.14-7.03(m,1.9H),6.22(s,0.3H),6.14(d,J＝7.2Hz,1.7H),5.80(t,J＝8.4Hz,0.3H),5.55(d,J＝6.8Hz,0.7H),3.62(d,J＝4.8Hz,3H),2.90-2.80(m,0.2H),2.76-2.67(m,0.8H),2.53-2.25(m,2.8H),2.06-1.96(m,0.2H)。

Compound 75D: LC-MS (ESI): r_T＝2.560min min，C₁₉H₁₆ClFN₄O₃Calculated mass of S434.1, found value of M/z 435.1[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IB 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝15.809min)。¹H NMR(400MHz,CDCl₃)δ8.61(s,0.3H),7.83(d,J＝2.4Hz,0.7H),7.81(s,0.3H),7.52(s,1.4H),7.45(s,0.3H),7.24-7.16(m,1H),7.13-7.04(m,2H),6.27(s,0.3H),6.12(s,0.7H),5.83-5.72(m,1.3H),5.59(d,J＝7.2Hz,0.7H),3.63(s,2H),3.60(s,1H),2.94-2.84(m,0.3H),2.80-2.71(m,0.7H),2.65-2.37(m,2.8H),2.21-2.10(m,0.2H)。

Compound 90: methyl 4- (2-chloro-4-fluorophenyl) -6-cyclopropyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 90(140mg, 0.358mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: IPA 95:5 at 11 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the stereoisomers compound 90A (46.2mg, 33% yield) and compound 90B (46.6mg, 33% yield) as yellow solids.

Compound 90A: LC-MS (ESI): r_T＝3.429min，C₁₈H₁₅ClFN₃O₂Calculated mass of S391.1, M/z found 391.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: IPA 95:5 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝7.842min)。¹H NMR(400MHz,DMSO-d₆)δ9.48(d,J＝3.2Hz,1H),7.99-7.97(m,2H),7.40(dd,J＝8.8,2.8Hz,1H),7.33(dd,J＝8.8,J＝6.4Hz,1H),7.21(td,J＝8.4,2.4Hz,1H),5.91(d,J＝3.2Hz,1H),3.54(s,3H),3.22-3.18(m,1H),1.23-1.18(m,1H),1.01-1.00(m,1H),0.87-0.83(m,1H),0.81-0.77(m,1H)。

Conversion of a primary dihydropyrimidine having the general formula I (from table 1):

a primary dihydropyrimidine having the general formula I:

compound 5: 6- (1-tert-Butoxycarbonyl-piperidin-4-yl) -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (mixture of 2 stereoisomers)

Compound 5(7.00g, 13.1mmol) was further separated by chiral preparative HPLC (column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 23 mL/min; temperature: 30 ℃ c; wavelength: 230nm) to give the stereoisomers compound 5A (2.44g, 35% yield) and compound 5B (1.56g, 22% yield).

Compound 5A: SFC (analytical conditions: column: Chiralpak IG; mobile phase: CO)₂MeOH 70:30 at 1.0 mL/min; temperature: 41 ℃; wavelength: 230nm, R_T＝2.59min)。¹H NMR(400MHz,CDCl₃)δ8.12(s,0.5H),7.81(t,J＝3.2Hz,1H),7.48(d,J＝3.2Hz,0.6H),7.44(d,J＝3.6Hz,0.4H),7.41(br s,0.5H),7.30-7.27(m,1H),7.15-7.11(m,1H),6.96-6.88(m,1H),6.19(s,0.4H),6.06(d,J＝2.8Hz,0.6H),4.35-4.21(m,2H),4.20-4.12(m,0.4H),3.96-3.89(m,0.6H),3.60(s,2.4H),3.59(s,0.6H),2.94-2.78(m,2H),2.10-1.79(m,3H),1.74-1.63(m,1H),1.50(s,9H)。

Compound 5B: LC-MS (ESI): r_T＝2.191min，C₂₅H₂₈ClFN₄O₄Calculated mass of S534.2M/z found value 534.9[ M + H]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.154min)。¹H NMR(400MHz,CDCl₃)δ8.12(s,0.5H),7.82(t,J＝3.2Hz,1H),7.47(dd,J＝20.4,3.0Hz,1H),7.41(br s,0.5H),7.30-7.28(m,1H),7.15-7.11(m,1H),6.96-6.88(m,1H),6.19(s,0.4H),6.06(d,J＝2.4Hz,0.6H),4.36-4.22(m,2H),4.20-4.12(m,0.4H),3.96-3.88(m,0.6H),3.60(s,2.4H),3.59(s,0.6H),2.95-2.79(m,2H),2.09-1.74(m,3H),1.63-1.58(m,1H),1.50(s,9H)。

Compound 10: methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 10(1.02g, 1.91mmol) was further separated by chiral preparative HPLC (column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: IPA ═ 95:5, at 20 mL/min; temperature: 30 ℃ c; wavelength: 230nm) to give the stereoisomer compound 10A (420mg, 42% yield) and compound 10B (384mg, 38% yield).

Compound 10A: LC-MS (ESI): r_T＝1.68min，C₂₅H₂₈ClFN₄O₄Calculated mass of S534.2M/z found 535.5[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: IPA: DEA: 95:5:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝10.336min)。¹H NMR(400MHz,CDCl₃)δ7.84(d,J＝2.8Hz,1H),7.50(d,J＝2.4Hz,1H),7.21-7.12(m,2H),7.06(t,J＝8.4Hz,1H),6.20(s,1H),4.28(br s,2H),4.06(br s,1H),3.60(s,3H),2.92-2.82(m,2H),1.89-1.74(m,4H),1.50(s,9H)。

Compound 12: methyl 4- (2-bromo-4-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝1.61min，C₂₅H₂₈BrFN₄O₄Calculated mass of S578.1M/z found value 579.4[ M + H [ ]]⁺。¹HNMR(400MHz,DMSO-d₆)δ9.46(d,J＝3.2Hz,0.8H),9.10(s,0.2H),7.99-7.97(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.58-7.54(m,1H),7.37-7.21(m,2H),5.98(s,0.3H),5.89(d,J＝3.2Hz,0.7H),4.18-3.98(m,2H),3.83-3.75(m,1H),3.53(s,2.1H),3.51(s,0.9H),2.82-2.71(m,2H),1.99-1.62(m,4H),1.44(s,9H)。

Compound 13: 6- (1-tert-Butoxycarbonyl-piperidin-4-yl) -4- (2-chloro-3-fluoro-phenyl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester

LC-MS(ESI)：R_T＝2.793min，C₂₅H₂₈ClFN₄O₄Calculated mass of S, M/z found value 534.7[ M + H]⁺。¹HNMR(400MHz,CDCl₃)δ8.22(s,1H),7.85-7.83(m,1H),7.54(d,J＝2.8Hz,0.2H),7.49(d,J＝3.6Hz,0.8H),7.35-7.29(m,1H),7.16-7.05(m,2H),5.78(s,0.8H),5.60(d,J＝2.8Hz,0.2H),4.29(br s,2H),4.15-4.08(m,1H),3.67(s,2.4H),3.65(s,0.6H),2.91-2.80(m,2H),1.90-1.82(m,2H),1.73-1.65(m,1H),1.59-1.54(m,1H),1.50(s,9H)。

Compound 14: methyl 6- (trans-4- ((tert-butoxycarbonyl) amino) cyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

¹H NMR(400MHz,DMSO-d₆)δ9.46(d,J＝3.2Hz,0.6H),9.07(s,0.4H),8.00-7.99(m,1.6H),7.93(d,J＝3.2Hz,0.4H),7.44-7.40(m,1H),7.36-7.29(m,1H),7.24-7.18(m,1H),6.82-6.75(m,1H),6.00(s,0.4H),5.90(d,J＝3.6Hz,0.6H),3.84-3.76(m,0.4H),3.60-3.54(m,0.6H),3.51(s,1.8H),3.50(s,1.2H),3.29-3.08(m,1H),1.94-1.73(m,6H),1.40(s,9H),1.30-1.18(m,2H)。

Compound 15: methyl 6- (cis-4- ((tert-butoxycarbonyl) amino) cyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.371min，C₂₆H₃₀ClFN₄O₄Calculated mass of S548.2, M/z found value 548.8[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.47-9.44(m,0.3H),9.25(s,0.7H),8.02-8.00(m,1.3H),7.95(d,J＝3.2Hz,0.7H),7.43(dd,J＝8.8,2.8Hz,1H),7.32(dd,J＝8.4,6.0Hz,1H),7.21(td,J＝8.4,2.4Hz,1H),7.17-7.15(m,0.3H),6.81-6.75(m,0.7H),6.01(s,0.7H),5.90(t,J＝4.0Hz,0.3H),3.90-3.85(m,1H),3.51(s,0.9H),3.50(s,2.1H),3.30-3.06(m,1H),1.88-1.60(m,8H),1.45(s,9H)。

Compound 16: methyl 4- (2-chloro-3-fluorophenyl) -6- (trans-4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 16(300mg, 0.08mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.2 at 12 mL/min; temperature: 30 ℃ c; wavelength: 214nm) to give the stereoisomers compound 16X (90mg, 30% yield) and compound 16Y (180mg, 60% yield) as yellow solids.

Compound 16X: LC-MS (ESI): r_T＝4.874min，C₂₃H₂₃ClFN₃O₄Calculated mass of S491.1, M/z found value 491.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral HPLC (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 90:10: 0.2; temperature: 30 ℃; wavelength: 230 nm; R_T＝10.425min)。¹H NMR(400MHz,DMSO-d₆) δ 9.47(d, J ═ 3.2Hz,0.6H),8.95(s,0.4H),7.99-7.98(m,1.6H),7.93(d, J ═ 3.2Hz,0.4H),7.39-7.28(m,2H),7.20-7.15(m,1H),6.06(s,0.4H),5.96(d, J ═ 3.6Hz,0.6H),3.86-3.78(m,0.4H),3.62-3.61(m,3H),3.59-3.54(m,0.6H),3.52-3.51(m,3H),2.35-2.31(m,0.6H),2.08-1.96(m,2H), 1.91-1.63 (m, 1.79(m, 1.76H), 1.48-1.48H (m, 1H). (0.4H overlap in DMSO solvent)

Compound 18: methyl 4- (2-chloro-4-fluorophenyl) -6-trans-4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 18(459mg, 0.93mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 80:20 at 13 mL/min; temperature: 30 ℃ c; wavelength: 230nm) to give the stereoisomers compound 18X (194mg, 85% yield) and compound 18Y (172mg, 75% yield).

Compound 18X: LC-MS (ESI): r_T＝4.176min，C₂₃H₂₃ClFN₃O₄Calculated mass of S491.1, M/z found value 491.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 80:20 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.660min)。¹H NMR(400MHz,DMSO-d₆) δ 9.41(s,0.6H),8.92(s,0.4H),7.99(s,1.6H),7.93(s,0.4H),7.45-7.40(m,1H),7.38-7.31(m,1H),7.23-7.18(m,1H),6.01(s,0.4H),5.92(s,0.6H),3.87-3.78(m,0.4H),3.62(s,3H),3.58-3.56(m,0.6H),3.53-3.52(m,3H),2.37-2.30(m,0.6H),2.08-1.88(m,3H),1.81-1.61(m,3H),1.47-1.36(m, 2H). (0.4H overlap in DMSO solvent)

Compound 20: ethyl 4- (2-chloro-4-fluorophenyl) -6- (trans-4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of two stereoisomers)

Compound 20(300mg, 0.59mmol) was further separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 80:20 at 20 mL/min; temperature: 30 ℃; wavelength: 254nm) to give the stereoisomers compound 20X (108mg, 36% yield) and compound 20Y (103mg, 34% yield) as yellow solids.

Compound 20X: LC-MS (ESI): r_T＝3.193min，C₂₄H₂₅ClFN₃O₄Calculated mass of S505.1M/z found 506.1[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 80:20 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, 100% ee, R_T＝6.130min)。¹H NMR(400MHz,CDCl₃)δ8.09(s,0.6H),7.82(t,J＝3.6Hz,1H),7.49(d,J＝3.2Hz,0.4H),7.45(d,J＝3.6Hz,0.5H),7.33-7.28(m,1.5H),7.14-7.11(m,1H),6.96-6.88(m,1H),6.20(s,0.6H),6.07(d,J＝2.8Hz,0.4H),4.06(q,J＝6.8Hz,2H),4.02-3.96(m,0.5H),3.79-3.72(m,0.5H),3.70(s,3H),2.45-2.38(m,1H),2.21-1.91(m,4H),1.80-1.63(m,3H),1.55-1.47(m,1H),1.14(t,J＝7.2Hz,3H)。

Compound 22: ethyl 4- (2-chloro-3-fluorophenyl) -6- (trans-4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 22(290mg, 0.574mmol) was further separated by SFC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: CO)₂50g/min MeOH (DEA) (60: 40: 0.3); co-solvent: MeOH; column temperature: 39.8 ℃; wavelength: 214nm, back pressure: 100 bar) to give the stereoisomers compound 22X (95mg, 22% yield) and compound 22Y (100mg, 34% yield) as a pale yellow solid.

Compound 22Y: LC-MS (ESI): r_T＝3.946min，C₂₄H₂₅ClFN₃O₄Calculated mass of S505.1, found value of M/z 506.1[ M + H [)]⁺. SFC analysis conditions: (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 60:40, at 3 mL/min; co-solvent: MeOH (0.2 DEA); column temperature: 40.2 ℃; wavelength: 214nm, back pressure: 100bar, R_T＝3.92min)。¹H NMR(400MHz,DMSO-d₆)δ9.50(d,J＝3.6Hz,0.6H),8.93(s,0.4H),7.99(d,J＝3.2Hz,1.5H),7.94(d,J＝3.6Hz,0.5H),7.38-7.29(m,2H),7.21-7.17(m,1H),6.08(s,0.5H),5.97(d,J＝3.6Hz,0.5H),4.00-3.93(m,2H),3.87-3.79(m,0.5H),3.62(s,3.5H),2.38-2.31(m,0.7H),2.05-1.98(m,2H),1.91-1.62(m,4.3H),1.45-1.39(m,2H),1.09-1.02(m,3H)。

Compound 24: cis-methyl 4- (2-chloro-3-fluorophenyl) -6- (3- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 24(1.91g) was further purified by silica gel column chromatography (petroleum ether: dichloromethane: ethyl acetate: 10:1) to give two sets of separable stereoisomers, group 1(964mg) and group 2(942 mg). Group 1(964mg) was separated by chiral preparative HPLC (first separation conditions: column: Chiralpak IA5 μ M20 × 250 mm; mobile phase: MeOH: DCM: DEA ═ 60:40:0.3 at 10 mL/min; temperature: 30 ℃; wavelength: 254 nm; second separation: column: Chiralpak IC5 μ M20 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 254nm) followed by further purification by preparative HPLC (column: xbridge C18(5 μ M19 × 150mm), mobile phase a: water (0.1% ammonium hydroxide), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 40% -80% (B)), yielding 24M (26 mg) of the stereoisomeric compound and 24% yield (297mg, 31mg, 297% N). Group 2(942mg) was separated by chiral preparative HPLC (first separation conditions: column: Chiralpak IE5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 230 nm; second separation: column: Chiralpak IC5 μm20 ℃; mobile phase: Hex: IPA: DEA ═ 80:20:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 230nm) followed by further purification by preparative HPLC (column: xbridge C18(5 μm19 ═ 150mm), mobile phase a: water (0.1% ammonium hydroxide), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 40% -80% (B)), yielding stereoisomeric compound 24P (212mg, 23% yield) and compound 24% Q (190% yield).

Compound 24Q: LC-MS (ESI): r_T＝3.789min，C₂₃H₂₃ClFN₃O₄Calculated mass of S491.1, M/z found value 491.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 1 ℃; temperature: C; temperature: temperature_T＝13.390min)。¹H NMR(400MHz,DMSO-d₆)δ9.55(d,J＝3.6Hz,0.6H),9.18(s,0.4H),8.00-7.98(m,1.6H),7.94(d,J＝3.2Hz,0.4H),7.40-7.29(m,2H),7.21-7.15(m,1H),6.06(s,0.4H),5.96(d,J＝4.0Hz,0.6H),3.99-3.91(m,0.4H),3.72-3.66(m,0.6H),3.61-3.59(m,3H),3.52-3.51(m,3H),2.44-2.37(m,1H),1.94-1.86(m,3H),1.79-1.69(m,3H),1.50-1.30(m,2H)。

Compound 26: methyl 4- (2-chloro-3-fluorophenyl) -6- (4- (2-ethoxy-2-oxoethyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝4.219min，C₂₅H₂₇ClFN₃O₄Calculated mass of S519.1, M/z found value 519.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51-9.39(m,0.6H),8.97(s,0.4H),8.00-7.97(m,1.6H),7.93(d,J＝3.2Hz,0.4H),7.39-7.27(m,2H),7.20-7.15(m,1H),6.06(s,0.4H),5.96(s,0.6H),4.07(q,J＝6.8Hz,2H),3.87-3.77(m,0.6H),3.62-3.55(m,0.4H),3.51(s,1.6H),3.50(s,1.4H),2.25-2.19(m,2H),1.96-1.51(m,8H),1.20(t,J＝6.8Hz,3H),1.14-1.04(m,1H)。

Compound 27: tert-butyl 5-methyl 6- (2-chloro-3-fluorophenyl) -4- (4- (2-ethoxy-2-oxoethyl) cyclohexyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate (mixture of 4 stereoisomers)

To a solution of methyl 4- (2-chloro-3-fluorophenyl) -6- (4- (2-ethoxy-2-oxoethyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 26(850mg, 2.0mmol) in 1, 4-dioxane (20mL) was added di-tert-butyl dicarbonate (713mg, 3.0mmol), 4-dimethylaminopyridine (210mg, 2.0mmol), and triethylamine (329mg, 3.0 mmol). After stirring at 67 ℃ overnight, the solvent was removed to give a residue which was purified by preparative HPLC (column: waters Xfringe C18(5 μm 19. multidot.150 mm) mobile phase A: water (0.2% ammonium acetate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 75% -90% (% B)) to give the title compound as a yellow solid (674mg, 67% yield).

Compound 27(670mg, 1.08mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 15 ml/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomers compound 27X (333mg, 50% yield, mixture of 3 stereoisomers) and compound 27Y (216mg, 32% yield).

Compound 27Y: LC-MS (ESI): RT 3.244min, calculated mass 619.2 for C30H35ClFN3O6S, found value 620.2[ M + H ] +. Chiral HPLC (column: Chiralpak IE5 μm4.6 × 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, RT ═ 9.770 min). 1H NMR (400MHz, DMSO-d6) δ 7.99(s,2H),7.38-7.34(m,1H),7.31-7.25(m,1H),6.87(d, J ═ 7.6Hz,1H),6.59(s,1H),4.07(q, J ═ 7.2Hz,2H),3.66(s,3H),3.49-3.43(m,1H),2.23(d, J ═ 6.8Hz,2H),1.95-1.50(m,8H),1.21-0.99(m, 13H).

Compound 30: methyl 6- (1- (tert-butoxycarbonyl) piperidin-3-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.002min，C₂₅H₂₈ClFN₄O₄Calculated mass of S534.2, found value of M/z 534.9[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝3.2Hz,0.8H),9.26(d,J＝18.4Hz,0.2H),8.00(s,1.5H),7.99-7.93(m,0.5H),7.40-7.31(m,2H),7.23-7.12(m,1H),6.07(s,0.2H),5.98(dd,J＝8.0,3.6Hz,0.8H),4.07-3.83(m,2H),3.70-3.60(m,1H),3.53-3.50(m,3H),3.32-3.30(m,1H),3.15-3.00(m,1H),2.81-2.63(m,1H),1.92-1.85(m,1H),1.78-1.71(m,2H),1.40(s,9H)。

Compound 9: ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

¹H NMR(400MHz,CDCl₃)δ8.11(br s,0.4H),7.82(d,J＝3.2Hz,1H),7.54-7.41(m,1H),7.35-7.29(m,0.6H),7.25-7.12(m,2H),7.10-7.00(m,1H),6.27(s,0.5H),6.14(s,0.5H),4.38-4.18(m,3H),4.08-3.90(m,2H),2.95-2.76(m,2H),2.01-1.61(m,4H),1.50(s,9H),1.11(t,J＝7.2Hz,3H)。

Compound 11: 6- (1-tert-Butoxycarbonyl-piperidin-4-yl) -4- (4-chloro-2-fluoro-phenyl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester

¹H NMR(400MHz,DMSO-d₆)δ9.46(d,J＝3.2Hz,0.8H),9.08(s,0.2H),8.00-7.98(m,1.8H),7.92(d,J＝3.2Hz,0.2H),7.44-7.42(m,1H),7.37-7.31(m,1H),7.23-7.18(m,1H),6.01(s,0.2H),5.92(d,J＝3.6Hz,0.8H),4.18-3.96(m,2H),3.82-3.74(m,1H),3.53(s,2.4H),3.52(s,0.6H),2.86-2.69(m,2H),1.87-1.66(m,3H),1.52-1.49(m,1H),1.44(s,9H)。

Compound 31: methyl 6- (1- (tert-butoxycarbonyl) piperidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝2.454min，C₂₅H₂₈ClFN₄O₄Calculated mass of S534.1M/z found 535.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.44(d,J＝18.4Hz,0.3H),7.82(d,J＝3.2Hz,0.7H),7.79-7.78(m,0.3H),7.49(d,J＝2.8Hz,0.7H),7.42(d,J＝5.6Hz,1H),7.33-7.25(m,1H),7.15-7.11(m,1H),6.97-6.88(m,1H),6.18(d,J＝8.0Hz,0.3H),6.08(d,J＝2.8Hz,0.4H),6.02(s,0.3H),4.38-3.95(m,2H),3.87-3.74(m,1H),3.62(s,2.1H),3.60(s,0.9H),3.33-3.10(m,1H),2.77(br s,1H),2.11-1.92(m,1H),1.88-1.68(m,3H),1.49(d,J＝4.4Hz,9H)。

Compound 34: methyl 6- (1- (tert-butoxycarbonyl) -4-fluoropiperidin-4-yl) -4- (2-chloro-3-fluoro-phenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.138min，C₂₅H₂₇ClF₂N₄O₄Calculated mass of S552.1, found value of M/z 552.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.24(d,J＝2.4Hz,1H),8.00(s,2H),7.44-7.35(m,2H),7.25(d,J＝7.2Hz,1H),5.82(d,J＝2.8Hz,1H),4.22(t,J＝6.6Hz,0.1H),3.94-3.91(m,1.9H),3.50(s,3H),2.95(br s,2H),2.25-2.04(m,2H),1.88(t,J＝12.4Hz,1H),1.77(t,J＝12.4Hz,1H),1.44(s,9H)。

Compound 40: (1R,5S,6R) -tert-butyl 6- (6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-ol-2-yl) -3, 6-dihydropyrimidin-4-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylate

LC-MS(ESI)：R_T＝1.78min，C₂₆H₂₈ClFN₄O₄Calculated mass of S546.2, found value of M/z 547.3[ M + H]⁺。¹H NMR(300MHz,DMSO-d₆)δ9.59(s,1H),7.98(s,2H),7.43-7.32(m,2H),7.25-7.14(m,1H),5.91(s,1H),3.96(q,J＝6.9Hz,2H),3.58-3.34(m,4H),2.96(s,1H),2.30(s,1H),2.10(s,1H),1.39(m,9H),1.05(t,J＝6.3Hz,3H)。

Compound 42: 1-tert-butyl 2-methyl 4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidine-1, 2-dicarboxylate (mixture of 4 stereoisomers)

LC-MS(ESI)：R_T＝4.148min，C₂₇H₃₀ClFN₄O₆Calculated mass of S592.2, M/z found value 592.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.09(br s,0.2H),7.83-7.80(m,1H),7.49(d,J＝2.8Hz,0.8H),7.44-7.39(m,1H),7.31-7.27(m,1H),7.13(dd,J＝8.4,2.4Hz,1H),6.98-6.87(m,1H),6.18(d,J＝4.0Hz,0.2H),6.05(s,0.8H),5.09-5.04(m,0.5H),4.92-4.86(m,0.5H),4.24-4.02(m,1H),3.82-3.78(m,4H),3.59(s,2.4H),3.57(s,0.6H),3.29-3.06(m,1H),2.50-2.31(m,1H),2.21-2.14(m,1H),2.08-2.02(m,0.5H),1.94-1.80(m,1.5H),1.51(s,4H),1.47(s,5H)。

Compound 43: cis-4- [6- (2-chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-3, 6-dihydro-pyrimidin-4-yl ] -piperidine-1, 3-dicarboxylic acid 1-tert-butyl ester

LC-MS(ESI)：R_T＝1.54min，C₂₆H₂₈ClFN₄O₆Calculated mass of S578.1, M/z found value 579.5[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.83(br s,0.1H),11.99(br s,0.4H),9.56(dd,J＝11.6,3.6Hz,0.7H),9.06-8.96(m,0.3H),8.01-7.91(m,2H),7.59(dd,J＝8.8,6.4Hz,0.3H),7.43-7.31(m,1.7H),7.25-7.06(m,1H),6.06(s,0.2H),5.99(s,0.2H),5.94(dd,J＝5.6,3.2Hz,0.6H),4.49-4.36(m,0.3H),4.23-3.78(m,2.7H),3.59-3.44(m,3.6H),3.40-3.34(m,0.4H),3.22-3.09(m,0.6H),3.00-2.92(m,0.4H),2.84-2.75(m,0.6H),2.68-2.63(m,0.4H),2.42-2.35(m,0.3H),2.14-1.94(m,0.7H),1.84-1.66(m,0.8H),1.60-1.55(m,0.2H),1.45-1.37(m,9H)。

Compound 44: cis-1-tert-butyl 3-methyl 4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidine-1, 3-dicarboxylate (mixture of 4 stereoisomers)

To a solution of cis-4- [6- (2-chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-3, 6-dihydro-pyrimidin-4-yl ] -piperidine-1, 3-dicarboxylic acid 1-tert-butyl ester compound 43(0.28g, 0.48mmol) in N, N-dimethylformamide (6mL) was added potassium carbonate (74mg, 0.53mmol) followed by iodomethane (76mg, 0.53mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. It was diluted with water (40mL) and extracted three times with ethyl acetate (30 mL). The combined organic layers were washed with brine (50mL), dried over Na2SO4(s) and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: xbridge C18(5 μm19 x 150mm), mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 15mL/min, gradient: 60% -80% (% B)) to give compound 44A (104mg, 36% yield, mixture of 2 stereoisomers) and compound 44B (84mg, 29% yield, mixture of 2 stereoisomers) as two mixtures of yellow solids.

Compound 44A: LC-MS (ESI): r_T＝4.446min，C₂₇H₃₀ClFN₄O₆Calculated mass of S592.2, M/z found value 592.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝3.6Hz,0.8H),8.67(s,0.2H),8.01-7.99(m,1.8H),7.94-7.93(m,0.2H),7.75-7.67(m,0.1H),7.44-7.35(m,1.9H),7.25-7.14(m,1H),5.99(s,0.2H),5.93(d,J＝3.2Hz,0.8H),4.23-4.66(m,2H),3.74-3.38(m,9H),2.78(dd,J＝10.8,4.4Hz,1H),2.30-2.15(m,1H),1.82-1.68(m,1H),1.42(s,9H)。

Compound 52: methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (2,4, 6-trifluorophenyl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝2.658min，C₂₈H₂₈ClF₄N₃O₄Calculated mass of 581.2M/z found value 581.7[ M + H ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ9.48(s,0.8H),9.41(s,0.2H),7.41-7.35(m,2H),7.28-7.20(m,3H),5.95(s,0.8H),5.85(s,0.2H),4.13-4.04(m,3H),3.50(s,3H),2.78-2.66(m,2H),1.71-1.59(m,4H),1.38(s,9H)。

Compound 55: ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (3, 5-difluoro-pyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝2.571min，C₂₈H₃₀ClF₃N₄O₄Calculated mass of 578.2, M/z found value 578.7[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.35(d,J＝3.2Hz,1H),8.61(s,1H),8.10-8.07(m,1H),7.59-7.55(m,1H),7.29-7.23(m,1H),7.21-7.15(m,1H),5.70(s,0.4H),5.51(d,J＝3.2Hz,0.6H),4.10-4.00(m,4.5H),3.78-3.77(m,0.5H),2.75-2.70(m,2H),1.72-1.59(m,4H),1.41(s,9H),1.19-1.15(m,3H)。

Compound 57: methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluoro-phenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝1.83min，C₂₅H₂₇ClF₂N₄O₄Calculated mass of S552.1M/z found 553.4[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.64(s,0.8H),9.23(s,0.2H),8.00(s,1.8H),7.94(s,0.2H),7.48-7.42(m,1H),7.21-7.15(m,0.8H),6.98(s,0.2H),6.01(s,0.2H),5.91(s,0.8H),4.08-4.00(m,2H),3.82-3.76(m,1H),3.52(s,2H),3.48(m,1H),2.82-2.69(m,2H),1.86-1.63(m,4H),1.43(s,5H),1.39-1.38(m,4H)。

Compound 60: methyl 6- (3- ((tert-butoxycarbonyl) amino) cyclopentyl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 8 stereoisomers)

Compound 60 was further purified by C18 column (acetonitrile: water 75% -85%) to give two sets of stereoisomers, i.e., set 1(1.11g) and set 2(2.57 g).

Group 1(1.61g, 3.01mmol) was separated by chiral preparative HPLC (column: Chiralpak AD 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 85:15:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give fraction 1(526mg), compound 60C (165mg, 10% yield, 100% de) and compound 60D (182mg, 11% yield, 100% de). Fraction 1(526mg) was further separated by chiral preparative HPLC (column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: IPA: DEA ═ 90:10:0.2 at 20 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the stereoisomeric compound 60A (150mg, 9% yield, 96.3% de) and compound 60B (120mg, 7% yield, 100% de).

Group 2(2.56g, 4.79mmol) was separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase:CO₂IPA 70:30 at 45 g/min; co-solvent: IPA; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar) to yield fraction 2(846mg) and fraction 3(1.1 g). Fraction 2(846mg) was further separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 x 250 mm; mobile phase: CO₂IPA, DEA 70:30:0.3 at 45 g/min; co-solvent: IPA; column temperature: 39.6 ℃; wavelength: 214nm, back pressure: 100 bar) to give the stereoisomer compound 60E (286mg, 11% yield, 100% de) and compound 60F (343mg, 13% yield, 100% de). Fraction 3(664mg) was further separated by chiral preparative HPLC (column: Chiralpak AS 5 μm20 × 250 mm; mobile phase: Hex: IPA: DEA ═ 80:20:0.3 at 13 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomer compound 60G (155mg, 10% yield, 100% de) and compound 60H (255mg, 17% yield, 100% de).

Compound 60B: LC-MS (ESI): r_T＝1.72min，C₂₅H₂₈ClFN₄O₄Calculated mass of S534.2, found value of M/z 535.4[ M + H [)]⁺. Chiral HPLC (column: Chiralpak AD-H5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.604min)。¹H NMR(400MHz,CDCl₃)δ8.10(s,0.4H),7.81(t,J＝2.8Hz,1H),7.49(d,J＝2.8Hz,0.6H),7.44(d,J＝2.8Hz,0.4H),7.41(br s,0.6H),7.24-7.14(m,1H),7.10-7.00(m,2H),6.24(s,0.4H),6.09(d,J＝2.4Hz,0.6H),4.72-4.55(m,1H),4.48-4.41(m,1H),4.35-4.22(m,1H),3.60(s,2H),3.59(s,1H),2.45-2.38(m,1H),2.32-2.20(m,1H),2.17-2.07(m,1.5H),1.94-1.83(m,2.5H),1.46(s,9H)。

Compound 60D: LC-MS (ESI): r_T＝1.69min，C₂₅H₂₈ClFN₄O₄Calculated mass of S534.2, found value of M/z 535.8[ M + H [)]⁺. Chiral HPLC (column: Chiralpak AD-H5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝10.882min)。¹H NMR(400MHz,CDCl₃)δ8.10(s,0.4H),7.81(t,J＝3.2Hz,1H),7.49(d,J＝3.6Hz,0.6H),7.44(d,J＝3.2Hz,0.4H),7.41(br s,0.6H),7.23-7.00(m,3H),6.24(s,0.4H),6.10(d,J＝2.4Hz,0.6H),4.71-4.53(m,1H),4.48-4.39(m,1H),4.27(br s,1H),3.60(s,2H),3.59(s,1H),2.362.18(m,2H),2.16-1.95(m,2H),1.77-1.66(m,2H),1.46(s,9H)。

Compound 60E: LC-MS (ESI): r_T＝1.78min，C₂₅H₂₈ClFN₄O₄Calculated mass of S534.2, found value of M/z 535.5[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: CO₂MeOH 75:25 at 3.0 mL/min; column temperature: 38.9 ℃; wavelength: 214nm, back pressure 100bar, R_T＝3.22min，100％de)。¹H NMR(400MHz,CDCl₃)δ8.29(s,0.1H),7.86-7.81(m,0.9H),7.57-7.44(m,2H),7.24-7.20(m,1H),7.10-7.03(m,2H),6.23(s,0.2H),6.13-6.10(m,1.8H),4.79-4.71(m,0.1H),4.55-4.47(m,0.9H),4.27-4.19(m,0.7H),4.13-4.05(m,0.3H),3.61(s,2H),3.59(s,1H),2.58-2.50(m,0.1H),2.39-2.31(m,0.7H),2.17-2.10(m,0.2H),2.02-1.67(m,5H),1.45(s,9H)。

Compound 60G: LC-MS (ESI): r_T＝1.79min，C₂₅H₂₈ClFN₄O₄Calculated mass of S534.2, found value of M/z 535.6[ M + H [)]⁺. Chiral HPLC (column: Chiralpak As-H5 μm4.6 x 250 mm; mobile phase: Hex: IPA: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, 100% de, R_T＝5.098min)。¹H NMR(400MHz,CDCl₃)δ8.24(s,0.1H),7.86-7.81(m,0.9H),7.56-7.44(m,2H),7.24-7.20(m,1H),7.13-7.07(m,2H),6.25-6.23(m,1H),6.13(d,J＝2.8Hz,1H),4.52-4.42(m,1H),4.24-4.16(m,0.8H),4.11-4.03(m,0.2H),3.61(s,2H),3.58(s,1H),2.50-2.41(m,0.1H),2.26-2.08(m,1.9H),2.01-1.91(m,2H),1.81-1.71(m,2H),1.46(s,9H)。

Compound 63: methyl 6- (1- (((9H-fluoren-9-yl) methoxy) carbonyl) pyrrolidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.965min，C₃₄H₂₈ClFN₄O₄Calculated mass of S642.2, M/z found value 643.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.64-9.59(m,1H),8.02-7.87(m,4H),7.69-7.61(m,2H),7.45-7.17(m,7H),6.03-5.93(m,1H),4.37-4.26(m,4H),3.74-3.54(m,6H),3.48-3.36(m,1H),2.27-2.06(m,2H)。

Compound 64: methyl 4- (2-chloro-4-fluorophenyl) -6- (pyrrolidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (1- (((9H-fluoren-9-yl) methoxy) carbonyl) pyrrolidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 63(400mg, 0.623mmol) in tetrahydrofuran (10mL) was added piperidine (2 mL). The mixture was stirred at room temperature for 2 hours. It was concentrated to give a residue which was purified by silica gel column chromatography (dichloromethane: methanol-30: 1 to 10:1) to give the title product as a yellow solid (220mg, 84% yield). LC-MS (ESI): r_T＝1.39min，C₁₉H₁₈ClFN₄O₂Calculated mass of S420.1, found value of M/z 421.4[ M + H]⁺。

Compound 66: methyl 6- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 66(2.80g, 5.39mmol) was further separated by chiral preparative HPLC (first separation conditions (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 20mL/min, temperature: 30 ℃; wavelength: 230nm) followed by second separation conditions (column: Chiralpak IA,5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 70:30, at 10mL/min, temperature: 30 ℃; wavelength: 214nm)) to give the stereoisomer compound 66A (416mg, 15% yield), compound 66B (474mg, 17% yield), compound 66C (518mg, 19% yield), and compound 66D (441mg, 16% yield).

Compound 66A: LC-MS (ESI): r_T＝4.485min，C₂₄H₂₆ClFN₄O₄Calculated mass of S520.1, found value of M/z 521.0[ M + H]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝9.495min)。¹H NMR(400MHz,DMSO-d₆)δ9.56(s,0.8H),9.21(s,0.2H),8.05-8.00(m,1.8H),7.98-7.89(m,0.2H),7.42(dd,J＝9.2,2.8Hz,1H),7.38-7.34(m,1H),7.24-7.19(m,1H),5.94(d,J＝3.2Hz,0.8H),5.75(s,0.2H),4.58-4.40(m,0.1H),4.34-4.23(m,0.9H),3.53(s,5H),3.33-3.20(m,2H),2.19-1.89(m,2H),1.43(s,9H)。

Compound 66D: LC-MS (ESI): r_T＝4.174min，C₂₄H₂₆ClFN₄O₄Calculated mass of S520.1, found value of M/z 521.0[ M + H]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝7.464min)。¹H NMR(400MHz,DMSO-d₆)δ9.58(s,0.9H),9.30(s,0.1H),8.02-8.00(m,1.8H),7.94-7.92(m,0.2H),7.42(dd,J＝8.8,2.8Hz,1H),7.39-7.32(m,1H),7.24-7.19(m,1H),5.93(d,J＝3.2Hz,0.8H),5.75(s,0.2H),4.61-4.52(m,0.1H),4.37-4.24(m,0.9H),3.54-3.52(m,3H),3.47-3.37(m,2H),3.31-3.20(m,2H),2.30-2.00(m,2H),1.43-1.41(m,9H)。

Compound 71: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (methoxycarbonyl) cyclopentyl) -2- (thiazol-2-yl) -1, 4-dihydro-pyrimidine-5-carboxylate (mixture of 8 stereoisomers)

Compound 71(2.3G, 4.8mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 80:20 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomer compound 71A (251mg, 11% yield), compound 71G (217mg, 9% yield), compound 71H (120mg, 5% yield), a mixture of compound 71E and compound 71F (419mg, 18% yield), and another mixture of compound 71B, compound 71C and compound 71D (526mg, 23% yield). A mixture of compound 71E and compound 71F (419mg, 0.900mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: EtOH 80:20 at 10 mL/min; temperature: 30 ℃; wavelength: 230) to give the stereoisomer compound 71E (135mg, 32% yield) and compound 71F (207mg, 49% yield). A mixture of compound 71B, compound 71C and compound 71D (526mg, 1.10mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA5 μm 5.0 × 250 mm; mobile phase: EtOH 100% at 51 mL/min; temperature: 35 ℃; wavelength: 254nm) to give the stereoisomer compound 71D (94mg, 18% yield) and a mixture of compound 71B and compound 71C (433mg, 82% yield). A mixture of compound 71B and compound 71C (433mg, 0.900mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak AS 50mm 250 mm; mobile phase: MeOH ═ 100% at 58 mL/min; temperature: 35 ℃; wavelength: UV214nm) to give the stereoisomers compound 71B (105mg, 24% yield) and compound 71C (127mg, 29% yield).

Compound 71C (column: Chiralpak AS-H5 μm4.6 × 150mm, mobile phase: MeOH 100% in 1.0mL/min, temperature: 35 ℃; wavelength: 254 nm; RT 3.508 min). 1H NMR (400MHz, DMSO-d6) δ 9.48(d, J ═ 3.2Hz,0.8H),9.11(s,0.2H),7.99(q, J ═ 3.2Hz,1.8H),7.93(d, J ═ 2.8Hz,0.2H),7.44-7.40(m,1H),7.37-7.29(m,1H),7.22(td, J ═ 8.4,2.4Hz,1H),6.00(s,0.2H),5.90(d, J ═ 3.2Hz,0.8H),4.35-4.29(m,0.2H),4.26-4.18(m,0.8H),3.64(s,0.6H),3.63(s,2.4H),3.52(s, 2.52H), 3.19 (m,2H), 1.19-2H), 1.19 (m,2H), 1.19H, 2H, 1.2H, 2H, 1.5.2H, 2H, 3.8H, 2H.

Compound 71F: LC-MS (ESI): RT 3.370min, calculated mass 477.1 for C22H21ClFN3O4S, found value of 478.1[ M + H ] +. Chiral HPLC (column: Chiralpak IA5 μm4.6 × 250 mm; mobile phase: Hex: EtOH ═ 80:20 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; RT ═ 6.327 min). 1H NMR (400MHz, DMSO-d6) δ 9.47(d, J ═ 3.6Hz,0.8H),9.05(s,0.2H),8.00(q, J ═ 2.8Hz,1.8H),7.93(d, J ═ 2.8Hz,0.2H),7.41(dd, J ═ 8.4,2.8Hz,1H),7.35-7.29(m,1H),7.21(td, J ═ 8.4,2.8Hz,1H),6.00(s,0.2H),5.91(d, J ═ 3.6Hz,0.8H),4.36-4.30(m,0.2H),4.26-4.18(m,0.8H),3.63(s,0.6H),3.62(s, 2.76H), 4.36-4.30(m,0.2H),4.26-4.18(m,0.8H),3.63(s,0.6H), 3.76 (s,2H), 1.85H), 1.2H, 1.6H, 1..

Compound 73: cis-methyl 4- (2-chloro-3-fluorophenyl) -6- (5- (methoxycarbonyl) tetrahydro-furan-2-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 73(320mg, 0.67mmol) was further separated by chiral preparative HPLC (column: Chiralpak ID5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 80:20, at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomer compound 73E (31mg, 10% yield), compound 73F (32mg, 10% yield), compound 73G (70mg, 22% yield) and compound 73H (83mg, 26% yield) as yellow solids.

Compound 73H: LC-MS (ESI): r_T＝3.649min，C₂₁H₁₉ClFN₃O₅Calculated mass of S479.1, found value of M/z 479.9[ M + H [)]⁺. Chiral HPLC (column: Chiralpak ID5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 80:20 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝14.785min)。¹H NMR(400MHz,CDCl₃)δ10.05(s,1H),7.89(d,J＝3.2Hz,1H),7.42(d,J＝3.2Hz,1H),7.18-7.09(m,2H),7.05-7.01(m,1H),6.29(s,1H),5.83(dd,J＝9.2,6.4Hz,1H),4.74(dd,J＝9.2,2.8Hz,1H),3.89(s,3H),3.58(s,3H),2.75-2.68(m,1H),2.53-2.43(m,1H),2.28-2.23(m,1H),2.01-1.90(m,1H)。

Compound 76: methyl 4- (2-chloro-3-fluorophenyl) -6- (3- (methoxycarbonyl) cyclopentyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.038min，C₂₂H₂₁ClFN₃O₄Calculated mass of S477.1, M/z found 477.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.58-9.53(m,0.8H),9.21-9.11(m,0.2H),8.01-7.98(m,1.8H),7.95-7.93(m,0.2H),7.43-7.29(m,2H),7.20-7.12(m,1H),6.07-6.04(m,0.2H),5.97-5.93(m,0.8H),4.41-4.34(m,0.3H),4.26-4.20(m,0.3H),4.15-4.09(m,0.4H),3.68-3.59(m,3H),3.51-3.49(m,3H),3.16-3.09(m,0.4H),3.03-2.98(m,0.2H),2.92-2.85(m,0.4H),2.20-1.77(m,6H)。

Compound 78: methyl 6- (1- (tert-butoxycarbonyl) azetidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 78(9.00g, 17.8mmol) was further separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: MeOH: EtOH ═ 70:30 at 20 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomer compound 78A (3.5g, 39% yield) and compound 78B (3.58g, 40% yield).

Compound 78A: LC-MS (ESI): r_T＝1.55min，C₂₃H₂₄ClFN₄O₄Calculated mass of S506.1, found value of M/z 507.6[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH ═ 70:30, at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.015min)；¹H NMR(400MHz,DMSO-d₆)δ9.65(d,J＝3.6Hz,1H),8.04-7.93(m,2H),7.42-7.38(m,2H),7.21(dt,J＝8.8,3.2Hz,Hz,1H),5.94(d,J＝3.2Hz,1H),4.48-4.40(m,1H),4.14-3.99(m,4H),3.52(s,3H),1.42(s,9H)。

Compound 85: 4- (2-chloro-4-fluoro-phenyl) -6- (3-methoxycarbonyl-cyclobutyl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (mixture of 4 stereoisomers)

Compound 85 was further purified by preparative HPLC (column: Gilson C185 μm19 x 150mm, mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 20mL/min, gradient: 35% -75% (% B)) to give two mixtures compound 85A (35mg, 8% yield, mixture of 2 stereoisomers) and compound 85B (86mg, 20% yield, mixture of 2 stereoisomers) as a yellow solid.

Compound 85A (90mg, 0.19mmol) was separated by chiral preparative HPLC (separation conditions: column: chiralpak ic5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 80:20 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomer compound 85C (36mg, 40% yield) and compound 85D (40mg, 44% yield) as yellow solids.

Compound 85C: LC-MS (ESI): r_T＝4.350min，C₂₁H₁₉ClFN₃O₄Calculated mass of S463.1, found value of M/z 463.9[ M + H]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 80:20 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.994min)。¹H NMR(400MHz,DMSO-d₆)δ9.55(d,J＝3.6Hz,0.9H),9.05(s,0.1H),8.02-8.01(m,1.8H),7.94(d,J＝2.8Hz,0.2H),7.43-7.32(m,2H),7.23-7.17(m,1H),5.99(s,0.1H),5.91(d,J＝3.6Hz,0.9H),4.63-4.57(m,0.1H),4.41-4.33(m,0.9H),3.68(s,0.5H),3.65(s,2.5H),3.51(s,3H),3.29-3.24(m,0.9H),3.19-3.13(m,0.1H),2.67-2.52(m,2H),2.49-2.32(m,2H)。

Compound 87 (trans): trans-methyl 6- (3- ((tert-butoxycarbonyl) amino) cyclobutyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.707min，C₂₄H₂₆ClFN₄O₄Calculated mass of S520.1, found value of M/z 520.9[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ8.38(br s,0.2H),7.83(d,J＝3.2Hz,1H),7.51(d,J＝3.2Hz,0.8H),7.45(s,1H),7.28-7.21(m,1H),7.13(d,J＝8.4,2.4Hz,1H),6.93(td,J＝8.4,2.4Hz,1H),6.18(s,0.2H),6.05(d,J＝2.4Hz,0.8H),5.07-4.84(m,1H),4.54-4.46(m,1.4H),4.24-4.06(m,0.6H),3.61(s,0.6H),3.58(s,2.4H),2.85-2.58(m,2H),2.41-2.16(m,2H),1.47(s,9H)。

Compound 87 (cis): (cis) -methyl 6- (3- ((tert-butoxycarbonyl) amino) cyclobutyl) -4- (2-chloro-4-fluoro-phenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.379min，C₂₄H₂₆ClFN₄O₄Calculated mass of S520.1, found value of M/z 520.9[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ8.60(brs,0.2H),7.85-7.83(m,1H),7.52-7.51(m,0.8H),7.45(s,1H),7.28-7.22(m,1H),7.13(d,J＝8.0Hz,1H),6.95-6.91(m,1H),6.17(s,0.3H),6.05(s,0.7H),5.06-4.85(m,1H),4.54-4.08(m,2H),3.61(s,2.2H),3.59(s,0.8H),2.75-2.58(m,2H),2.37-2.21(m,2H),1.47(s,9H)。

Compound 91: ethyl 6- (2- (2- (tert-butoxy) -2-oxoethyl) cyclopropyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 91 was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give two mixtures, compound 91E (360mg, 12% yield, mixture of 2 stereoisomers) and compound 91F (250mg, 8% yield, mixture of 2 stereoisomers) as a yellow solid.

Compound 91E (360mg, 0.629mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 12 mL/min; temperature: 30 ℃ c; wavelength: 230nm) to give the stereoisomer compound 91G (44mg, 1.5% yield) and compound 91H (46mg, 1.5% yield).

Compound 91H: chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R: X; pH: 1, 0: (b): 1.0 mL/min; temperature_T＝7.059min)。

Compound 91F (250mg, 0.481mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 90:1 at 12 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the stereoisomer compound 91I (51mg, 1.7% yield), and compound 91J (49mg, 1.7% yield).

Compound 91J: chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R: X; pH: 1, 0: (b): 1.0 mL/min; temperature_T＝8.766min)。

Compound 6: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((1-methoxy-2-methyl-1-oxoprop-2-yl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 6(230mg, 0.385mmol) was further separated by chiral preparative HPLC (column: Chiralpak IE5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 60:40 at 9 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomers compound 6A (78mg, 34% yield) and compound 6B (50mg, 22% yield).

Compound 6B: LC-MS (ESI): r_T＝1.55min，C₂₅H₂₈ClFN₄O₆S₂598.1, found value of m/z 598.9. Chiral HPLC (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝13.955min)。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.3H),7.83(t,J＝2.8Hz,1H),7.51(d,J＝3.2Hz,0.7H),7.45-7.43(m,1H),7.29-7.24(m,1H),7.15-7.11(m,1H),6.96-6.88(m,1H),6.18(s,0.3H),6.06(d,J＝2.4Hz,0.7H),4.24-4.15(m,0.3H),4.01-3.89(m,2.7H),3.82-3.81(m,3H),3.60(s,2H),3.59(s,1H),3.19-3.06(m,2H),2.25-2.15(m,1H),2.09-1.98(m,1H),1.91-1.75(m,2H),1.67(s,4H),1.65(s,2H)。

Compound 94: methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (methoxycarbonyl) cycloheptyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T3.021min and 3.150min, C₂₄H₂₅ClFN₃O₄Calculated mass of S505.1, M/z found 505.9[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.93-7.87(m,1H),7.74(s,1H),7.40-7.36(m,1H),7.24-7.20(m,1H),7.07-7.01(m,1H),6.12(s,0.6H),6.04(s,0.4H),4.12(br s,0.6H),3.93(br s,0.4H),3.69-3.68(m,3H),3.59(s,1.2H),3.58(s,1.8H),2.71-2.61(m,1H),2.17-1.48(m,10H)。

The 94R racemic mixture (870mg, 1.72mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: IPA: DEA: 80:20:0.3 at 13 mL/min; temperature: 30 ℃ C.; wavelength: 214nm) to give two sets of stereoisomers as yellow solids, i.e., set 1(400mg) and set 2(120 mg).

Group 1(400mg, 0.792mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak AD-H5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 90:10, at 15 mL/min; temperature: 30 ℃; wavelength: 254nm) to give fraction 1(200mg), 94P (25mg, 3 yield, 100% stereopurity) and 94Q (25mg, 3 yield, 98.3% stereopurity) as yellow solids. Fraction 1(200mg, 0.396mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC 10 μm50 x 250 mm; mobile phase: Hex: IPA: DEA ═ 95:5:0.1 at 60 mL/min; temperature: 35 ℃; wavelength: 254nm) to give fractions 2 and 94J (60mg, 7% yield, 97.8% stereopurity) and pure 94N (68mg, 8% yield, 96.7% stereopurity) as yellow solids. Fraction 2 was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE 10 μ M50 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 95:5:0.1 at 60 mL/min; temperature: 35 ℃; wavelength: 254nm) to give the title compound 94K (25mg, 3 yield, 97.3% stereopurity) and 94M (20mg, 2 yield, 97.3% stereopurity) as yellow solids.

Group 2 was separated by chiral preparative HPLC (separation conditions: column: Chiralpak OJ 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 97:3:0.1 at 30 mL/min; temperature: 35 ℃; wavelength: 254nm) to give the title compound 94S (30mg, 3 yield, 99.4% stereopurity) and 94T (25mg, 3 yield, 98.8% stereopurity) as yellow solids.

Compound 94J: chiral analysis (column: Chiralpak IE 4.6 × 150 mm; mobile phase: Hex: IPA: DEA: 95:5:0.1 at 1 mL/min; temperature: 35 ℃; wavelength: 254nm, R-_T＝6.900min)。

Compound 94K: chiral analysis (column: Chiralpak IE 4.6 × 150 mm; mobile phase: Hex: EtOH: DEA: 95:5:0.1 at 1 mL/min; temperature: 35 ℃ C.; wavelength: 254nm, R: 1_T＝10.427min)。

Compound 94M: chiral analysis (column: Chiralpak IE 4.6 × 150 mm; mobile phase: Hex: EtOH: DEA: 95:5:0.1 at 1 mL/min; temperature: 35 ℃ C.; wavelength: 254nm, R: 1_T＝13.160min)。

Compound 94N: chiral analysis (column: Chiralpak IE 4.6 × 150 mm; mobile phase: Hex: IPA: DEA: 95:5:0.1 at 1 mL/min; temperature: 35 ℃; wavelength: 254nm, R-_T＝12.257min)。

Compound 94P: LC-MS (ESI): r_T＝4.480min，C₂₄H₂₅ClFN₃O₄Calculated mass of S505.1, M/z found 505.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak AD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak AD-H5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA ═ 90:10: 0.2; temperature: 30_T＝9.150min)。¹H NMR(400MHz,DMSO-d₆)δ9.41(d,J＝3.2Hz,0.5H),9.07(s,0.5H),7.99-7.97(m,1.5H),7.93(d,J＝2.8Hz,0.5H),7.44-7.40(m,1H),7.36-7.29(m,1H),7.24-7.18(m,1H),6.00(s,0.4H),5.90(d,J＝3.6Hz,0.6H),4.00-3.92(m,0.4H),3.84-3.75(m,0.6H),3.61(s,1.2H),3.60(s,1.8H),3.52(s,1.8H),3.51(s,1.2H),2.74-2.66(m,0.5H),2.59-2.55(m,0.5H),2.06-1.65(m,9H),1.62-1.52(m,1H)。

Compound 94Q: LC-MS (ESI): r_T＝4.495min，C₂₄H₂₅ClFN₃O₄Calculated mass of S505.1, M/z found 505.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak AD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak AD-H5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA ═ 90:10: 0.2; temperature: 30_T＝11.406min)。¹H NMR(400MHz,DMSO-d₆)δ9.41(d,J＝3.6Hz,0.5H),9.03(s,0.5H),8.00-7.97(m,1.5H),7.93(d,J＝3.2Hz,0.5H),7.44-7.40(m,1H),7.36-7.29(m,1H),7.24-7.18(m,1H),5.99(s,0.4H),5.89(d,J＝3.6Hz,0.6H),3.99-3.91(m,0.4H),3.84-3.76(m,0.6H),3.63(s,1.2H),3.61(s,1.8H),3.52(s,1.8H),3.51(s,1.2H),2.70-2.63(m,0.5H),2.60-2.55(m,0.5H),2.07-1.60(m,9H),1.50-1.40(m,1H)。

Compound 94S: LC-MS (ESI): r_T＝4.406min，C₂₄H₂₅ClFN₃O₄Calculated mass of S505.1, M/z found 505.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 95:5:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 95:5: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝17.041min)。¹H NMR(400MHz,DMSO-d₆)δ9.38(d,J＝3.2Hz,0.5H),9.04(s,0.5H),7.99-7.96(m,1.5H),7.92(d,J＝3.2Hz,0.5H),7.43-7.39(m,1H),7.35-7.29(m,1H),7.23-7.17(m,1H),6.00(s,0.4H),5.90(d,J＝3.6Hz,0.6H),4.02-3.91(m,0.5H),3.84-3.75(m,0.5H),3.61(s,1.2H),3.60(s,1.8H),3.52(s,1.8H),3.51(s,1.2H),2.74-2.65(m,0.7H),2.59-2.58(m,0.3H),2.04-1.55(m,10H)。

Compound 94T: LC-MS (ESI): r_T＝4.414min，C₂₄H₂₅ClFN₃O₄Calculated mass of S505.1, M/z found 505.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 95:5:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 95:5: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝20.533min)。¹H NMR(400MHz,DMSO-d₆)δ9.39(d,J＝4.0Hz,0.5H),9.01(s,0.5H),7.99-7.97(m,1.5H),7.92(d,J＝2.8Hz,0.5H),7.43-7.39(m,1H),7.36-7.31(m,1H),7.24-7.18(m,1H),5.99(s,0.4H),5.89(d,J＝3.6Hz,0.6H),3.99-3.90(m,0.4H),3.84-3.75(m,0.6H),3.62(s,1.2H),3.61(s,1.8H),3.52(s,1.8H),3.51(s,1.2H),2.80-2.71(m,0.5H),2.62-2.58(m,0.5H),2.09-1.58(m,10H)。

Compound 143: ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chlorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of stereoisomers)

Compound 143(1.10g, 96% purity) was isolated by chiral preparative SFC (column: chiralpak IG5 μm20 x 250 mm; mobile phase: CO₂MeOH 70:30 at 50 g/min; column temperature: 30 ℃; wavelength: 230 nm; back pressure: 100 bar) to give compound 143A (500mg, 45% yield, 100% stereopure) and compound 143B (592mg, 54% yield, 100% stereopure).

Compound 143B: chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 3.0 g/min; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100bar, R_T＝3.88min)。¹H NMR(300MHz,DMSO-d₆)δ9.35(d,J＝3.3Hz,0.8H),8.97(s,0.2H),7.96-7.94(m,1.8H),7.90-7.88(m,0.2H),7.43-7.39(m,1H),7.32-7.25(m,3H),6.05-6.03(m,0.2H),5.94-5.91(m,0.8H),4.11-3.88(m,4.2H),3.81-3.73(m,0.8H),2.84-2.65(m,2H),1.91-1.67(m,3H),1.50-1.37(m,10H),1.07-1.02(m,3H)。

Compound 147: ethyl 4- (2-bromophenyl) -6- ((trans) -4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝8.237min，C₂₄H₂₆BrN₃O₄Calculated mass of S531.1, M/z found value 531.8[ M + H [ ]]⁺。

Compound 147A: (trans) -Ethyl 4- (2-bromophenyl) -6- (4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 147(507mg, 0.929mmol) was separated by chiral SFC (column: ChiralpakIC 5 μm20 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 50 g/min; column temperature: 40 ℃; wavelength: 230nm, back pressure: 100 bar) to give 147A (260mg, 48% yield) and 147B (240mg, 47% yield) as yellow solids.

Compound 147A: LC-MS (ESI): r_T＝3.989min，C₂₄H₂₆BrN₃O₄Calculated mass of S531.1, found value of M/z 534.1[ M + H]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 2.999 g/min; column temperature: 41.2 ℃; wavelength: 230nm, back pressure: 100bar, R_T＝4.39min)。¹H NMR(400MHz,DMSO-d₆)δ9.23(d,J＝3.6Hz,0.5H),8.84(s,0.5H),7.99-7.98(m,1.5H),7.93(d,J＝3.6Hz,0.5H),7.61(d,J＝7.6Hz,1H),7.37-7.31(m,2H),7.22-7.16(m,1H),6.03(s,0.4H),5.92(d,J＝3.6Hz,0.6H),4.01-3.93(m,2H),3.86-3.82(m,0.5H),3.63(s,3H),3.60-3.56(m,0.5H),2.57-2.54(m,0.4H),2.38-2.32(m,0.6H),2.08-1.99(m,2H),1.91-1.63(m,4H),1.50-1.37(m,2H),1.10-1.03(m,3H)。

Compound 149: ethyl 4- (2-bromo-3-fluorophenyl) -6- ((1r,4r) -4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.647min，C₂₄H₂₅BrFN₃O₄Calculated mass of S549.1, M/z found value 552.0[ M + H [ ]]⁺. Compound 149A: (trans) -Ethyl 4- (2-bromo-3-fluorophenyl) -6- (4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 149(920mg, 1.67mmol) was separated by chiral preparative SFC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: CO)₂MeOH 70:30 at 50 g/min; column temperature: 40 ℃; wavelength: 230nm, back pressure: 100 bar) to yield the title compound 149A (280mg, 30% yield) and 149B (320mg, 34% yield) as yellow solids.

Compound 149A: LC-MS (ESI): r_T＝2.842min，C₂₄H₂₅BrFN₃O₄Calculated mass of S549.1, found value of M/z 552.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 3.0 g/min; column temperature: 40 ℃; wavelength: 230nm, back pressure: 100bar, R_T＝4.04min)。¹H NMR(400MHz,DMSO-d₆)δ9.42(s,0.5H),8.93(s,0.5H),7.99(d,J＝2.8Hz,1.5H),7.93(d,J＝2.8Hz,0.5H),7.44-7.36(m,1H),7.29-7.26(m,1H),7.20-7.12(m,1H),6.06(s,0.5H),5.96(s.0.5H),3.99-3.94(m,2H),3.88-3.79(m,0.5H),3.62(s,1.5H),3.61(s,1.5H),3.59-3.32(m,0.5H),2.38-2.27(m,1H),2.08-1.97(m,2H),1.89-1.61(m,4H),1.47-1.36(m,2H),1.09-1.01(m,3H)。

Compound 151: methyl 4- (2-bromo-3-fluorophenyl) -6- ((1r,4r) -4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝1.84min，C₂₃H₂₃BrFN₃O₄Calculated mass of S535.1, found M/z 538.8[ M + H [ ]]⁺。

Compound 151A: (trans) -methyl 4- (2-bromo-3-fluorophenyl) -6- (4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 151(420mg, 0.780mmol) was separated by chiral preparative SFC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: CO)₂MeOH 70:30 at 50 g/min; column temperature: 30 ℃; wavelength: 230 nm; back pressure: 100 bar) to yield the title compound 151B (176mg, 42% yield) and 151A (176mg, 42% yield).

Compound 151A: LC-MS (ESI): r_T＝4.439min，C₂₃H₂₃BrFN₃O₄Calculated mass of S535.1, found value of M/z 535.8[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 × 250mm, mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; column temperature: 30 ℃; wavelength: 230nm, R_T＝7.003min)。¹H NMR(400MHz,CDCl₃)δ8.12(s,0.7H),7.83-7.80(m,1H),7.49(d,J＝3.2Hz,0.5H),7.47(s,0.3H),7.44(d,J＝3.2Hz,0.5H),7.25-7.17(m,1H),7.12(d,J＝7.6Hz,1H),7.06-6.98(m,1H),6.24(s,0.5H),6.08(d,J＝2.8Hz,0.5H),4.05-3.97(m,0.4H),3.81-3.73(m,0.6H),3.70(s,3H),3.61(s,1H),3.59(s,2H),2.45-2.39(m,1H),2.21-1.92(m,4H),1.80-1.63(m,3H),1.56-1.45(m,1H)。

Compound 153: LC-MS (ESI): r_T＝3.874min，C₂₅H₂₇F₂N₃O₄Calculated mass of S503.2, found value of M/z 504.1[ M + H [)]⁺. Compound 153(300mg, 0.596mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 85:15, 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give compound 153(300mg, 0.596mmol)To the title compounds 153B (125mg, 42% yield) and 153A (120mg, 40% yield) as yellow solids.

Compound 153A: LC-MS (ESI): r_T＝4.904min，C₂₅H₂₇F₂N₃O₄Calculated mass of S503.2, found value of M/z 504.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.281min)。

Compound 155: ethyl 4- (2-bromo-4-fluorophenyl) -6- (4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.000min，C₂₄H₂₅BrFN₃O₄Calculated mass of S549.1, M/z found value 552.0[ M + H [ ]]⁺。

Compound 155(300mg, about 90% purity) was isolated by chiral preparative SFC (column: chiralpak IC5 μm20 x 250 mm; mobile phase: CO₂MeOH 70:30 at 50 g/min; column temperature: 30 ℃; wavelength: 230nm, back pressure: 100 bar) gave group 1(137mg, 46% yield, 100% stereopure) and group 2(143mg, 48% yield, 100% stereopure) as yellow solids. Fractions from group 1(45mg) and group 2(45mg) were further purified by preparative HPLC (column: Gilson X-bridge C18(5 μm 19X 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 254nm, flow rate: 15mL/min, gradient: 70% -95% (% B)) to give the title compound 155B (18.0mg, 40% yield) and 155A (19.5mg, 43% yield) as yellow solids.

Compound 155A: LC-MS (ESI): r_T＝3.279min，C₂₄H₂₅BrFN₃O₄Calculated mass of S549.1, found value of M/z 550.0[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC,5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 2.999 g/min; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100bar, R_T＝3.67min)。

Compound 159: methyl 4- (2-bromo-3, 4-difluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-MS (R), (DESI)：R_T＝1.96min，C₂₅H₂₇BrF₂N₄O₄Calculated mass of S596.1, found value of M/z 599.3[ M + H]⁺。

Compound 159A: compound 159(950mg, 1.59mmol) was further separated by chiral preparative SFC (column: Chiralpak IG5 μm20 × 250 mm; mobile phase: CO)₂50g/min MeOH (DEA) (70: 30: 0.2); the column temperature is 41.1 ℃; wavelength: 214 nm; back pressure: 100 bar) to yield the title compound 159B (450mg, 47% yield) and 159A (460mg, 48% yield) as yellow solids. For 159A, LC-MS (ESI): r_T＝1.85min，C₂₅H₂₇BrF₂N₄O₄Calculated mass of S596.1, found value of M/z 597.5[ M + H]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH: DEA: 70:30:0.2 at 2.999 g/min; temperature: 40 ℃; wavelength: 230nm, R_T＝3.99min)。

Compound 167A: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- ((trans) -4- (N-methylsulfamoyl) cyclohexyl) -2- (2,4, 6-trifluorophenyl) -1, 4-dihydropyrimidine-5-carboxylate, isolation conditions: a C18 column (acetonitrile: water 20% to 95%) gave a yellow solid (65mg, 19% yield) which was separated by chiral preparative HPLC (column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: EtOH 90:10 at 25 mL/min; temperature: 30 ℃; wavelength: 214 nm). LC-MS (ESI): r_T＝3.492min，C₂₅H₂₃ClF₅N₃O₄Calculated mass of S591.1, M/z found value 592.0[ M + H]⁺. Chiral analysis (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝7.243min)。¹H NMR(400MHz,DMSO-d₆)δ9.44(s,1H),7.57-7.44(m,1H),7.30-7.24(m,2.3H),7.20-7.16(m,0.7H),6.99-6.95(m,0.8H),6.85-6.81(m,0.2H),5.96(s,0.8H),5.87(d,J＝3.2Hz,0.2H),3.94-3.85(m,0.8H),3.64-3.57(m,0.2H),3.52(s,1H),3.51(s,2H),3.06-2.96(m,0.2H),2.88-2.79(m,0.8H),2.59(d,J＝4.8Hz,2H),2.57(d,J＝4.8Hz,1H),2.20-2.04(m,2H),1.92-1.61(m,4H),1.54-1.40(m,2H)。

Compound 168A: methyl 4- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -6- ((trans) -4- (N-methylsulfamoyl) cyclohexyl) -1, 4-dihydropyrimidine-5-carboxylate: (separation conditions: column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: EtOH 70:30 at 25 mL/min; temperature: 30 ℃; wavelength: 214nm)

LC-MS(ESI)：R_T＝3.676min，C₂₄H₂₃ClF₄N₄O₄Calculated mass of S574.1, found M/z value 575.0[ M + H [)]⁺. Chiral analysis (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.312min)。¹H NMR(400MHz,DMSO-d₆)δ9.20-9.17(m,1H),8.56(d,J＝2.0Hz,1H),8.09-8.04(m,1H),7.51-7.42(m,1H),7.25-7.16(m,1H),6.98-6.94(m,0.7H),6.87-6.83(m,0.3H),6.04(s,0.7H),5.93(d,J＝3.6Hz,0.3H),3.92-3.83(m,0.7H),3.62-3.57(m,0.3H),3.53(s,1H),3.52(s,2H),3.05-2.95(m,1H),2.61-2.59(m,3H),2.22-2.06(m,2H),2.00-1.92(m,0.6H),1.88-1.66(m,3.4H),1.56-1.42(m,2H)。

Compound 169A: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (pyrrolidin-1-ylsulfonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (separation conditions, column: chiralpak IE5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.3 at 10 mL/min; temperature: 30 ℃; wavelength: 214 nm). LC-MS (ESI): r_T＝4.293min，C₂₅H₂₇ClF₂N₄O₄S₂Calculated mass 584.1, M/z found value 584.7[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE,5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; chiral analysis (column: Chiralpak IE,5 μm 4.6: 0.2; mobile phase: Hex: EtOH: DEA ═ 50: 0.2; temperature: 230 ℃; wavelength: R_T＝12.642min)。¹H NMR(400MHz,DMSO-d₆)δ9.55(d,J＝3.6Hz,0.6H),8.89(s,0.4H),8.01-7.98(m,1.6H),7.95(d,J＝3.2Hz,0.4H),7.48-7.42(m,1H),7.20-7.14(m,1H),6.02(s,0.4H),5.92(d,J＝3.2Hz,0.6H),3.88-3.81(s,0.4H),3.61-3.57(m,0.6H),3.53(s,1.8H),3.52(s,1.2H),3.31-3.26(m,4H),3.24-3.18(m,1H),2.19-2.09(m,2H),1.97-1.85(m,7H),1.76-1.69(m,1H),1.59-1.51(m,2H)。

Compound 170: methyl 4- (2-chloro-3-fluorophenyl) -6- (3- (N-methylacetamido) cyclopentyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.858min，C₂₃H₂₄ClFN₄O₃Calculated mass of S490.1, M/z found 491.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.55(s,0.8H),9.42-9.29(br s,0.2H),8.01-7.94(m,2H),7.41-7.31(m,2H),7.22-7.17(m,1H),6.06(br s,0.2H),5.97(s,0.8H),5.23(br s,0.2H),4.99(br s,0.3H),4.62-4.54(m,0.2H),4.32-4.16(m,1.3H),3.52(s,3H),2.98-2.96(m,1H),2.88-2.83(m,1.4H),2.74-2.73(m,0.6H),2.14-1.62(m,9H)。

Compound 171: (cis) -methyl 4- (2-chloro-3-fluorophenyl) -6- (4-methyltetrahydrofuran-2-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.839min，C₂₀H₁₉ClFN₃O₃Calculated mass of S435.1, found value of M/z 436.0[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.27-8.90(m,1H),8.02-8.00(m,1H),7.98-7.95(m,1H),7.43-7.29(m,2H),7.25-7.18(m,0.4H),7.16-7.09(m,0.6H),6.11(s,0.7H),6.06(s,0.3H),5.58-5.53(m,0.2H),5.50-5.41(m,0.8H),4.26-4.18(m,0.2H),4.11-4.04(m,0.8H),3.64-3.58(m,1H),3.52(s,3H),2.82-2.69(m,1H),2.47-2.36(m,1H),1.63-1.53(m,0.6H),1.44-1.35(m,0.4H),1.08(d,J＝6.8Hz,2H),1.01(d,J＝6.8Hz,1H)。

Compound 172: methyl 4- (2-chloro-4-fluorophenyl) -6- ((cis) -3- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝4.317min，C₂₃H₂₃ClFN₃O₄Calculated mass of S491.1, M/z found value 491.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.15-8.12(m,0.5H),7.82(d,J＝3.2Hz,1H),7.49(d,J＝2.8Hz,0.5H),7.44(d,J＝3.2Hz,0.5H),7.41-7.38(m,0.5H),7.32-7.28(m,1H),7.15-7.11(m,1H),6.97-6.88(m,1H),6.18(d,J＝4.0Hz,0.5H),6.04(d,J＝2.8Hz,0.5H),4.11-4.04(m,0.5H),3.89-3.82(m,0.5H),3.76-3.67(m,3H),3.63(s,1.5H),3.59(s,1.5H),2.63-2.50(m,1H),2.26-2.11(m,3H),1.96-1.84(m,1H),1.72-1.62(m,1H),1.57-1.40(m,3H)。

Compound 174A: methyl 4- (2-chloro-4-fluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -6- ((trans) -4- (methoxycarbonyl) cyclohexyl) -1, 4-dihydropyrimidine-5-carboxylate

Racemic compound 174(1.30g, 2.50mmol) was separated by chiral preparative HPLC (column: Chiralpak IG5 μm20 × 250 mm; mobile phase: CO₂50g/min MeOH (DEA) (75: 25: 0.2); column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar) to yield the title compound 174A (202mg, 16% yield, 100% stereopure) and 174B (170mg, 13% yield, 97.7% stereopure) as yellow solids.

Compound 174A: LC-MS (ESI): r_T＝2.716min，C₂₅H₂₃ClF₃N₃O₄Calculated mass 521.1, M/z found value 521.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: CO₂MeOH, DEA, 80:20:0.2 at 3.0 g/min; column temperature: 40.1 ℃; wavelength: 230nm, back pressure: 100bar, R_T＝3.01min)。¹H NMR(400MHz,DMSO-d₆)δ9.22(br s,0.6H),9.03(br s,0.4H),8.57(br s,1H),8.06(t,J＝9.6Hz,1H),7.41(d,J＝8.0Hz,1H),7.35(t,J＝7.2Hz,1H),7.22(t,J＝8.0Hz,1H),6.03(s,0.7H),5.92(s,0.3H),3.90-3.79(m,1H),3.61(s,3H),3.52(s,3H),2.39-2.29(m,1H),2.08-1.98(m,2H),1.89-1.66(m,4H),1.50-1.35(m,2H)。

Compound 175: (cis) -tert-butyl 5- (3-methoxy-3-oxopropanoyl) hexahydro-cyclopenta [ c]Pyrrole-2 (1H) -carboxylate, LC-ms (esi): r_T＝1.54min，C₁₆H₂₅NO₅Calculated mass of 311.2, found value of M/z 256.2[ M + H-56 ]]⁺。¹H NMR(400MHz,CDCl₃)δ12.04(s,0.1H),5.01(s,0.1H),3.73(s,2.7H),3.72(s,0.3H),3.48(s,1.8H),3.47-3.43(m,2H),3.28-3.07(m,3H),2.77-2.71(m,0.2H),2.69-2.58(m,1.8H),2.21-2.04(m,2H),1.68-1.56(m,2H),1.44(s,9H)。

Compound 188: methyl 6- (4- ((tert-butoxycarbonyl) amino) cycloheptyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.816min，C₂₇H₃₂ClFN₄O₄Calculated mass of S562.2, found value of M/z 563.1[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.05(br s,0.5H),7.83-7.81(m,1H),7.49(d,J＝2.4Hz,0.4H),7.44-7.43(m,0.6H),7.37-7.31(m,0.5H),7.31-7.28(m,1H),7.14-7.11(m,1H),6.93-6.89(m,1H),6.17(s,0.5H),6.03(d,J＝2.8Hz,0.5H),4.69-4.49(m,0.6H),4.01-3.94(m,1H),3.94-3.86(m,0.4H),3.77-3.68(m,1H),3.59(s,3H),2.20-2.16(m,1.4H),2.09-1.54(m,8.6H),1.46(s,9H)。

Compound 191: ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (2,4, 6-trifluorophenyl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝2.294min，C₂₉H₂₉ClF₅N₃O₄Calculated mass of 613.2, M/z found value 614.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.16-7.03(m,2H),6.70-6.64(m,2H),6.23(s,0.7H),5.99(d,J＝2.8Hz,1H),4.33-3.99(m,4.6H),3.92-3.86(m,0.4H),2.90-2.66(m,2H),1.91-1.83(m,2H),1.74-1.60(m,0.5H),1.56-1.49(m,1H),1.46-1.42(m,9.5H),1.18-1.12(m,3H)。

Compound 196: ethyl 4- (2-bromo-3, 4-difluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-MS: R_T＝2.02min，C₂₆H₂₉BrF₂N₄O₄Calculated mass of S610.1, found value of M/z 613.5[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝2.8Hz,0.7H),9.08(s,0.3H),7.99-7.96(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.52-7.44(m,1H),7.22-7.14(m,1H),6.02(s,0.3H),5.92(d,J＝3.2Hz,0.7H),4.11-3.93(m,4.3H),3.82-3.76(m,0.7H),2.86-2.69(m,2H),1.90-1.67(m,3H),1.53-1.50(m,1H),1.44(s,9H),1.09-1.03(m,3H)。

Racemic compound 196 was separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 95:5:0.2 at 25 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 196A (400mg, 27% yield, 100% stereopurity) and 196B (500mg, 33% yield, 97.7% stereopurity) as yellow solids.

Compound 196A: chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 95:5:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 95:5: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝10.303min)。

Compound 202: methyl 6- (3- ((tert-butoxycarbonyl) amino) bicyclo [1.1.1]Pent-1-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.397min，C₂₅H₂₅ClF₂N₄O₄Calculated mass of S550.1, found value of M/z 551.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 2.999 g/min; column temperature: 40 ℃; wavelength: 230nm, back pressure: 100bar R_T2.71min and 3.94 min).¹H NMR(300MHz,CDCl₃)δ7.93(br s,0.8H),7.84-7.81(m,1H),7.51-7.50(m,0.2H),7.46(d,J＝3.0Hz,0.8H),7.42-7.40(m,0.2H),7.09-7.02(m,2H),6.16(s,0.8H),6.03(br s,0.2H),5.04(br s,1H),3.66(s,0.5H),3.61(s,2.5H),2.55(s,5H),2.47(s,1H),1.49(s,9H)。

Racemic compound 202(700mg, 1.27mmol) was separated by chiral preparative HPLC (column: Chiralpak IG5 μm20 x 250 mm; mobile phase: CO₂MeOH 70:40 at 50 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar) to yield the title compound 202A (330mg, 47% yield, 100% stereopure) and 202B (340mg, 49% yield, 100% stereopure) as yellow solids.

Compound 202A: LC-MS (ESI): r_T＝2.253min，C₂₅H₂₅ClF₂N₄O₄Calculated mass of S550.1, found value of M/z 551.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 2.999 g/min; column temperature: 39.8 ℃; wavelength: 230nm, back pressure: 100bar, R_T＝2.72min)。¹H NMR(300MHz,CDCl₃)δ7.92(s,0.8H),7.82-7.81(m,1H),7.51-7.50(m,0.2H),7.46-7.45(m,0.8H),7.42-7.40(m,0.2H),7.09-7.02(m,2H),6.16(s,0.8H),6.03(s,0.2H),5.06(br s,1H),3.66(s,0.5H),3.61(s,2.5H),2.55(s,5H),2.47(s,1H),1.49(s,9H)。

Compound 211: methyl 4- (2-chloro-3-fluorophenyl) -6- (5-ethoxycarbonyltetrahydrofuran-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 8 stereoisomers), LC-ms (esi): r_T3.768,3.851 and 3.946min, C₂₂H₂₁ClFN₃O₅Calculated mass of S493.1, M/z found value 494.1[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.93-7.90(m,0.2H),7.89-7.88(m,0.8H),7.77-7.76(m,0.8H),7.75-7.73(m,0.2H),7.31-7.14(m,3H),6.20-6.17(m,0.2H),6.16(s,0.3H),6.12(m,0.5H),4.88-4.79(m,0.5H),4.64-4.52(m,1.5H),4.29-3.94(m,4H),3.60-3.57(m,3H),2.96-2.83(m,0.4H),2.712.57(m,1H),2.47-2.40(m,0.2H),2.32-2.18(m,0.4H),1.32-1.30(m,2.4H),1.29-1.19(m,0.6H)。

The racemic mixture of 211 (810mg, 1.64mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: IPA: DEA ═ 60:40:0.2 at 15 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 211S as a yellow solid (71mg, 9% yield, 100% stereopurity), group 1(325mg, 40% yield) and group 2(177mg, 22% yield). Group 1(325mg, 0.66mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: IPA: DEA ═ 80:20:0.2 at 15 mL/min; temperature: 30 ℃; wavelength: 230) to give the title compound 211U (32mg, 10% yield, 97.7% stereopurity), group a (117mg, 36% yield) and 211N (51mg, 16% yield, including both isomers) as yellow solids. Group 2(177mg, 0.36mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: IPA: DEA ═ 85:15:0.2 at 15 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 211V (54mg, 31% yield, 100% stereopurity) and 211T (43mg, 24% yield, 100% stereopurity) as yellow solids. Group a (117mg, 0.24mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μ M20 × 250 mm; mobile phase: Hex: IPA: DEA ═ 85:15:0.2 at 15 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 211M (31mg, 26% yield, 98.7% stereopurity) and 211X (38mg, 32% yield, 100% stereopurity) as yellow solids.

Intermediate 211M: LC-MS (ESI): r_T＝4.092min，C₂₂H₂₁ClFN₃O₅Calculated mass of S493.1, M/z found value 493.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; chiral analysis (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20: 0.2; temperature: 230 ℃; wavelength: 230 nm; R_T＝13.062min)。¹H NMR(400MHz,CD₃OD)δ7.90(d,J＝2.4Hz,1H),7.77(d,J＝2.4Hz,0.7H),7.72(d,J＝2.8Hz,0.3H),7.32-7.25(m,1.3H),7.20-7.14(m,1.7H),6.18(s,0.2H),6.15(s,0.8H),4.87-4.82(m,0.2H),4.80-4.77(m,1H),4.59-4.52(m,0.8H),4.39-4.30(m,1H),4.23(q,J＝7.2Hz,2H),4.18-4.15(m,0.2H),4.11(t,J＝6.8Hz,0.8H),3.59(s,0.9H),3.58(s,2.1H),2.75-2.68(m,0.7H),2.65-2.58(m,0.3H),2.49-2.44(m,0.3H),2.17-2.10(m,0.7H),1.30(t,J＝7.2Hz,3H)。

Compound 217: methyl 4- (2-chloro-4-fluorophenyl) -6- (oxetan-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.061min，C₁₈H₁₅ClFN₃O₃Calculated mass of S407.1, found value of M/z 407.9[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)8.03(s,2H),7.45-7.41(m,2H),7.24-7.19(m,1H),5.94(s,1H),4.86-4.68(m,5H),3.50(s,3H)。

The racemic mixture of 217 (250mg, 0.614mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC 5um 20 mm; mobile phase: Hex: EtOH ═ 80:20 at 13 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 217A (76.9mg, 31% yield, 100% stereopurity) and 217B (53.2mg, 21% yield, 100% stereopurity) as yellow solids. Compound 217A: LC-MS (ESI): r_T＝3.996min，C₁₈H₁₅ClFN₃O₃Calculated mass of S407.1, found value of M/z 408.1[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 80:20 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝10.020min)；¹H NMR(400MHz,DMSO-d₆)9.73(s,0.9H),9.28(s,0.1H),8.05-7.95(m,2H),7.47-7.41(m,2H),7.25-7.20(m,1H),6.01(s,0.1H),5.93(s,0.9H),4.94-4.62(m,5H),3.49(s,3H)。

Compound 218: methyl 4- (2-chloro-4-fluorophenyl) -6- (1, 4-dioxaspiro [4.5]]Decan-7-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.437min，C₂₃H₂₃ClFN₃O₄Calculated mass of S491.1, M/z found value 492.2[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.48-9.44(m,0.6H),9.20(s,0.2H),9.12(s,0.2H),8.00-7.99(m,1.6H),7.94-7.93(m,0.4H),7.44-7.41(m,1H),7.36-7.29(m,1H),7.25-7.20(m,1H),6.01-6.00(m,0.3H),5.91(dd,J＝8.4,3.6Hz,0.7H),4.14(s,0.3H),3.91-3.85(m,4.7H),3.53-3.51(m,3H),2.12-1.87(m,1H),1.83-1.42(m,7H)。

Compound 220: (cis) -methyl 6- (4- (((tert-butyldiphenylsilyl) oxy) methyl) -tetrahydrofuran-2-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.899min，C₃₆H₃₇ClFN₃O₄Calculated mass of SSi 689.2, M/z found value 690.2[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ7.76(d,J＝3.9Hz,0.4H),7.70-7.60(m,4.6H),7.47-7.28(m,8H),7.25-7.15(m,1H),7.05-7.00(m,2H),6.28(s,0.5H),6.23(s,0.5H),5.61-5.53(m,1H),4.14-4.08(m,2H),3.73-3.63(m,2H),3.59(s,3H),2.84-2.63(m,2H),1.69-1.57(m,0.5H),1.53-1.49(m,0.5H),1.07(s,5H),1.02(s,4H)。

Compound 224: (trans) -methyl 4- (2-bromo-4-fluorophenyl) -6- (4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.856min，C₂₃H₂₃BrFN₃O₄Calculated mass of S535.1, found M/z 538.2[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.47-9.39(m,0.5H),8.99-8.93(m,0.5H),7.99(s,1.5H),7.94-7.91(m,0.5H),7.57(d,J＝8.0Hz,1H),7.37-7.30(m,1H),7.27-7.22(m,1H),5.98(s,0.5H),5.88(s,0.5H),3.89-3.83(m,0.5H),3.78-3.69(m,0.5H),3.62(s,3H),3.52(s,3H),2.68-2.62(m,0.5H),2.37-2.29(m,0.5H),2.02-1.98(m,2H),1.88-1.78(m,3H),1.72-1.59(m,1H),1.50-1.37(m,2H)。

The racemic mixture of 224 (450mg, 0.840mmol) was separated by chiral preparative HPLC (column: chiralpak ic5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 13 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 224X (193mg, 43% yield, 100% stereopurity) and 224Y (190mg, 42% yield, 99.0% stereopurity).

Compound 224X: LC-MS (ESI): r_T＝3.841min，C₂₃H₂₃BrFN₃O₄Calculated mass of S535.1, found M/z 535.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 85:15: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝7.151min)。¹H NMR(400MHz,DMSO-d₆)δ9.47-9.41(m,0.5H),9.01-8.94(m,0.5H),8.00-7.99(m,1.5H),7.95-7.93(m,0.5H),7.57(dd,J＝8.4,2.4Hz,1H),7.39-7.30(m,1H),7.28-7.23(m,1H),5.98(s,0.5H),5.88(s,0.5H),3.87-3.79(m,0.5H),3.62(s,3H),3.60-3.57(m,0.5H),3.52(s,3H),2.40-2.29(m,0.8H),2.08-1.98(m,2.2H),1.91-1.79(m,2.2H),1.74-1.61(m,1.8H),1.50-1.36(m,2H)。

Compound 224Y: LC-MS (ESI): r_T＝3.847min，C₂₃H₂₃BrFN₃O₄Calculated mass of S535.1, found value of M/z 535.8[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 85:15: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝10.245min)。¹H NMR(400MHz,DMSO-d₆)δ9.44(d,J＝3.6Hz,0.6H),8.96(s,0.4H),8.00-7.99(m,1.5H),7.94(d,J＝3.6Hz,0.5H),7.59-7.55(m,1H),7.36-7.33(m,1H),7.30-7.22(m,1H),5.98(s,0.4H),5.88(d,J＝3.6Hz,0.6H),3.88-3.78(m,0.5H),3.62(s,1.2H),3.61(s,1.8H),3.59-3.57(m,0.5H),3.53(s,1.6H),3.51(s,1.4H),2.38-2.30(m,0.7H),2.07-1.97(m,2.3H),1.91-1.82(m,2H),1.79-1.60(m,2H),1.51-1.36(m,2H)。

Compound 226: (trans) -methyl 4- (3, 4-difluoro-2-methylphenyl) -6- (4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate，LC-MS(ESI)：R_T＝4.206min，C₂₄H₂₅F₂N₃O₄Calculated mass of S489.2, M/z found value 490.3[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝3.6Hz,0.7H),8.96(s,0.3H),7.99-7.97(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.25-7.17(m,1H),7.10-7.07(m,0.7H),6.98-6.94(m,0.3H),5.81(s,0.3H),5.67(d,J＝3.2Hz,0.7H),3.90-3.79(m,0.3H),3.62-3.53(m,3.7H),3.52(s,3H),2.56-2.53(m,0.3H),2.47-2.43(m,2.7H),2.37-2.29(m,1H),2.04-1.96(m,2H),1.90-1.60(m,4H),1.49-1.35(m,2H)。

Rac 226(200mg, 0.410mmol) was separated by chiral preparative HPLC (column: Chiralpak IC5 μ M20 × 250 mm; mobile phase: Hex: EtOH ═ 85:15 at 8 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 226M (80.0mg, 40% yield, 100% stereopurity) and 226N (90.0mg, 45% yield, 99.8% stereopurity) as yellow solids.

Compound 226M: LC-MS (ESI): r_T＝4.302min，C₂₄H₂₅F₂N₃O₄Calculated mass of S489.2, M/z found 490.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.758min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.6Hz,0.7H),8.95(s,0.3H),8.00-7.97(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.25-7.17(m,1H),7.11-7.08(m,0.7H),6.98-6.94(m,0.3H),5.82(s,0.3H),5.68(d,J＝3.6Hz,0.7H),3.90-3.80(m,0.3H),3.62-3.53(m,3.7H),3.52(s,3H),2.55-2.53(m,0.3H),2.47-2.43(m,2.7H),2.38-2.30(m,1H),2.08-1.97(m,2H),1.94-1.60(m,4H),1.49-1.36(m,2H)。

Compound 228: (trans) -methyl 4- (2-bromo-3, 4-difluorophenyl) -6- (4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.469min，C₂₃H₂₂BrF₂N₃O₄Calculated mass of S553.1, M/z found value 553.8[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝4.0Hz,0.5H),8.98(s,0.5H),7.99-7.98(m,1.5H),7.94-7.93(m,0.5H),7.52-7.44(m,1H),7.21-7.12(m,1H),6.00(s,0.5H),5.91(d,J＝3.2Hz,0.5H),3.87-3.80(m,0.5H),3.62-3.61(m,3.5H),3.52-3.51(m,3H),2.37-2.31(m,0.6H),2.08-1.65(m,6.4H),1.51-1.36(m,2H)。

228 (400mg, 0.72mmol) were separated by chiral preparative HPLC (column: chiralpak ia5 μ M20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 25.0 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compounds 228M (160mg, 40% yield, 100% stereopurity) and 228N (170mg, 43% yield, 98.2% stereopurity) as yellow solids.

Compound 228M: LC-MS (ESI): r_T＝3.342min，C₂₃H₂₂BrF₂N₃O₄Calculated mass of S553.1, found M/z value 556.1[ M + H]⁺. Chiral analysis (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IA5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30 ℃; wavelength: 230_T＝5.698min)。¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝3.2Hz,0.5H),8.99(s,0.5H),8.00-7.99(m,1.5H),7.94-7.93(m,0.5H),7.52-7.44(m,1H),7.21-7.12(m,1H),6.00(s,0.5H),5.91(d,J＝3.6Hz,0.5H),3.87-3.80(m,0.5H),3.62-3.61(m,3.5H),3.52-3.51(m,3H),2.37-2.31(m,0.7H),2.04-1.61(m,6.3H),1.50-1.39(m,2H)。

Compound 228N: LC-MS (ESI): r_T＝3.346min，C₂₃H₂₂BrF₂N₃O₄Calculated mass of S553.1, found M/z value 556.1[ M + H]⁺. Chiral analysis (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IA5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30 ℃; wavelength: 230_T＝6.157min)。¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝3.6Hz,0.5H),8.99(s,0.5H),8.00-7.99(m,1.5H),7.94-7.93(m,0.5H),7.52-7.44(m,1H),7.22-7.12(m,1H),6.00(s,0.5H),5.91(d,J＝3.6Hz,0.5H),3.88-3.81(m,0.5H),3.62-3.57(m,3.5H),3.52-3.51(m,3H),2.37-2.31(m,0.6H),2.07-1.64(m,6.4H),1.50-1.41(m,2H)。

Compounds 233M and 233N: (cis) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N, N-dimethylsulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N, N-dimethylsulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 233M: LC-MS (ESI): r_T＝3.477min，C₂₃H₂₅ClF₂N₄O₄S₂Calculated mass of 558.1, M/z found value 559.2[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.36(s,0.6H),7.84(d,J＝3.2Hz,0.6H),7.82(d,J＝3.2Hz,0.4H),7.51(d,J＝3.2Hz,0.4H),7.42(d,J＝3.2Hz,1H),7.09-6.98(m,2H),6.18(s,0.6H),6.06(d,J＝2.4Hz,0.4H),4.12-4.06(m,0.6H),3.95-3.91(m,0.4H),3.60(s,1.2H),3.58(s,1.8H),3.33-3.30(m,0.6H),3.23-3.20(m,0.4H),2.98-2.95(m,6H),2.44-2.41(m,2.2H),2.25-2.14(m,1.8H),1.97-1.77(m,3.7H),1.67-1.62(m,0.3H)。

Compound 233N: LC-MS (ESI): r_T＝4.172min，C₂₃H₂₅ClF₂N₄O₄S₂Calculated mass of 558.1, M/z found value 559.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.09(s,0.5H),7.84-7.81(m,1H),7.51(d,J＝3.2Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.39(s,0.5H),7.06-7.00(m,2H),6.18(s,0.5H),6.05(d,J＝2.4Hz,0.5H),4.04-3.98(m,0.4H),3.80-3.75(m,0.6H),3.62(s,1.8H),3.60(s,1.2H),3.14-3.06(m,1H),2.96(d,J＝4.4Hz,6H),2.35-2.19(m,2.3H),2.13-2.03(m,1H),2.01-1.74(m,3.7H),1.64-1.60(m,0.3H),1.50-1.48(m,0.7H)。

Rac 233M (60mg, 0.105mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IF5 μ M20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 85:15:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 233A (5.0mg, 8% yield, 98.8% stereopurity) and 233B (5.5mg, 9% yield, 98.2% stereopurity) as yellow solids.

Compound 233A: LC-MS (ESI): r_T＝4.329min，C₂₃H₂₅ClF₂N₄O₄S₂Calculated mass of 558.1, M/z found value 558.9[ M + H [ ]]⁺. Chiral analysis (column: Chir)alpak IF5 μm4.6 x 250 mm; mobile phase: hex EtOH 80:20 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝10.706min)。¹H NMR(400MHz,CDCl₃)δ8.36(s,0.6H),7.84(d,J＝3.2Hz,0.6H),7.82(d,J＝3.2Hz,0.4H),7.51(d,J＝3.2Hz,0.4H),7.42(d,J＝3.2Hz,1H),7.09-7.00(m,2H),6.18(s,0.6H),6.06(d,J＝2.8Hz,0.4H),4.13-4.06(m,0.6H),3.96-3.92(m,0.4H),3.60(s,1.2H),3.58(s,1.8H),3.33-3.30(m,0.6H),3.23-3.20(m,0.4H),2.98-2.97(m,6H),2.44-2.41(m,2.2H),2.28-2.15(m,1.8H),2.01-1.76(m,4H)。

Compound 233B: LC-MS (ESI): r_T＝4.329min，C₂₃H₂₅ClF₂N₄O₄S₂Calculated mass of 558.1, M/z found value 558.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 80:20 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝13.239min)。¹H NMR(400MHz,CDCl₃)δ8.36(s,0.6H),7.84(d,J＝3.2Hz,0.6H),7.82(d,J＝2.8Hz,0.4H),7.51(d,J＝3.2Hz,0.4H),7.42(d,J＝3.2Hz,1H),7.09-6.98(m,2H),6.18(s,0.6H),6.06(d,J＝2.8Hz,0.4H),4.12-4.06(m,0.6H),3.96-3.91(m,0.4H),3.60(s,1.2H),3.58(s,1.8H),3.33-3.30(m,0.6H),3.23-3.21(m,0.4H),2.98-2.97(m,6H),2.44-2.41(m,2.2H),2.30-2.21(m,1.8H),2.02-1.75(m,4H)。

Racemic 233N (200mg, 0.36mmol) was separated by chiral preparative SFC (separation conditions: column: ChiralpakIF 5 μm20 × 250 mm; mobile phase: CO₂EtOH, DEA 75:25:0.3 at 50 g/min; column temperature: 30 ℃; wavelength: 214 nm; back pressure: 100 bar) to give the title compound 233C (46.8mg, 23% yield, 99.4% stereopure) and 233D (40.9mg, 21% yield, 100% stereopure) as yellow solids.

Compound 233C: LC-MS (ESI): r_T＝4.244min，C₂₃H₂₅ClF₂N₄O₄S₂Calculated mass of 558.1, M/z found value 558.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: CO)₂EtOH, DEA 75:25:0.2 at 3.0 g/min; column temperature: 41.2 ℃; wavelength: 214nm, back pressure:100bar, R_T＝5.87min)。¹H NMR(400MHz,CDCl₃)δ8.10(s,0.5H),7.84(d,J＝3.2Hz,0.5H),7.81(d,J＝2.8Hz,0.5H),7.51(d,J＝2.8Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.40(s,0.5H),7.07-7.01(m,2H),6.18(s,0.5H),6.05(d,J＝2.8Hz,0.5H),4.05-3.98(m,0.4H),3.80-3.78(m,0.6H),3.62-3.58(m,3H),3.14-3.04(m,1H),2.99-2.95(m,6H),2.35-2.19(m,2.5H),2.12-1.96(m,1.5H),1.93-1.73(m,3H),1.66-1.61(m,0.5H),1.53-1.47(m,0.5H)。

Compound 233D: LC-MS (ESI): r_T＝4.242min，C₂₃H₂₅ClF₂N₄O₄S₂Calculated mass of 558.1, M/z found value 558.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: CO)₂EtOH, DEA 75:25:0.2 at 3.0 g/min; column temperature: 40.5 ℃; wavelength: 214nm, back pressure: 100bar, R_T＝7.38min)。¹H NMR(400MHz,CDCl₃)δ8.10(s,0.5H),7.84(d,J＝3.2Hz,0.5H),7.81(d,J＝3.2Hz,0.5H),7.51(d,J＝2.8Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.40(s,0.5H),7.07-6.98(m,2H),6.18(s,0.5H),6.05(d,J＝2.4Hz,0.5H),4.04-3.98(m,0.4H),3.80-3.75(m,0.6H),3.62(s,1.8H),3.60(s,1.2H),3.14-3.07(m,1H),2.96(d,J＝4.8Hz,6H),2.35-2.21(m,2.5H),2.18-1.93(m,1.5H),1.91-1.74(m,3H),1.65-1.63(m,0.5H),1.57-1.47(m,0.5H)。

Compounds 234M and 234N: (cis) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N-isopropylsulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N-isopropylsulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Intermediate 234M (enantiomeric mixture): LC-MS (ESI): r_T＝2.619min，C₂₄H₂₇ClF₂N₄O₄S₂Calculated mass of 572.1, M/z found value 573.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.33(s,0.6H),7.83-7.81(m,1H),7.49(d,J＝2.8Hz,0.4H),7.42-7.41(m,1H),7.09-6.97(m,2H),6.17(s,0.7H),6.06(d,J＝2.0Hz,0.3H),4.14-4.07(m,0.7H),4.00-3.91(m,1H),3.86-3.84(m,0.3H),3.71-3.63(m,1H),3.60-3.58(m,3H),3.19(s,0.7H),3.10-3.03(m,0.3H),2.53-2.42(m,2H),2.28-2.13(m,1.6H),2.08-1.91(m,2H),1.87-1.73(m,1.4H),1.27-1.22(m,6H)。

Intermediate 234N (enantiomeric mixture): LC-MS (ESI): r_T＝2.603min，C₂₄H₂₇ClF₂N₄O₄S₂Calculated mass of 572.1, M/z found value 572.9[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.12(s,0.4H),7.86-7.83(m,1H),7.53-7.47(m,1H),7.42(s,0.6H),7.10-7.02(m,2H),6.19(s,0.5H),6.06(s,0.5H),4.09-4.03(m,0.4H),3.87-3.72(m,2.6H),3.67-3.61(m,3H),2.99(s,1H),2.44-2.30(m,2H),2.24-1.94(m,2H),1.84-1.75(m,3H),1.30-1.28(m,6H)。

The racemic mixture of (cis) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N-isopropylsulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 234M (60mg, 0.105mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE5 μ M20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 234A (20mg, 33% yield, 100% stereopurity) and 234B (20mg, 33% yield, 99.4% stereopurity) as yellow solids.

Compound 234A: LC-MS (ESI): r_T＝4.001min，C₂₄H₂₇ClF₂N₄O₄S₂Calculated mass of 572.1, M/z found value 573.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of chiral structure (column: Chiralpak IE5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 80:20: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝9.378min)。¹H NMR(400MHz,CDCl₃)δ8.33(s,0.6H),7.83-7.81(m,1H),7.49(d,J＝3.2Hz,0.4H),7.42-7.41(m,1H),7.09-6.97(m,2H),6.17(s,0.7H),6.06(d,J＝2.8Hz,0.3H),4.14-4.07(m,0.7H),4.00-3.92(m,1H),3.86-3.83(m,0.3H),3.69-3.64(m,1H),3.60-3.59(m,3H),3.20(s,0.7H),3.07(s,0.3H),2.54-2.42(m,2H),2.28-2.12(m,1.7H),2.06-1.92(m,2H),1.88-1.75(m,1.3H),1.27-1.22(m,6H)。

Compound 234B: LC-MS (ESI): r_T＝3.998min，C₂₄H₂₇ClF₂N₄O₄S₂Calculated mass of 572.1, M/z found value 573.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of chiral structure (column: Chiralpak IE5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 80:20: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝11.824min)。¹H NMR(400MHz,CDCl₃)8.33(s,0.6H),7.83-7.81(m,1H),7.49(d,J＝2.8Hz,0.4H),7.42-7.41(m,1H),7.09-6.97(m,2H),6.17(s,0.7H),6.06(d,J＝2.0Hz,0.3H),4.14-4.07(m,0.7H),4.00-3.91(m,1H),3.86-3.84(m,0.3H),3.71-3.63(m,1H),3.60-3.58(m,3H),3.19(s,0.7H),3.10-3.03(m,0.3H),2.53-2.42(m,2H),2.28-2.13(m,1.6H),2.08-1.91(m,2H),1.87-1.73(m,1.4H),1.27-1.22(m,6H)。

The racemic mixture of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N-isopropylsulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 234N (200mg, 0.34mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 70:30 at 12 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 234C (90mg, 45% yield, 100% stereopurity) and 234D (40.0mg, 45% yield, 100% stereopurity) as yellow solids.

Compound 234C: LC-MS (ESI): r_T＝4.181min，C₂₄H₂₇ClF₂N₄O₄S₂Calculated mass of 572.1, M/z found value 573.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝10.101min)。¹H NMR(400MHz,CDCl₃)δ8.10(s,0.5H),7.84-7.81(m,1H),7.51(d,J＝2.8Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.40(s,0.5H),7.06-6.98(m,2H),6.18(s,0.5H),6.05(d,J＝2.8Hz,0.5H),4.04-3.97(m,0.5H),3.86-3.74(m,1.5H),3.72-3.65(m,1H),3.64-3.60(m,3H),3.01-2.92(m,1H),2.48-2.29(m,2H),2.23-1.91(m,2H),1.83-1.70(m,2.7H),1.55-1.48(m,0.3H),1.28-1.26(m,6H)。

Compound 234D: LC-MS (ESI): r_T＝4.191min，C₂₄H₂₇ClF₂N₄O₄S₂Calculated mass of 572.1, M/z found value 573.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝13.624min)。¹H NMR(400MHz,CDCl₃)δ8.10(s,0.5H),7.84-7.81(m,1H),7.51(d,J＝2.8Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.40(s,0.5H),7.06-6.98(m,2H),6.18(s,0.5H),6.05(d,J＝2.4Hz,0.5H),4.05-3.98(m,0.5H),3.86-3.74(m,1.5H),3.73-3.67(m,1H),3.64-3.60(m,3H),3.00-2.92(m,1H),2.42-2.29(m,2H),2.23-1.92(m,2H),1.87-1.64(m,2.6H),1.55-1.48(m,0.4H),1.28-1.26(m,6H)。

Compound 235: (trans) -methyl 6- (4- ((tert-butoxycarbonyl) amino) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

¹H NMR(400MHz,DMSO-d₆)δ9.60(d,J＝3.2Hz,0.7H),9.17(s,0.3H),8.00-7.98(m,1.7H),7.93(d,J＝2.8Hz,0.3H),7.47-7.42(m,1H),7.22-7.13(m,1H),6.02(s,0.3H),5.93(d,J＝3.6Hz,0.7H),4.07-4.02(m,2H),3.94-3.89(m,0.2H),3.82-3.76(m,0.8H),3.53(s,2H),3.52(s,1H),2.83-2.71(m,2H),2.01-1.94(m,1H),1.89-1.81(m,1.5H),1.74-1.65(m,1.5H),1.53-1.49(m,1H),1.44(s,9H)。

Compound 239: (trans) -methyl 4- (2-bromo-4-fluorophenyl) -6- (4- (methoxycarbonyl) cyclohexyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.219min，C₂₄H₂₅BrFN₃O₄Calculated mass of S549.1M/z found value 549.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.33(d,J＝2.8Hz,0.6H),8.84(s,0.4H),7.56-7.55(m,1.6H),7.47(s,0.4H),7.37-7.24(m,2H),5.96(s,0.4H),5.87(d,J＝3.6Hz,0.6H),3.81(br s,0.4H),3.62(s,1H),3.61(s,2H),3.58-3.56(m,0.6H),3.52(s,2H),3.51(s,1H),2.43(s,1H),2.39(s,2H),2.33-2.29(m,1H),2.03-1.97(m,2H),1.89-1.80(m,1H),1.76-1.75(m,2H),1.68-1.63(m,1H),1.46-1.38(m,2H)。

The racemic mixture of 239 (350mg, 0.638mmol) was separated by chiral preparative HPLC (column: chiralpak ic5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 85:15 at 25.0 mL/min; temperature: 30 ℃; wavelength: 214nm) and purified by preparative HPLC (column: Gilson X-bridge C18(5 μm19 ═ 150mm) mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 60% -95% (% B)) to give the title compound 239X (110mg, 31% yield, 100% stereopurity) and 239Y (109mg, 31% yield, 100% stereopurity) as yellow solids.

Compound 239X: LC-MS (ESI): r_T＝4.207min，C₂₄H₂₅BrFN₃O₄Calculated mass of S549.1M/z found value 549.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝7.110min)。¹H NMR(400MHz,DMSO-d₆)δ9.33(d,J＝3.6Hz,0.6H),8.83(s,0.4H),7.56(d,J＝2.4Hz,0.6H),7.55(s,1H),7.47(s,0.4H),7.36-7.30(m,1H),7.28-7.21(m,1H),5.96(s,0.4H),5.87(d,J＝3.6Hz,0.6H),3.85-3.78(m,0.4H),3.62(s,1H),3.61(s,2H),3.59-3.55(m,0.6H),3.52(s,2H),3.51(s,1H),2.43(s,1H),2.39(s,2H),2.36-2.29(m,1H),2.08-1.96(m,2H),1.92-1.86(m,1H),1.83-1.73(m,2H),1.70-1.59(m,1H),1.50-1.38(m,2H)。

Compound 239Y: LC-MS (ESI): r_T＝4.214min，C₂₄H₂₅BrFN₃O₄Calculated mass of S549.1M/z found to be 549.8[ M + H]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝10.035min)。¹H NMR(400MHz,DMSO-d₆)δ9.33(d,J＝3.6Hz,0.6H),8.84(s,0.4H),7.56(d,J＝2.4Hz,0.6H),7.54(s,1H),7.47(s,0.4H),7.36-7.21(m,2H),5.96(s,0.4H),5.87(d,J＝3.6Hz,0.6H),3.85-3.80(m,0.4H),3.62(s,1H),3.61(s,2H),3.59-3.57(m,0.6H),3.52(s,2H),3.51(s,1H),2.43(s,1H),2.39(s,2H),2.37-2.29(m,1H),2.07-1.96(m,2H),1.92-1.86(m,1H),1.83-1.73(m,2H),1.70-1.59(m,1H),1.49-1.38(m,2H)。

Compound 257: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (methoxycarbonyl) -bicyclo [1.1.1]Pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-ylAcid esters, LC-MS (ESI): r_T＝3.835min，C₂₂H₁₉ClFN₃O₄Calculated mass of S475.1, M/z found value 476.1[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ8.02(d,J＝2.4Hz,1H),7.92(s,1H),7.43-7.40(m,1H),7.30-7.28(m,1H),7.12-7.08(m,1H),6.13(s,1H),3.71(s,3H),3.62(s,3H),2.52(s,6H)。

Racemic mixture of methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (methoxycarbonyl) bicyclo [1.1.1] pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 257 (350mg, 0.740mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IF5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.3, at 13 mL/min; temperature: 30 ℃; wavelength: 254nm) and further purified by preparative HPLC (column: Gilson X-bridgeC18(5 μm19 × 150mm), mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 60% -95% (% B)), the title compound 257X (86mg, 25% yield, 100% stereopure) and 257Y (92mg, 26% yield, 98.1% stereopure) were obtained as yellow solids.

Compound 257X: LC-MS (ESI): r_T＝4.141min，C₂₂H₁₉ClFN₃O₄Calculated mass of S, M/z 475.1 found 476.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; chiral analysis (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 90:10: 0.2; temperature: 230 ℃; wavelength: 230 nm; R_T＝8.113min)。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝3.2Hz,0.6H),7.89(d,J＝3.2Hz,0.4H),7.76-7.74(m,1H),7.38-7.34(m,1H),7.25-7.21(m,1H),7.06-7.02(m,1H),6.10(s,0.6H),6.03(s,0.4H),3.71(s,1.8H),3.70(s,1.2H),3.61(s,1.2H),3.60(s,1.8H),2.56(s,3.5H),2.44(s,2.5H)。

Compound 257Y: LC-MS (ESI): r_T＝2.397min，C₂₂H₁₉ClFN₃O₄Calculated mass of S, M/z 475.1 found a value of 475.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; chiral analysis (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 90:10: 0.2; temperature: 230 ℃; wavelength: 230 nm; R_T＝9.805min)。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝3.6Hz,0.6H),7.89(d,J＝3.2Hz,0.4H),7.76-7.74(m,1H),7.38-7.34(m,1H),7.25-7.21(m,1H),7.09-7.01(m,1H),6.10(s,0.6H),6.03(s,0.4H),3.71(s,1.6H),3.70(s,1.4H),3.61(s,1.4H),3.60(s,1.6H),2.56(s,3.5H),2.44(s,2.5H)。

Compounds 259A and 259B: (cis) methyl 4- (2-chloro-3-fluorophenyl) -6- (4- (N-methylsulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (trans) -methyl 4- (2-chloro-3-fluorophenyl) -6- (4- (N-methylsulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Separation conditions are as follows: preparative HPLC (column: Gilson X-bridge C18(5 μm 19X 150mm) mobile phase A: water (+ 0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 40% -80% (% B))

Compound 259A:¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.2Hz,0.7H),8.29(s,0.3H),8.01-7.97(m,2H),7.41-7.29(m,2H),7.22-7.15(m,1.4H),6.95-6.91(m,0.6H),6.08(s,0.3H),5.97(d,J＝3.6Hz,0.7H),3.96-3.87(m,0.3H),3.73-3.66(m,0.7H),3.51(s,3H),3.19-3.17(m,0.9H),2.67(br s,0.1H),2.61-2.58(m,3H),2.33-1.77(m,6.3H),1.70-1.60(m,1H),1.55-1.45(m,0.7H)。

compound 259B:¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝3.6Hz,0.6H),8.95(s,0.4H),8.00-7.99(m,1.5H),7.95-7.94(m,0.5H),7.40-7.29(m,2H),7.21-7.16(m,1H),7.00-6.95(m,0.4H),6.92-6.88(m,0.6H),6.06(s,0.3H),5.97(d,J＝3.6Hz,0.7H),3.89-3.83(m,0.4H),3.61-3.51(m,3.6H),3.26-3.16(m,0.4H),3.09-3.01(m,0.6H),2.62(d,J＝4.4Hz,3H),2.22-2.09(m,2H),2.01-1.71(m,4H),1.56-1.42(m,2H)。

the racemic mixture of (cis) -methyl 4- (2-chloro-3-fluorophenyl) -6- (4- (N-methylsulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 259A (70mg, 0.133mmol) was separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 13 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 259C (7.6mg, 11% yield, 100% stereopurity) and 259D (17.1mg, 24% yield, 100% stereopurity) as yellow solids.

Compound 259C: LC-MS (ESI): r_T＝3.455min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass of 526.1, found value of M/z 526.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; temperature: 30 ℃; wavelength: 230 nm; and_T＝9.436min)。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.6Hz,0.6H),8.29(s,0.4H),8.00-7.98(m,2H),7.40-7.30(m,2H),7.22-7.15(m,1.4H),6.96-6.90(m,0.6H),6.08(s,0.4H),5.97(d,J＝3.2Hz,0.6H),3.97-3.86(m,0.3H),3.74-3.66(m,0.7H),3.51(s,3H),3.22-3.14(m,0.9H),2.67(br s,0.1H),2.59-2.58(m,3H),2.30-1.77(m,6.3H),1.70-1.59(m,1H),1.55-1.46(m,0.7H)。

compound 259D: LC-MS (ESI): r_T＝4.356min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass of 526.1, found value of M/z 526.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; temperature: 30 ℃; wavelength: 230 nm; and_T＝13.128min)。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.2Hz,0.7H),8.29(s,0.3H),8.01-7.97(m,2H),7.41-7.29(m,2H),7.22-7.15(m,1.4H),6.95-6.91(m,0.6H),6.08(s,0.3H),5.97(d,J＝3.6Hz,0.7H),3.96-3.87(m,0.3H),3.74-3.65(m,0.7H),3.51(s,3H),3.19-3.17(m,0.9H),2.67(br s,0.1H),2.61-2.58(m,3H),2.30-1.78(m,6.3H),1.69-1.60(m,1H),1.54-1.46(m,0.7H)。

the racemic mixture of (trans) -methyl 4- (2-chloro-3-fluorophenyl) -6- (4- (N-methylsulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 259B (250mg, 0.474mmol) was separated by chiral preparative HPLC (column: Chiralpak IF5 μm20 x 250 mm; mobile phase: Hex: EtOH ═ 50:50 at 10 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 259E (74.8mg, 30% yield, 100% stereopurity) and 259F (72.9mg, 29% yield, 98.4% stereopurity) as a yellow solid.

Compound 259E: LC-MS (ESI): r_T＝4.085min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass 526.1, M/z found 527.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝5.843min)。¹H NMR(400MHz,CDCl₃)δ8.10(s,0.3H),7.83(d,J＝2.8Hz,0.6H),7.81(d,J＝3.2Hz,0.4H),7.50(d,J＝3.2Hz,0.6H),7.46(d,J＝3.2Hz,0.4H),7.43(s,0.7H),7.22-7.02(m,3H),6.25(s,0.4H),6.11(d,J＝3.2Hz,0.6H),4.09-3.95(m,1.3H),3.85-3.77(m,0.7H),3.61(s,1.8H),3.59(s,1.2H),3.11-3.01(m,1H),2.88-2.86(m,3H),2.41-1.76(m,7.3H),1.55-1.50(m,0.7H)。

Compound 259F: LC-MS (ESI): r_T＝4.071min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass 526.1, M/z found 527.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝7.833min)。¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝3.6Hz,0.6H),8.95(s,0.4H),8.00-7.99(m,1.5H),7.95-7.94(m,0.5H),7.40-7.29(m,2H),7.21-7.16(m,1H),7.00-6.95(m,0.4H),6.92-6.88(m,0.6H),6.06(s,0.3H),5.97(d,J＝3.6Hz,0.7H),3.89-3.83(m,0.4H),3.61-3.51(m,3.6H),3.26-3.16(m,0.4H),3.09-3.01(m,0.6H),2.62(d,J＝4.4Hz,3H),2.22-2.09(m,2H),2.01-1.71(m,4H),1.56-1.42(m,2H)。

Compound 260: (cis) -ethyl 6- (4- ((tert-butoxycarbonyl) amino) tetrahydrofuran-2-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.571min，C₂₅H₂₈ClFN₄O₅Calculated mass of S550.2, M/z found value 551.2[ M + H [ ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ8.96(s,1H),8.01-7.95(m,2H),7.39-7.24(m,3H),7.08-7.01(br s,1H),6.08(s,1H),5.48-5.42(m,1H),4.09-4.02(m,1H),4.00-3.92(m,4H),2.83-2.74(m,1H),1.89-1.80(m,1H),1.40-1.32(m,9H),1.05-1.01(m,3H)。

Compound 263: methyl 4- (2-chloro-3-fluorophenyl) -6- (4- (methylamino)Formyl) -tetrahydrofuran-2-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.169,3.328,3.437min，C₂₁H₂₀ClFN₄O₄Calculated mass of S478.1, found value of M/z 478.9[ M + H [)]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂EtOH 60:40 at 2.999 g/min; column temperature: 40.4 ℃; wavelength: 214nm, back pressure: 100bar, R_T＝1.96,2.24,2.56,2.78,3.04,3.19,3.44,3.68min)。¹H NMR(400MHz,CDCl₃)δ9.14(d,J＝11.6Hz,0.3H),8.93(s,0.1H),8.73(s,0.02H),8.67(s,0.05H),8.51(s,0.03H),7.88-7.78(m,1H),7.55-7.39(m,1.5H),7.26-6.99(m,3.5H),6.92(s,0.2H),6.84-6.68(m,0.3H),6.28-6.22(m,0.5H),6.16-6.08(m,0.5H),5.71-5.52(m,1H),4.77-4.69(m,0.3H),4.67-4.58(m,0.3H),4.57-4.48(m,0.4H),4.43-4.23(m,1H),4.19-3.92(m,1H),3.64-3.57(m,3H),3.12-3.02(m,0.4H),3.02-2.92(m,0.6H),2.89-2.79(m,3H),2.62-2.33(m,0.4H),2.27-2.14(m,0.4H),2.09-2.00(m,0.2H)。

Compound 264: ethyl 6- (6- (tert-butoxycarbonyl) tetrahydro-2H-pyran-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Separation conditions are as follows: silica gel column chromatography (petroleum ether: ethyl acetate ═ 15:1) gave two sets of stereoisomers, group 1(1.30g) and group 2(2.10 g). Group 1(1.30g, 2.36mmol) was further separated by preparative purification HPLC (column: Xtimate C18(10 μm50 x 250mm), mobile phase A: water (0.1% trifluoroacetic acid), mobile phase B: acetonitrile, UV: 214nm, flow rate: 80mL/min, gradient: 60% -85% (% B)) to give two sets of stereoisomers, group A (250mg) and group B (440 mg). Group 2(2.10g, 3.82mmol) was further separated by preparative purification HPLC (column: Xtimate C18(10 μm50 x 250mm), mobile phase A: water (0.1% trifluoroacetic acid), mobile phase B: acetonitrile, UV: 214nm, flow rate: 80mL/min, gradient: 60% -85% (% B)) to give two sets of stereoisomers, group C (700mg) and group D (800 mg).

Group A (250mg, 0.455mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak ID5 μ M20 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 95:5:0.3 at 18 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 264M (70mg, 100% ee) and 264N (58mg, 99.1% ee), which was further purified by preparative HPLC (column: Gilson-2x-bridge C18(5 μ M15: 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 70% -95% (% B)) to give the title compound 264M (60mg, 24% ee, 100% ee) and 264N (48mg, 19% yield, 99.0%) as a yellow solid.

Group B (440mg, 0.800mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.3 at 13 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 264U (150mg, 100% ee) and 264V (110mg, 100% ee), which was further purified by preparative HPLC (column: Gilson-2x-bridge C18(5 μm 15 x 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 55% -95% (% B)) to give the title compound 264U (120mg, 27% ee, 100% ee) and 264V (110mg, 100% ee) as yellow solids.

Group C (350mg, 0.636mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2 at 12 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compounds 264S (109mg, 100% ee) and 264T (103mg, 100% ee), which was further separated by preparative purification HPLC (column: Gilson-2x-bridge C18(5 μm19 × 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 60% -95% (% B)) to give the title compounds 264S (82mg, 23% ee, 100% ee) and 264T (91mg, 26% yield, 100%) as yellow solids.

Group D (400mg, 0.727mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IG5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compounds 264X (130mg, 100% ee) and 264Y (120mg, 100% ee), which were further separated by preparative purification HPLC (column: Gilson-5X-bridge C18(5 μm19 [. 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 60% -100% (% B)) to give the title compound 264X (108mg, 27% ee, 100% ee) and 264Y (93mg, 23% yield, 100%) as a yellow solid.

Compound 264U: LC-MS (ESI): r_T＝3.888min，C₂₆H₂₉ClFN₃O₅Calculated mass of S549.2, M/z found value 550.2[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; time: 0.2; time: 0.C; time: 1.0mL/min_T＝8.913min)。¹H NMR(400MHz,DMSO-d₆)δ9.50(s,0.8H),9.26(br s,0.2H),8.01-7.99(m,1.7H),7.94(br s,0.3H),7.42(dd,J＝8.8,2.8Hz,1H),7.37-7.33(m,1H),7.23-7.18(m,1H),6.04(s,0.2H),5.92(d,J＝3.2Hz,0.8H),4.16-4.13(m,0.3H),4.04-3.96(m,3.3H),3.87-3.70(m,2.4H),2.02-1.93(m,2H),1.81-1.78(m,1H),1.55-1.53(m,1H),1.43(s,9H),1.09-1.03(m,3H)。¹H NMR(400MHz,CD₃OD +1M aqueous HCl (1 drop)) δ 8.08(d, J ═ 2.8Hz,1H),8.01(d, J ═ 3.2Hz,1H),7.47(dd, J ═ 8.4,5.6Hz,1H),7.31(dd, J ═ 8.8,2.4Hz,1H),7.16-7.11(M,1H),6.20(s,1H),4.20(dd, J ═ 10.0,2.0Hz,1H),4.12-3.95(M,5H),2.13-2.08(M,2H),2.03-2.02(M,1H),1.73-1.70(M,1H),1.51(s,9H),1.15(t, J ═ 7.2, 3H).

Compound 264Y: LC-MS (ESI): r_T＝3.788min，C₂₆H₂₉ClFN₃O₅Calculated mass of S549.2, M/z found value 550.2[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral HPLC (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝12.361min)。¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝3.6Hz,0.8H),9.20(s,0.2H),8.02-7.98(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.44-7.41(m,1H),7.38-7.34(m,1H),7.24-7.19(m,1H),6.03(s,0.2H),5.93(d,J＝3.6Hz,0.8H),4.21-4.18(m,0.2H),4.03-3.92(m,2.5H),3.89-3.82(m,1.8H),3.80-3.77(m,0.7H),3.67-3.61(m,0.8H),2.13-2.10(m,1H),1.98-1.96(m,2H),1.56-1.50(m,1H),1.45(s,2H),1.43(s,7H),1.10-1.01(m,3H)。

Compound 275: methyl 4- (2-bromo-3-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,¹H NMR(400MHz,CDCl₃)δ8.13(s,0.5H),7.85-7.80(m,1H),7.52-7.47(m,1H),7.47-7.43(m,0.5H),7.25-7.18(m,1H),7.14-6.98(m,2H),6.25(s,0.5H),6.12-6.07(m,0.5H),4.41-4.16(m,2.5H),4.01-3.90(m,0.5H),3.65-3.56(m,3H),2.97-2.78(m,2H),2.02-1.80(m,2H),1.75-1.64(m,2H),1.54-1.47(m,9H)。

racemic compound 275(6.40g, 107mmol) was separated by chiral preparative SFC (column: Chiralpak IG5 μm20 × 250 mm; mobile phase: CO)₂MeOH 70:30 at 50 g/min; column temperature: 30 ℃; wavelength: 214nm, back pressure: 100 bar) to yield the title compound 275A (2.60g, 38% yield, 100% stereopurity) and 275B (2.90g, 38% yield, 99.5% stereopurity) as yellow solids.

Intermediate 275A: chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; CO₂MeOH 70:30 at 3.0 g/min; column temperature: 40 ℃; wavelength: 254nm, back pressure: 100bar, R_T＝3.25min)。¹H NMR(400MHz,CDCl₃)δ8.13(s,0.5H),7.83-7.81(m,1H),7.50-7.49(m,1H),7.45-7.44(m,0.5H),7.26-7.14(m,1H),7.10-6.98(m,2H),6.25(s,0.5H),6.10(s,0.5H),4.41-4.13(m,2.5H),4.00-3.92(m,0.5H),3.60-3.58(m,3H),2.97-2.77(m,2H),2.00-1.74(m,2H),1.64-1.55(m,2H),1.54-1.45(m,9H)。

Intermediate 275B: chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; CO₂MeOH 70:30 at 3.0 g/min; temperature: 40 ℃; wavelength: 254nm, R_T＝4.31min)。¹H NMR(400MHz,CDCl₃)δ8.13(s,0.5H),7.83-7.81(m,1H),7.52-7.48(m,1H),7.44-7.43(m,0.5H),7.26-7.17(m,1H),7.12-6.97(m,2H),6.25(s,0.5H),6.10(s,0.5H),4.37-4.09(m,2.5H),4.98-3.94(m,0.5H),3.63-3.59(m,3H),2.96-2.79(m,2H),2.01-1.81(m,2H),1.74-1.58(m,2H),1.51-1.45(m,9H)。

Compound 279: ethyl 4- (2-bromo-4-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.252min，C₂₆H₃₀BrFN₄O₄Calculated mass of S592.1, M/z found value 593.0[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.09(s,0.4H),7.83-7.81(m,1H),7.50(d,J＝3.2Hz,0.6H),7.44(d,J＝3.2Hz,0.4H),7.39(s,0.6H),7.33-7.28(m,2H),7.01-6.93(m,1H),6.19(s,0.4H),6.05(d,J＝2.4Hz,0.6H),4.35-4.19(m,2.2H),4.08-3.91(m,2.8H),2.91-2.81(m,2H),2.00-1.67(m,3H),1.61-1.58(m,1H),1.51(s,9H),1.15-1.10(m,3H)。

Ethyl 4- (2-bromo-4-fluorophenyl) -6- (1- (tert-butoxycarbonyl)

Racemic mixture of piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 279 (10.0g, 15.2mmol, according to¹H NMR purity 90%) was separated by chiral preparative SFC (separation conditions: column: chiralpak IG5 μm20 mm 250 mm; mobile phase: CO2₂MeOH 75:25 at 50 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar) to yield the title compound 279A as a yellow solid (4.7g, 50% yield, according to¹H NMR purity 95%, 100% stereopure) and 279B as a yellow solid (4.9g, 49% yield according to¹H NMR purity 90%, 100% stereopure).

Compound 279A: LC-MS (ESI): r_T＝2.236min，C₂₆H₃₀BrFN₄O₄Calculated mass of S592.1, M/z found value 593.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 mm 250 mm; mobile phase: CO)₂MeOH 70:30 at 3.0 g/min; column temperature: 40 ℃; wavelength: 254nm, back pressure: 100bar, R_T＝2.86min)¹H NMR(400MHz,CDCl₃)δ8.09(s,0.4H),7.83-7.81(m,1H),7.50(d,J＝2.8Hz,0.6H),7.44(d,J＝3.2Hz,0.4H),7.38(d,J＝2.0Hz,0.6H),7.34-7.28(m,2H),7.02-6.93(m,1H),6.19(s,0.4H),6.05(d,J＝2.4Hz,0.6H),4.36-4.15(m,2.3H),4.08-4.02(m,2H),3.96-3.90(m,0.7H),2.91-2.83(m,2H),2.07-1.58(m,4H),1.50(s,9H),1.15-1.10(m,3H)

Compound 279B: LC-MS (ESI): r_T＝2.325min，C₂₆H₃₀BrFN₄O₄Calculated mass of S592.1, M/z found value 596.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG5 μm46mm by 250 mm; mobile phase: CO2₂MeOH 70:30 at 3.0 g/min; column temperature: 40 ℃; wavelength: 254nm, back pressure: 100bar, R_T＝3.82min)¹H NMR(400MHz,CDCl₃)δ8.09(s,0.4H),7.83-7.81(m,1H),7.50(d,J＝3.2Hz,0.6H),7.44(d,J＝3.2Hz,0.4H),7.38(d,J＝1.2Hz,0.6H),7.33-7.28(m,2H),7.02-6.93(m,1H),6.18(s,0.4H),6.05(d,J＝2.4Hz,0.6H),4.33-4.15(m,2.4H),4.08-4.02(m,2H),3.96-3.90(m,0.6H),2.91-2.83(m,2H),2.08-1.58(m,4H),1.50(s,9H),1.15-1.10(m,3H)。

Compound 283: methyl 4- (2-chloro-3-fluorophenyl) -6- (-5-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) pyrrolidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Separation conditions are as follows: silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) followed by further purification through a C18 column (acetonitrile: water ═ 5% to 100%) gave the title compound 283M (18mg, 2% yield) as a yellow solid and 283N (16mg, 2% yield) as a yellow solid.

Intermediate 283M:¹H NMR(300MHz,CDCl₃)δ7.87(d,J＝2.7Hz,1H),7.55(s,2H),7.28-7.22(m,1H),7.17-7.10(m,2H),6.19(s,1H),4.84-4.75(m,2H),3.96-3.90(m,1H),3.83-3.78(m,1H),3.66-3.56(m,6H),3.03-2.95(m,1H),2.68-2.59(m,1H),1.03-0.95(m,2H),0.04(s,3H),0.00(s,6H)。

intermediate 283N:¹H NMR(300MHz,CDCl₃)δ7.87(s 1H),7.58(s,1H),7.55(s,1H),7.30-7.25(m,1H),7.14(t,J＝6.9Hz,2H),6.16(s,1H),4.88-4.77(m,2H),3.81-3.75(m,1H),3.66(s,3H),3.63-3.57(m,4H),3.20-3.11(m,1H),2.84-2.74(m,1H),1.01-0.94(m,2H),0.04(s,9H)。

compound 288: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.849min，C₂₃H₂₂ClF₂N₃O₄Calculated mass of S509.1, M/z found value 509.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.14(s,0.6H),7.82(s,1H),7.50(s,0.4H),7.46(s,0.6H),7.37(s,0.4H),7.08-6.98(m,2H),6.18(s,0.6H),6.04(s,0.4H),4.02-3.96(m,0.6H),3.81-3.75(m,0.4H),3.70(s,3H),3.62(s,1H),3.60(s,2H),2.46-2.39(m,1H),2.24-1.90(m,5H),1.76-1.66(m,2H),1.55-1.45(m,1H)。

The racemic mixture of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 288 (420mg, 96% purity, 0.790mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μ M30 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 85:15:0.3 at 23 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 288M (190mg, 98% purity, 46% yield, 100% stereopurity) and 288(190mg, 97% purity, 46% yield, 100% stereopurity) as yellow solids.

Compound 288M: LC-MS (ESI): r_T＝3.319min，C₂₃H₂₂ClF₂N₃O₄Calculated mass of S509.1, M/z found value 509.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; chiral analysis of the chiral structure of the protein_T＝7.204min)。¹H NMR(400MHz,DMSO-d₆)δ9.54(s,0.6H),8.99(s,0.4H),8.00-7.94(m,2H),7.46-7.39(m,1H),7.21-7.11(m,1H),6.03(s,0.4H),5.93(s,0.6H),3.89-3.80(m,0.6H),3.62(s,3.4H),3.54(s,3H),2.39-2.29(m,0.6H),2.05-1.66(m,6.4H),1.51-1.36(m,2H)。

Compound 288N: LC-MS (ESI): r_T＝3.313min，C₂₃H₂₂ClF₂N₃O₄Calculated mass of S509.1, M/z found value 509.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; chiral analysis of the chiral structure of the protein_T＝9.765min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(br s,0.5H),8.99(s,0.5H),8.01-7.99(m,1.5H),7.94(d,J＝3.2Hz,0.5H),7.49-7.41(m,1H),7.21-7.14(m,1H),6.02(s,0.4H),5.93(s,0.6H),3.88-3.81(m,0.5H),3.62-3.61(m,3H),3.58-3.56(m,0.5H),3.53-3.35(m,3H),2.37-2.30(m,0.7H),2.08-1.97(m,2H),1.90-1.82(m,4.3H),1.50-1.39(m,2H)。

Compound 290: first of allThe group 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (2-ethoxy-2-oxoethyl) sulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝1.76min，C₂₅H₂₇ClF₂N₄O₆S₂Calculated mass of 616.1, M/z found value 617.3[ M + H ]]⁺。

A mixture of methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (2-ethoxy-2-oxoethyl) sulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 290(1.20g, 1.90mmol) was purified by C18 column (acetonitrile: water (+ 0.1% ammonium bicarbonate) ═ 49% to 70%) to give the title compound 290R as a yellow solid (700mg, 58% yield) and 290S as a yellow solid (40mg, 3% yield).

Compound 290R: LC-MS (ESI): r_T＝3.603min，C₂₅H₂₇ClF₂N₄O₆S₂Calculated mass of 616.1, M/z found value 617.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.6Hz,0.7H),8.31(s,0.3H),8.00-7.99(m,1.7H),7.97-7.96(m,0.3H),7.86(t,J＝6.4Hz,0.3H),7.61-7.58(m,0.7H),7.49-7.39(m,1H),7.22-7.17(m,1H),6.03(s,0.3H),5.92(d,J＝3.6Hz,0.7H),4.16-4.09(m,2H),3.94-3.88(m,0.6H),3.85-3.79(m,2H),3.72-3.66(m,0.7H),3.52(s,3H),3.18-3.12(m,0.7H),2.39-2.33(m,2H),2.28-2.17(m,0.7H),2.14-2.08(m,0.6H),2.05-1.94(m,0.7H),1.90-1.76(m,2.3H),1.68-1.64(m,1H),1.59-1.53(m,0.7H),1.23-1.19(m,3H)。

Compound 290S: LC-MS (ESI): r_T＝3.447min，C₂₅H₂₇ClF₂N₄O₆S₂Calculated mass of 616.1, M/z found value 617.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝3.6Hz,0.6H),9.02(s,0.4H),8.00(s,1H),7.99-7.98(m,0.6H),7.95-7.94(m,0.4H),7.67-7.58(m,1H),7.49-7.42(m,1H),7.21-7.14(m,1H),6.01(s,0.4),5.92(d,J＝4.0Hz,0.6),4.14(q,J＝7.2Hz,2H),3.84-3.83(m,2H),3.59-3.56(m,0.7H),3.53(s,2H),3.52(s,1H),3.18-3.12(m,0.6H),,3.04-2.97(m,0.7H),2.26-2.19(m,2H),1.97-1.81(m,3H),1.72-1.67(m,1H),1.54-1.42(m,2H),1.25-1.21(m,3H)。

Compound 292: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (((R) -3- (methoxycarbonyl) pyrrolidin-1-yl) sulfonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T4.523min and 4.650min, C₂₇H₂₉ClF₂N₄O₆S₂Calculated mass of 642.1, M/z found value 643.2[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.94-7.91(m,0.5H),7.90-7.87(m,0.5H),7.77-7.73(m,1H),7.26-7.17(m,2H),6.14(s,0.2H),6.13(s,0.3H),6.07(s,0.2H),6.06(s,0.3H),4.12-4.04(m,0.2H),4.02-3.93(m,0.4H),3.90-3.81(m,0.2H),3.76-3.69(m,3.2H),3.67-3.62(m,2H),3.61-3.57(m,3H),3.53-3.46(m,2.4H),3.28-3.15(m,1.6H),2.50-2.39(m,0.5H),2.37-2.18(m,4H),2.16-2.08(m,0.5H),2.04-1.91(m,1.6H),1.87-1.66(m,3.4H)。

Methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (((R) -3- (methoxycarbonyl)

Pyrrolidin-1-yl) sulfonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 292 mixture (1.20g, 90% purity, 1.68mmol) was separated by preparative HPLC (column: gilson X-bridge C18(5 μm19 × 150mm), mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 60% -65% (% B)) to give the title compound 292M (247mg, 96.3% pure, 21% yield) and 292N (762mg, 99.4% pure, 64% yield) as a yellow solid.

Compound 292M: LC-MS (ESI): r_T＝9.612min，C₂₇H₂₉ClF₂N₄O₆S₂Calculated mass of 642.1, M/z found value 643.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.34(s,0.6H),7.84-7.81(m,1H),7.51(d,J＝3.2Hz,0.4H),7.42-7.40(m,1H),7.09-6.98(m,2H),6.18(s,0.6H),6.06(d,J＝2.8Hz,0.4H),4.13-4.06(m,0.7H),3.96-3.90(m,0.3H),3.79-3.72(m,4H),3.60-3.58(m,5H),3.55-3.49(m,1.3H),3.35-3.29(m,0.7H),3.22-3.12(m,1H),2.53-2.41(m,2H),2.28-2.14(m,4H),2.04-1.76(m,4H)。

Compound 292N: LC-MS (ESI): r_T＝3.593min，C₂₇H₂₉ClF₂N₄O₆S₂Calculated mass of 642.1, M/z found value 643.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.11(s,0.4H),7.84-7.81(m,1H),7.52-7.46(m,1H),7.40(s,0.6H),7.08-7.00(m,2H),6.18(s,0.4H),6.05(d,J＝2.8Hz,0.6H),4.04-3.97(m,0.5H),3.78-3.73(m,4.5H),3.62-3.58(m,4H),3.54-3.48(m,2H),3.19-3.03(m,2H),2.41-2.35(m,2H),2.29-2.22(m,3H),2.13-1.94(m,1H),1.88-1.72(m,3H),1.52-1.44(m,1H)。

(trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (((R) -3- (methoxycarbonyl) pyrrolidin-1-yl) sulfonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester 292N racemic mixture (500mg, 99.4% purity, 0.774mmol) was passed through a chiral preparative SFC (separation conditions: column: Chiralpak IG5 μm20 × 250 mm; mobile phase: CO:. sup. C:. sub.₂EtOH, DEA 60:40:0.3 at 50 g/min; column temperature: 30 ℃; wavelength: 230nm, back pressure: 100 bar) to yield 292W (146mg, 29% yield, 99.3% purity, 100% stereopurity) and 292Z (160mg, 32% yield, 99.4% purity, 99.8% stereopurity) as yellow solids.

Compound 292W: LC-MS (ESI): r_T＝4.527min，C₂₇H₂₉ClF₂N₄O₆S₂Calculated mass of 642.1, M/z found value 643.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂EtOH, DEA 60:40:0.2 at 2.999 g/min; column temperature: 40.1 ℃; wavelength: 230nm, back pressure: 100bar, R_T＝4.45min)。¹H NMR(400MHz,CDCl₃)δ8.11(s,0.4H),7.84-7.81(m,1H),7.51(d,J＝3.2Hz,0.5H),7.46(d,J＝2.8Hz,0.5H),7.41(s,0.6H),7.06-7.01(m,2H),6.18(s,0.4H),6.05(d,J＝2.4Hz,0.6H),4.06-3.97(m,0.5H),3.80-3.78(m,0.5H),3.74-3.71(m,4H),3.62-3.57(m,4H),3.55-3.48(m,2H),3.19-3.07(m,2H),2.38-2.35(m,1H),2.29-2.20(m,3H),2.13-2.00(m,1H),1.95-1.74(m,4H),1.58-1.51(m,1H)。

Compound 292Z: LC-MS (ESI): r_T＝4.042min，C₂₇H₂₉ClF₂N₄O₆S₂Calculated mass of 642.1, M/z found value 643.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂EtOH, DEA 60:40:0.2 at 2.999 g/min; (ii) a Column temperature: 40.1 ℃; wavelength: 230nm, back pressure: 100bar, R_T＝5.5min)。¹H NMR(400MHz,CDCl₃)δ8.11(s,0.5H),7.84-7.81(m,1H),7.51(d,J＝2.8Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.41(s,0.5H),7.07-7.01(m,2H),6.18(s,0.4H),6.05(d,J＝2.8Hz,0.6H),4.04-3.95(m,0.5H),3.79-3.76(m,0.5H),3.74-3.71(m,4H),3.62-3.60(m,4H),3.55-3.48(m,2H),3.19-3.09(m,2H),2.41-2.33(m,1H),2.26-2.18(m,3H),2.14-2.01(m,1H),1.97-1.76(m,4H),1.59-1.51(m,1H)。

Compound 294: methyl 6- (3- ((tert-butyldiphenylsilyl) oxy) cyclobutyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.08min，C₃₅H₃₅ClFN₃O₃Calculated mass of SSi 659.2, M/z found value 660.6[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.41(br s,0.5H),7.89-7.87(m,1H),7.76-7.69(m,4H),7.56-7.55(m,0.5H),7.48-7.35(m,7H),7.31-7.29(m,0.3H),7.26-7.19(m,0.7H),7.16-7.10(m,1H),6.98-6.88(m,1H),6.19-6.16(m,0.5H),6.05-6.00(m,0.5H),4.36-4.25(m,1H),3.96-3.84(m,1H),3.61-3.56(m,3H),2.76-2.32(m,3H),2.25-2.14(m,1H),1.10(s,9H)。

Compound 296: (trans) -methyl 6- (4- ((tert-butoxycarbonyl) amino) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝1.93min，C₂₈H₂₉ClF₄N₄O₄Calculated mass 596.2, found value M/z 597.4[ M + H]⁺。¹H NMR(300MHz,DMSO-d₆)δ9.30(s,0.8H),9.14(s,0.2H),8.58(s,1H),8.10-8.03(m,1H),7.51-7.42(m,1H),7.20-7.13(m,1H),6.83-6.73(m,1H),6.03(s,0.8H),5.92(s,0.2H),4.04-4.01(m,0.5H),3.89-3.84(m,0.5H),3.51(s,3H),1.90-1.65(m,5H),1.39(s,9H),1.35-1.23(m,4H)。

Compound 299: methyl 6- (-3- ((tert-butoxycarbonyl) amino) cyclopentyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, isolation conditions: preparative HPLC (Xtimate C18(10 μm50 x 250mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 80mL/min, gradient: 60% -90% (% B)) gave group 1(299A-D,1.3g, 26% yield) and group 2(299E-H,1.5g, 30% yield) as yellow oils. Group 1(299A-D,1.3g, 2.4mmol) was separated by chiral preparative HPLC (column: Chiralpak IG5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compounds 299A (280mg, 22%), 299B (230mg, 18%), 299C (320mg, 25%) and 299D (330mg, 25%) as yellow solids. Group 2(299E-H,1.5G, 2.7mmol) was separated by chiral preparative HPLC (column: Chiralpak IG5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.3 at 25 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 299E (300mg, 20%), 299F (350mg, 23%), 299G (380mg, 25%) and 299H (350mg, 23%) as yellow solids.

Compound 299A: LC-MS (ESI): r_T＝2.310min，C₂₅H₂₇ClF₂N₄O₄Calculated mass of S552.1, found value of M/z 453.0[ M + H-Boc]⁺。¹H NMR(400MHz,CDCl₃)δ8.11(br s,0.4H),7.83-7.81(m,1H),7.49(d,J＝3.2Hz,0.6H),7.45(d,J＝3.2Hz,0.4H),7.37(br s,0.6H),7.08-7.01(m,2H),6.18(s,0.4H),6.04(d,J＝2.8Hz,0.6H),4.69-4.54(m,1.4H),4.47-4.39(m,0.6H),4.32-4.25(m,1H),3.61(s,1.8H),3.59(s,1.2H),2.45-2.06(m,3H),1.98-1.82(m,2H),1.67-1.61(m,1H),1.47(s,5H),1.46(s,4H)。

Compound 299B:¹H NMR(400MHz,CDCl₃)δ8.11(br s,0.4H),7.82(t,J＝3.2Hz,1H),7.50(d,J＝3.2Hz,0.6H),7.45(d,J＝2.8Hz,0.4H),7.38(br s,0.6H),7.10-6.99(m,2H),6.18(s,0.4H),6.04(d,,J＝2.8Hz,0.6H),4.70-4.53(m,1.4H),4.47-4.39(m,0.6H),4.33-4.24(m,1H),3.61(s,1.8H),3.60(s,1.2H),2.44-2.06(m,3H),1.98-1.82(m,2H),1.67-1.61(m,1H),1.47(s,9H)。

compound 299C: LC-MS (ESI): r_T＝2.324min，C₂₅H₂₇ClF₂N₄O₄Calculated mass of S552.1, found value of M/z 453.0[ M + H-Boc]⁺。¹H NMR(400MHz,CDCl₃)δ8.10(br s,0.4H),7.82(t,J＝3.2Hz,1H),7.50(d,J＝2.8Hz,0.6H),7.45(d,J＝2.8Hz,,0.4H),7.37(br s,0.6H),7.09-6.98(m,2H),6.17(s,0.4H),6.04(d,J＝2.8Hz,0.6H),4.66-4.52(m,1.3H),4.46-4.38(m,0.7H),4.26(br s,1H),3.61(s,1.8H),3.59(s,1.2H),2.33-1.96(m,4H),1.74-1.63(m,2H)1.46(s,9H)。

Compound 299D: LC-MS (ESI): r_T＝2.313min，C₂₅H₂₇ClF₂N₄O₄Calculated mass of S552.1, found value of M/z 453.0[ M + H-Boc]⁺。¹H NMR(400MHz,CDCl₃)δ8.11(br s,0.4H),7.82(t,J＝3.2Hz,1H),7.50(d,J＝3.2Hz,0.6H),7.45(d,J＝2.8Hz,0.4H),7.37(br s,0.6H),7.09-6.98(m,2H),6.17(s,0.4H),6.04(d,J＝2.8Hz,0.6H),4.66-4.52(m,1.3H),4.46-4.38(m,0.7H),4.26(br s,1H),3.61(s,1.8H),3.59(s,1.2H),2.34-1.96(m,4H),1.77-1.61(m,2H),1.46(s,9H)。

Compound 299E: LC-MS (ESI): r_T＝2.207min，C₂₅H₂₇ClF₂N₄O₄Calculated mass of S552.1, found value of M/z 453.0[ M + H-Boc]⁺。¹H NMR(400MHz,CDCl₃)δ8.32(br s,0.2H),7.87(d,J＝13.6Hz,0.8H),7.82(d,J＝10.0Hz,0.2H),7.57-7.55(m,1.6H),7.47(d,J＝13.2Hz,0.2H),7.11-7.01(m,2H),6.17(s,0.2H),6.07(br s,0.8H),6.05(d,J＝2.4Hz,0.8H),5.84(br s,0.2H),4.72(br s,0.1H),4.52-4.43(m,1H),4.29(m,0.6H),4.17-4.03(m,0.3H)3.62(s,2.4H),3.59(s,0.6H),2.61-2.44(m,0.1H),2.38-2.25(m,0.9H),2.18-2.12(m,0.4H),2.02-1.60(m,4.6H),1.46(s,9H)。

Compound 299F: LC-MS (ESI): r_T＝2.368min，C₂₅H₂₇ClF₂N₄O₄Calculated mass of S552.1, found value of M/z 453.1[ M + H-Boc]⁺。¹H NMR(400MHz,CDCl₃)δ8.32(br s,0.2H),7.86(d,J＝2.8Hz,0.8H),7.82(d,J＝2.8Hz,0.2H),7.57-7.48(m,1.6H),7.45(d,J＝3.2Hz,0.2H),7.11-7.01(m,2H),6.16(s,0.2H),6.07(br s,0.8H),6.05(d,J＝2.8Hz,0.8H),5.82(br s,0.2H),4.80-4.70(m,0.1H),4.54-4.45(m,1H),4.23-4.22(m,0.7H),4.12-4.05(m,0.2H)3.62(s,2H),3.59(s,1H),2.59-2.47(m,0.2H),2.38-2.29(m,0.8H),2.24-2.08(m,0.6H),2.03-1.89(m,4.4H),1.60(s,9H)。

Compound 299G: LC-MS (ESI): r_T＝2.354min，C₂₅H₂₇ClF₂N₄O₄Calculated mass of S552.1, found value of M/z 453.1[ M + H-Boc]⁺。¹H NMR(400MHz,CDCl₃)δ8.28(br s,0.1H),7.88(d,J＝14.8Hz,0.8H),7.81(d,J＝5.2Hz,0.2H),7.57-7.48(m,1.7H),7.45(d,J＝3.6Hz,0.2H),7.13-7.00(m,2H),6.19-6.17(m,1H),6.08-6.07(m,1H),4.76-4.65(m,0.1H),4.50-4.38(m,1H),4.25-4.20(m,0.7H),4.15-4.03(m,0.2H),3.61(s,2.4H),3.59(s,0.6H),2.53-2.42(m,0.1H),2.29-2.17(m,1.9H),2.04-1.91(m,2H),1.78-1.65(m,2H),1.59(s,9H)。

Compound 299H: LC-MS (ESI): r_T＝2.177min，C₂₅H₂₇ClF₂N₄O₄Calculated mass of S552.1, found value of M/z 453.0[ M + H-Boc]⁺。¹H NMR(400MHz,CDCl₃)δ8.26(br s,0.1H),7.86(d,J＝2.4Hz,0.8H),7.81(d,J＝3.2Hz,0.2H),7.57-7.54(m,1.7H),7.45(d,J＝3.2Hz,0.2H),7.12-7.00(m,2H),6.17-6.16(m,1H),6.08(d,J＝2.4Hz,1H),4.78-4.69(m,0.1H),4.49-4.41(m,1H),4.21-4.17(m,0.7H),4.10-4.05(m,0.2H),3.62(s,2H),3.59(s,1H),2.54-2.40(m,0.2H),2.23-2.08(m,1.8H),1.99-1.89(m,2H),1.80-1.60(m,2H),1.50(s,9H)。

Compound 301: ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (methoxycarbonyl) -cycloheptyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝1.73min，C₂₅H₂₆ClF₂N₃O₄Calculated mass of S537.1, found value of M/z 538.5[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.50(d,J＝2.8Hz,0.6H),9.09-8.96(m,0.4H),8.03-7.96(m,1.6H),7.93(d,J＝2.8Hz,0.4H),7.52-7.41(m,1H),7.24-7.13(m,1H),6.01(s,0.4H),5.91(d,J＝3.2Hz,0.6H),4.02-3.91(m,2.4H),3.86-3.76(m,0.6H),3.65-3.59(m,3H),2.65-2.54(m,1H),2.08-1.58(m,9.4H),1.49-1.37(m,0.6H),1.07(t,J＝7.2Hz,1.8H),1.05(t,J＝7.2Hz,1.2H)。

Mixture of Compounds 301 (2.00g, 3.72)mmol) was separated by chiral preparative HPLC (first separation conditions: column: chiralpak IC5 μm20 × 250 mm; mobile phase: CO2₂MeOH 75:25 at 50 g/min; wavelength: 214 nm; second separation conditions: column: chiralpak AD-H5 μm20 × 250 mm; mobile phase: hex EtOH DEA 90:10:0.3 at 15 mL/min; wavelength: 230 nm; third separation conditions: column: superchiral S-OJ 5 μm 21 × 250 mm; mobile phase: hex: EtOH 95:5 at 20 mL/min; wavelength: 254 nm; fourth separation conditions: column: chiralpak IC5 μm50 × 250 mm; mobile phase: hex: IPA: DEA: 95:5:0.1 at 60 mL/min; wavelength: 254 nm; fifth separation conditions: column: chiralpak IE5 μm50 × 250 mm; mobile phase: hex: IPA: DEA: 95:5:0.1 at 60 mL/min; wavelength: 254nm) to give 301M (190mg, 99.9% pure, 9.5% yield, 100% stereopure), 301N (185mg, 99.9% pure, 9.3% yield, 100% stereopure), 301P (170mg, 99.9% pure, 8.5% yield, 100% stereopure), 301Q (190mg, 99.9% pure, 9.5% yield, 100% stereopure), 301U (150mg, 99.9% pure, 7.5% yield, 99.8% stereopure), 301V (130mg, 99.9% pure, 6.5% yield, 100% stereopure), 301X (245mg, 98.5% pure, 12.3% yield, 97.8% stereopure) and 301Y (260mg, 99.1% pure, 13.0% yield, 100% stereopure) as yellow solids.

Compound 301M: LC-MS (ESI): r_T＝4.614min，C₂₅H₂₆ClF₂N₃O₄Calculated mass of S537.1, found value of M/z 538.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: IPA: DEA: 95:5:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R; (R))_T＝10.942min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝2.8Hz,0.6H),8.99(s,0.4H),8.02-7.96(m,1.6H),7.94(s,0.4H),7.50-7.43(m,1H),7.23-7.15(m,1H),6.01(s,0.4H),5.91(d,J＝2.8Hz,0.6H),4.02-3.92(m,2.4H),3.85-3.76(m,0.6H),3.62(s,3H),2.68-2.57(m,1H),2.15-1.94(m,3H),1.91-1.74(m,4H),1.72-1.58(m,2H),1.46-1.34(m,1H),1.11-1.01(m,3H)。

Compound 301N: LC-MS (ESI): r_T＝4.615min，C₂₅H₂₆ClF₂N₃O₄Calculated mass of S537.1, found value of M/z 538.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: IPA: DEA: 95:5:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R; (R))_T＝13.356min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝2.8Hz,0.6H),8.99(s,0.4H),8.02-7.96(m,1.6H),7.94(d,J＝3.2Hz,0.4H),7.51-7.43(m,1H),7.23-7.16(m,1H),6.01(s,0.4H),5.91(d,J＝3.6Hz,0.6H),4.00-3.94(m,2.4H),3.84-3.76(m,0.6H),3.62(s,3H),2.65-2.57(m,1H),2.15-1.94(m,3H),1.91-1.74(m,4H),1.72-1.58(m,2H),1.45-1.35(m,1H),1.11-1.03(m,3H)。

Compound 301P: LC-MS (ESI): r_T＝4.576min，C₂₅H₂₆ClF₂N₃O₄Calculated mass of S537.1, found value of M/z 538.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 75:25 at 3 g/min; col temp. 40 deg.C; wavelength: 214 nm; back pressure: 100 bar; r_T＝3.82min)。¹H NMR(400MHz,DMSO-d₆)δ9.50(d,J＝2.8Hz,0.6H),9.04(s,0.4H),8.03-7.96(m,1.6H),7.93(d,J＝3.2Hz,0.4H),7.50-7.43(m,1H),7.22-7.16(m,1H),6.01(s,0.4H),5.91(d,J＝3.2Hz,0.6H),4.00-3.93(m,2.4H),3.85-3.77(m,0.6H),3.61(s,3H),2.78-2.72(m,0.4H),2.61-2.55(m,0.6H),2.08-1.99(m,1.5H),1.95-1.85(m,3H),1.81-1.56(m,5.5H),1.10-1.03(m,3H)。

Compound 301Q: LC-MS (ESI): r_T＝4.611min，C₂₅H₂₆ClF₂N₃O₄Calculated mass of S537.1, found value of M/z 538.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak AD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak AD-H5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA ═ 90:10: 0.2; temperature: 30_T＝5.704min)。¹H NMR(400MHz,DMSO-d₆)δ9.50(s,0.6H),9.03(s,0.4H),8.03-7.95(m,1.6H),7.94-7.91(m,0.4H),7.50-7.40(m,1H),7.21-7.12(m,1H),6.01(s,0.4H),5.91(s,0.6H),4.00-3.91(m,2.4H),3.85-3.77(m,0.6H),3.65-3.55(m,3H),2.69-2.63(m,0.4H),2.60-2.54(m,0.6H),2.07-1.75(m,7.5H),1.71-1.58(m,1.5H),1.49-1.37(m,1H),1.09-1.03(m,3H)。

Compound 301U: LC-MS (ESI): r_T＝3.046min，C₂₅H₂₆ClF₂N₃O₄Calculated mass of S537.1, found value of M/z 538.2[ M + H]⁺. Chiral analysis (column: Chiralpak AD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak AD-H5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA ═ 90:10: 0.2; temperature: 30_T＝8.566min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.6Hz,0.6H),9.03(s,0.4H),8.02-7.96(m,1.6H),7.94(d,J＝3.2Hz,0.4H),7.50-7.43(m,1H),7.21-7.12(m,1H),6.01(s,0.4H),5.91(d,J＝3.2Hz,0.6H),4.00-3.93(m,2.4H),3.86-3.77(m,0.6H),3.63(s,1.2H),3.61(s,1.8H),2.69-2.63(m,0.4H),2.60-2.54(m,0.6H),2.04-1.76(m,7.5H),1.71-1.59(m,1.5H),1.48-1.39(m,1H),1.09-1.03(m,3H)。

Compound 301V: LC-MS (ESI): r_T＝3.113min，C₂₅H₂₆ClF₂N₃O₄Calculated mass of S537.1, found value of M/z 538.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 75:25 at 3 g/min; col temp. 40 deg.C; wavelength: 230 nm; back pressure: 100 bar; r_T＝4.06min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.6Hz,0.6H),9.08(s,0.4H),8.03-7.96(m,1.6H),7.93(d,J＝3.2Hz,0.4H),7.50-7.43(m,1H),7.21-7.13(m,1H),6.01(s,0.4H),5.91(d,J＝3.2Hz,0.6H),4.00-3.93(m,2.4H),3.84-3.77(m,0.6H),3.61(s,1.2H),3.60(s,1.8H),2.73-2.67(m,0.4H),2.59-2.54(m,0.6H),2.08-1.96(m,1.5H),1.95-1.80(m,3.5H),1.77-1.66(m,4H),1.61-1.52(m,1H),1.09-1.03(m,3H)。

Compound 301X: LC-MS (ESI): r_T＝3.380min，C₂₅H₂₆ClF₂N₃O₄Calculated mass of S537.1, found value of M/z 538.2[ M + H]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 75:25 at 3 g/min; col temp. 40 deg.C; wavelength: 230 nm; back pressure: 100 bar; r_T＝4.62min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.6Hz,0.6H),9.08(s,0.4H),8.03-7.96(m,1.6H),7.93(d,J＝3.2Hz,0.4H),7.50-7.43(m,1H),7.21-7.13(m,1H),6.01(s,0.4H),5.91(d,J＝3.2Hz,0.6H),4.00-3.93(m,2.4H),3.84-3.77(m,0.6H),3.61(s,1.2H),3.60(s,1.8H),2.73-2.67(m,0.4H),2.59-2.54(m,0.6H),2.08-1.96(m,1.5H),1.95-1.80(m,3.5H),1.77-1.66(m,4H),1.61-1.52(m,1H),1.09-1.03(m,3H)。

Compound 301Y: LC-MS (ESI): r_T＝3.396min，C₂₅H₂₆ClF₂N₃O₄Calculated mass of S537.1, found value of M/z 538.2[ M + H]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 75:25 at 3 g/min; col temp. 40 deg.C; wavelength: 214 nm; back pressure: 100 bar; r_T＝5.88min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝2.8Hz,0.6H),9.05(s,0.4H),8.02-7.96(m,1.6H),7.94(d,J＝2.8Hz,0.4H),7.50-7.43(m,1H),7.22-7.15(m,1H),6.01(s,0.4H),5.91(d,J＝3.2Hz,0.6H),4.00-3.93(m,2.4H),3.86-3.76(m,0.6H),3.61(s,3H),2.80-2.72(m,0.4H),2.63-2.57(m,0.6H),2.10-1.99(m,1.5H),1.95-1.84(m,3H),1.82-1.55(m,5.5H),1.09-1.03(m,3H)。

Compound 306: methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (3, 4-difluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝1.96min，C₂₆H₃₀F₂N₄O₄Calculated mass of S532.2M/z found 533.3[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.2Hz,0.8H),9.13(s,0.2H),7.99-7.91(m,2H),7.25-7.18(m,1H),7.11-7.08(m,0.8H),6.97-6.94(m,0.2H),5.82(s,0.2H),5.69(d,J＝3.2Hz,0.8H),4.14-4.00(m,2.2H),3.81-3.75(m,0.8H),3.52(s,3H),2.85-2.68(m,2H),2.43(s,3H),1.91-1.64(m,3H),1.52-1.48(m,1H),1.44(s,9H)。

306 (600mg, 1.13mmol) were separated by chiral preparative SFC (separation conditions: column: Chiralpak IG5 μm20 × 250 mm; mobile phase: CO:. sup.₂50g/min MeOH (DEA) (80: 20: 0.2); the column temperature is 40 ℃; wavelength: 214 nm; back pressure: 100 bar) to yield the title compound 306A (260mg, 43% yield, 100% stereopure) and 306B (270mg, 45% yield, 98.6% stereopure) as yellow solids.

Compound 306A: LC-MS (ESI): r_T＝1.87min，C₂₆H₃₀F₂N₄O₄Calculated mass of S532.2M/z found 533.6[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG; mobile phase: CO)₂MeOH, DEA, 80:20:0.2 at 3.0 g/min; column temperature: 40.1 ℃; wavelength: 230nm, back pressure: 100bar, R_T＝3.08min)。¹H NMR(300MHz,CDCl₃)δ8.10(s,0.7H),7.80(s,1H),7.51(d,J＝2.1Hz,0.3H),7.43(d,J＝2.4Hz,0.7H),7.09-7.06(m,0.3H),7.04(s,0.2H),6.97-6.85(m,1.8H),5.93(s,0.8H),5.85(s,0.2H),4.39-4.16(m,2.8H),3.85-3.78(m,0.2H),3.60(s,3H),2.94-2.79(m,2H),2.57(s,2.3H),2.42(s,0.7H),2.00-1.97(m,1H),1.87-1.63(m,3H),1.50(s,9H)。

Compound 306B: LC-MS (ESI): r_T＝1.87min，C₂₆H₃₀F₂N₄O₄Calculated mass of S532.2M/z found 533.7[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG; mobile phase: CO)₂MeOH, DEA, 80:20:0.2 at 3.0 g/min; column temperature: 39.9 ℃; wavelength: 230nm, R_T＝3.96min)。¹H NMR(300MHz,CDCl₃)δ8.10(s,0.7H),7.80-7.79(m,1H),7.51(d,J＝2.1Hz,0.3H),7.43(d,J＝2.1Hz,0.7H),7.09-7.07(m,0.3H),7.05(s,0.2H),6.95-6.87(m,1.8H),5.93(s,0.8H),5.85(s,0.2H),4.37-4.15(m,2.7H),3.84-3.78(m,0.3H),3.60(s,3H),2.94-2.80(m,2H),2.57(s,2.3H),2.43(s,0.7H),2.01-1.97(m,1H),1.75-1.60(m,3H),1.50(s,9H)。

Compound 314: (trans) -methyl 6- (-4- (N- (2- ((tert-butyldimethylsilyl) oxy) ethyl) methylsulfonamido) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.077min，C₃₀H₄₁ClF₂N₄O₅S₂Calculated mass of Si 702.2, found value of M/z 702.8[ M + H [ ]]⁺。

Compound 316: ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝1.75min，C₂₆H₃₀ClFN₄O₄Calculated mass of S548.2, M/z found value 549.6[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.12(s,0.5H),7.83(s,1H),7.51-7.50(m,0.5H),7.46-7.45(m,0.5H),7.38(d,J＝0.6Hz,0.5H),7.19-7.05(m,3H),6.29(s,0.5H),6.16(s,0.5H),4.32-4.03(m,5H),2.90-2.84(m,2H),2.05-1.86(m,3H),1.62-1.52(m,1H),1.50(s,9H),1.15-1.10(m,3H)。

Compound 326: ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.01min，C₂₆H₃₀ClFN₄O₄Calculated mass of S548.2, M/z found value 549.5[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.47(d,J＝2.4Hz,0.7H),9.04(s,0.3H),8.01-7.99(m,1.7H),7.93-7.92(m,0.3H),7.43-7.34(m,2H),7.24-7.18(m,1H),6.03(s,0.2H),5.92(d,J＝3.2Hz,0.8H),4.11-4.01(m,2H),3.99-3.94(m,2H),3.83-3.75(m,1H),2.84-2.69(m,2H),1.91-1.66(m,3H),1.57-1.49(m,1H),1.43(s,9H),1.10-1.02(m,3H)。

The racemic mixture of ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 326 (2.50g, 4.55mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IG5 μm20 x 250 mm; mobile phase: CO:. sup. mobile phase: Chiralpak:. sup.₂MeOH 70:30 at 50 g/min; temperature: 30 ℃; wavelength: 214 nm; back pressure: 100 bar) to yield the title compound 326A (1.00g, 40% yield, 100% stereopure) and 326B (1.20g, 48% yield, 99.8% stereopure) as yellow solids.

Compound 326A: chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 3 g/min; temperature: 30 ℃; wavelength: 230 nm; back pressure: 100 bar; r_T＝2.5min)。

Compound 326B: chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 3 g/min; temperature: 30 ℃; wavelength: 230 nm; back pressure: 100 bar; r_T＝3.4min)。

Compound 336: ethyl 4- (2-)Bromo-3-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,¹H NMR(400MHz,DMSO-d₆)δ9.48(d,J＝3.2Hz,0.7H),9.06(s,0.3H),8.04-7.92(m,2H),7.44-7.37(m,1H),7.31-7.24(m,1H),7.21-7.15(m,1H),6.07(s,0.3H),5.97(d,J＝3.6Hz,0.7H),4.16-3.93(m,4.3H),3.83-3.76(m,0.7H),2.85-2.67(m,2H),1.96-1.64(m,3.3H),1.54-1.50(m,0.7H),1.44(s,9H),1.08-1.01(m,3H)。

compound 340: ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (3, 4-difluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝2.879min，C₂₇H₃₂F₂N₄Calculated mass of O4S 546.2, found value of M/z 546.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.08(s,1H),7.80(d,J＝3.2Hz,1H),7.50(d,J＝3.2Hz,0.2H),7.43(d,J＝3.2Hz,0.8H),7.10-7.05(0.4H),6.93-6.90(m,1.6H),5.95(s,0.8H),5.86-5.85(m,0.2H),4.36-4.28(m,2H),4.21-4.05(m,2.7H),3.84-3.79(m,0.3H),2.92-2.83(m,2H),2.57-2.56(m,2.3H),2.43-2.42(m,0.7H),2.01-1.98(m,1H),1.86-1.83(m,1H),1.77-1.68(m,2H),1.50(s,9H),1.13(t,J＝2.8Hz,3H)。

Racemic 340(2.40g, 4.39mmol) was separated by preparative chiral SFC (separation conditions: column: ChiralpakIG 5 μm20 × 250 mm; mobile phase: CO)₂MeOH 80:20 at 50 g/min; the column temperature is 40 ℃; wavelength: 230 nm; back pressure: 100 bar) to yield the title compound 340A (700mg, 29% yield, 100% stereopure) and 340B (800mg, 33% yield, 99.4% stereopure) as yellow solids.

Compound 340A: chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH (DEA) (80: 20: 0.2) at a rate of 3.0 mL/min; temperature: 40.1 ℃; wavelength: 230nm, R_T＝3.00min)。¹H NMR(300MHz,DMSO-d₆)δ9.60(s,0.7H),9.12(s,0.3H),8.00-7.93(m,2H),7.47-7.41(m,1H),7.23-7.17(m,1H),6.03(s,0.3H),5.93(s,0.7H),4.19-3.75(m,5H),2.89-2.64(m,2H),2.51(s,2H),2.49(s,1H),2.00-1.57(m,4H),1.53(s,9H),1.10-1.02(m,3H)。

Compound 340B: hand (W.E.)Sexual analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH (DEA) (80: 20: 0.2) at a rate of 3.0 mL/min; temperature: 39.9 ℃; wavelength: 230nm, R_T＝3.85min)。¹H NMR(300MHz,DMSO-d₆)δ9.60(s,0.7H),9.12(s,0.3H),8.03-7.93(m,2H),7.50-7.41(m,1H),7.22-7.16(m,1H),6.03(s,0.3H),5.93(s,0.7H),4.14-3.75(m,5H),2.83-2.66(m,2H),2.51(s,2H),2.49(s,1H),1.92-1.57(m,4H),1.53(s,9H),1.10-1.02(m,3H)。

Compound 344: (trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.884min，C₂₄H₂₄ClF₂N₃O₄Calculated mass of S523.1, found value of M/z 524.1[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.2Hz,0.6H),8.92(br s,0.4H),8.05-7.99(m,1.6H),7.93(d,J＝3.6Hz,0.4H),7.49-7.41(m,1H),7.21-7.15(m,1H),6.02(s,0.4H),5.92(d,J＝3.6Hz,0.6H),4.00-3.93(m,2H),3.86-3.80(m,0.4H),3.62(s,1.3H),3.61(s,1.7H),3.58-3.54(m,0.6H),2.55-2.51(m,0.4H),2.36-2.30(m,0.6H),2.07-1.98(m,2H),1.89-1.65(m,4H),1.48-1.35(m,2H),1.09-1.03(m,3H)。

Rac 344(500mg, 0.955mmol) is separated by chiral preparative HPLC (column: Chiralpak IC5 μ M20 × 250 mm; mobile phase: Hex: EtOH ═ 85:15 at 25 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 344M (220mg, 44% yield, 100% stereopurity) and 344N (220mg, 44% yield, 100% stereopurity) as yellow solids.

Compound 344M: LC-MS (ESI): r_T＝3.866min，C₂₄H₂₄ClF₂N₃O₄Calculated mass of S523.1, M/z found value 524.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.857min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(br s,0.6H),8.92(br s,0.4H),8.03-7.98(m,1.6H),7.93(d,J＝3.6Hz,0.4H),7.48-7.42(m,1H),7.21-7.15(m,1H),6.02(s,0.4H),5.92(s,0.6H),4.00-3.93(m,2H),3.87-3.80(m,0.5H),3.62(s,1.3H),3.61(s,1.7H),3.58-3.53(m,0.5H),2.55-2.52(m,0.5H),2.36-2.30(m,0.5H),2.04-1.97(m,2H),1.90-1.65(m,4H),1.48-1.38(m,2H),1.09-1.03(m,3H)。

Compound 344N: LC-MS (ESI): r_T＝3.859min，C₂₄H₂₄ClF₂N₃O₄Calculated mass of S523.1, found value of M/z 524.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝8.931min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.2Hz,0.6H),8.92(br s,0.4H),8.05-7.99(m,1.6H),7.93(d,J＝2.8Hz,0.4H),7.49-7.42(m,1H),7.20-7.15(m,1H),6.02(s,0.4H),5.92(d,J＝2.8Hz,0.6H),4.00-3.93(m,2H),3.87-3.79(m,0.5H),3.62(s,1.3H),3.61(s,1.7H),3.58-3.54(m,0.5H),2.55-2.53(m,0.5H),2.35-2.31(m,0.5H),2.08-1.97(m,2H),1.90-1.65(m,4H),1.45-1.39(m,2H),1.09-1.03(m,3H)。

Compound 346: (trans) -ethyl 4- (2-bromo-3, 4-difluorophenyl) -6- (4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,¹H NMR(400MHz,DMSO-d₆)δ9.45(s,0.5H),8.94(s,0.5H),7.99-7.90(m,2H),7.56-7.45(m,1H),7.23-7.14(m,1H),6.01(s,0.5H),5.92(s,0.5H),3.99-3.91(m,1H),3.87-3.78(m,0.5H),3.61(s,3H),3.54-3.49(m,0.5H),2.50-2.49(m,0.5H),2.39-2.26(m,0.5H),2.10-2.01(m,2H),1.93-1.72(m,4H),1.43-1.36(m,2H),1.06-1.00(m,3H)。

rac 346(700mg, 1.23mmol) was separated by chiral preparative SFC (column: Chiralpak IC5 μm20 x 250 mm; mobile phase: CO₂MeOH 70:30 at 50 g/min; column temperature: 39.9 ℃; wavelength: 214nm, back pressure: 100 bar) to yield the title compound 346M (300mg, 50% yield, 100% stereopure) and 346N (200mg, 33% yield, 100% stereopure) as yellow solids.

Compound 346M: LC-MS (ESI): r_T＝4.110min，C₂₄H₂₄BrF₂N₃O₄Calculated mass of S567.1, M/z found value 568.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250mm,mobile phase: CO2₂MeOH 70:30 at 2.999 g/min; column temperature: 39.9 ℃; wavelength: 230nm, back pressure: 100bar, R_T＝3.30min)。¹H NMR(400MHz,DMSO-d₆)δ9.47(s,0.5H),8.92(s,0.5H),7.99(s,1.5H),7.93(d,J＝2.8Hz,0.5H),7.55-7.46(m,1H),7.22-7.12(m,1H),6.01(s,0.5H),5.92(s,0.5H),3.99-3.95(m,2H),3.87-3.80(m,0.5H),3.58(s,3H),3.55-3.51(m,0.5H),2.36-2.29(m,0.6H),2.05-2.01(m,2.4H),1.90-1.82(m,2H),1.76-1.59(m,2H),1.46-1.42(m,2H),1.10-1.03(m,3H)。

Compound 346N: LC-MS (ESI): r_T＝4.122min，C₂₄H₂₄BrF₂N₃O₄Calculated mass of S567.1, M/z found value 568.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250mm, mobile phase: CO₂MeOH 70:30 at 2.999 g/min; column temperature: 39.9 ℃; wavelength: 230nm, back pressure: 100bar, R_T＝4.78min)。¹H NMR(400MHz,DMSO-d₆)δ9.49(s,0.5H),8.92(s,0.5H),7.99(s,1.5H),7.93(d,J＝3.2Hz,0.5H),7.54-7.43(m,1H),7.22-7.12(m,1H),6.01(s,0.5H),5.91(d,J＝3.2Hz,0.5H),3.99-3.95(m,2H),3.90-3.75(m,0.5H),3.62(s,1.5H),3.61(s,1.5H),3.57-3.52(m,0.5H),2.38-2.31(m,1H),2.09-2.01(m,2H),1.87-1.59(m,4H),1.51-1.40(m,2H),1.10-1.03(m,3H)。

Compound 349: ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝1.806min，C₂₈H₂₉ClF₄N₄O₄Calculated mass 596.2, found value M/z 597.2[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ8.61(s,0.7H),8.31(d,J＝2.4Hz,0.7H),8.25(d,J＝2.0Hz,0.3H),7.75(s,0.3H),7.33-7.28(m,1H),7.09-6.97(m,2H),6.32(s,0.7H),6.07(d,J＝2.4Hz,0.3H),4.39-4.18(m,2.7H),4.10-3.89(m,2.3H),2.97-2.78(m,2H),1.88-1.82(m,1H),1.70-1.57(m,3H),1.51(s,6.3H),1.49(s,2.7H),1.16-1.11(m,3H)。

Rac 349(300mg, 0.052mmol) was separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: IPA ═ 90:10 at 25 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compounds 349A (120mg, 40% yield, 100% stereopurity) and 349A (135mg, 45% yield, 100% stereopurity).

Intermediate 349A: LC-MS (ESI): r_T3.116 and 3.294min, C₂₈H₂₉ClF₄N₄O₄Calculated mass 596.2, found value M/z 597.1[ M + H]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: IPA 90:10 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝14.784min)。¹H NMR(400MHz,DMSO-d₆)δ9.27(s,0.6H),9.17(d,J＝3.6Hz,0.4H),8.56(d,J＝2.0Hz,1H),8.08-8.02(m,1H),7.49-7.43(m,1H),7.24-7.18(m,1H),6.04(s,0.6H),5.94(d,J＝2.8Hz,0.4H),4.17-3.94(m,4.6H),3.82-3.75(m,0.4H),2.84-2.67(m,2H),1.84-1.61(m,3.6H),1.53-1.46(m,0.4H),1.41(s,9H),1.09-1.02(m,3H)。

Intermediate 349A: LC-MS (ESI): r_T2.896 and 3.173min, C₂₈H₂₉ClF₄N₄O₄Calculated mass 596.2, found value M/z 597.1[ M + H]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: IPA 90:10 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝19.839min)。¹H NMR(400MHz,DMSO-d₆)δ9.28(s,0.6H),9.17(s,0.4H),8.56(d,J＝2.4Hz,1H),8.07-8.02(m,1H),7.51-7.43(m,1H),7.24-7.17(m,1H),6.04(s,0.6H),5.94(d,J＝2.8Hz,0.4H),4.15-3.94(m,4.6H),3.82-3.73(m,0.4H),2.84-2.67(m,2H),1.84-1.68(m,3.6H),1.52-1.46(m,0.4H),1.41(s,9H),1.09-1.00(m,3H)。

Compounds 359E and 359F: (cis) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (2-methoxyethyl) sulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (2-methoxyethyl) sulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Separation conditions are as follows: preparative HPLC separation (separation conditions: column: Gilson X-bridge C18(5 μm19 mm 150mm), mobile phase A: water (+ 0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 254nm, flow rate: 15mL/min, gradient: 50% -70% (% B)) gave the title compounds 359E (130mg, 9% yield) and 359F (430mg, 29% yield) as yellow solids.

Compound 359E: LC-MS (ESI): r_T＝3.771min，C₂₄H₂₇ClF₂N₄O₅S₂Calculated mass of 588.1, M/z found value 589.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.56(s,0.7H),8.31(s,0.3H),8.00-7.96(m,2H),7.49-7.37(m,1.3H),7.22-7.19(m,1H),7.11(t,J＝6.0Hz,0.7H),6.04(s,0.3H),5.93(s,0.7H),3.93-3.87(m,0.3H),3.69(br s,0.7H),3.52(s,3H),3.41-3.37(m,2H),3.27-3.25(m,3.3H),3.17-3.08(m,2.7H),2.37-1.78(m,6.3H),1.65-1.62(m,1H),1.52-1.48(m,0.7H)。

Compound 359F: LC-MS (ESI): r_T＝3.648min，C₂₄H₂₇ClF₂N₄O₅S₂Calculated mass of 588.1, M/z found value 589.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝3.6Hz,0.6H),8.99(s,0.4H),8.00-7.94(m,2H),7.49-7.41(m,1H),7.21-7.10(m,2H),6.01(s,0.4H),5.92(d,J＝3.6Hz,0.6H),3.89-3.81(m,0.4H),3.61-3.52(m,3.6H),3.41-3.37(m,2H),3.29(s,3H),3.16-3.10(m,2.4H),3.07-2.99(m,0.6H),2.20-2.13(m,2H),2.01-1.68(m,4H),1.56-1.41(m,2H)。

Rac 359E (120mg, 0.200mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 25 mL/min; temperature: 30 ℃ c; wavelength: 214nm) to give the title compounds 359A (40mg, 33% yield, 100% stereopurity) and 359B (45mg, 38% yield, 100% stereopurity) as yellow solids.

Compound 359A: LC-MS (ESI): r_T＝2.375min，C₂₄H₂₇ClF₂N₄O₅S₂Calculated mass of 588.1, M/z found value 589.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IA5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30 ℃; wavelength: 230_T＝7.183min)。¹H NMR(400MHz,DMSO-d₆)δ9.57(s,0.7H),8.31(s,0.3H),8.01-7.96(m,2H),7.49-7.37(m,1.3H),7.22-7.18(m,1H),7.12(t,J＝6.0Hz,0.7H),6.03(s,0.3H),5.92(s,0.7H),3.94-3.86(m,0.3H),3.72-3.66(m,0.7H),3.52(s,3H),3.40-3.35(m,2H),3.27-3.25(m,3H),3.18-3.08(m,3H),2.38-1.76(m,6.3H),1.66-1.62(m,1H),1.51-1.45(m,0.7H)。

Compound 359B: LC-MS (ESI): r_T＝2.361min，C₂₄H₂₇ClF₂N₄O₅S₂Calculated mass of 588.1, M/z found value 589.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IA5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30 ℃; wavelength: 230_T＝9.264min)。¹H NMR(400MHz,DMSO-d₆)δ9.57(s,0.7H),8.31(s,0.3H),8.01-7.96(m,2H),7.50-7.37(m,1.3H),7.22-7.18(m,1H),7.12(t,J＝6.0Hz,0.7H),6.03(s,0.3H),5.92(s,0.7H),3.94-3.86(m,0.3H),3.72-3.66(m,0.7H),3.52(s,3H),3.41-3.35(m,2H),3.27-3.25(m,3H),3.18-3.08(m,3H),2.37-1.74(m,6.3H),1.65-1.60(m,1H),1.52-1.45(m,0.7H)。

Rac 359F (380mg, 0.65mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 50:50 at 10 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compounds 359C (150mg, 39% yield, 100% stereopurity) and 359D (130mg, 34% yield, 100% stereopurity) as yellow solids.

Compound 359C: LC-MS (ESI): r_T＝3.082min，C₂₄H₂₇ClF₂N₄O₅S₂Calculated mass of 588.1, M/z found value 589.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝9.329min)。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.6Hz,0.6H),8.97(s,0.4H),8.00-7.94(m,2H),7.48-7.41(m,1H),7.21-7.15(m,1.4H),7.10(t,J＝6.0Hz,0.6H),6.01(s,0.4H),5.92(d,J＝3.6Hz,0.6H),3.88-3.80(m,0.4H),3.61-3.52(m,3.6H),3.41-3.37(m,2H),3.28(s,3H),3.18-3.11(m,2.4H),3.06-2.99(m,0.6H),2.20-2.09(m,2H),1.98-1.67(m,4H),1.55-1.41(m,2H)。

Compound 359D: LC-MS (ESI): r_T＝3.086min，C₂₄H₂₇ClF₂N₄O₅S₂Calculated mass of 588.1, M/z found value 589.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝11.758min)。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.2Hz,0.6H),8.97(s,0.4H),8.00-7.94(m,2H),7.48-7.41(m,1H),7.21-7.16(m,1.4H),7.10(t,J＝5.6Hz,0.6H),6.02(s,0.4H),5.92(d,J＝3.6Hz,0.6H),3.89-3.80(m,0.4H),3.62-3.52(m,3.6H),3.41-3.37(m,2H),3.29(s,3H),3.16-3.11(m,2.4H),3.06-3.00(m,0.6H),2.20-2.09(m,2H),1.99-1.68(m,4H),1.55-1.41(m,2H)。

Compound 361: (trans) -methyl 6- (4- (N- (3- (tert-butoxy) -2, 2-dimethyl-3-oxopropyl) sulfamoyl) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate purified by preparative HPLC (column: Gilson Xbridge C18(5 μm19 x 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 70% -90% (% B)) to give the title compound as a yellow solid (200mg, 24% yield). LC-MS (ESI): r_T＝4.561min，C₃₀H₃₇ClF₂N₄O₆S₂Calculated mass of 686.2, M/z found value 686.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.58(d,J＝3.6Hz,0.6H),9.00(s,0.4H),8.02-8.01(m,1H),7.99(d,J＝6.4Hz,0.6H),7.96-7.93(m,0.4H),7.49-7.41(m,1H),7.22-7.14(m,1H),7.10-7.06(m,0.4H),7.00-6.96(m,0.6H),6.01(s,0.4H),5.92(d,J＝4.0Hz,0.6H),3.89-3.80(m,0.4H),3.61-3.56(m,0.6H),3.53(s,1.8H),3.52(s,1.2H),3.17-3.13(m,0.4H),3.11-3.05(m,2H),3.03-2.96(m,0.6H),2.23-2.10(m,2H),2.04-1.91(m,1H),1.89-1.75(m,2H),1.73-1.67(m,1H),1.56-1.45(m,2H),1.42(s,9H),1.09(s,2.4H),1.08(s,3.6H)。

Rac 361(190mg, 0.227mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 14 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 361X (65mg, 34% yield, 100% stereopurity) and 361Y (65mg, 34% yield, 99.9% stereopurity) as yellow solids.

Compound 361X: LC-MS (ESI): r_T＝4.288min，C₃₀H₃₇ClF₂N₄O₆S₂Calculated mass of 686.2, M/z found value 687.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; temperature: 30 ℃; wavelength: 230 nm; and_T＝10.214min)。¹H NMR(400MHz,CDCl₃)δ8.10(S,0.5H),7.84-7.81(m,1H),7.51(d,J＝2.8Hz,0.5H),7.46(d,J＝2.8Hz,0.5H),7.39(s,0.5H),7.07-7.01(m,2H),6.18(s,0.5H),6.05(d,J＝2.0Hz,0.5H),4.93-4.84(m,1H),4.04-3.98(m,0.5H),3.80-3.75(m,0.5H),3.62-3.60(m,3H),3.16-3.13(m,2H),3.06-3.00(m,1H),2.44-1.95(m,4H),1.83-1.64(m,3H),1.46(s,9H),1.23(m,6H)。

compound 361Y: LC-MS (ESI): r_T＝3.650min，C₃₀H₃₇ClF₂N₄O₆S₂Calculated mass of 686.2, M/z found value 687.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; temperature: 30 ℃; wavelength: 230 nm; and_T＝13.723min)。¹H NMR(400MHz,CDCl₃)δ8.10(s,0.5H),7.84-7.81(m,1H),7.51(d,J＝3.2Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.39(s,0.5H),7.07-7.01(m,2H),6.18(s,0.5H),6.05(d,J＝2.8Hz,0.5H),4.93-4.84(m,1H),4.10-3.98(m,0.5H),3.80-3.75(m,0.5H),3.62-3.60(m,3H),3.16-3.13(m,2H),3.06-3.00(m,1H),2.43-1.95(m,4H),1.84-1.70(m,3H),1.46(s,9H),1.23(m,6H)。

compound 362 a: ethyl 4- (2-chloro-4-fluorophenyl) -6- (5-ethoxycarbonyltetrahydro-2H-pyran-2-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.471min，C₂₄H₂₅ClFN₃O₅The calculated mass of S is 521.1,m/z found 522.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.86(s,0.2H),8.80(s,0.2H),8.74(d,J＝4.8Hz,0.6H),8.01-7.96(m,2H),7.45-7.42(m,2H),7.23-7.21(m,1H),6.07(d,J＝2.8Hz,0.5H),6.01(d,J＝5.6Hz,0.5H),5.25-5.08(m,1H),4.46-4.41(m,0.5H),4.34-4.09(m,2.5H),3.99-3.94(m,2H),3.89-3.76(m,0.6H),3.68-3.34(m,0.4H),2.83-2.62(m,1H),2.31-2.12(m,1.5H),2.02-1.65(m,2H),1.61-1.48(m,0.5H),1.33-1.26(m,2H),1.22-1.18(m,1H),1.09-1.04(m,3H)。

Compound 362R: ethyl 4- (2-chloro-4-fluorophenyl) -6- (5-ethoxycarbonyltetrahydro-2H-pyran-2-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T3.606 and 3.694min, C₂₄H₂₅ClFN₃O₅Calculated mass of S521.1, found value of M/z 522.2[ M + H [)]⁺。¹H NMR(400MHz,CD₃OD)δ7.93-7.89(m,1H),7.76-7.75(m,1H),7.49-7.44(m,0.5H),7.41-7.34(m,0.5H),7.24-7.22(m,1H),7.10-7.02(m,1H),6.18(d,J＝4.4Hz,0.5H),6.12(d,J＝3.2Hz,0.5H),5.34-5.20(m,1H),4.60-4.55(m,0.5H),4.21-4.16(m,1.8H),4.15-4.12(m,0.7H),4.03(q,J＝6.8Hz,2H),3.88-3.83(m,0.7H),3.70-3.63(m,0.3H),2.81-2.75(m,0.2H),2.65(br s,0.6H),2.41-2.33(m,0.6H),2.28-2.13(m,0.6H),1.96-1.82(m,2.2H),1.79-1.56(m,0.8H),1.38-1.35(m,2H),1.29-1.25(m,1H),1.15-1.11(m,3H)。

362a (676mg, 1.30mmol) and 362R (962mg, 1.85mmol) were further purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 6:1) to give the title compound 362W (1.40g, 2.69mmol) which was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give group 1(690mg), group 2(92mg), group 3(80mg), group 4(146mg) and the title compound 362Y (48mg, 3% yield, 92.7% stereopurity). Group 2 was further purified by preparative HPLC (column: waters kinete EVO C18(5 μm 21.2 × 150mm), mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 65% -70% (% B)) to give the title compound 362V (50mg, 4% yield, 100% stereopurity), group 3 was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 90:10, at 25 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 362X (48mg, 3% yield, 99.2% stereopurity), and group 4 was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 mm; Hex: 90:10 mL; temperature: 30 μm20 mm; 10:10 nm; 10:10 mL; wavelength: 20 nm), the title compound 362T was obtained (90mg, 6% yield, 99.7% stereopure). Group 1 was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 95:5 at 25 mL/min; temperature: 30 ℃; wavelength: 214) to give group 5(140mg), group 6(130mg), group 7(110mg) and the title compound 362U (60mg, 4% yield, 100% stereopurity). Group 5 was further purified by preparative HPLC (column: Gilson X-bridgeC18(5 μ M21.2X 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 65% -85% (% B) to give the title compound 362M (110mg, 8% yield, 96.9% stereopurity.) group 6 was further purified by preparative HPLC (column: Waters kinete EVO C18(5 μ M21.2X 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 50% -95% (% B) to give the title compound 362N (88mg, 6% yield, 96.9% stereopurity), group 7 was further purified by preparative HPLC (column: Waters X-bridgemingC 8926 (5 μ M18), mobile phase A: 0.19% ammonia carbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 65% -95% (% B) to give the title compound 362S (86mg, 6% yield, 94.6% stereopure).

Compound 362m (cis): LC-MS (ESI): r_T＝3.344min，C₂₄H₂₅ClFN₃O₅Calculated mass of S521.1, found value of M/z 521.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 95:5 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝9.833min)。¹H NMR(400MHz,CDCl₃)δ8.92(br s,1H),7.77(d,J＝2.8Hz,1H),7.42-7.38(m,2H),7.11(dd,J＝8.4,2.4Hz,1H),6.93-6.88(m,1H),6.16(s,1H),5.33(dd,J＝10.8,2.0Hz,1H),4.63-4.60(m,1H),4.38-4.22(m,2H),4.06-3.98(m,2H),3.82-3.78(m,1H),2.57(br s,1H),2.40-2.37(m,1H),2.02-1.88(m,2H),1.78-1.65(m,1H),1.37(t,J＝7.2Hz,3H),1.12(t,J＝7.2Hz,3H)。

Compound 362n (cis): LC-MS (ESI): r_T＝3.348min，C₂₄H₂₅ClFN₃O₅Calculated mass of S521.1, found value of M/z 521.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 95:5 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝11.383min)。¹H NMR(400MHz,CDCl₃)δ9.25(br s,1H),7.89(br s,1H),7.62(br s,1H),7.46-7.42(m,1H),7.14(dd,J＝8.8,2.4Hz,1H),6.96-6.93(m,1H),6.25(br s,1H),5.34(d,J＝10.0Hz,1H),4.62(d,J＝11.6Hz,1H),4.38-4.22(m,2H),4.10-4.01(m,2H),3.82-3.79(m,1H),2.59(br s,1H),2.42-2.38(m,1H),2.00-1.89(m,2H),1.77-1.68(m,1H),1.37(t,J＝7.2Hz,3H),1.14(t,J＝7.2Hz,3H)。

Compound 362s (cis): LC-MS (ESI): r_T＝3.334min，C₂₄H₂₅ClFN₃O₅Calculated mass of S521.1, found value of M/z 521.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 95:5 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝13.153min)。¹H NMR(400MHz,CDCl₃)δ8.84(br s,1H),7.80(d,J＝3.2Hz,1H),7.41(d,J＝2.8Hz,1H),7.29-7.28(m,1H),7.12(dd,J＝8.8,2.4Hz 1H),6.94-6.89(m,1H),6.22(s,1H),5.32-5.29(m,1H),4.63(d,J＝11.6Hz,1H),4.39-4.32(m,1H),4.29-4.23(m,1H),4.08-3.98(m,2H),3.82-3.78(m,1H),2.58(brs,1H),2.44-2.41(m,1H),2.11-2.08(m,1H),1.97-1.88(m,2H),1.39(t,J＝6.8Hz,3H),1.14(t,J＝6.8Hz,3H)。

Compound 362t (cis): LC-MS (ESI): r_T＝4.093min，C₂₄H₂₅ClFN₃O₅Calculated mass of S521.1, found value of M/z 522.2[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R: C; chiral analysis; column: Chiralpak IC5 μm4.6 x 10 mm; mobile phase: Hex: EtOH ═ 90: 10; temperature: 30 ℃; wavelength: 230 nm; R_T＝15.229min)。¹H NMR(400MHz,CDCl₃)δ8.84(br s,1H),7.80(d,J＝3.2Hz,1H),7.41(d,J＝3.2Hz,1H),7.29-7.27(m,1H),7.11(dd,J＝8.8,2.8Hz,1H),6.94-6.88(m,1H),6.22(s,1H),5.32-5.29(m,1H),4.63(d,J＝11.2Hz,1H),4.39-4.34(m,1H),4.28-4.23(m,1H),4.08-3.98(m,2H),3.82-3.78(m,1H),2.58(br s,1H),2.43-2.41(m,1H),2.11-2.08(m,1H),1.97-1.87(m,2H),1.39(t,J＝7.2Hz,3H),1.14(t,J＝7.2Hz,3H)。

Compound 362u (trans): LC-MS (ESI): r_T＝4.304min，C₂₄H₂₅ClFN₃O₅Calculated mass of S521.1, found value of M/z 522.2[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 95:5 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝8.729min)。¹H NMR(400MHz,CDCl₃)δ8.82(br s,1H),7.84(d,J＝3.2Hz,1H),7.44-7.39(m,2H),7.12(dd,J＝8.4,2.4Hz,1H),6.95-6.90(m,1H),6.17(s,1H),5.25(dd,J＝10.8,2.0Hz,1H),4.37(dd,J＝8.4,5.2Hz,1H),4.16(q,J＝7.2Hz,2H),4.05-4.00(m,2H),3.67(t,J＝11.6Hz,1H),2.78-2.70(m,1H),2.45-2.18(m,2H),1.96-1.85(m,1H),1.57-1.47(m,1H),1.27(t,J＝7.2Hz,3H),1.12(t,J＝7.2Hz,3H)。

Compound 362v (trans): LC-MS (ESI): r_T＝3.711min，C₂₄H₂₅ClFN₃O₅Calculated mass of S521.1, found value of M/z 522.2[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R: C; chiral analysis; column: Chiralpak IC5 μm4.6 x 10 mm; mobile phase: Hex: EtOH ═ 90: 10; temperature: 30 ℃; wavelength: 230 nm; R_T＝9.631min)。¹H NMR(400MHz,CDCl₃)δ8.82(br s,1H),7.83(d,J＝3.2Hz,1H),7.43-7.39(m,2H),7.12(dd,J＝8.8,2.4Hz,1H),6.95-6.89(m,1H),6.17(s,1H),5.25(dd,J＝11.2,2.0Hz,1H),4.38(dd,J＝10.0,2.8Hz,1H),4.16(q,J＝7.2Hz,2H),4.03(q,J＝7.2Hz,2H),3.68(m,J＝11.6Hz,1H),2.78-2.70(m,1H),2.25-2.18(m,2H),1.96-1.85(m,1H),1.58-1.47(m,1H),1.27(t,J＝7.2Hz,3H),1.12(t,J＝6.8Hz,3H)。

Compound 362x (trans): LC-MS (ESI): r_T＝4.313min，C₂₄H₂₅ClFN₃O₅Meter for SCalculated mass 521.1, found M/z value 522.2[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R: C; chiral analysis; column: Chiralpak IC5 μm4.6 x 10 mm; mobile phase: Hex: EtOH ═ 90: 10; temperature: 30 ℃; wavelength: 230 nm; R_T＝11.369min)。¹H NMR(400MHz,CDCl₃)δ8.83(br s,1H),7.84(d,J＝3.2Hz,1H),7.43(d,J＝3.2Hz,1H),7.30-7.27(m,1H),7.13(dd,J＝8.8,2.4Hz,1H),6.93-6.89(m,1H),6.23(s,1H),5.24(dd,J＝10.8,1.6Hz,1H),4.39(dd,J＝7.6,4.0Hz,1H),4.16(q,J＝7.2Hz,2H),4.07-3.97(m,2H),3.69-3.63(m,1H),2.78-2.68(m,1H),2.30-2.25(m,2H),2.00-1.89(m,1H),1.73-1.66(m,1H),1.27(t,J＝7.2Hz,3H),1.15(t,J＝7.2Hz,3H)。

Compound 362y (trans): LC-MS (ESI): r_T＝4.306min，C₂₄H₂₅ClFN₃O₅Calculated mass of S522.2, found value of M/z 521.9[ M + H]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R: C; chiral analysis; column: Chiralpak IC5 μm4.6 x 10 mm; mobile phase: Hex: EtOH ═ 90: 10; temperature: 30 ℃; wavelength: 230 nm; R_T＝13.057min)。¹H NMR(400MHz,CDCl₃)δ8.83(br s,1H),7.84(d,J＝3.2Hz,1H),7.43(d,J＝3.2Hz,1H),7.30-7.27(m,1H),7.13(dd,J＝8.4,2.0Hz,1H),6.95-6.88(m,1H),6.23(s,1H),5.24-5.21(m,1H),4.41-4.37(m,1H),4.16(q,J＝7.2Hz,2H),4.06-4.01(m,2H),3.69-3.63(m,1H),2.78-2.69(m,1H),2.30-2.25(m,2H),1.99-1.88(m,1H),1.70-1.66(m,1H),1.28(t,J＝7.2Hz,3H),1.15(t,J＝7.2Hz,3H)。

Compound 368: ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.05min，C₂₆H₂₉ClF₂N₄O₄Calculated mass of S566.2, found value of M/z 567.7[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.36(s,0.5H),7.82(d,J＝3.2Hz,1H),7.51(d,J＝2.8Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.38(s,0.5H),7.10-6.99(m,2H),6.20(s,0.5H),6.08(s,0.5H),4.30(br s,1.5H),4.09-3.99(m,2H),3.97-3.89(m,0.5H),2.91-2.79(m,2H),1.80-1.74(m,3H),1.61-1.58(m,2H),1.50(s,9H),1.13(t,J＝6.8Hz,3H)。

Rac 368(13.0g, 22.9mmol) was separated by chiral preparative HPLC (column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 95:5, at 25mL/min, temperature: 30 ℃ c; wavelength: 214nm) to give the title compound 368A (5g, 38% yield, 99.7% stereopurity) and 368B (5g, 38% yield, 98.4% stereopurity).

Compound 368A: LC-MS (ESI): r_T＝2.05min，C₂₆H₂₉ClF₂N₄O₄Calculated mass of S566.2, M/z found value 567.6[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 95:5 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝7.937min)。¹H NMR(400MHz,CDCl₃)δ8.12(s,0.5H),7.83-7.82(m,1H),7.51(d,J＝3.2Hz,0.4H),7.46(d,J＝3.2Hz,0.6H),7.34(s,0.5H),7.10-6.99(m,2H),6.20(s,0.6H),6.08(d,J＝2.4Hz,0.4H),4.36-4.14(m,2.6H),4.10-3.99(m,2H),3.97-3.89(m,0.4H),2.91-2.78(m,2H),2.10-1.63(m,3.5H),1.58-1.56(m,0.5H),1.50(s,9H),1.14(t,J＝7.2Hz,3H)。

Compound 368B: LC-MS (ESI): r_T＝2.05min，C₂₆H₂₉ClF₂N₄O₄Calculated mass of S566.2, M/z found value 567.6[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 95:5 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝8.930min)。¹H NMR(400MHz,CDCl₃)δ8.12(s,0.5H),7.83-7.82(m,1H),7.51(d,J＝3.2Hz,0.4H),7.46(d,J＝3.2Hz,0.6H),7.34(s,0.5H),7.10-6.99(m,2H),6.20(s,0.6H),6.08(d,J＝2.4Hz,0.4H),4.36-4.14(m,2.6H),4.10-3.99(m,2H),3.97-3.89(m,0.4H),2.91-2.78(m,2H),2.10-1.63(m,3.5H),1.58-1.56(m,0.5H),1.50(s,9H),1.14(t,J＝7.2Hz,3H)。

Compound 371: methyl 6- (3- ((tert-butoxycarbonyl) amino) bicyclo [1.1.1]Pent-1-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.454min，C₂₅H₂₆ClFN₄O₄Calculated mass of S532.1, found value of M/z 532.8[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ7.91-7.86(m,0.8H),7.82-7.79(m,1H),7.48(d,J＝2.8Hz,0.2H),7.43(d,J＝3.2Hz,0.8H),7.41(br s,0.2H),7.31-7.27(m,0.7H),7.25-7.24(m,0.3H),7.14-7.11(m,1H),6.96-6.89(m,1H),6.15(s,0.8H),6.01(d,J＝2.8Hz,0.2H),5.04(br s,1H),3.64(s,0.7H),3.60(s,2.3H),2.53(s,4.6H),2.45(s,1.4H),1.47(s,9H)。

Rac 371(1.20g, 2.26mmol) was separated by chiral preparative SFC (column: Chiralpak IG5 μm20 x 250 mm; mobile phase: CO₂MeOH 70:30 at 45 g/min; column temperature: 39 ℃; wavelength: 214nm, back pressure: 100 bar) to give the title compound 371A (608mg, 51% yield, 100% stereopurity) and 371B (576mg, 48% yield, 100% stereopurity) as yellow solids.

Compound 371A: LC-MS (ESI): r_T＝2.455min，C₂₅H₂₆ClFN₄O₄Calculated mass of S532.1, found value of M/z 532.8[ M + H [)]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 2.999 g/min; column temperature: 40 ℃; wavelength: 230nm, back pressure: 100bar, R_T＝2.92min)。¹H NMR(400MHz,CDCl₃)δ7.88(br s,0.8H),7.81(d,J＝3.6Hz,0.2H),7.80(d,J＝2.8Hz,0.8H),7.48(d,J＝2.8Hz,0.3H),7.43(d,J＝3.2Hz,0.7H),7.40(br s,0.2H),7.31-7.27(m,0.7H),7.25-7.24(m,0.3H),7.12(dd,J＝8.8,2.8Hz,1H),6.96-6.89(m,1H),6.15(s,0.7H),6.01(s,0.3H),5.03(br s,1H),3.64(s,0.7H),3.60(s,2.3H),2.53(s,4.3H),2.45(s,1.7H),1.47(s,9H)。

Compound 371B: LC-MS (ESI): r_T＝2.456min，C₂₅H₂₆ClFN₄O₄Calculated mass of S532.1, found value of M/z 532.8[ M + H [)]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 2.999 g/min; column temperature: 40 ℃; wavelength: 230nm, back pressure: 100bar, R_T＝4.32min)。¹H NMR(400MHz,CDCl₃)δ7.88(br s,0.8H),7.81(d,J＝3.2Hz,0.2H),7.80(d,J＝3.2Hz,0.8H),7.48(d,J＝3.2Hz,0.3H),7.43(d,J＝3.2Hz,0.7H),7.40(br s,0.2H),7.31-7.27(m,0.7H),7.25-7.24(m,0.3H),7.14-7.11(m,1H),6.97-6.89(m,1H),6.15(s,0.7H),6.01(d,J＝2.4Hz,0.3H),5.03(br s,1H),3.64(s,0.7H),3.60(s,2.3H),2.53(s,4.3H),2.45(s,1.7H),1.47(s,9H)。

Compound 377: ethyl 6- (-1- (tert-butoxycarbonyl) -2- (((tert-butyldiphenylsilyl) oxy) methyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 377a (racemate):¹H NMR(400MHz,CDCl₃)δ8.09(s,0.2H),7.82(d,J＝2.8Hz,0.8H),7.70-7.66(m,4H),7.50(d,J＝2.4Hz,0.6H),7.45-7.38(m,6H),7.34-7.29(m,1.4H),7.13(d,J＝8.0Hz,1H),6.96-6.88(m,1H),6.23(d,J＝9.2Hz,0.4H),6.10(d,J＝12.8Hz,0.6H),4.77-4.68(m,0.3H),4.54-4.37(m,1H),4.26-4.13(m,1H),3.99-3.94(m,2H),3.89-3.79(m,1H),3.72-3.65(m,0.7H),2.93-2.79(m,1H),2.22-2.05(m,1H),1.97-1.88(m,1H),1.85-1.68(m,2H),1.58(s,3H),1.55-1.40(m,9H),1.28-1.21(m,1H),1.08-0.98(m,9H)。

compound 377b (racemate):¹H NMR(400MHz,CDCl₃)δ8.14-8.11(m,0.3H),7.84-7.80(m,0.7H),7.73-7.65(m,4H),7.50(d,J＝2.8Hz,0.6H),7.45-7.26(m,7.4H),7.16-7.11(m,1H),6.91-6.84(m,1H),6.21-6.18(m,0.4H),6.07-6.04(m,0.6H),4.83-4.74(m,0.3H),4.58-4.32(m,1.2H),4.23-4.10(m,1.4H),4.04-3.96(m,1.6H),3.89-3.65(m,1.5H),2.93-2.65(m,1H),2.38-2.18(m,1.6H),2.05-2.00(m,0.4H),1.98-1.84(m,2H),1.63(s,3H),1.49-1.42(m,9H),1.28-1.24(m,1H),1.08-1.00(m,9H)。

compound 380: (trans) -methyl 6- (4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.152min，C₂₇H₃₅ClFN₃O₃Calculated mass of SSi 563.2, M/z found value 564.2[ M + H [ ]]⁺。

Compound 382: tert-butyl 4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) azepane-1-carboxylate, LC-ms (esi): r_T＝1.92min，C₂₆H₃₀ClFN₄O₄Calculated mass of S548.2, M/z found value 549.4[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.08-8.06(m,0.5H),7.82-7.78(m,1H),7.49-7.39(m,1.5H),7.32-7.26(m,1H),7.15-7.12(m,1H),7.00-6.89(m,1H),6.19-6.16(m,0.5H),6.04-6.03(m,0.5H),4.15-4.06(m,0.5H),3.96-3.71(m,1.5H),3.61-3.59(m,3H),3.56-3.18(m,3H),2.15-1.67(m,6H),1.51(s,4H),1.50(s,5H)。

Compound 385: methyl 4- (2-chloro-4-fluorophenyl) -6- (1, 4-dioxaspiro [4.5]]Decan-8-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,¹h NMR, 41% yield) as a yellow solid.¹H NMR(300MHz,CDCl₃)δ8.20(br s,0.6H),7.83-7.77(m,1H),7.46(br s,0.4H),7.43-7.40(m,1H),7.33-7.28(m,1H),7.15-7.07(m,1H),6.95-6.86(m,1H),6.18(s,0.7H),6.04(s,0.3H),3.99(s,4H),3.94-3.90(m,1H),3.63-3.58(m,3H),2.06-2.00(m,1H),1.91-1.88(m,2H),1.83-1.75(m,4H),1.66-1.55(m,1H)。

Compound 394: (trans) -methyl 6- (4- ((tert-butoxycarbonyl) amino) cyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,¹H NMR(300MHz,CDCl₃)δ8.67-8.64(m,0.7H),8.31-8.28(m,0.7H),8.25-8.22(m,0.3H),7.84-7.80(m,0.3H),7.33-7.28(m,1H),7.15-7.11(m,1H),6.97-6.82(m,2H),6.29-6.26(m,0.7H),6.02-6.00(m,0.3H),4.51-4.42(m,1H),4.05-3.96(m,1H),3.60(s,1.2H),3.58(s,1.8H),2.21-2.07(m,4H),1.98-1.90(m,2H),1.61-1.54(m,1H),1.46(s,9H),1.32-1.28(m,1H)。

compound 397: (cis) -methyl 6- (4- ((tert-butoxycarbonyl) amino) cyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,¹H NMR(300MHz,CDCl₃)δ8.67-8.61(m,0.7H),8.32-8.29(m,0.6H),8.26-8.23(m,0.4H),7.84-7.80(m,0.3H),7.30-7.28(m,1H),7.13-7.11(m,1H),6.98-6.96(m,1H),6.90-6.87(m,1H),6.30-6.26(m,0.7H),6.04-6.00(m,0.3H),4.46-4.39(m,1H),3.99-3.94(m,1H),3.58(s,3H),2.13-2.07(m,3H),1.98-1.91(m,3H),1.71-1.67(m,2H),1.48(s,4H),1.45(s,5H)。

compound 407: methyl 4- (2-bromo-4-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.207min，C₂₅H₂₈BrFN₄O₄Calculation of SMass 578.1, found M/z value 579.0[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.12(s,0.4H),7.83-7.81(m,1H),7.51-7.45(m,1.6H),7.34-7.30(m,1H),7.01-6.94(m,1H),6.17(s,0.4H),6.02(d,J＝2.8Hz,0.6H),4.32-4.17(m,2H),3.94-3.93(m,0.3H),3.61-3.60(m,3H),3.50-3.49(m,0.7H),2.86(br s,2H),2.10-1.66(m,3.3H),1.51(s,9H),1.46-1.35(m,0.7H)。

Racemic compound 407(5.00g, 8.65mmol) was separated by chiral SFC (column: Chiralpak IG5 μm20 × 250 mm;, mobile phase: CO2: MeOH ═ 70:30, at 50g/min, temperature: 30 ℃; wavelength: 214nm, back pressure: 100 bar) to give 407A (1.6g, 32% yield, 100% stereopurity) as a yellow solid and 407B (1.8g, 36% yield, 100% stereopurity) as a yellow solid.

Compound 407A: chiral HPLC analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO₂MeOH 70:30, at 3.0 g/min; temperature: 40 ℃; wavelength: 220 nm; r_T＝2.98min)。¹H NMR(400MHz,CDCl₃)δ8.12(s,0.4H),7.84-7.81(m,1H),7.55-7.45(m,1.6H),7.33-7.31(m,1H),7.01-6.93(m,1H),6.17(s,0.4H),6.02(d,J＝2.8Hz,0.6H),4.36-4.14(m,2.4H),3.96-3.91(m,0.6H),3.61-3.60(m,3H),2.89(br s,2H),2.12-1.64(m,3.5H),1.58(s,0.5H),1.51(s,9H)。

Compound 407B: chiral HPLC analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO₂MeOH 70:30 at 3.0 g/min; temperature: 40 ℃; wavelength: 230 nm; r_T＝4.46min)。¹H NMR(400MHz,CDCl₃)δ8.12(s,0.4H),7.83-7.81(m,1H),7.50-7.44(m,1.6H),7.35-7.33(m,1H),7.01-6.93(m,1H),6.17(s,0.4H),6.02(d,J＝2.8Hz,0.6H),4.37-4.14(m,2.4H),3.96-3.91(m,0.6H),3.61-3.60(m,3H),2.96-2.77(m,2H),2.11-1.63(m,3.5H),1.58(s,0.5H),1.51(s,9H)。

Compound 411: ethyl 4- (2-bromo-3-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.11min，C₂₆H₃₀BrFN₄O₄Calculated mass of S592.1, M/z found value 594.9[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.10(s,0.4H),7.82-7.80(m,1H),7.50-7.47(m,0.6H),7.44-7.39(m,1H),7.24-7.17(m,1H),7.13-7.11(m,1H),7.10-6.95(m,1H),6.26(s,0.5H),6.11(d,J＝2.4Hz,0.5H),4.36-4.14(m,2.4H),4.08-3.90(m,2.6H),2.94-2.77(m,2H),2.08-1.71(m,3H),1.62-1.54(m,1H),1.50(s,9H),1.13-1.08(m,3H)。

Compounds 411A and 411B: ethyl 4- (2-bromo-3-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and Ethyl 4- (2-bromo-3-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Racemic compound 411(7.60g, 95% purity, 12.2mmol) was separated by chiral preparative SFC (separation conditions: column: Chiralpak IG5 μm20 × 250 mm; mobile phase: CO₂MeOH 75:25 at 50 g/min; column temperature: 40 ℃; wavelength: 254 nm; back pressure: 100 bar) to yield the title compound 411A as a yellow solid (3.20g, 95% pure, 42% yield, 100% stereopure) and 411B as a yellow solid (3.20g, 95% pure, 42% yield, 99.3% stereopure).

Compound 411A: LC-MS (ESI): r_T＝2.268min，C₂₆H₃₀BrFN₄O₄Calculated mass of S592.1, found value of M/z 593.1[ M + H]⁺. Chiral analysis (column: Chiralpak IG5 μm20 × 250 mm; mobile phase: CO)₂MeOH 75:25 at 3.0 g/min; column temperature: 40 ℃; wavelength: 254 nm; back pressure: 100Bar, R_T＝3.98min)。¹H NMR(300MHz,CDCl₃)δ8.09(s,0.4H),7.82-7.80(m,1H),7.49-7.40(m,1.6H),7.24-7.17(m,1H),7.17-7.11(m,1H),7.07-6.98(m,1H),6.26(s,0.5H),6.12(s,0.5H),4.35-3.91(m,5H),2.93-2.78(m,2H),2.01-1.81(m,2H),1.71-1.56(m,2H),1.50(s,9H),1.10(t,J＝7.2Hz,3H)。

Compound 411B: LC-MS (ESI): r_T＝2.249min，C₂₆H₃₀BrFN₄O₄Calculated mass of S592.1, M/z found value 593.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG5 μm20 × 250 mm; mobile phase: CO)₂MeOH 75:25 at 3.0 g/min; column temperature: 40 ℃; wavelength: 254 nm; back pressure: 100Bar, R_T＝4.84min)。¹H NMR(300MHz,CDCl₃)δ8.14-8.08(m,0.3H),7.81(d,J＝3.0Hz,1H),7.51-7.34(m,1.7H),7.24-7.20(m,1H),7.07-7.00(m,1H),6.27-6.10(m,1H),4.39-3.90(m,5H),2.98-2.76(m,2H),2.06-1.77(m,2.5H),1.68-1.57(m,1.5H),1.50(s,9H),1.10(t,J＝7.2Hz,3H)。

Compound 417: ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (4-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝2.169min，C₂₇H₃₃FN₄O₄Calculated mass of S528.2, M/z found value 529.1[ M + H [ ]]⁺。¹HNMR(400MHz,CDCl₃)δ8.07(s,1H),7.80-7.78(m,1H),7.50(d,J＝3.2Hz,0.3H),7.42(d,J＝3.2Hz,0.7H),7.06-6.79(m,3H),5.96(s,0.7H),5.87(d,J＝2.0Hz,0.3H),4.34-4.15(m,2.7H),4.07-4.00(m,2H),3.85-3.79(m,0.3H),2.89-2.86(m,2H),2.63(s,2H),2.48(s,1H),2.03-2.00(m,1H),1.87-1.83(m,1H),1.70-1.55(m,2H),1.50(s,9H),1.14-1.10(m,3H)。

Rac 417(6.00g, 90% purity, 10.2mmol) was separated by chiral preparative SFC (column: ChiralpakIG 5 μm20 mm 250 mm; mobile phase: CO₂50g/min MeOH (DEA) (75: 25: 0.3); column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar) to give the title compound 417A (2.70g, 90% purity, 45% yield, 100% stereopurity) and 417B (2.60g, 90% purity, 43% yield, 99.2% stereopurity) as yellow solids.

Compound 417A: chiral analysis (column: Chiralpak IG5 μm4.6 mm 250 mm; mobile phase: CO)₂MeOH: DEA: 75:25:0.2 at 3.00 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100bar, R_T＝2.73min)。¹H NMR(400MHz,CDCl₃)δ8.05(s,0.7H),7.80-7.79(m,1H),7.50(d,J＝3.2Hz,0.3H),7.42(d,J＝3.2Hz,0.7H),7.32-7.28(m,0.3H),7.18-7.15(m,0.7H),7.00(s,0.3H),6.90-6.76(m,2H),5.96(s,0.7H),5.87(s,0.3H),4.35-4.16(m,2.7H),4.09-3.99(m,2H),3.84-3.79(m,0.3H),2.92-2.83(m,2H),2.63(s,2H),2.48(s,1H),2.03-2.00(m,1H),1.87-1.84(m,1H),1.72-1.59(m,2H),1.50(s,9H),1.14-1.09(m,3H)。

Compound 417B:chiral analysis (column: Chiralpak IG5 μm4.6 mm 250 mm; mobile phase: CO)₂MeOH: DEA: 75:25:0.2 at 3.00 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100bar, R_T＝3.59min)。¹H NMR(400MHz,CDCl₃)δ8.05(s,0.7H),7.79(d,J＝2.8Hz,1H),7.50(d,J＝3.2Hz,0.3H),7.42(d,J＝2.8Hz,0.7H),7.32-7.28(m,0.3H),7.18-7.15(m,0.7H),6.99(s,0.3H),6.90-6.76(m,2H),5.96(s,0.7H),5.87(d,J＝2.0Hz,0.3H),4.36-4.16(m,2.7H),4.09-3.99(m,2H),3.84-3.78(m,0.3H),2.92-2.83(m,2H),2.63(s,2H),2.49(s,1H),2.03-2.00(m,1H),1.87-1.79(m,1H),1.73-1.69(m,1H),1.61-1.56(m,1H),1.50(s,9H),1.15-1.10(m,3H)。

Compound 426: ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝2.143min，C₂₇H₃₃FN₄O₄Calculated mass of S528.2, M/z found value 529.1[ M + H [ ]]⁺。¹HNMR(400MHz,CDCl₃)δ8.08(s,1H),7.80-7.78(m,1H),7.49(d,J＝2.8Hz,0.3H),7.42(d,J＝2.8Hz,0.7H),7.08-7.01(m,2H),6.95-6.88(m,1H),6.01(s,0.7H),5.92(d,J＝2.0Hz,0.3H),4.31-4.17(m,3H),4.08-3.99(m,2H),2.89-2.82(m,2H),2.54(d,J＝2.0Hz,2H),2.39(d,J＝1.6Hz,1H),2.03-2.00(m,1H),1.87-1.84(m,1H),1.69-1.56(m.2H),1.50(s,9H),1.13-1.09(m,3H)。

Rac 426(3.0g, 85% pure, 4.82mmol) was separated by chiral preparative HPLC (column: chiralpak ic5 μm20 mm 250 mm; mobile phase: Hex: EtOH: DEA ═ 98:2:0.3 at 22 mL/min; temperature: 30 ℃ c; wavelength: 214nm) to give the title compound 426A (950mg, 32% yield, 90% pure, 100% stereopure) and 426B (650mg, 23% yield, 90% pure, 99.3% stereopure) as yellow solids.

Compound 426A: chiral HPLC (column: Chiralpak IC5 μm4.6 mm 250 mm; mobile phase: Hex: EtOH: DEA ═ 98:2:0.2 at 1 mL/min; column temperature: 40 ℃; wavelength: 254nm, R_T＝17.28min)。¹H NMR(400MHz,CDCl₃)δ8.06(s,0.7H),7.79(d,J＝3.2Hz,1H),7.49(d,J＝3.2Hz,0.3H),7.42(d,J＝3.2Hz,0.7H),7.16-7.01(m,2.3H),6.95-6.88(m,1H),6.01(s,0.7H),5.92(d,J＝2.4Hz,0.3H),4.38-4.17(m,2.7H),4.09-3.99(m,2H),3.86-3.80(m,0.3H),2.93-2.82(m,2H),2.53(s,2.2H),2.39(s,0.8H),2.06-2.00(m,1H),1.87-1.68(m,2H),1.62-1.55(m,1H),1.50(s,9H),1.13-1.09(m,3H)。

Compound 426B: chiral HPLC (column: Chiralpak IC5 μm4.6 mm 250 mm; mobile phase: Hex: EtOH: DEA ═ 98:2:0.2 at 1 mL/min; column temperature: 40 ℃; wavelength: 254nm, R_T＝19.61min)。¹H NMR(400MHz,CDCl₃)δ8.06(s,0.7H),7.79(d,J＝2.8Hz,1H),7.50(d,J＝3.2Hz,0.3H),7.42(d,J＝3.2Hz,0.7H),7.15-7.01(m,2.3H),6.95-6.88(m,1H),6.01(s,0.7H),5.92(d,J＝2.0Hz,0.3H),4.35-4.17(m,2.7H),4.10-3.99(m,2H),3.86-3.81(m,0.3H),2.89-2.83(m,2H),2.54(s,2.2H),2.40(s,0.8H),2.03-2.00(m,1H),1.87-1.84(m,1H),1.73-1.68(m,1H),1.62-1.56(m,1H),1.50(s,9H),1.14-1.09(m,3H)

Compound 430: methyl 6- (4- (azetidin-1-ylsulfonyl) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

And (3) purification conditions: purification by silica gel column chromatography (petroleum ether: ethyl acetate: 3:1) followed by further purification through a C18 column (acetonitrile: water: 5% to 80%) gave 170mg of the racemic product as a yellow solid. The racemic mixture (170mg, 0.298mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak ID5 μm20 × 250 mm; mobile phase: Hex: EtOH 70:30 at 12 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 430A (4.7mg, 3% yield, 100% stereopurity), 430B (5.1mg, 3% yield, 93.7% stereopurity), 430C (10mg, 6% yield, 100% stereopurity) and 430D (11mg, 6% yield, 99.1% stereopurity) as yellow solids.

Compound 430a (cis): LC-MS (ESI): r_T＝4.455min，C₂₄H₂₅ClF₂N₄O₄S₂Calculated mass of 570.0, found M/z value of 570.9[ M + H ]]⁺. Chiral HPLC (column: Chiralpak ID5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝7.861min)。¹H NMR(400MHz,DMSO-d₆)δ9.59(s,0.7H),8.22(s,0.3H),8.03-8.00(m,1.7H),7.97(d,J＝2.8Hz,0.3H),7.50-7.40(m,1H),7.22-7.18(m,1H),6.03(s,0.3H),5.92(s,0.7H),3.91-3.84(m,4.2H),3.73-3.67(m,0.8H),3.51(s,3H),3.21-3.15(m,1H),2.35-2.17(m,5H),2.14-1.97(m,1H),1.93-1.77(m,2H),1.71-1.62(m,1H),1.56-1.41(m,1H)。

Compound 430b (cis): LC-MS (ESI): r_T＝4.264min，C₂₄H₂₅ClF₂N₄O₄S₂Calculated mass of 570.0, found M/z value of 570.9[ M + H ]]⁺. Chiral HPLC (column: Chiralpak ID5 μm4.6 × 250 mm; mobile phase: Hex: EtOH ═ 70:30, at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R); temperature: 30 ℃; wavelength: 230 nm; R;)_T＝8.867min)。¹H NMR(400MHz,DMSO-d₆)δ9.59(s,0.7H),8.30(s,0.3H),8.04-7.96(m,2H),7.48-7.46(m,1H),7.22-7.18(m,1H),6.03(s,0.3H),5.92(d,J＝3.2Hz,0.7H),3.91-3.84(m,4.2H),3.72-3.69(m,0.8H),3.52(s,1.2H),3.51(s,1.8H),3.19-3.16(m,1H),2.37-2.19(m,5H),2.10-1.92(m,1H),1.88-1.80(m,2H),1.70-1.68(m,1H),1.62-1.55(m,1H)。

Compound 430c (trans): LC-MS (ESI): r_T＝3.966min，C₂₄H₂₅ClF₂N₄O₄S₂Calculated mass of 570.0, M/z found value 571.2[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE5 μm4.6 × 250 mm; mobile phase: Hex: EtOH ═ 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R-_T＝9.127min)。¹HNMR(400MHz,DMSO-d₆)δ9.61(s,0.7H),8.95(s,0.3H),8.03-7.94(m,2H),7.49-7.46(m,1H),7.24-7.16(m,1H),6.01(s,0.4H),5.93(s,0.6H),3.95-3.86(m,4.5H),3.53-3.51(m,3.5H),3.05-2.96(m,0.4H),2.87(br s,0.6H),2.26-2.07(m,5H),1.97-1.90(m,2H),1.85-1.80(m,1H),1.59-1.46(m,2H)。

Compound 430d (trans): LC-MS (ESI): r_T＝3.961min，C₂₄H₂₅ClF₂N₄O₄S₂Calculated mass of 570.0, M/z found value 571.2[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝12.662min)。¹H NMR(400MHz,DMSO-d₆)δ9.60(s,0.6H),8.93(s,0.4H),8.01-8.00(m,1.6H),7.98-7.94(m,0.4H),7.52-7.42(m,1H),7.23-7.13(m,1H),5.99(s,0.4H),5.93(s,0.6H),3.97-3.86(m,4.4H),3.62-3.52(m,3.6H),3.22-3.16(m,0.5H),3.08-3.04(m,0.5H),2.20-2.13(m,4H),1.95-1.81(m,2.7H),1.76-1.66(m,1.3H),1.55-1.43(m,2H)。

Compound 432: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1, 4-dioxaspiro [4.5] decan-8-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝3.6Hz,0.6H),8.63(s,0.4H),8.02-7.95(m,2H),7.48-7.39(m,1H),7.21-7.17(m,1H),6.02(s,0.3H),5.92(d,J＝3.6Hz,0.7H),3.93-3.86(m,4H),3.63-3.57(m,1H),3.53(s,2.7H),3.49(s,0.3H),2.07-1.97(m,1H),1.94-1.88(m,1H),1.82-1.68(m,4H),1.57-1.52(m,2H)。

Compound 435: ethyl 6- (3- ((tert-butoxycarbonyl) amino) -2, 2-dimethylcyclobutyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝1.930min，C₂₇H₃₂ClFN₄O₄Calculated mass of S563.1, M/z found 563.0[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.86-7.85(m,1H),7.51(d,J＝2.8Hz,1H),7.41-7.37(m,1H),7.15-7.11(m,1H),6.99-6.90(m,1H),6.18-6.14(m,1H),4.23(br s,0.3H),4.08-4.02(m,2.6H),3.90(br s,1H),3.76(br s,0.3H),2.49-2.30(m,2H),1.46(s,12H),1.14-1.09(m,6H)。

Racemic 435(910mg, 1.60mmol) was separated by chiral preparative SFC (separation conditions: column: ChiralpakIE 5 μm 20. mu.250 mm, mobile phase: CO₂MeOH 75:25 at 50 g/min; temperature: 40 ℃; wavelength: 214nm) to give the title compound 435b (450mg, 49% yield) and 435a (440mg, 48% yield) as a yellow solid.

435a(cis)：¹H NMR(400MHz,CDCl₃)δ8.14(s,0.2H),7.85-7.84(m,0.8H),7.52-7.51(m,1H),7.45-7.38(m,1H),7.36-7.34(m,1H),7.15-7.11(m,1H),7.00-6.91(m,1H),6.24(s,0.2H),6.15(d,J＝2.4Hz,0.8H),4.07-4.03(m,2H),3.98-3.94(m,1H),3.91-3.85(m,0.7H),3.81-3.67(m,0.3H),2.48-2.31(m,2H),1.45(s,13H),1.36-1.24(m,2H),1.16-1.11(m,3H)。

435b(trans)：¹H NMR(400MHz,CDCl₃)δ8.17(s,0.2H),7.86-7.85(m,0.8H),7.54-7.45(m,2H),7.32-7.29(m,1H),7.14-7.11(m,1H),6.95-6.87(m,1H),6.25(s,0.2H),6.09(d,J＝2.8Hz,0.8H),4.23-4.14(m,1.3H),4.10-4.00(m,2H),3.93-3.87(m,0.7H),2.63-2.46(m,2H),1.47-1.44(m,13H),1.29-1.26(m,2H),1.12(t,J＝7.2Hz,3H)。

Compound 441: methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.133min，C₂₆H₃₁FN₄O₄Calculated mass of S514.6, found value of M/z 515.1[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.10(br s,1H),7.79-7.78(m,1H),7.49(d,J＝3.2Hz,0.3H),7.42(d,J＝3.2Hz,0.7H),7.17-7.00(m,2H),6.95-6.88(m,1H),6.01(s,0.7H),5.91(s,0.3H),4.40-4.17(m,2.7H),3.88-3.80(m,0.3H),3.59-3.58(m,3H),2.99-2.79(m,2H),2.54(d,J＝2Hz,2.2H),2.38(d,J＝2Hz,0.8H),2.04-1.59(m,4H),1.50(s,9H)。

Rac 441(5.0g, 90% purity, 8.77mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IG5 μm20 × 250 mm; mobile phase: CO₂50g/min MeOH (DEA) (75: 25: 0.3); temperature: 30 ℃; wavelength: 230nm) to give the title compounds 441a (2.2g, 90% purity, 44% yield, 99.1% stereopurity) and 441b (2.0g, 90% purity, 40% yield, 100% stereopurity) as yellow solids.

Compound 441 a: chiral analysis: (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 75:25 at 3 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100bar, R_T＝3.38min)。¹H NMR(400MHz,CDCl₃)δ8.09(s,1H),7.79-7.78(m,1H),7.50(d,J＝3.2Hz,0.3H),7.42(d,J＝3.2Hz,0.7H),7.16-7.04(m,2H),6.99-6.88(m,1H),6.00(s,0.7H),5.91(s,0.3H),4.43-4.16(m,2.7H),3.87-3.81(m,0.3H),3.59-3.58(m,3H),2.98-2.78(m,2H),2.54(d,J＝2Hz,2.2H),2.37(d,J＝2.4Hz,0.8H),2.03-1.59(m,4H),1.50(s,9H)。

Compound 441 b: chiral analysis: (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 75:25 at 3 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100bar, R_T＝2.91min)。¹H NMR(400MHz,CDCl₃)δ8.10(s,1H),7.79-7.78(m,1H),7.49(d,J＝3.2Hz,0.3H),7.42(d,J＝3.2Hz,0.7H),7.17-7.12(m,2H),7.00-6.88(m,1H),6.01(s,0.7H),5.91(d,J＝3.2Hz,0.3H),4.43-4.17(m,2.7H),3.88-3.80(m,0.3H),3.59-3.58(m,3H),2.98-2.79(m,2H),2.54(d,J＝2Hz,2.2H),2.39(d,J＝2Hz,0.8H),2.04-1.56(m,4H),1.50(s,9H)。

Compound 445: methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (4-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝1.79min，C₂₆H₃₁FN₄O₄Calculated mass of S514.2, found value of M/z 515.4[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.09(s,0.7H),7.79(d,J＝2.8Hz,1H),7.49(d,J＝3.2Hz,0.3H),7.42(d,J＝2.8Hz,0.7H),7.32-7.28(m,0.3H),7.17-7.13(m,0.7H),7.07(s,0.3H),6.90-6.76(m,2H),5.95(s,0.7H),5.85(s,0.3H),4.40-4.20(m,2H),3.59(s,2H),3.58(s,1H),2.97-2.79(m,2H),2.63(s,2H),2.47(s,1H),2.02-1.97(m,1H),1.90-1.81(m,1H),1.72-1.59(m,3H),1.50(s,9H)。

Racemic 445(2.00g, 3.88mmol) was separated by chiral preparative SFC (column: Chiralpak IG5 μm20 x 250 mm; mobile phase: CO₂50g/min MeOH (DEA) (75: 25: 0.3); the column temperature is 40 ℃; wavelength: 214 nm; back pressure: 100 bar) to give the title compound 445A as a yellow solid (684mg, 34% yield, 99.3% stereopurity) and 445B as a yellow solid (607mg, 30% yield, 100% stereopurity).

Compound 445A: LC-MS (ESI): r_T＝1.89min，C₂₆H₃₁FN₄O₄Calculated mass of S514.2, found value of M/z 515.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO2: MeOH: DEA ═ 75:25:0.2 at 3.0 g/min; column temperature: 40 ℃; wavelength: 250 mm; chiral analysis: 280nm, back pressure: 100 bar; r_T＝3.81min)。

Compound 445B: LC-MS (ESI): r_T＝1.88min，C₂₆H₃₁FN₄O₄Calculated mass of S514.2, found value of M/z 515.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO2: MeOH: DEA ═ 75:25:0.2 at 3.0 g/min; column temperature: 40 ℃; wavelength: 280nm, back pressure: 100 bar; R_T＝2.93min)。

Compound 472: trans-methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (3-methoxy-3-oxopropyl) sulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.937min，C₂₅H₂₇ClF₂N₄O₆S₂Calculated mass of 616.1, M/z found value 617.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝3.6Hz,0.6H),8.97(s,0.4H),7.99-7.94(m,2H),7.49-7.42(m,1H),7.22-7.11(m,2H),6.02(s,0.4H),5.92(d,J＝3.6Hz,0.6H),3.90-3.80(m,0.4H),3.63(s,3H),3.61-3.52(m,3.6H),3.26-3.14(m,2.4H),3.07-2.99(m,0.6H),2.57-2.54(m,2H),2.22-2.11(m,2H),2.00-1.70(m,4H),1.56-1.40(m,2H)。

Section I: one-step conversion (deprotection and coupling) of the principal dihydropyrimidines of the general formula I

Compound 96: ethyl 4- (2-chloro-3-fluorophenyl) -6- (1- (methylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Method O: to a solution of ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 9(200mg, 0.340mmol) in methanol (5mL) at 0 ℃ was added 2M hydrochloric acid in methanol (5mL, 10 mmol). After stirring at room temperature for 2 hours, the mixture was concentrated to give a residue, which was dissolved in dichloromethane (5mL) under a nitrogen atmosphere and triethylamine (150mg, 1.50mmol) and methanesulfonyl chloride (114mg, 1.00mmol) were added. After stirring overnight, the reaction mixture was washed twice with water (30mL) and Na₂SO_4(s)Drying, filtering and concentrating under reduced pressure to obtainTo the residue, it was purified with C18 (acetonitrile: water 40% to 55%) to give the title compound as a pale yellow solid (240mg, 86% yield).

Compound 96(200mg, 0.380mmol) was further separated by chiral preparative HPLC (column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 70:30, at 11 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomers compound 96A (62mg, 31% yield) and compound 96B (61.5mg, 31% yield) as yellow solids.

Compound 96B: LC-MS (ESI): r_T＝4.103min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass 526.1, M/z found 527.2[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝8.673min)。¹H NMR(400MHz,CDCl₃)δ8.16(br s,0.3H),7.83(d,J＝3.2Hz,1H),7.53(d,J＝2.8Hz,0.7H),7.45(d,J＝2.8Hz,0.3H),7.38(brs,0.7H),7.24-7.03(m,3H),6.28(br s,0.3H),6.15(d,J＝2.8Hz,0.7H),4.23-3.88(m,5H),2.89-2.76(m,5H),2.34-1.72(m,4H),1.13-1.07(m,3H)。

Compound 97: 4- (4-chloro-2-fluoro-phenyl) -6- (1-methanesulfonyl-piperidin-4-yl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (mixture of 2 stereoisomers)

The method P comprises the following steps: to a solution of methyl 6- (1-tert-butoxycarbonyl-piperidin-4-yl) -4- (4-chloro-2-fluoro-phenyl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylate compound 11(300mg, 0.562mmol) in dichloromethane (3mL) was added trifluoroacetic acid (3mL, 40.2 mmol). After stirring at room temperature for 1 hour, the mixture was concentrated to give a residue, which was used without further purification. To a solution of the residue (700mg, 0.562mmol) and triethylamine (170mg, 1.69mmol) in dichloromethane (6mL) was added methanesulfonyl chloride (71mg, 0.62 mmol). After stirring at room temperature for 2h, the mixture was concentrated and the residue was purified by preparative HPLC (column: Gilson X-bridge C18(5 μm 19X 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 15 mL/min; gradient: 15% -95% (% B)) to give the title compound as a yellow solid (81mg, 28% yield). Compound 97(250mg, 0.488mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 18mL/min, temperature: 30 ℃; wavelength: 230nm) to give the stereoisomer compound 97A (47.0mg, 19% yield) and compound 97B (36.0mg, 15% yield) as yellow solids.

Compound 97B: LC-MS (ESI): r_T＝4.388min，C₂₁H₂₂ClFN₄O₄S₂Calculated mass of 512.1, M/z found value 512.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; temperature: R-_T＝11.437min)。¹H NMR(400MHz,DMSO-d₆)δ9.60(br s,0.8H),9.26(br s,0.2H),8.05-8.00(m,1.8H),7.95-7.94(m,0.2H),7.42(d,J＝10.4Hz,1H),7.31-7.26(m,2H),5.89(s,0.2H),5.77(s,0.8H),3.72-3.63(m,3H),3.55(s,3H),2.91(s,0.6H),2.90(s,2.4H),2.80-2.72(m,2H),2.08-1.95(m,1H),1.90-1.72(m,2H),1.63-1.61(m,1H)。

Similarly using a similar procedure (method O or method P), the following products were prepared:

compound 98: methyl 4- (2-chloro-3-fluorophenyl) -6- (1- (methylsulfonyl) piperidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 98(300mg, 0.59mmol) was further separated by chiral preparative HPLC (first separation conditions: column: Chiralpak IE5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 12 mL/min; temperature: 30 ℃; wavelength: 230 nm; second separation conditions: column: Chiralpak IC5 μm 20:250mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.3 at 10 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 98A (17.2mg, 6% yield), compound 98B (18.0mg, 6% yield), compound 98C (18.7mg, 6% yield) and compound 98D (25.9mg, 9% yield) as yellow solids.

Compound 98A: LC-MS (ESI): r_T＝3.335min，C₂₁H₂₂ClFN₄O₄S₂Calculated mass of 512.1, m/z found value 512.9. Chiral HPLC (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; temperature: R-_T＝12.265min)。¹H NMR(400MHz,DMSO-d₆)δ9.62(s,0.8H),9.36(s,0.2H),8.01-7.94(m,2H),7.43-7.30(m,2H),7.21(d,J＝8.4Hz,0.8H),7.19(d,J＝7.2Hz,0.2H),6.10(s,0.2H),5.99(s,0.8H),4.14-4.06(m,0.2H),3.84-3.74(m,0.8H),3.71-3.63(m,1.5H),3.53(s,2H),3.51(s,1H),3.49-3.43(m,0.5H),3.04(t,J＝11.2Hz,1H),2.97(s,1H),2.93(s,2H),2.75-2.67(m,1H),1.85-1.69(m,3H),1.62-1.53(m,1H)。

Compound 41: ethyl 4- (2-chloro-4-fluorophenyl) -6- ((1R,5S,6R) -3- (methylsulfonyl) -3-azabicyclo- [3.1.0] hex-6-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 41(170mg, 0.32mmol) was further separated by SFC (separation conditions: column: Chiralpak IA5 μm20 x 250 mm; mobile phase: CO)₂EtOH 70:30 at 45 g/min; co-solvent: EtOH; column temperature: 39.8 ℃; wavelength: 214nm, back pressure: 100 bar) to give the stereoisomers compound 41A (45.9mg, 27% yield) and compound 41B (58.8mg, 35% yield) as a pale yellow solid.

Compound 41A: LC-MS (ESI): r_T＝3.687min，C₂₂H₂₂ClFN₄O₄S₂Calculated mass of (524.1), M/z found value 525.1[ M + H ]]⁺. SFC analysis (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: CO)₂EtOH 70:30, in order to4 mL/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100bar, R_T＝2.88min)。¹H NMR(400MHz,DMSO-d₆)δ9.64(d,J＝2.8Hz,1H),8.01(s,2H),7.44-7.41(m,1H),7.39-7.35(m,1H),7.25-7.20(m,1H),5.93(d,J＝2.8Hz,1H),3.98(q,J＝7.2Hz,2H),3.53-3.46(m,3H),3.43(s,0.6H),3.40(s,0.4H),3.28(t,J＝2.8Hz,1H),2.94(s,3H),2.40-2.37(m,1H),2.20-2.17(m,1H),1.07(t,J＝6.8Hz,3H)。

Compound 56: ethyl 4- (2-chloro-4-fluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -6- (1- (methylsulfonyl) piperidin-4-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 56(150mg, 0.270mmol) was further separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 60:40 at 18 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomers compound 56A (43.2mg, 29% yield) and compound 56B (37.7mg, 25% yield) as yellow solids.

Compound 56A: LC-MS (ESI): r_T＝3.648min，C₂₄H₂₄ClF₃N₄O₄Calculated mass of S556.1, found M/z 557.1[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 210nm, R_T＝9.583min)。¹H NMR(400MHz,DMSO-d₆)δ9.44(s,0.4H),9.41(d,J＝3.2Hz,0.6H),8.63-8.62(m,1H),8.11-8.06(m,1H),7.60-7.56(m,1H),7.31-7.28(m,1H),7.22-7.16(m,1H),5.71(s,0.4H),5.52(d,J＝3.6Hz,0.6H),4.11-4.03(m,2H),3.95-3.93(m,0.4H),3.73-3.62(m,2.6H),2.89-2.88(m,3H),2.78-2.71(m,2H),2.02-1.61(m,4H),1.19-1.12(m,3H)。

Compound 61B: methyl 4- (2-chloro-3-fluorophenyl) -6- (3- (methylsulfonamido) cyclopentyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.666min，C₂₁H₂₂ClFN₄O₄S₂Calculated mass of (2) 512.1, found value of M/z 513.1[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: CO₂MeOH 70:30, at 4.0 mL/min; column temperature: 40.2 ℃; wavelength: 214nm, back pressure: 100bar, Rt 6.50 min).¹H NMR(400MHz,DMSO-d₆)δ9.54(brs,0.7H),9.16(s,0.3H),8.00-7.99(m,1.7H),7.93(d,J＝2.8Hz,0.3H),7.41-7.31(m,2H),7.21-7.12(m,2H),6.05(s,0.2H),5.94(s,0.8H),4.48-4.43(m,0.2H),4.33-4.25(m,0.8H),4.05-3.97(m,1H),3.52(s,3H),2.93(s,3H),2.28-2.22(m,1H),2.14-2.07(m,1H),1.98-1.77(m,2H),1.70-1.54(m,2H)。

Compound 61D: methyl 4- (2-chloro-3-fluorophenyl) -6- (3- (methylsulfonamido) cyclopentyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.625min，C₂₁H₂₂ClFN₄O₄S₂Calculated mass of (2) 512.1, found value of M/z 513.1[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: CO₂MeOH 70:30, at 4.0 mL/min; column temperature: 40.3 ℃; wavelength: 214nm, back pressure: 100bar, R_T＝5.79min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(brs,0.8H),9.14(s,0.2H),8.02-7.99(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.40-7.31(m,2H),7.22-7.11(m,2H),6.05(s,0.2H),5.96(s,0.8H),4.50-4.40(m,0.2H),4.31-4.23(m,0.8H),4.08-3.93(m,1H),3.52(s,3H),2.92(s,3H),2.18-1.98(m,3H),1.92-1.77(m,1H),1.70-1.53(m,2H)。

Compound 61E: methyl 4- (2-chloro-3-fluorophenyl) -6- (3- (methylsulfonamido) cyclopentyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.976min，C₂₁H₂₂ClFN₄O₄S₂Calculated mass of 512.1, M/z found value 512.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak AD-H5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝11.038min)。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.6Hz,0.7H),8.94(s,0.3H),8.03-8.01(m,1.5H),7.97(dd,J＝14.0,3.0Hz,0.5H),7.41-7.29(m,2H),7.19-7.14(m,2H),6.06(s,0.3H),5.96(d,J＝3.6Hz,0.7H),4.35-4.26(m,0.3H),4.17-4.08(m,0.7H),3.87-3.79(m,0.3H),3.76-3.66(m,0.7H),3.52-3.51(m,3H),2.98(s,1H),2.94(s,2H),2.44-2.37(m,0.3H),2.24-2.18(m,0.7H),2.02-1.64(m,5H)。

Compound 61G: methyl 4- (2-chloro-3-fluorophenyl) -6- (3- (methylsulfonamido) cyclopentyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.770min，C₂₁H₂₂ClFN₄O₄S₂Calculated mass of 512.1, M/z found value 512.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: CO₂MeOH 60:40, at 3.0 mL/min; column temperature: 40 ℃; wavelength: 214nm, back pressure 100bar, R_T＝7.31min)。¹H NMR(400MHz,DMSO-d₆)δ9.58(s,0.7H),8.96(s,0.3H),8.04-7.95(m,2H),7.41-7.29(m,2H),7.20-7.14(m,2H),6.06(s,0.3H),5.96(s,0.7H),4.34-4.25(m,0.3H),4.15-4.07(m,0.7H),3.82-3.75(m,0.3H),3.74-3.66(m,0.7H),3.52-3.50(m,3H),2.96-2.93(m,3H),2.29-2.23(m,0.3H),2.07-1.97(m,2.7H),1.89-1.65(m,3H)。

Compound 62B: methyl 6- (3-acetamido cyclopentyl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.704min，C₂₂H₂₂ClFN₄O₃Calculated mass of S476.1, M/z found 477.0[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝16.977min)。¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝3.6Hz,0.8H),9.08(s,0.2H),8.03-8.00(m,2H),7.94-7.90(m,1H),7.41-7.29(m,2H),7.19(d,J＝7.6Hz,0.8H),7.13(d,J＝7.2Hz,0.2H),6.05(s,0.2H),5.94(d,J＝3.6Hz,0.8H),4.48-4.38(m,0.2H),4.35-4.24(m,1.8H),3.52-3.51(m,3H),2.22-2.12(m,1H),2.09-2.01(m,1H),1.94-1.82(m,1H),1.79(s,3H),1.76-1.67(m,2H),1.56-1.43(m,1H)。

Compound 62D: methyl 6- (3-acetamido cyclopentyl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.675min，C₂₂H₂₂ClFN₄O₃Calculated mass of S476.1, M/z found 477.0[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝9.898min)。¹H NMR(400MHz,DMSO-d₆)δ9.55(d,J＝2.8Hz,0.8H),9.13(s,0.2H),8.00-7.88(m,3H),7.40-7.31(m,2H),7.20-7.12(m,1H),6.05(s,0.2H),5.96(d,J＝2.0Hz,0.8H),4.50-4.39(m,0.2H),4.33-4.22(m,1.8H),3.52(s,3H),2.10-1.98(m,3H),1.91-1.83(m,1H),1.79(s,3H),1.59-1.43(m,2H)。

Compound 62G: methyl 6- (3-acetamido cyclopentyl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.489min，C₂₂H₂₂ClFN₄O₃Calculated mass of S476.1, M/z found 477.0[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IB 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝11.172min)。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.6Hz,0.7H),8.69(s,0.3H),8.04-8.01(m,1.7H),7.99(d,J＝3.2Hz,0.3H),7.96(d,J＝3.6Hz,0.3H),7.90(d,J＝7.6Hz,0.7H),7.41-7.30(m,2H),7.20-7.15(m,1H),6.07(s,0.3H),5.96(d,J＝3.6Hz,0.7H),4.37-4.27(m,0.3H),4.15-4.01(m,1.7H),3.52-3.51(m,3H),2.20-2.13(m,0.3H),2.06-1.87(m,4.7H),1.80(s,2H),1.74-1.57(m,2H)。

Compound 65: 4- (2-chloro-4-fluoro-phenyl) -6- (1-methanesulfonyl-pyrrolidin-3-yl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (mixture of 4 stereoisomers)

Compound 65(240mg, 0.482mmol) was further purified by chiral preparative HPLC (first separation conditions (column: Chiralpak IB 5 μm20 × 250mm, mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 15mL/min, temperature: 30 ℃, wavelength: 230nm) and second separation conditions (column: Chiralpak IE5 μm20 × 250mm, mobile phase: Hex: EtOH: DEA ═ 50:50:0.3 at 10mL/min, temperature: 30 ℃, wavelength: 230nm)) to afford the stereoisomer compound 65A (22.4mg, 9% yield), compound 65B (36.8mg, 15% yield), compound 65C (42.7mg, 18% yield) and compound 65D (23.4mg, 10% yield).

Compound 65A: LC-MS (ESI): r_T＝3.750min，C₂₀H₂₀ClFN₄O₄S₂Calculated mass of 498.1, M/z found value 498.9[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 1 ℃; temperature: C; temperature: temperature_T＝8.523min)。¹H NMR(400MHz,DMSO-d₆)δ9.60(s,0.9H),9.33(s,0.1H),8.01(s,1.9H),7.94(s,0.1H),7.43-7.36(m,2H),7.23-7.19(m,1H),6.03(s,0.1H),5.95(s,0.9H),4.58-4.53(m,0.1H),4.40-4.33(m,0.9H),3.62-3.37(m,7H),3.03(s,0.3H),2.97(s,2.7H),2.22-2.13(m,1H),2.05-1.97(m,1H)。

Compound 65C: LC-MS (ESI): r_T＝3.709min，C₂₀H₂₀ClFN₄O₄S₂Calculated mass of 498.1, M/z found value 498.9[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 1 ℃; temperature: C; temperature: temperature_T＝10.361min)。¹H NMR(400MHz,DMSO-d₆)δ9.62(s,0.9H),9.28(s,0.1H),8.02-7.93(m,2H),7.43-7.35(m,2H),7.24-7.19(m,1H),6.03(s,0.1H),5.94(d,J＝2.4Hz,0.9H),4.59-4.55(m,0.1H),4.41-4.33(m,0.9H),3.59-3.34(m,7H),3.03(s,0.3H),2.95(s,2.7H),2.33-2.24(m,1H),2.18-2.11(m,1H)。

Compound 176: methyl 4- (2-chloro-4-fluorophenyl) -6- ((cis) -2- (methylsulfonyl) -octahydrocyclopenta [ c ] pyrrol-5-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and methyl

Rac 176 was isolated using the following: c18 column (acetonitrile: water 70% -80%) and preparative HPLC (column: Waters Kinate EVO C18(5 μm 21.2 × 150mm), mobile phase a: water (+ 0.1% trifluoroacetic acid), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 30% -60% (% B)), gave 176X (17mg, 10% yield) and 176Y (60mg, 35% yield) as yellow solids.

Compound 176X was then prepared using chiralityType HPLC separation (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: CO)₂IPA 60:40 at 50 g/min; co-solvent: IPA; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar) to yield the title compounds 176A (26mg, 17% yield, 100% stereopure) and 176B (23mg, 15% yield, 98.3% stereopure) as yellow solids.

Compound 176A: LC-MS (ESI): r_T＝3.923min，C₂₃H₂₄ClFN₄O₄S₂Calculated mass of 538.1, M/z found value 539.2[ M + H [ ]]⁺. Chiral SFC (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO₂IPA 60:40 at 2.999 g/min; column temperature: 40.2 ℃; wavelength: 214nm, back pressure: 100bar, R_T＝3.85min)。¹H NMR(400MHz,DMSO-d₆)δ9.44(d,J＝2.8Hz,0.8H),9.00(s,0.2H),7.99(d,J＝1.6Hz,1.8H),7.93(br s,0.2H),7.42(dd,J＝9.2,2.4Hz,1H),7.34-7.31(m,1H),7.30-7.18(m,1H),6.00(s,0.2H),5.91(d,J＝2.8Hz,0.8H),4.47-4.38(m,0.2H),4.32-4.24(m,0.8H),3.54(s,3H),3.48-3.37(m,2H),2.99-2.92(m,4H),2.91(s,3H),2.22-2.14(m,1H),2.08-2.01(m,1H),1.87-1.81(m,0.3H),1.77-1.72(m,1H),1.62-1.58(m,0.7H)。

Compound 176Y was then separated using chiral preparative HPLC (column: Chiralpak IA5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 70: 30; temperature: 30 ℃; wavelength: 230nm) to give the title compounds 176C (26mg, 17% yield, 100% stereopurity) and 176D (23mg, 15% yield, 99.5% stereopurity) as yellow solids.

176D：LC-MS(ESI)：R_T＝3.686min，C₂₃H₂₄ClFN₄O₄S₂Calculated mass of 538.1, M/z found value 538.9[ M + H [ ]]⁺. Chiral SFC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 2.999 g/min; column temperature: 39.7 ℃; wavelength: 230nm, back pressure 100bar, R_T＝4.41min)。¹H NMR(400MHz,CDCl₃)δ8.25(br s,0.2H),7.84-7.82(m,1H),7.50(d,J＝3.2Hz,0.7H),7.44(d,J＝3.2Hz,0.3H),7.42(br s,0.8H),7.25-7.23(m,1H),7.15-7.11(m,1H),6.97-6.88(m,1H),6.19(s,0.2H),6.05(d,J＝2.8Hz,0.8H),4.44-4.27(m,1H),3.60(s,2H),3.59(s,1H),3.45-3.41(m,3.5H),3.27-3.19(m,0.5H),2.90(s,1H),2.88(s,2H),2.87-2.77(m,2H),2.53-2.43(m,0.3H),2.38-2.23(m,1H),2.11-2.02(m,2H),1.90-1.83(m,0.7H)。

Compound 261: (cis) -ethyl 4- (2-chloro-3-fluorophenyl) -6- (4- (methylsulfonylamino) -tetrahydrofuran-2-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.735min，C₂₁H₂₂ClFN₄O₅S₂Calculated mass of 528.1, found M/z of 528.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.14(s,0.4H),8.99(s,0.4H),8.95(s,0.1H),8.87(s,0.1H),8.03-8.00(m,1H),7.97-7.95(m,0.8H),7.60-7.55(m,0.2H),7.51(d,J＝4.4Hz,0.4H),7.38-7.27(m,3H),6.13(s,0.4H),6.08(s,0.4H),6.02-6.00(m,0.1H),5.96-5.94(m,0.1H),5.70-5.59(m,0.2H),5.50-5.44(m,0.8H),4.32-4.24(m,0.2H),4.13-4.07(m,1.3H),3.99-3.95(m,3.3H),3.80-3.75(m,0.2H),2.99-2.95(m,3H),2.92-2.85(m,0.8H),2.64-2.61(m,0.2H),2.58-2.55(m,0.7H),2.45-2.42(m,0.3H),2.26-2.19(m,0.1H),2.09-2.03(m,0.5H),1.86-1.79(m,0.4H),1.07-1.00(m,3H)。

Compound 262: (cis) -ethyl 6- (4-acetamidotetrahydrofuran-2-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.620min，C₂₁H₂₂ClFN₄O₄S₂Calculated mass of 492.1, M/z found value 492.9[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.94-7.91(m,1H),7.75-7.73(m,1H),7.31-7.26(m,1.5H),7.21-7.11(m,1.5H),6.23(s,0.5H),6.20(s,0.5H),5.73-5.67(m,0.2H),5.62-5.52(m,0.8H),4.46-4.41(m,0.5H),4.39-4.33(m,0.5H),4.17-4.14(m,0.5H),4.08-4.00(m,3.3H),3.88-3.84(m,0.2H),3.07-2.98(m,0.8H),2.70-2.65(m,0.2H),2.02-1.96(m,1H),1.95-1.91(m,1.3H),1.86-1.80(m,1.7H),1.12-1.09(m,3H)。

Compounds 300B, 300D and 300E: methyl 6- (-3-acetamido cyclopentyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 300B: preparative HPLC separation (column: gilson X-bridge C18(5 μm 19. multidot.150 mm), mobile phase A: water (0)1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 35% -65% (% B)) to give the title compound 300B (120mg, 61% yield, 100% ee) as a yellow solid. LC-MS (ESI): r_T＝4.358min，C₂₂H₂₁ClF₂N₄O₃Calculated mass of S494.1, M/z found value 495.0[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: CO₂MeOH 70:30 at 2.999 g/min; column temperature: 39.9 ℃; wavelength: 230nm, back pressure: 100bar, R_T＝2.85min)。¹H NMR(400MHz,CDCl₃)δ8.13(br s,0.3H),7.83-7.81(m,1H),7.50(d,J＝3.2Hz,0.6H),7.45(d,J＝3.2Hz,0.4H),7.39(d,J＝0.8Hz,0.7H),7.08-7.01(m,2H),6.18(s,0.4H),6.04(d,J＝2.8Hz,0.6H),5.63(d,J＝6.4Hz,0.4H),5.55(d,J＝6.8Hz,0.6H),4.64-4.59(m,1H),4.55-4.41(m,1H),3.60(s,2H),3.59(s,1H),2.48-2.41(m,0.6H),2.39-2.24(m,1H),2.19-2.05(m,1.4H),2.00(s,3H),1.97-1.96(m,0.7H),1.91-1.81(m,1.3H),1.72-1.63(m,0.6H),1.54-1.51(s,0.4H)。

Compound 300D: purification by preparative HPLC (column: gilson X-bridge C18(5 μm 19X 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 35% -65% (% B)) gave the title compound 300D (210mg, 71% yield, 100% ee) as a yellow solid. LC-MS (ESI): r_T＝3.573min，C₂₂H₂₁ClF₂N₄O₃Calculated mass of S494.1, M/z found value 494.7[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝7.839min)。¹H NMR(400MHz,CDCl₃)δ8.13(s,0.4H),7.82(d,J＝3.2Hz,1H),7.51(d,J＝3.2Hz,0.6H),7.45(d,J＝3.2Hz,0.4H),7.38(d,J＝2.0Hz,0.6H),7.08-7.01(m,2H),6.18(s,0.4H),6.05(d,J＝2.8Hz,0.6H),5.58(d,J＝10.4Hz,0.4H),5.50(d,J＝6.8Hz,0.6H),4.62-4.56(m,1H),4.54-4.41(m,1H),3.60(s,2H),3.59(s,1H),2.40-2.31(m,1H),2.29-2.22(m,1H),2.19-2.09(m,1H),2.09-2.01(m,1H),1.99(s,1H),1.98(s,2H),1.79-1.68(m,2H)。

Compound 300G: purification by preparative HPLC (column: gilson X-bridge C18(5 μm 19X 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 35% -65% (% B)) gave the title compound 300G (200mg, 59% yield, 99.5% ee) as a yellow solid. LC-MS (ESI): r_T＝3.593min，C₂₂H₂₁ClF₂N₄O₃Calculated mass of S494.1, M/z found value 494.7[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: CO₂MeOH 70:30 at 2.999 g/min; column temperature: 40 ℃; wavelength: 230nm, back pressure: 100bar, R_T＝5.77min)。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.1H),7.89(d,J＝3.2Hz,0.8H),7.80(d,J＝3.2Hz,0.2H),7.55(d,J＝3.2Hz,0.9H),7.53(br s,0.9H),7.46(d,J＝2.8Hz,0.1H),7.13-7.02(m,2H),6.19(s,0.1H),6.09(d,J＝2.8Hz,0.9H),4.49-4.43(m,1.8H),4.39-4.31(m,0.2H),3.61(s,2.5H),3.59(s,0.5H),2.51-2.43(m,0.1H),2.34-2.27(m,0.9H),2.25-2.14(m,0.2H),2.13-2.11(m,1H),2.00(s,3H),1.97-1.93(m,0.8H),1.89-1.74(m,3H)。

Compound 372: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (methylsulfonylamino) bicyclo [1.1.1]Pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.314min，C₂₁H₂₀ClFN₄O₄S₂Calculated mass of 510.1, M/z found value 510.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.46(d,J＝3.6Hz,0.5H),8.35(s,0.5H),8.17(s,0.5H),8.02-8.00(m,0.5H),8.00(s,1.5H),7.96(d,J＝2.8Hz,0.5H),7.46-7.41(m,1H),7.35-7.30(m,1H),7.25-7.19(m,1H),5.97(s,0.5H),5.87(d,J＝3.6Hz,0.5H),3.55(s,1.5H),3.53(s,1.5H),2.96(s,1.4H),2.93(s,1.6H),2.44(s,3H),2.28(s,3H)。

Rac 372(180mg, 0.353mmol) was separated by chiral preparative HPLC (column: Chiralpak IG5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 70:30 at 13 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compounds 372X (56.3mg, 31% yield, 100% stereopurity) and 372Y (50.1mg, 28% yield, 99.7% stereopurity).

Compound 372X: LC-MS (ESI): r_T＝3.125min，C₂₁H₂₀ClFN₄O₄S₂Calculated mass of 510.1, M/z found value 511.2[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝8.003min)。¹H NMR(400MHz,DMSO-d₆)δ9.47-9.40(m,0.5H),8.37-8.32(m,0.5H),8.18-8.13(m,0.5H),8.01-8.00(m,2H),7.96-7.94(m,0.5H),7.44-7.42(m,1H),7.34-7.31(m,1H),7.24-7.20(m,1H),5.97(s,0.5H),5.87(s,0.5H),3.54(s,3H),2.95(s,1.3H),2.94(s,1.7H),2.44(s,3H),2.28(s,3H)。

Compound 372Y: LC-MS (ESI): r_T＝3.164min，C₂₁H₂₀ClFN₄O₄S₂Calculated mass of 510.1, M/z found value 511.2[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝10.326min)。¹H NMR(400MHz,DMSO-d₆)δ9.47-9.41(m,0.5H),8.37-8.32(m,0.5H),8.18-8.13(m,0.5H),8.00-7.99(m,2H),7.96-7.93(m,0.5H),7.44-7.42(m,1H),7.34-7.30(m,1H),7.24-7.20(m,1H),5.97(s,0.5H),5.87(s,0.5H),3.54(s,3H),2.95(s,1.3H),2.94(s,1.7H),2.44(s,3H),2.28(s,3H)。

Compound 378 a: ethyl 6- ((trans) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -1- (methylsulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.861，C₃₉H₄₄ClFN₄O₅S₂S_iCalculated mass of 794.2, M/z found value 795.3[ M + H ]]⁺。

Compound 378 b: ethyl 6- ((trans) -2- (((tert-butyldiphenylsilyl) oxy) methyl) -1- (methylsulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.831min，C₃₉H₄₄ClFN₄O₅S₂S_iCalculated mass 794.2, m/zFound value 795.3[ M + H]⁺。

Compound 383: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (methylsulfonyl) azepan-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.891min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass 526.1, M/z found 527.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.12(s,0.4H),7.84-7.83(s,1H),7.50(d,J＝3.2Hz,0.6H),7.45(d,J＝3.2Hz,0.4H),7.42-7.40(m,0.6H),7.32-7.29(m,0.6H),7.25-7.24(m,0.4H),7.15-7.12(m,1H),6.98-6.90(m,1H),6.19(s,0.2H),6.16(s,0.2H),6.05(s,0.6H),4.23-4.17(m,0.4H),4.04-3.98(m,0.6H),3.79-3.68(m,1H),3.61-3.55(m,4H),3.45-3.22(m,2H),2.94-2.90(m,3H),2.26-1.81(m,6H)。

Racemic 383(251mg, 0.480mmol) was separated by chiral preparative SFC (separation conditions: column: ChiralpakIA 5 μm20 × 250 mm; mobile phase: CO)₂MeOH 70:30 at 45 g/min; the column temperature is 41.1 ℃; wavelength: 214 nm; back pressure: 100 bar; column: chiralpak IA5 μm20 × 250 mm; mobile phase: hex: IPA: DEA: 80:20:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 230 nm; column: chiralpak IC5 μm20 × 250 mm; mobile phase: hex EtOH DEA 70:30:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compounds 383A (25mg, 10% yield, 100% stereopure) and 383B (22mg, 9% yield, 99.4% stereopure), 383C (23mg, 32% yield, 99.2% stereopure) and 383D (31mg, 12% yield, 100% stereopure) as yellow solids.

Compound 383A: LC-MS (ESI): r_T＝3.909min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass 526.1, M/z found 527.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; temperature: 30 ℃; wavelength: 230 nm; and_T＝14.425min)。¹H NMR(400MHz,DMSO-d₆)δ9.49(s,0.7H),9.13(s,0.3H),8.00(s,1.6H),7.94(s,0.4H),7.44-7.42(m,1H),7.38-7.31(m,1H),7.24-7.20(m,1H),6.01(s,0.3H),5.91(s,0.7H),4.04(s,0.3H),3.84-3.80(m,0.7H),3.53-3.36(m,5H),3.28-3.19(m,2H),2.94(s,3H),2.13-1.62(m,6H)。

compound 383B: LC-MS (ESI): r_T＝3.635min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass of 526.1, found value of M/z 526.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; temperature: 30 ℃; wavelength: 230 nm; and_T＝16.887min)。¹H NMR(400MHz,DMSO-d₆)δ9.47(d,J＝3.6Hz,0.7H),9.12(s,0.3H),8.00-7.99(m,1.6H),7.94-7.93(m,0.4H),7.45-7.41(m,1H),7.38-7.31(m,1H),7.24-7.19(m,1H),6.01(s,0.3H),5.91(d,J＝3.6Hz,0.7H),4.07-4.01(m,0.3H),3.84-3.78(m,0.7H),3.55-3.39(m,5H),3.26-3.20(m,2H),2.93(s,3H),2.14-1.62(m,6H)。

compound 383C: LC-MS (ESI): r_T＝3.619min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass of 526.1, found value of M/z 526.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA; mobile phase: CO)₂MeOH 70:30 at 2.999 mL/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100bar, R_T＝3.73min)。¹H NMR(400MHz,DMSO-d₆)δ9.48(d,J＝3.6Hz,0.7H),9.08(s,0.3H),8.00-7.99(m,1.6H),7.94-7.93(m,0.4H),7.44-7.41(m,1H),7.38-7.30(m,1H),7.25-7.20(m,1H),6.00(s,0.3H),5.91(d,J＝3.2Hz,0.7H),4.06-4.00(m,0.3H),3.84-3.79(m,0.7H),3.52-3.41(m,5H),3.31-3.21(m,2H),2.93(s,3H),2.13-1.66(m,6H)。

Compound 383D: LC-MS (ESI): r_T＝3.617min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass of 526.1, found value of M/z 526.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA; mobile phase: CO)₂MeOH 70:30 at 2.999 mL/min; temperature: 40 ℃; wavelength: 214nm, R_T＝4.63min)。¹H NMR(400MHz,DMSO-d₆)δ9.48(d,J＝3.6Hz,0.7H),9.08(s,0.3H),8.00-7.99(m,1.6H),7.94-7.93(m,0.4H),7.44-7.41(m,1H),7.38-7.33(m,1H),7.25-7.19(m,1H),6.00(s,0.3H),5.91(d,J＝3.6Hz,0.7H),4.06-4.00(m,0.3H),3.84-3.79(m,0.7H),3.52-3.42(m,5H),3.31-3.22(m,2H),2.93(s,3H),2.13-1.66(m,6H)。

Compound 384: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (oxetane-3-sulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.381min，C₂₄H₂₆ClFN₄O₅S₂Calculated mass of (568.1), M/z found value 569.2[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.47(d,J＝3.6Hz,0.6H),9.04(s,0.4H),8.00-7.98(m,1.5H),7.94(d,J＝3.2Hz,0.5H),7.51-7.41(m,2H),7.35-7.29(m,1H),7.23-7.19(m,1H),5.99(s,0.4H),5.90(d,J＝3.6Hz,0.6H),4.84-4.78(m,2H),4.72-4.59(m,3H),3.85-3.76(m,0.5H),3.55(br s,0.5H),3.51(s,2H),3.50(s,1H),3.32(br s,0.4H),3.13-3.11(m,0.6H),2.01-1.59(m,6H),1.35-1.23(m,2H)。

Rac 384(110mg, 0.190mmol) was separated by chiral preparative HPLC (column: Chiralpak IE5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 50:50 at 10.0 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 384A (43.1mg, 39% yield, 100% stereopurity) and 384B (42.3mg, 38% yield, 100% stereopurity).

Compound 384A: LC-MS (ESI): r_T＝3.309min，C24H₂₆ClFN₄O₅S₂Calculated mass of (568.1), M/z found value 569.2[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝9.233min)。¹H NMR(400MHz,DMSO-d₆)δ9.46(d,J＝3.2Hz,0.6H),9.03(s,0.4H),7.99-7.98(m,1.5H),7.94(d,J＝3.2Hz,0.5H),7.49-7.41(m,2H),7.35-7.29(m,1H),7.22-7.21(m,1H),5.99(s,0.4H),5.90(d,J＝2.8Hz,0.6H),4.84-4.78(m,2H),4.68-4.58(m,3H),3.82-3.76(m,0.4H),3.68(br s,0.6H),3.51(s,2H),3.50(s,1H),3.31-3.27(m,0.4H),3.14-3.09(m,0.6H),1.94-1.59(m,6H),1.34-1.29(m,2H)。

Compound 384B: LC-MS (ESI): r_T＝3.264min，C₂₄H₂₆ClFN₄O₅S₂Calculated mass of (568.1), M/z found value 569.2[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝13.064min)。¹H NMR(400MHz,DMSO-d₆)δ9.46(d,J＝3.6Hz,0.6H),9.03(s,0.4H),7.99-7.98(m,1.6H),7.94(d,J＝2.8Hz,0.4H),7.50-7.40(m,2H),7.35-7.29(m,1H),7.23-7.19(m,1H),6.00(s,0.4H),5.90(d,J＝3.6Hz,0.6H),4.84-4.78(m,2H),4.70-4.58(m,3H),3.82-3.76(m,0.4H),3.57-3.55(m,0.6H),3.51(s,2H),3.50(s,1H),3.31-3.30(m,0.4H),3.15-3.09(m,0.6H),1.98-1.59(m,6H),1.34-1.28(m,2H)。

Section II: boc protection for removal of primary dihydropyrimidines of the general formula I

Hydrochloride salt

Compound 99: methyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester hydrochloride

To a solution of methyl 6- (1-tert-butoxycarbonyl-piperidin-4-yl) -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylate compound 5B (1.56g, 2.92mmol) in methanol (15mL) was added 4M hydrochloric acid in methanol (15mL, 60.0mmol) at room temperature. After stirring at room temperature for 20 minutes, the mixture was concentrated to give the title compound as a yellow solid (1.69g,>100% yield). LC-MS (ESI): r_T＝1.444min，C₂₀H₂₁C_l2FN₄O₂Calculated mass of S470.1, found value of M/z 434.9[ M-HCl + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.00(br s,1H),8.60(br s,1H),8.02(dd,J＝4.4,3.2Hz,2H),7.43(dd,J＝8.8,2.8Hz,1H),7.36(dd,J＝8.8,6.0Hz,1H),7.21(td,J＝8.4,2.8Hz,1H),5.94(s,1H),3.86-3.79(m,1H),3.54(s,3H),3.40-3.35(m,2H),3.02-2.89(m,2H),2.19-2.02(m,2H),1.88(d,J＝14.4Hz,1H),1.72(d,J＝14.4Hz,1H)。

Similarly using a similar procedure, the following amine hydrochloride salt was prepared:

compound 109: methyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester hydrochloride

Compound 5 was then de-Boc to afford compound 109. LC-MS (ESI): r_T0.834min, M/z found 434.7[ M + H [ ]]⁺。

Compound 111: methyl 4- (2-chloro-3-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester hydrochloride

Compound 10 was substituted with de-Boc to give compound 111. LC-MS (ESI): r_T＝1.33min，C₂₀H₂₁Cl₂FN₄O₂Calculated mass of S470.1, found in M/z value 435.4[ M-HCl + H]⁺。

Compound 117: 4- (2-chloro-3-fluoro-phenyl) -6-piperidin-4-yl-2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride

Compound 10A was substituted with de-Boc to give compound 117. LC-MS (ESI): r_T＝1.34min，C₂₀H₂₁Cl₂FN₄O₂Calculated mass of S470.1, found value of M/z 434.9[ M-HCl + H]⁺。

Compound 119: methyl 4- (2-bromo-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester hydrochloride

Compound 12 was purified by de-Boc to give compound 119. LC-MS (ESI): r_T＝1.45min，C₂₀H₂₁BrClFN₄O₂Calculated mass of S514.0, found value of M/z 479.1[ M-HCl + H]⁺。

Compound 32: methyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 31 was then de-Boc to afford compound 32. LC-MS (ESI): r_T＝3.416min，C₂₀H₂₁Cl₂FN₄O₂Calculated mass of S470.1, found value of M/z 434.9[ M-HCl + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.67(br s,1H),9.26(br s,0.4H),9.10(br s,0.6H),8.77(br s,1H),8.05-8.00(m,2H),7.45-7.33(m,2H),7.24-7.17(m,1H),5.97(s,0.6H),5.94(s,0.4H),4.09-3.99(m,1H),3.55(s,3H),3.37-3.20(m,3H),2.96-2.83(m,1H),1.93-1.71(m,4H)。

Compound 35: methyl 4- (2-chloro-3-fluorophenyl) -6- (4-fluoro-piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 34 was then purified by de-Boc to give compound 35. LC-MS (ESI): r_T＝1.44min，C₂₀H₁₉ClF₂N₄O₂Calculated mass of S452.1, found value of M/z 453.4[ M + H ]]⁺。

Compound 45: methyl 4- (2-chloro-4-fluorophenyl) -6- (cis-3- (methoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester hydrochloride

Compound 44A was then subjected to de-Boc to give compound 45. LC-MS (ESI): r_T＝1.46min，C₂₂H₂₂ClFN₄O₄Calculated mass of S492.1, M/z found value 493.5[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.75(s,1H),9.15(s,1H),8.88(s,1H),8.06(d,J＝3.2Hz,1H),8.03(d,J＝3.2Hz,1H),7.55-7.48(m,0.2H),7.44-7.36(m,1.8H),7.23-7.18(m,1H),5.95(s,1H),3.95-3.87(m,1H),3.55(s,3H),3.46(s,3H),3.42-3.37(m,1H),3.30-3.28(m,0.5H),3.24-3.17(m,3.5H),2.21-2.08(m,2H)。

Compound 53: methyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (2,4, 6-trifluorophenyl) -1, 4-dihydropyrimidine-5-carboxylic acid ester hydrochloride

Compound 52 was subjected to de-Boc to give compound 53. LC-MS (ESI): r_T＝0.90min，C₂₃H₂₀ClF₄N₃O₂Calculated mass of 517.1M/z found to be 482.1[ M + H-HCl ]]⁺。

Compound 67A: methyl 4- (2-chloro-4-fluorophenyl) -6- (pyrrolidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester hydrochloride

Compound 66A was substituted with de-Boc to give compound 67. (LC-MS (ESI): R)_T＝3.198min，C₁₉H₁₉Cl₂FN₄O₂Calculated mass of S456.1, M/z found value 420.9[ M-HCl + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.46-9.07(m,2H),8.06-8.03(m,2H),7.45-7.41(m,2H),7.23-7.18(m,1H),5.95(s,0.8H),5.76(s,0.2H),4.44-4.32(m,2H),3.54(s,3H),3.33-3.34(m,2H),3.28-3.17(m,1H),2.13-2.08(m,2H)。

Compound 67D: methyl 4- (2-chloro-4-fluorophenyl) -6- (pyrrolidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester hydrochloride

Compound 66D was e-Boc to give compound 67D, LC-ms (esi): r_T＝1.95min，C₁₉H₁₈ClFN₄O₄Calculated mass of S420.9, M/z found value 421.1[ M + H [ ]]⁺。

Compound 79: methyl 6- (azetidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester hydrochloride

Compound 78A was then subjected to de-Boc to give compound 79.¹H NMR(400MHz,DMSO-d₆)δ9.27(br s,2H),8.07(d,J＝2.8Hz,1H),8.04(d,J＝2.8Hz,1H),7.49-7.45(m,1H),7.42(dd,J＝8.8,2.4Hz,1H),7.19(td,J＝11.2,2.4Hz,1H),5.95(s,1H),4.58-4.50(m,1H),4.30-4.04(m,4H),3.52(s,3H)。

Compound 297: (trans) -methyl 6- (4-aminocyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester hydrochloride,¹H NMR(300MHz,DMSO-d₆)δ8.78-8.73(m,1H),8.38-8.20(m,2H),8.12-8.01(m,1H),7.67-7.52(m,1H),7.43-7.27(m,1H),6.23-6.15(m,1H),4.16(s,3H),3.79-3.71(m,1H),3.60(s,0.5H),3.57(s,2.5H),3.08-2.90(m,1H),2.09-2.01(m,3H),1.93-1.78(m,3H),1.54-1.46(m,2H)。

compound 350: ethyl 4- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -6- (piperidin-4-yl) -1, 4-dihydropyrimidine-5-carboxylate hydrochloride

Compound 349 was subjected to de-Boc to give compound 350, LC-ms (esi): r_T＝2.05min，C₂₆H₂₉ClF₂N₄O₄Calculated mass of S566.2, found value of M/z 567.7[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.36(s,0.5H),7.82(d,J＝3.2Hz,1H),7.51(d,J＝2.8Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.38(s,0.5H),7.10-6.99(m,2H),6.20(s,0.5H),6.08(s,0.5H),4.30(br s,1.5H),4.09-3.99(m,2H),3.97-3.89(m,0.5H),2.91-2.79(m,2H),1.80-1.74(m,3H),1.61-1.58(m,2H),1.50(s,9H),1.13(t,J＝6.8Hz,3H)。

Compound 350A: ethyl 4- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -6- (piperidin-4-yl) -1, 4-dihydropyrimidine-5-carboxylate hydrochloride

Compound 349A was exposed to de-Boc to give compound 350A, LC-ms (esi): r_T＝1.512min，C₂₃H₂₂Cl₂F₄N₄O₂Calculated mass of 532.1, found value of M/z 497.1[ M + H-HCl ]]⁺。

Compound 350B: ethyl 4- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -6- (piperidin-4-yl) -1, 4-dihydropyrimidine-5-carboxylate hydrochloride

Compound 349B was subjected to de-Boc to give compound 350B, LC-ms (esi): r_T＝1.504min，C₂₃H₂₂Cl₂F₄N₄O₂Calculated mass of 532.1, found value of M/z 497.0[ M + H-HCl ]]⁺。

Compound 369: ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 368 was protected with de-Boc to give compound 369, LC-ms (esi): r_T＝1.55min，C₂₁H₂₁ClF₂N₄O₂Calculated mass of S466.1, M/z found value 467.1[ M + H [ ]]⁺。

Compound 369A: ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 368A was protected with de-Boc to afford compound 369A,¹H NMR(400MHz,DMSO-d₆)δ8.02(s,2H),7.50-7.43(m,1H),7.24-7.20(m,1H),5.97(s,1H),3.98(q,J＝6.8Hz,2H),3.88-3.75(m,1H),3.32-3.23(m,2H),2.89-2.77(m,2H),2.10-1.79(m,3H),1.67-1.64(m,1H),1.08(t,J＝6.8Hz,3H)。

compound 369B: ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 368B was protected with de-Boc to afford compound 369B,¹H NMR(400MHz,DMSO-d₆)δ8.02(s,2H),7.49-7.42(m,1H),7.23-7.19(m,1H),5.95(s,1H),3.98(q,J＝6.8Hz,2H),3.84-3.76(m,1H),3.36-3.31(m,2H),2.97-2.82(m,2H),2.15-1.97(m,2H),1.89-1.83(m,1H),1.72-1.66(m,1H),1.07(t,J＝6.8Hz,3H)。

compound 373: methyl 6- (3-aminobicyclo [1.1.1] pent-1-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 371 was substituted with de-boc to give compound 373, LC-MS (ESI): r_T＝1.41min，C₂₀H₁₈ClFN₄O₂Calculated mass of S432.1, M/z found value 433.5[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.85(s,0.8H),7.81(d,J＝3.6Hz,1H),7.48(d,J＝2.8Hz,0.2H),7.43(d,J＝2.8Hz,0.8H),7.39(s,0.2H),7.30-7.27(m,0.6H),7.25-7.23(m,0.4H),7.13-7.10(m,1H),6.93-6.89(m,1H),6.15(s,0.8H),6.00(d,J＝2.4Hz,0.2H),3.63(s,0.5H),3.60(m,2.5H),2.31(s,5H),2.25(s,1H)。

Compound 373A: methyl 6- (3-aminobicyclo [1.1.1] pent-1-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 371A was substituted with de-boc to give compound 373A, LC-ms (esi): r_T＝0.982min，C₂₀H₁₈ClFN₄O₂Calculated mass of S432.1, M/z found value 432.8[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.85-7.81(m,1.7H),7.44-7.43(m,1.3H),7.29-7.27(m,0.6H),7.26-7.25(m,0.4H),7.12(dd,J＝8.8,2.8Hz,1H),6.92-6.91(m,1H),6.15(s,0.8H),6.00(s,0.2H),3.67(s,0.3H),3.64(s,0.7H),3.60(s,2H),2.32(s,4H),2.30(s,1H),2.27(s,1H)。

Compound 373B: methyl 6- (3-aminobicyclo [1.1.1] pent-1-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 371B was substituted with de-boc to give compound 373B, LC-ms (esi): r_T＝1.883min，C₂₀H₁₈ClFN₄O₂Calculated mass of S432.1, M/z found value 432.8[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.95(d,J＝3.2Hz,0.3H),7.85(s,0.7H),7.81(d,J＝2.8Hz,1H),7.55-7.51(m,0.5H),7.49-7.38(m,1.2H),7.29-7.28(m,0.6H),7.26-7.25(m,0.2H),7.23-7.17(m,0.2H),7.13-7.11(m,1H),7.07-7.00(m,0.3H),6.94-6.89(m,1H),6.15(s,0.8H),6.00(s,0.2H),3.63-3.60(m,3H),2.32-2.27(m,6H)。

Trifluoroacetic acid salt

Compound 121: methyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate trifluoroacetate salt

To a suspension of methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 5(2.00g, 3.75mmol) in dichloromethane (10mL) was added 2,2, 2-trifluoroacetic acid (10 mL). After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to give the title compound (2.50g,>100% yield). LC-MS (ESI): r_T＝1.45min，C₂₂H₂₀ClF₄N₄O₃Calculated mass of S531.1, found value of M/z 435.4[ M-CF₃COOH+H]⁺。

Similarly using a similar procedure, the following amine trifluoroacetates were prepared:

compound 123: 4- (4-chloro-3-fluoro-phenyl) -6-piperidin-4-yl-2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester trifluoroacetate salt

Compound 13 was then purified by de-Boc to give compound 123. LC-MS (ESI): r_T＝2.035min，C₂₀H₂₀ClFN₄O₂Calculated mass of S434.1, found value of M/z 435.1[ M + H [)]⁺。

Compound 125: methyl 6- (trans-4-aminocyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate trifluoroacetate salt

Compound 14 was then purified by de-Boc to afford compound 125. LC-MS (ESI): r_T＝2.288min，C₂₃H₂₂ClF₄N₄O₃Calculated mass of S545.1, M/z found 448.8[ M + H-TFA]⁺。

Compound 127: methyl 6- (cis-4-aminocyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydro-pyrimidine-5-carboxylate trifluoroacetate salt

Compound 15 was then de-Boc to afford compound 127. LC-MS (ESI): r_T＝0.299min，C₂₃H₂₂ClF₄N₄O₃Calculated mass of S545.1, M/z found 448.8[ M + H-TFA]⁺。

Compound 28: methyl 4- (2-chloro-3-fluorophenyl) -6- (trans-4- (2-ethoxy-2-oxoethyl) -cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 27Y was substituted with de-Boc to afford compound 28. LC-MS (ESI): r_T＝3.324min，C₂₅H₂₇ClFN₃O₄Calculated mass of S519.1, M/z found 520.0[ M + H [ ]]⁺. Chiral HPLC (column: Chiralcel OJ-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH 80:20 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R: L; chiral HPLC (column: Chiralcel OJ-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH ═ 80: 20; temperature: 30 ℃; wavelength: 230 nm; R: L_T＝7.308min)。¹H NMR(400MHz,DMSO-d₆)δ9.46(s,0.5H),8.99(m,0.5H),7.99(d,J＝2.8Hz,1H),7.98-7.94(m,1H),7.39-7.29(m,2H),7.19-7.17(m,1H),6.05-5.96(m,1H),4.07(q,J＝7.2Hz,2H),3.81-3.58(m,1H),3.51(s,3H),2.22(d,J＝7.2Hz,2H),1.91-1.59(m,8H),1.20(t,J＝7.2Hz,3H),1.12-1.08(m,1H)。

Free amine:

compound 58: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 57(280mg, 0.507mmol) in dichloromethane (3mL) at room temperature was added trifluoroacetic acid (3 mL). After stirring for 1 hour, the mixture was concentrated to dryness and then taken up into 5M ammonia in methanol (3 mL). Stirring was continued for 0.5 h. The reaction mixture was concentrated to leave a residue, which was purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1) to give the title compound (160mg, 70% yield) as a yellow solid. LC-MS (ESI): r_T＝1.48min，C₂₀H₁₉ClF₂N₄O₂Calculated mass of S452.1M/z found 453.3[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.00(s,2H),7.49-7.42(m,1H),7.20-7.17(m,1H),6.02-5.92(m,1H),4.01-3.91(m,0.5H),3.73-3.70(m,0.5H),3.52(s,3H),3.07-3.00(m,2H),2.59-2.54(m,2H),1.90-1.57(m,4H)。

Compound 88 (trans): trans-methyl 6- (3-aminocyclobutyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

A solution of trans-methyl 6- (3- ((tert-butoxycarbonyl) amino) cyclobutyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 87(400mg, 0.769mmol) in 5M hydrochloric acid (in methanol) (10mL, 50mmol) was stirred at room temperature for 1 hour. The mixture was then concentrated at room temperature under reduced pressure to give a residue, which was dissolved in 4M ammonia in methanol (20mL, 80mmol) and stirred at room temperature for 30 min. The resulting mixture was concentrated to give the crude title compound as a yellow solid (283mg, 88% yield). LC-MS (ESI): r_T＝2.178min，C₁₉H₁₈ClFN₄O₂Calculated mass of S420.1, M/z found 420.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.38(brs,0.3H),7.84(d,J＝3.2Hz,0.7H),7.82(d,J＝3.2Hz,0.3H),7.50(d,J＝3.2Hz,0.7H),7.45(d,J＝3.2Hz,1H),7.30-7.25(m,1H),7.13(dt,J＝8.4,2.8Hz,1H),6.96-6.88(m,1H),6.18(s,0.3H),6.05(d,J＝2.8Hz,0.7H),4.59-4.52(m,0.4H),4.48-4.40(m,0.6H),3.93-3.86(m,0.6H),3.80-3.72(m,0.4H),3.60(s,2H),3.58(s,1H),2.82-2.75(m,0.6H),2.63-2.46(m,1.4H),2.37-2.23(m,0.6H),2.21-2.03(m,1.4H)。

Similarly using a similar procedure, the following free amines were prepared:

compound 88 (cis): (cis) -methyl 6- (3-aminocyclobutyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.168min，C₁₉H₁₈ClFN₄O₂Calculated mass of S420.1, M/z found 420.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ9.82(br s,0.4H),7.83(d,J＝3.2Hz,1H),7.51-7.45(m,1H),7.29-7.26(m,1H),7.12(dd,J＝4.8,2.8Hz,1H),6.95-6.87(m,1H),6.18-6.05(m,1H),4.51-4.16(m,1H),3.69-3.47(m,4H),2.84-2.49(m,2H),2.23-1.82(m,2H)。

Compound 83: methyl 6- (azetidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 78 was then subjected to de-Boc to give compound 83. LC-MS (ESI): r_T＝1.32min，C₁₈H₁₆ClFN₄O₂Calculated mass of S406.1, found value of M/z 407.4[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆+D₂O)δ8.01(d,J＝3.2Hz,1H),7.95(s,1H),7.44-7.40(m,2H),7.20(td,J＝8.0,2.0Hz,1H),5.98(s,1H),4.58(s,1H),3.96-3.88(m,4H),3.51(s,3H)。

Compound 144: ethyl 4- (2-chlorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 143B was substituted with de-Boc to afford compound 144. LC-MS (ESI): r_T＝1.47min，C₂₁H₂₃ClN₄O₂Calculated mass of S430.10, found value of M/z 431.4[ M + H [ ]]⁺。

Compound 160: methyl 4- (2-bromo-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 159A was substituted with de-Boc to give compound 160. LC-MS (ESI): r_T＝1.64min，C₂₀H₁₉BrF₂N₄O₂Calculated mass of S496.0, found M/z value 499.4[ M +3 ]]⁺。

Compound 189: methyl 6- (4-aminocycloheptyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 188 was substituted with de-Boc to give compound 189, LC-ms (esi): r_T2.154min and 2.282min, C₂₂H₂₄ClFN₄O₂Calculated mass of S462.1, found value of M/z 463.1[ M + H [)]⁺。

Compound 192: ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (2,4, 6-trifluorophenyl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 191 was then subjected to de-Boc to give compound 192. LC-MS (ESI): r_T＝1.986min，C₂₄H₂₁ClF₅N₃O₂Calculated mass 513.1, M/z found value 514.0[ M + H [ ].]⁺。

Compound 197A: ethyl 4- (2-bromo-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester hydrochloride

Compound 196A was substituted with de-Boc to give compound 197A, LC-MS: r_T＝1.52min，C₂₁H₂₁BrF₂N₄O₂Calculated mass of S510.05, m/z found value: 513.4[ M-HCl + H]⁺。

Compound 203: methyl 6- (3-aminobicyclo [1.1.1] pent-1-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 202 was protected with de-Boc to give compound 203, LC-ms (esi): r_T＝1.844min，C₁₂H₁₉NO₄Calculated mass of 241.1, M/z found value 242.2[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ4.96(br s,1H),3.70(s,3H),2.30(s,6H),1.46(s,9H)。

Compound 202A was protected by de-Boc to give compound 203A. LC-MS (ESI): r_T＝1.489min，C₂₀H₁₇ClF₂N₄O₂Calculated mass of S450.1, found value of M/z 450.9[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ7.90(brs,1H),7.82(d,J＝2.4Hz,1H),7.46(d,J＝2.4Hz,1H),7.06-7.03(m,2H),6.14(br s,1H),3.61(s,3H),2.43(s,6H)。

Compound 202B was subjected to de-Boc to give compound 203B. LC-MS (ESI): r_T＝2.249min，C₂₅H₂₅ClF₂N₄O₄Calculated mass of S550.1, found value of M/z 551.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 2.999 g/min; column temperature: 40.1 ℃; wavelength: 230nm, back pressure: 100bar, R_T＝3.95min)。¹H NMR(300MHz,CDCl₃)δ7.91-7.89(m,0.8H),7.81-7.78(m,1H),7.49-7.48(m,0.2H),7.44-7.42(m,0.8H),7.40-7.38(m,0.2H),7.08-7.01(m,2H),6.14(br s,0.8H),6.01(br s,0.2H),5.03(br s,1H),3.64(s,0.5H),3.60(s,2.5H),2.53(s,5H),2.45(s,1H),1.47(s,9H)。

Compound 236: (trans) -methyl 6- (4-aminocyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 235 was subjected to de-Boc to give compound 236,¹H NMR(400MHz,CDCl₃)δ8.14(br s,0.7H),7.83-7.80(m,1H),7.48(d,J＝3.2Hz,0.3H),7.44(d,J＝3.2Hz,0.7H),7.41-7.38(m,0.3H),7.08-7.05(m,1H),7.04-6.97(m,1H),6.17(s,0.7H),6.03(s,0.3H),3.97-3.89(m,0.7H),3.72-3.68(m,0.3H),3.61(s,1H),3.59(s,2H),2.79-2.72(m,1H),2.05-2.02(m,2.5H),1.96-1.92(m,1.5H),1.65-1.50(m,2H),1.36-1.26(m,2H)。

compound 238: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (sulfamoylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 237 was protected with de-Boc to give compound 238, LC-MS (ESI): r_T＝3.924min，C₂₁H₂₂ClF₂N₅O₄S₂Calculated mass of 545.1, M/z found value 546.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.54(br s,0.6H),9.05(br s,0.4H),7.99-7.94(m,2H),7.49-7.40(m,1H),7.22-7.11(m,1H),6.56-6.43(m,3H),6.00(s,0.4H),5.91(s,0.6H),3.84-3.75(m,0.4H),3.61-3.56(m,0.6H),3.51(s,3H),3.25-3.20(m,0.4H),3.12-3.07(m,0.6H),2.12-2.02(m,2H),1.90-1.69(m,3H),1.65-1.53(m,1H),1.30-1.23(m,2H)。

Compound 247: methyl 6- (1- (azetidin-3-ylsulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 246 was substituted with de-Boc to give compound 247, LC-ms (esi): r_T＝1.598min，C₂₃H₂₄ClF₂N₅O₄S₂Calculated mass of 571.1, M/z found value 571.9[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.28(s,0.3H),7.85(s,1H),7.56(s,0.7H),7.48-7.45(m,1H),7.14-7.05(m,2H),6.19(s,0.3H),6.08(s,0.7H),4.21-4.08(m,4H),4.03-3.90(m,4H),3.61(s,3H),3.01-2.88(m,2H),2.26-2.16(m,1H),2.06-1.87(m,2H),1.74-1.67(m,1H)。

Compound 250: (trans) -methyl 6- (4- (azetidine-3-sulfonylamino) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 249 was substituted with de-Boc to give compound 250, LC-ms (esi): r_T＝1.589min，C₂₄H₂₆ClF₂N₅O₄S₂Calculated mass of 585.1, M/z found value 585.9[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.16(s,0.5H),7.84(s,1H),7.57-7.53(m,0.5H),7.48-7.47(m,0.5H),7.42(s,0.5H),7.10-7.00(m,2H),6.18(s,0.5H),6.05(s,0.5H),4.25-4.04(m,4H),3.99-3.87(m,2H),3.82-3.67(m,1H),3.61(s,1.5H),3.60(s,1.5H),3.50-3.32(m,1H),2.21-1.99(m,4H),1.75-1.36(m,4H)。

Compound 276A: methyl 4- (2-bromo-3-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 275A was substituted with de-Boc to afford compound 276A,¹H NMR(400MHz,CDCl₃)δ7.82(d,J＝6.4Hz,1H),7.56-7.52(m,0.9H),7.50(d,J＝2.8Hz,1H),7.42-7.42(m,0.1H),7.25-7.18(m,1H),7.11-7.04(m,2H),7.01-6.98(m,0.2H),6.25(s,0.1H),6.12(d,J＝2.8Hz,0.9H),4.37-4.27(m,0.3H),4.08-4.00(m,0.7H),3.75-3.62(m,2H),3.61-3.56(m,3H),3.13-3.00(m,2H),2.64-2.53(m,1H),2.47-2.36(m,1H),2.34-2.12(m,1H),1.95-1.84(m,1H)。

compound 276B: methyl 4- (2-bromo-3-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 275B was exposed to de-Boc to afford compound 276B,¹H NMR(400MHz,CDCl₃)δ9.59-9.01(m,1H),7.82(s,1H),7.58-7.37(m,2H),7.30-7.27(m,0.5H),7.25-7.23(m,0.5H),6.24(s,0.2H),6.14-6.09(m,0.5H),4.09-4.01(m,0.8H),3.74(s,0.2H),3.67-3.51(m,5H),3.17-3.02(m,2H),2.53-2.38(m,1H),2.34-2.23(m,1H),2.13-2.07(m,1H),1.93-1.83(m,1H)。

compound 280: ethyl 4- (2-bromo-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 279 was substituted with de-Boc to give compound 280, LC-ms (esi): r_T＝1.01min，C₂₁H₂₂BrFN₄O₂Calculated mass of S492.1, M/z found value 495.4[ M + H]⁺。¹H NMR(300MHz,CDCl₃)δ8.27-8.20(m,0.6H),7.85-7.78(m,1H),7.50(d,J＝3.0Hz,0.4H),7.46-7.43(m,0.6H),7.34-7.31(m,2.4H),7.04-6.91(m,1H),6.19(s,0.6H),6.06(s,0.4H),4.25-3.88(m,3H),3.35-3.15(m,2H),2.93-2.74(m,2H),2.24-2.06(m,1H),1.90-1.60(m,3H),1.19-1.07(m,3H)。

Compound 280A: ethyl 4- (2-bromo-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 279A was substituted with de-Boc to give compound 280A, LC-ms (esi): r_T＝1.57min，C₂₁H₂₂BrFN₄O₂Calculated mass of S492.1, M/z found 494.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.26(brs,1H),7.83(d,J＝2.8Hz,0.6H),7.80(d,J＝3.2Hz,0.4H),7.52(d,J＝3.2Hz,0.6H),7.43(d,J＝2.8Hz,0.4H),7.33-7.28(m,2H),7.03-6.94(m,1H),6.18(s,0.4H),6.06(s,0.6H),4.22-4.17(m,0.4H),4.08-3.97(m,2.6H),3.47-3.38(m,1.2H),3.30-3.23(m,1H),3.02-2.84(m,2.8H),2.34-2.10(m,1.3H),2.00-1.97(m,1H),1.88-1.73(m,1.7H),1.13(q,J＝7.2Hz,3H)。

Compound 280B: ethyl 4- (2-bromo-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 279B was substituted with de-Boc to give compound 280B, LC-ms (esi): r_T＝1.55min，C₂₁H₂₂BrFN₄O₂Calculated mass of S492.1, M/z found 494.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.28(brs,1H),7.83(d,J＝3.2Hz,0.6H),7.80(d,J＝3.2Hz,0.4H),7.52(d,J＝3.2Hz,0.6H),7.43(d,J＝2.8Hz,0.4H),7.33-7.28(m,2H),7.03-6.93(m,1H),6.18(s,0.4H),6.07(s,0.6H),4.23-4.17(m,0.4H),4.07-3.99(m,2.6H),3.51-3.41(m,1.8H),3.32-3.25(m,1H),3.05-2.83(m,2.2H),2.38-2.13(m,1.3H),2.02-1.98(m,1H),1.89-1.76(m,1.7H),1.12(q,J＝7.2Hz,3H)。

Compound 307A: methyl 4- (3, 4-difluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 306A was substituted with de-Boc to give compound 307A, LC-ms (esi): r_T＝1.908min，C₂₁H₂₂F₂N₄O₂Calculated mass of S432.1, M/z found value 432.9[ M + H [ ]]⁺。

Compound 307B: methyl 4- (3, 4-difluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 306B was protected with de-Boc to give compound 307B, LC-ms (esi): r_T＝1.896min，C₂₁H₂₂F₂N₄O₂Calculated mass of S432.1, M/z found value 432.9[ M + H [ ]]⁺。

Compound 317: ethyl 4- (2-chloro-3-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 316 was substituted with de-Boc to give compound 317: LC-MS (ESI): r_T＝0.85min，C₂₁H₂₂ClFN₄O₂Calculated mass of S448.1, found value of M/z 449.5[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ7.82(d,J＝3.6Hz,1H),7.52(d,J＝3.6Hz,0.6H),7.46-7.43(m,0.4H),7.24-7.00(m,3H),6.28(s,0.4H),6.17(s,0.6H),4.78-4.29(m,2.4H),4.09-4.01(m,2.6H),3.66-3.51(m,1.4H),3.44-3.33(m,0.6H),3.12-2.84(m,2H),2.55-2.22(m,1.4H),2.05-1.78(m,2.6H),1.14-1.09(m,3H)。

Compound 327A: ethyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 326A was protected with de-Boc to give compound 327A, LC-ms (esi): r_T＝1.899min，C₂₁H₂₂ClFN₄O₂Calculated mass of S448.1, M/z found value 449.1[ M + H [ ]]⁺。

Compound 327B: ethyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 326B was protected with de-Boc to give compound 327B, LC-ms (esi): r_T＝1.897min，C₂₁H₂₂ClFN₄O₂Calculated mass of S448.1, M/z found value 449.1[ M + H [ ]]⁺。

Compound 337: ethyl 4- (2-bromo-3-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,

compound 336 was protected with de-Boc to give compound 337, LC-ms (esi): r_T＝1.42min，C₂₁H₂₂BrFN₄O₄Calculated mass of S492.1, M/z found value 495.4[ M + H]⁺。

Compound 341A: ethyl 4- (3, 4-difluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 340A was protected with de-Boc to give 341A,¹H NMR(300MHz,DMSO-d₆)δ8.63(s,0.2H),7.98-7.94(m,1.8H),7.25-7.19(m,1H),7.10-7.00(m,1H),5.82(s,0.3H),5.68(s,0.7H),4.02-3.94(m,2.3H),3.72-3.65(m,0.7H),3.08-3.00(m,2H),2.62-2.55(m,2H),2.44(s,3H),1.92-1.78(m,2H),1.63-1.59(m,1.3H),1.45-1.42(m,0.7H),1.07(t,J＝5.4Hz,3H)。

compound 341B: ethyl 4- (3, 4-difluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 340B was protected with de-Boc to give 341B,¹H NMR(300MHz,DMSO-d₆)δ8.63(s,0.2H),7.98(s,1.8H),7.25-7.18(m,1H),7.09-6.99(m,1H),5.82(s,0.3H),5.68(s,0.7H),4.00-3.94(m,2.2H),3.73-3.65(m,0.8H),3.08-3.01(m,2H),2.61-2.55(m,2H),2.45(s,3H),1.89-1.75(m,2H),1.66-1.58(m,1.2H),1.45-1.42(m,0.8H),1.06(t,J＝5.4Hz,3H)。

compound 395: (trans) -methyl 6- (4-aminocyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 394 is substituted with de-Boc to afford compound 395,¹H NMR(300MHz,CDCl₃)δ8.66-8.57(m,0.6H),8.34-8.29(m,0.6H),8.26-8.21(m,0.4H),7.86-7.80(m,0.2H),7.62-7.55(m,0.2H),7.34-7.28(m,1H),7.16-7.10(m,1H),6.93-6.84(m,1H),6.32-6.27(m,0.6H),6.06-5.97(m,0.4H),4.13-3.94(m,1H),3.77-3.64(m,1H),3.56(s,3H),2.14-2.05(m,3H),2.00-1.93(m,1H),1.62-1.37(m,4H)。

compound 408A: methyl 4- (2-bromo-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 407A was substituted with de-Boc to give compound 408A, LC-ms (esi): r_T＝1.799min，C₂₀H₂₀BrFN₄O₂Calculated mass of S478.1, found value of M/z 479.0[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.28(s,0.4H),7.84-7.79(m,1H),7.52-7.51(m,0.6H),7.44-7.43(m,0.5H),7.33-7.29(m,1.5H),7.02-6.93(m,1H),6.16(s,0.4H),6.03(s,0.6H),4.20-4.11(m,0.5H),4.02-3.96(m,0.5H),3.61-3.60(m,3H),3.44-3.35(m,1H),3.28-3.23(m,1H),3.01-2.81(m,3H),2.32-2.23(m,0.6H),2.12-2.08(m,0.4H),1.98-1.94(m,1H),1.88-1.72(m,2H)。

Compound 408B: methyl 4- (2-bromo-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 407B was substituted with de-Boc to give compound 408B, LC-ms (esi): r_T＝1.903min，C₂₀H₂₀BrFN₄O₂Calculated mass of S478.1, found value of M/z 479.0[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.34(s,0.3H),7.84-7.80(m,1H),7.53-7.52(m,1H),7.43-7.42(m,0.3H),7.34-7.31(m,1.2H),7.26-7.25(m,0.5H),7.03-6.93(m,1H),6.16(s,0.3H),6.04(s,0.7H),4.25-4.21(m,0.3H),4.06-4.00(m,0.7H),3.61-3.60(m,3H),3.56-3.49(m,1H),3.37-3.30(m,0.7H),3.09-2.85(m,3H),2.48-2.39(m,1.2H),2.35-2.21(m,0.8H),2.02-1.99(m,0.6H),1.92-1.81(m,1.4H)。

Compound 398: (cis) -methyl 6- (4-aminocyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 397 is reacted with de-Boc to give compound 398,¹H NMR(300MHz,CDCl₃)δ8.93-8.89(m,0.3H),8.76-8.73(m,0.1H),8.62-8.60(m,0.2H),8.33-8.28(m,0.7H),8.27-8.24(m,0.5H),7.84-7.79(m,0.2H),7.32-7.27(m,2H),7.14-7.11(m,1H),6.91-6.86(m,1H),6.28(s,0.7H),6.04-6.00(m,0.3H),4.10-3.92(m,1H),3.61(s,1H),3.58(s,2H),3.39-3.33(m,1H),2.04-1.93(m,5H),1.60-1.38(m,3H)。

compound 412A: ethyl 4- (2-bromo-3-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 411A quiltde-Boc to give compound 412A, LC-MS (ESI): r_T＝1.57min，C₂₁H₂₂BrFN₄O₂Calculated mass of S492.1, M/z found value 494.8[ M + H]⁺。¹H NMR(300MHz,CDCl₃)δ8.23(s,0.5H),7.81(d,J＝3.0Hz,0.4H),7.78(d,J＝3.3Hz,0.6H),7.49(d,J＝3.0Hz,0.4H),7.42(d,J＝3.0Hz,0.6H),7.21-7.12(m,1.5H),7.07-6.98(m,1H),6.25(s,0.6H),6.11(s,0.4H),4.22-3.92(m,3H),3.33-3.18(m,2H),2.88-2.77(m,2H),2.10-2.04(m,0.3H),1.83-1.62(m,3.7H),1.11(t,J＝7.2Hz,3H)。

Compound 412B: ethyl 4- (2-bromo-3-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 411B was substituted with de-Boc to give compound 412B, LC-ms (esi): r_T＝1.58min，C₂₁H₂₂BrFN₄O₂Calculated mass of S492.1, M/z found value 494.8[ M + H]⁺。¹H NMR(300MHz,CDCl₃)δ8.25(s,0.5H),7.83(d,J＝3.0Hz,0.4H),7.80(d,J＝2.7Hz,0.6H),7.51(d,J＝3.0Hz,0.4H),7.44(d,J＝3.0Hz,0.6H),7.23-7.14(m,1.5H),7.09-6.98(m,1H),6.27(s,0.6H),6.13(s,0.4H),4.24-3.97(m,3H),3.34-3.20(m,2H),2.94-2.80(m,2H),2.20-2.09(m,0.8H),1.93-1.63(m,3.2H),1.13(t,J＝7.2Hz,3H)。

Compound 418B: ethyl 4- (4-fluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 417B was substituted with de-Boc to give compound 418B, LC-ms (esi): r_T＝1.536min，C₂₂H₂₅FN₄O₂Calculated mass of S428.2, found value of M/z 429.1[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ8.49(s,0.3H),7.81-7.79(m,1H),7.53(d,J＝3.2Hz,0.7H),7.39(d,J＝2.8Hz,0.3H),7.30-7.28(m,0.7H),7.17-7.13(m,0.3H),7.09(s,0.7H),6.90-6.84(m,1.7H),6.81-6.76(m,0.3H),5.95(s,0.3H),5.88(d,J＝1.6Hz,0.7H),4.41-4.35(m,0.3H),4.06-3.92(m,2.7H),3.60-3.53(m,2H),3.11-3.00(m,2H),2.62(s,1H),2.48(s,2H),2.45-2.08(m,3H),2.01-1.97(m,0.3H),1.86-1.83(m,0.7H),1.13-1.08(m,3H)。

Compound 427A: ethyl 4- (3-fluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 426A was substituted with de-Boc to give compound 427A, LC-ms (esi): r_T＝1.52min，C₂₂H₂₅FN₄O₂Calculated mass of S428.2, found value of M/z 429.0[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.48(s,0.3H),7.81-7.79(m,1H),7.52(d,J＝3.2Hz,0.7H),7.38(d,J＝3.2Hz,0.3H),7.14-7.01(m,2.7H),6.97-6.88(m,1H),6.01(s,0.3H),5.93(d,J＝1.6Hz,0.7H),4.43-4.37(m,0.3H),4.06-3.94(m,2.7H),3.61-3.54(m,2H),3.12-3.01(m,2H),2.52(s,1H),2.45-2.29(m,4H),2.25-2.09(m,1H),2.05-2.01(m,0.3H),1.87-1.83(m,0.7H),1.13-1.08(m,3H)。

Compound 427B: ethyl 4- (3-fluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 426B was substituted with de-Boc to give compound 427B, LC-ms (esi): r_T＝1.53min，C₂₂H₂₅FN₄O₂Calculated mass of S428.2, found value of M/z 429.0[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.37(s,0.4H),7.79(d,J＝3.2Hz,1H),7.52(d,J＝3.2Hz,0.6H),7.40(d,J＝3.2Hz,0.4H),7.14-7.01(m,2.6H)，6.97-6.88(m,1H),6.01(s,0.3H),5.93(s,0.7H),4.35-4.29(m,0.4H),4.06-3.93(m,2.6H),3.59-3.42(m,2H),3.10-2.93(m,2H),2.53(s,1H),2.39(s,2H),2.37-2.26(m,1H),2.15-2.08(m,1.3H),2.01-1.82(m,1.7H),1.13-1.08(m,3H)。

Compound 436 a: (cis) -ethyl 6- (3-amino-2, 2-dimethylcyclobutyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 435a was protected with de-Boc to give compound 436a, LC-ms (esi): r_T＝1.83min，C₂₂H₂₄ClFN₄O₂Calculated mass of S462.1, M/z found value 463.5[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ10.8(s,0.7H),7.81(d,J＝2.0Hz,1H),7.63-7.37(m,2.3H),7.19-7.11(m,1H),6.92(br s,1H),6.25(s,0.7H),6.16(s,0.3H),4.50-4.37(m,0.7H),4.29-4.24(m,0.3H),4.23-4.19(m,0.3H),4.11-3.91(m,2.7H),3.34-3.22(m,0.7H),3.19-3.08(m,0.3H),2.67-2.47(m,0.6H),2.46-2.21(m,0.4H),1.36(s,3H),1.14-1.10(m,6H)。

Compound 442 a: methyl-4- (3-fluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 441a was substituted with de-Boc to give compound 442a, LC-ms (esi): r_T＝1.481min，C₂₁H₂₃FN₄O₂Calculated mass of S414.5, M/z found 415.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.26(s,1H),7.76(d,J＝2.8Hz,1H),7.50(d,J＝2.8Hz,0.4H),7.39(d,J＝3.2Hz,0.6H),7.26-7.06(m,2H),7.00-6.87(m,1H),5.99(s,0.6H),5.90(s,0.4H),4.25-4.17(m,0.6H),3.97-3.88(m,0.4H),3.58(s,3H),3.52-3.44(m,0.7H),3.32-3.25(m,1.3H),3.04-2.82(m,2H),2.53(s,2H),2.38(s,1H),2.35-2.19(m,1H),2.00-1.73(m,3H)。

Compound 442 b: methyl-4- (3-fluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 441b was protected with de-Boc to give compound 442b, LC-ms (esi): r_T＝1.47min，C₂₁H₂₃FN₄O₂Calculated mass of S414.5, M/z found value 414.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.27(s,1H),7.77(d,J＝2.8Hz,1H),7.51(d,J＝2.8Hz,0.4H),7.40(d,J＝3.2Hz,0.6H),7.15-7.01(m,2H),6.97-6.88(m,1H),6.00(s,0.6H),5.91(s,0.4H),4.27-4.18(m,0.6H),3.98-3.89(m,0.4H),3.59(s,3H),3.53-3.45(m,0.7H),3.33-3.26(m,1.3H),3.05-2.83(m,2H),2.54(s,2H),2.39(s,1H),2.36-2.21(m,1H),1.87-1.73(m,3H)。

Compound 446A: methyl 4- (4-fluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 445A was substituted with de-Boc to give compound 446A, LC-ms (esi): r_T＝1.40min，C₂₁H₂₃FN₄O₂Calculated mass of S414.2, found value of M/z 415.1[ M + H [)]⁺。¹H NMR(400MHz,CD₃OD)δ7.79(d,J＝3.2Hz,1H),7.64(d,J＝3.2Hz,1H),7.22-7.19(m,1H),6.83-6.73(m,2H),5.78(s,1H),4.03-3.79(m,1H),3.50(s,3H),3.19-3.13(m,2H),2.78-2.69(m,2H),2.46(s,3H),2.14-1.81(m,3H),1.65-1.62(m,1H)。

Compound 446B: methyl 4- (4-fluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 445B was substituted with de-Boc to give compound 446B, LC-ms (esi): r_T＝1.38min，C₂₁H₂₃FN₄O₂Calculated mass of S414.2, found value of M/z 415.1[ M + H [)]⁺。¹H NMR(400MHz,CD₃OD)δ7.80(d,J＝3.2Hz,1H),7.64(d,J＝3.2Hz,1H),7.22-7.19(m,1H),6.83-6.73(m,2H),5.78(m,1H),4.00-3.80(m,1H),3.50(s,3H),3.19-3.13(m,2H),2.78-2.69(m,2H),2.46(s,3H),2.12-1.81(m,3H),1.65-1.62(m,1H)。

Section III: coupling reaction with the resulting amine (section II) of the main dihydropyrimidine of the general formula I

Compound 100: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (cyclopropylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Method M: to a solution of methyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate hydrochloride compound 99(80.0mg, 0.170mmol) and triethylamine (51.5mg, 0.510mmol) in dichloromethane (3mL) was added cyclopropanesulfonyl chloride (31.1mg, 0.221mmol) at 20 ℃. After stirring overnight at room temperature, the mixture was quenched with water (10mL) and then extracted three times with dichloromethane (50 mL). The combined organic layers were washed twice with water (20mL), twice with brine (20mL), and over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was separated by preparative HPLC (column: X-bridge C18(5 μm 19X 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 20mL/min, gradient: 25% -75% (% B)) to give the title compound as a yellow solid (34.0mg, 37% yield). LC-MS (ESI): r_T＝4.061min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass of 538.1, M/z found value 538.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝7.052min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.2Hz,0.8H),9.11(s,0.2H),8.00-7.98(m,1.6H),7.92(d,J＝3.2Hz,0.4H),7.42(dd,J＝8.8,2.8Hz,1H),7.39-7.32(m,1H),7.24-7.19(dd,J＝8.8,2.8Hz,1H),6.02(s,0.2H),5.93(d,J＝3.6Hz,0.8H),4.01-3.96(m,0.1H),3.81-3.69(m,2.9H),3.53(s,2.4H),3.52(s,0.6H),2.90(q,J＝12.0Hz,2H),2.68-2.59(m,1H),2.12-1.98(m,1H),1.93-1.76(m,2H),1.63(d,J＝11.6Hz,1H),1.06-1.00(m,2H),0.99-0.92(m,2H)。

Compound 108: methyl-4- (2-chloro-4-fluorophenyl) -6- (1- (1- (methoxycarbonyl) cyclopropane-1-carbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

The method N comprises the following steps: to a solution of 1- (methoxycarbonyl) cyclopropanecarboxylic acid (55mg, 0.38mmol) in N, N-dimethylformamide (6mL) were added N, N-diisopropylethylamine (123mg, 0.957mmol) and 2- (3H- [1,2, 3mmol)]Triazolo [4,5-b]Pyridin-3-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (V) (145mg, 0.383 mmol). After stirring at room temperature for 30 minutes, methyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate hydrochloride compound 99(150mg, 0.319mmol) was added to the mixture and stirring was continued at room temperature for 2 hours. It was then poured into water (40mL) and extracted twice with ethyl acetate (40 mL). The combined organic layers were washed twice with water (40mL), twice with brine (40mL), concentrated and purified by preparative HPLC (column: Gilson X-bridge C18(5 μm 19X 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 20mL/min, gradient: 25% -80% (% B)) to give the title compound as a yellow solid (105mg, 59% yield, 100% ee). LC-MS (ESI): r_T＝3.831min，C₂₆H₂₆ClFN₄O₅Calculated mass of S560.1, M/z found value 560.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH ═ 70:30, at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝23.052min)。¹H NMR(400MHz,DMSO-d₆)δ9.48(d,J＝3.2Hz,0.7H),9.03(s,0.2H),8.94(s,0.1H),8.00-7.98(m,1.8H),7.92(d,J＝2.8Hz,0.2H),7.43-7.31(m,2H),7.23-7.17(m,1H),6.02(s,0.3H),5.92(d,J＝3.6Hz,0.7H),4.58-4.46(m,1H),4.10-3.82(m,2H),3.72-3.70(m,3H),3.54(s,3H),3.14-3.05(m,1H),2.70-2.61(m,1H),2.01-1.56(m,4H),1.43-1.27(m,4H)。

Similarly using a similar procedure (method M or method N), the product can be prepared as shown below:

compound 101: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (ethylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.991min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass of 526.1, found value of M/z 526.9[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝7.516min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.6Hz,0.8H),9.14(s,0.2H),8.00(s,1.8H),7.93(d,J＝2.8Hz,0.2H),7.42(dd,J＝9.2,2.8Hz,1H),7.38-7.34(m,1H),7.23-7.18(m,1H),6.02(s,0.2H),5.92(d,J＝3.6Hz,0.8H),4.01-3.90(m,0.2H),3.79-3.69(m,2.8H),3.53(s,3H),3.08(q,J＝7.2Hz,2H),2.94-2.80(m,2H),2.10-1.95(m,1H),1.91-1.75(m,2H),1.65-1.60(m,1H),1.25(t,J＝7.2Hz,3H)。

Compound 102: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (cyclopropanecarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.851min，C₂₄H₂₄ClFN₄O₃Calculated mass of S502.1, found value of M/z 502.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 80:20 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝15.920min)。¹H NMR(400MHz,DMSO-d₆)δ9.48(d,J＝3.6Hz,0.7H),9.23-9.16(m,0.3H),7.98(dd,J＝6.4,3.2Hz,1.7H),7.91(d,J＝3.2Hz,0.3H),7.43-7.40(m,1H),7.38-7.31(m,1H),7.20(dd,J＝8.8,2.8Hz,1H),6.02(s,0.3H),5.92(d,J＝3.6Hz,0.7H),4.61-4.33(m,2H),4.18-4.07(m,0.3H),3.92-3.84(m,0.7H),3.54(s,2.1H),3.53(s,0.9H),3.20-3.08(m,1H),2.59-2.54(m,1H),2.06-1.93(m,1.2H),1.49-1.23(m,3.8H),0.81-0.69(m,4H)。

Compound 103: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (methylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝4.495min，C₂₁H₂₂ClFN₄O₄S₂Calculated mass of 512.1, M/z found value 512.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 1 ℃; temperature: C; temperature: temperature_T＝10.842min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝4.0Hz,0.8H),9.14(s,0.2H),8.00-7.98(m,1.5H),7.93-7.92(m,0.5H),7.43-7.40(m,1H),7.39-7.32(m,1H),7.23-7.19(m,1H),6.02(s,0.2H),5.93(d,J＝4.0Hz,0.8H),4.00-3.91(m,0.2H),3.74-3.64(m,2.8H),3.53-3.52(m,3H),2.91-2.90(m,3H),2.82-2.73(m,2H),2.15-1.80(m,3.2H),1.67-1.64(m,0.8H)。

Compound 104: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3-methoxy-3-oxopropyl) -sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝4.371min，C₂₄H₂₆ClFN₄O₆S₂Calculated mass 584.1, M/z found value 585.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝4.0Hz,0.8H),9.14(s,0.2H),8.00-7.89(m,2H),7.42(dd,J＝8.8,2.8Hz,1H),7.38-7.32(m,1H),7.24-7.19(m,1H),6.02(s,0.2H),5.92(d,J＝3.6Hz,0.8H),3.83-3.70(m,2.4H),3.66(s,3H),3.63-3.61(m,0.6H),3.54(s,2.4H),3.53(s,0.6H),3.34(t,J＝3.2Hz,2H),2.94-2.85(m,2H),2.76(t,J＝3.2Hz,2H),2.02-1.93(m,1H),1.89-1.75(m,2H),1.64-1.61(m,1H)。

Compound 106: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((2-methoxy-2-oxoethyl) sulfonyl) -piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.985min，C₂₃H₂₄ClFN₄O₆S₂Calculated mass of 570.1, found M/z value of 570.9[ M + H [ ]]⁺. Chiral HPLC (Chiralpak IA5 μm4.6 × 250mm, mobile phase: Hex: EtOH ═ 70:30, at 1.0mL/min, temperature: 30 ℃, wavelength: 230nm, R_T＝12.627min)；¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝2.4Hz,0.8H),9.17(s,0.2H),8.05-7.96(m,1.8H),7.92(d,J＝2.8Hz,0.2H),7.46-7.41(m,1H),7.38-7.31(m,1H),7.26-7.16(m,1H),6.02(s,0.2H),5.92(d,J＝2.8Hz,0.8H),4.30(s,2H),4.00-3.91(m,0.2H),3.83-3.68(m,5.8H),3.53(s,3H),2.99-2.83(m,2H),2.06-1.93(m,1H),1.91-1.75(m,2H),1.65(d,J＝11.2Hz,1H)。

Compound 110: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (oxetan-3-ylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 110(330mg, 0.595mmol) was further separated by chiral preparative HPLC (column: chiralpak ia5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.3 at 8.0 mL/min; temperature: 30 ℃ c; wavelength: 214nm) to give the stereoisomer compound 110A (110mg, 33% yield) and compound 110B (105mg, 32% yield).

Compound 110B: LC-MS (ESI): r_T＝2.890min，C₂₃H₂₄ClFN₄O₅S₂Calculated mass of554.1, M/z found a value of 554.9[ M + H]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R-_T＝9.357min)。¹H NMR(400MHz,DMSO-d₆)δ9.56(s,0.8H),9.18(s,0.2H),8.03-7.99(m,1.8H),7.93(d,J＝2.8Hz,0.2H),7.43(dd,J＝8.8,2.4Hz,1H),7.38-7.34(m,1H),7.23-7.18(m,1H),6.01(s,0.2H),5.92(s,0.8H),4.89-4.86(m,2H),4.83-4.79(m,1H),4.76(t,J＝5.2Hz,2H),3.72(t,J＝11.6Hz,3H),3.52-3.51(m,3H),2.88-2.79(m,2H),1.95-1.89(m,1H),1.80-1.75(m,2H),1.62-1.59(m,1H)。

Compound 122: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (2-hydroxyacetyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 122(340mg, 0.690mmol) was further separated by chiral preparative HPLC (column: chiralpak ia5 μm20 × 250 mm; mobile phase: Hex: IPA: DEA ═ 50:50:0.3 at 8 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the stereoisomer compound 122A (93.9mg, 28% yield) and compound 122B (88.4mg, 26% yield).

Compound 122B: LC-MS (ESI): r_T＝3.385min，C₂₂H₂₂ClFN₄O₄Calculated mass of S492.1, M/z found value 492.9[ M + H]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R-_T＝9.523min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.6Hz,0.7H),9.30(s,0.2H),9.19(s,0.1H),8.00-7.97(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.42(dd,J＝8.4,2.4Hz,1H),7.37-7.33(m,1H),7.23-7.19(m,1H),6.01(s,0.3H),5.92(d,J＝3.6Hz,0.7H),4.53-4.50(m,2H),4.19-4.06(m,2.3H),3.87-3.75(m,1.7H),3.53(s,2.1H),3.52(s,0.9H),3.03-2.97(m,1H),2.71-2.61(m,1H),1.87-1.59(m,4H)。

Compound 129: 6- [1- (2-tert-Butoxycarbonylamino-acetyl) -piperidin-4-yl ] -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester

LC-MS(ESI)：R_T＝4.362min，C₂₇H₃₁ClFN₅O₅Calculated mass of S591.2, M/z found value 592.0[ M + H]⁺. Chiral HPLC (column: Chiralpak IA5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝9.371min)。¹H NMR(400MHz,DMSO-d₆)δ9.47(d,J＝2.8Hz,0.7H),9.15-9.12(m,0.3H),7.98(d,J＝4.4Hz,1.7H),7.92(s,0.3H),7.41(dd,J＝8.8,2.4Hz,1H),7.37-7.31(m,1H),7.22-7.18(m,1H),6.76-6.64(m,1H),6.01(s,0.3H),5.93(d,J＝3.6Hz,0.7H),4.64-4.42(m,1H),4.14-4.05(m,0.2H),3.99-3.75(m,3.8H),3.53(s,3H),3.12-2.98(m,1H),2.67-2.56(m,1H),2.00-1.64(m,3.2H),1.61-1.50(m,0.8H),1.40(s,9H)。

Compound 112: methyl 4- (2-chloro-3-fluorophenyl) -6- (1- (methylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 112(90mg, 0.18mmol) was further separated by chiral preparative HPLC (column: Chiralpak IF5 μm20 × 250 mm; mobile phase: Hex: IPA ═ 60:40 at 10 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the stereoisomer compound 112A (24.4mg, 27% yield) and compound 112B (20.6mg, 23% yield) as yellow solids.

Compound 112B: LC-MS (ESI): r_T＝2.384min，C₂₁H₂₂ClFN₄O₄S₂Calculated mass of 512.1, M/z found value 512.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IF5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝10.487min)。¹H NMR(400MHz,DMSO-d₆)δ9.60(d,J＝3.6Hz,0.8H),9.20(s,0.2H),8.02-7.99(m,1.8H),7.93(d,J＝2.8Hz,0.2H),7.41-7.31(m,2H),7.23-7.17(m,1H),6.08(s,0.2H),5.98(d,J＝3.6Hz,0.8H),4.01-3.92(m,0.2H),3.75-3.63(m,2.8H),3.53(s,3H),2.90(d,J＝6.0Hz,3H),2.82-2.73(m,2H),2.17-1.97(m,1H),1.94-1.86(m,1H),1.81(d,J＝12.8Hz,1H),1.66(d,J＝14.8Hz,1H)。

Compound 113: 4- (2-chloro-3-fluoro-phenyl) -6- [1- (2-methoxycarbonyl-ethanesulfonyl) -piperidin-4-yl ] -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (mixture of 2 stereoisomers)

Compound 113(380mg, 0.650mmol) was further separated by chiral preparative HPLC (column: chiralpak ie5 μm4.6 × 250 mm; mobile phase: MeOH: EtOH: DEA ═ 50:50:0.2:, at 10 mL/min; temperature: 30 ℃ c; wavelength: 254nm) to give the stereoisomer compound 113P (170mg, 44% yield) and compound 113Y (180mg, 47% yield) as yellow solids.

Compound 113Y: LC-MS (ESI): r_T＝4.081min，C₂₄H₂₆ClFN₄O₆S₂Calculated mass 584.1, M/z found value 585.1[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: MeOH: EtOH: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 0 ℃; chiral HPLC (column: Chiralpak IE 5 μm 4.6: 0.2; mobile phase: 1.0 mL/min; chiral HPLC; temperature: 30 ℃; wavelength: 230_T＝8.353min)。¹H NMR(400MHz,CDCl₃)δ8.18(br s,0.3H),7.83(t,J＝3.2Hz,1H),7.52(d,J＝3.2Hz,0.7H),7.45(d,J＝3.2Hz,1H),7.23-7.02(m,3H),6.25(s,0.3H),6.12(d,J＝2.8Hz,0.7H),4.22-3.90(m,3H),3.76(s,3H),3.60(s,2.1H),3.59(s,0.9H),3.29(t,J＝7.6Hz,2H),3.00-2.84(m,4H),2.27-1.71(m,4H)。

Compound 118: 3- ((4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) benzoic acid

LC-MS(ESI)：R_T＝4.112min，C₂₇H₂₄ClFN₄O₆S₂Calculated mass of 618.1, M/z found value 618.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: IPA: TFA: 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; and_T＝10.487min)。¹H NMR(400MHz,CD₃OD)δ8.41(s,1H),8.33(d,J＝7.6Hz,1H),8.05(d,J＝7.6Hz,1H),7.92(d,J＝2.8Hz,1H),7.79-7.75(m,2H),7.30-7.25(m,1H),7.19-7.13(m,2H),6.11(s,1H),4.00-3.92(m,2H),3.80-3.69(m,1H),3.52(s,3H),2.47(q,J＝12.0Hz,2H),2.17-1.95(m,2H),1.90(d,J＝12.8Hz,1H),1.74(d,J＝12.8Hz,1H)。

compound 115: 4- (2-chloro-3-fluoro-phenyl) -6- (1-methylsulfamoyl-piperidin-4-yl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (mixture of 2 stereoisomers)

Compound 115(150mg, 0.280mmol) was further separated by chiral preparative HPLC (column: chiralpak ie 5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 70:30 at 12 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomer compound 115A (34.3mg, 23% yield) and compound 115B (20.6mg, 23% yield) as yellow solids.

Compound 115B: LC-MS (ESI): r_T＝3.935min，C₂₁H₂₃ClFN₅O₄S₂Calculated mass of 527.1, M/z found value 527.9[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝13.838min)。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝3.2Hz,0.8H),9.09(s,0.2H),8.00-7.99(m,1.8H),7.93(d,J＝2.8Hz,0.2H),7.40-7.29(m,2H),7.22-7.05(m,2H),6.07(s,0.2H),5.97(d,J＝3.6Hz,0.8H),3.96-3.90(m,0.2H),3.72-3.60(m,2.8H),3.53(s,2.4H),3.52(s,0.6H),2.77-2.67(m,2H),2.57(d,J＝4.8Hz,3H),2.10-1.76(m,3H),1.62(d,J＝10.8Hz,1H)。

Compound 120: methyl 4- (2-bromo-4-fluorophenyl) -6- (1- (methylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 120(193mg, 0.350mmol) was further separated by chiral preparative HPLC (column: chiralpakff 5 μm20 × 250 mm; mobile phase: Hex: IPA ═ 60:40 at 10 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the stereoisomers compound 120A (65mg, 34% yield) and compound 120B (64mg, 33% yield).

Compound 120A: LC-MS (ESI): r_T＝2.589min，C₂₁H₂₂BrFN₄O₄S₂Calculated mass of 556.0, M/z found value 556.8[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IF 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝8.568min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(s,0.8H),9.16(s,0.2H),8.00(s,2H),7.56(dd,J＝8.4,2.4Hz,1H),7.39-7.35(m,1H),7.28-7.23(m,1H),5.99(s,0.2H),5.91(s,0.8H),3.71-3.64(m,3H),3.53(s,3H),2.90(s,3H),2.78(q,J＝12.0Hz,2H),2.16-1.97(m,1H),1.94-1.79(m,2H),1.67-1.63(m,1H)。

Compound 120B: LC-MS (ESI): r_T＝2.539min，C₂₁H₂₂BrFN₄O₄S₂Calculated mass of 556.0, M/z found value 556.8[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IF 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝10.530min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.6Hz,0.8H),9.16(s,0.2H),8.01-7.98(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.59-7.55(m,1H),7.37(dd,J＝8.8,7.0Hz,0.7H),7.34-7.22(m,1.3H),5.99(s,0.2H),5.90(d,J＝3.6Hz,0.8H),4.00-3.91(m,0.2H),3.76-3.63(m,2.8H),3.53(s,2.4H),3.52(s,0.6H),2.91(s,1H),2.90(s,2H),2.82-2.72(m,2H),2.09-1.97(m,1H),1.95-1.78(m,2H),1.67-1.64(d,J＝13.6Hz,1H)。

Compound 124: 4- (4-chloro-3-fluoro-phenyl) -6- (1-methanesulfonyl-piperidin-4-yl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (mixture of 2 stereoisomers)

Compound 124(150mg, 0.514mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 12 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomer compound 124A (36.5mg, 24% yield) and compound 124B (35.3mg, 24% yield) as yellow solids.

Compound 124B: LC-MS (ESI): r_T＝4.261min，C₂₁H₂₂ClFN₄O₄S₂Calculated mass of 512.1, M/z found value 512.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; temperature: R-_T＝10.524min)。¹H NMR(400MHz,DMSO-d₆)δ9.78(d,J＝3.2Hz,1H),8.03(d,J＝3.2Hz,2H),7.58(t,J＝8.0Hz,1H),7.24(d,J＝8.4Hz,1H),7.14(dd,J＝8.0,1.6Hz,1H),5.50(s,1H),3.77-3.63(m,3H),3.59(s,3H),2.90(s,3H),2.76(q,J＝12.4Hz,2H),2.06-1.94(m,1H),1.87-1.77(m,2H),1.65(d,J＝12.0Hz,1H)。

Compound 126: methyl 4- (2-chloro-4-fluorophenyl) -6- (trans-4- (methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 126(280mg, 0.530mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IF 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 10 mL/min; temperature: 30 ℃ c; wavelength: 230nm) to give the stereoisomers compound 126A (26mg, 19% yield) and compound 126B (20mg, 14% yield).

Compound 126B: LC-MS (ESI): r_T＝3.529min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass 526.1, M/z found value 527.1[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IF 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; and_T＝10.664min)。¹H NMR(400MHz,DMSO-d₆)δ9.42(d,J＝3.2Hz,0.6H),8.97(s,0.4H),8.00-7.98(m,1.6H),7.93(d,J＝3.2Hz,0.4H),7.43-7.40(m,1H),7.36-7.30(m,1H),7.23-7.17(m,1H),7.09-7.04(m,1H),6.00(s,0.4H),5.90(d,J＝3.6Hz,0.6H),3.83-3.75(m,0.4H),3.58-3.54(m,0.6H),3.52(s,1.8H),3.50(s,1.2H),3.19-3.09(m,1H),2.94(s,1.8H),2.93(s,1.2H),2.04-1.97(m,2H),1.88-1.67(m,3H),1.62-1.53(m,1H),1.42-1.28(m,2H)。

compound 128: methyl 4- (2-chloro-4-fluorophenyl) -6- (cis-4- (methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 128(400mg, 0.800mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IF 5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 70:30 at 10 mL/min; temperature: 30 ℃; wavelength: 214nm) to give stereoisomer compound 128C (19mg, 10% yield) and compound 128D (37mg, 19% yield).

Compound 128D: LC-MS (ESI): r_T＝3.605min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass 526.1, M/z found value 527.1[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak AS-H5 μm4.6 x 250 mm; mobile phase: Hex: EtOH ═ 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R-_T＝8.617min)。¹H NMR(400MHz,DMSO-d₆)δ9.41(d,J＝4.0Hz,0.2H),9.13(s,0.8H),8.12-8.00(m,1.2H),7.94(d,J＝2.8Hz,0.8H),7.47(d,J＝9.6Hz,0.8H),7.43(dd,J＝8.4,2.8Hz,1H),7.32(dd,J＝8.4,6.0Hz,1H),7.21(td,J＝8.4,2.8Hz,1H),6.86(d,J＝4.4Hz,0.2H),6.01(s,0.8H),5.91(d,J＝4.0Hz,0.2H),3.96-3.84(m,1H),3.72-3.63(m,1H),3.52(s,0.6H),3.50(s,2.4H),2.98(s,2.4H),2.93(s,0.6H),2.11-1.80(m,4H),1.68-1.49(m,4H)。

Compound 33: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (methylsulfonyl) piperidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

Compound 33(210mg, 0.410mmol) was further purified by chiral preparative HPLC (first column: Chiralpak IE 5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 60:40 at 10 mL/min; temperature: 30 ℃; wavelength: 214nm and second column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 50:50 at 10 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomer compound 33A (17.0mg, 8% yield), compound 33B (22.7mg, 11% yield), compound 33C (23.4mg, 11% yield), and compound 33D (20.1mg, 10% yield) as a yellow solid.

Compound 33A: LC-MS (ESI): r_T＝4.383min，C₂₁H₂₂ClFN₄O₄S₂Calculated mass of 512.1, M/z found value 512.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝8.720min)。¹H NMR(400MHz,DMSO-d₆)δ9.55(d,J＝2.8Hz,0.8H),9.33(s,0.2H),8.01-7.98(m,1.5H),7.94-7.93(m,0.5H),7.44-7.41(m,1H),7.39-7.34(m,1H),7.25-7.21(m,1H),6.04(s,0.2H),5.94(d,J＝2.8Hz,0.8H),4.16-4.03(m,0.2H),3.81-3.74(m,0.8H),3.72-3.63(m,1.6H),3.54-3.52(m,3H),3.49-3.42(m,0.4H),3.06-3.03(m,1H),3.01-2.93(m,3H),2.75-2.67(m,1H),1.85-1.68(m,3H),1.64-1.54(m,1H)。

Compound 33C: LC-MS (ESI): r_T＝4.325min，C₂₁H₂₂ClFN₄O₄S₂Calculated mass of 512.1, M/z found value 512.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝9.380min)。¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝3.6Hz,0.8H),9.25(s,0.2H),8.00-7.96(m,1.5H),7.93-7.91(m,0.5H),7.43-7.41(m,1H),7.41-7.34(m,1H),7.24-7.19(m,1H),6.01(s,0.2H),5.93(d,J＝4.0Hz,0.8H),4.15-4.05(m,0.2H),3.84-3.77(m,0.8H),3.67-3.58(m,1H),3.54-3.51(m,4H),2.96-2.90(m,4H),2.74-2.66(m,1H),2.07-1.96(m,0.3H),1.89-1.85(m,2.7H),1.67-1.58(m,1H)。

Compound 36: methyl 4- (2-chloro-3-fluorophenyl) -6- (4-fluoro-1- (methylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

LC-MS(ESI)：R_T＝3.604min，C₂₁H₂₁ClF₂N₄O₄S₂Calculated mass of 530.1, M/z found value 530.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆) δ 9.29(d, J ═ 2.8Hz,1H),8.02-8.00(m,2H),7.45-7.35(m,2H),7.27-7.26(m,1H),6.08(s,0.1H),5.84(d, J ═ 3.2Hz,0.9H),3.59-3.55(m,2H),3.50(s,3H),2.96-2.89(m,5H),2.39-2.21(m,2H),2.09-1.90(m, 2H). Compound 36(150mg, 0.283mmol) was further separated by chiral preparative HPLC (column: Chiralpak IE 5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 50:50 at 9.0 mL/min; temperature: 30 ℃ c; wavelength: 230nm) to give the stereoisomers compound 36A (13.2mg, 9% yield) and compound 36B (19.6mg, 13% yield) as yellow solids.

Compound 46: methyl 4- (2-chloro-4-fluorophenyl) -6- (cis-3- (methoxycarbonyl) -1- (methylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

LC-MS(ESI)：R_T＝1.65min，C₂₃H₂₄ClFN₄O₆S₂Calculated mass of 570.1, M/z found value 571.5[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.64(s,1H),8.00(s,2H),7.43-7.37(m,2H),7.23(t,J＝9.2Hz,1H),5.96(s,1H),4.26-4.17(m,1H),4.02-3.97(m,1H),3.74-3.66(m,1H),3.50(s,3H),3.47(s,3H),3.46-3.40(m,1H),3.32-3.21(m,1H),3.12-3.00(m,1H),2.92(s,3H),2.17-2.08(m,1H),2.04-1.95(m,1H)。

Compound 54: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (methylsulfonyl) piperidin-4-yl) -2- (2,4, 6-trifluorophenyl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 54(250mg, 0.45mmol) was further separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 85:15, at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomer compound 54A (51.7mg, 21% yield) and compound 54B (51.9mg, 21% yield).

Compound 54A: LC-MS (ESI): r_T＝3.004min，C₂₄H₂₂ClF₄N₃O₄Calculated mass of S559.1M/z found value 559.9[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 85:15 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝12.463min)。¹H NMR(400MHz,DMSO-d₆)δ9.57(s,0.7H),9.44(d,J＝2.8Hz,0.3H),7.47-7.35(m,2H),7.28-7.20(m,3H),5.97(s,0.7H),5.87(d,J＝2.8Hz,0.3H),4.04-3.98(m,1H),3.74-3.63(m,2H),3.52(s,1H),3.51(s,2H),2.89(s,2H),2.86(s,1H),2.78-2.73(m,2H),2.01-1.95(m,1H),1.88-1.73(m,3H)。

Compound 59: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (methylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 59(90mg, 0.17mmol) was further separated by chiral preparative HPLC (column: Chiralpak IE 5 μm20 × 250mm, mobile phase: Hex: EtOH ═ 50:50, at 8 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomer compound 59A (31.5mg, 35% yield) and compound 59B (27.7mg, 31% yield) as yellow solids.

Compound 59B: LC-MS (ESI): RT-4.264 min, C₂₁H₂₁ClF₂N₄O₄S₂Calculated mass of 530.1, M/z found value 531.1[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝11.213min)。¹H NMR(400MHz,DMSO-d₆)δ9.68(d,J＝2.8Hz,0.8H),9.28(s,0.2H),8.03-8.00(m,1.8H),7.95(d,J＝2.8Hz,0.2H),7.50-7.43(m,1H),7.23-7.14(m,1H),6.02(s,0.2H),5.94(d,J＝3.2Hz,0.8H),4.00-3.93(m,0.2H),3.75-3.64(m,2.8H),3.53(s,3H),2.91(s,0.6H),2.90(s,2.4H),2.84-2.73(m,2H),2.21-2.11(m,0.2H),2.04-2.01(m,1H),1.96-1.79(m,2H),1.68-1.64(m,0.8H)。

Compound 68: methyl 4- (2-chloro-4-fluorophenyl) -6- (1-pivaloylpyrrolidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝4.126min，C₂₄H₂₆ClFN₄O₃Calculated mass of S504.1, M/z found 505.0[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH ═ 70:30, at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝7.737min)。¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝3.2Hz,0.9H),9.10(s,0.1H),8.00(s,1.8H),7.94(d,J＝9.2Hz,0.2H),7.44-7.36(m,2H),7.21(t,J＝11.2Hz,1H),6.04(s,0.1H),5.94(d,J＝5.2Hz,0.9H),4.25(br s,1H),4.03-3.60(m,3H),3.54(s,3H),2.27-1.90(m,2H),1.23-1.19(m,9H)。

Compound 84: 4- (2-chloro-4-fluoro-phenyl) -6- (1-methanesulfonyl-azetidin-3-yl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (mixture of 2 stereoisomers)

Compound 84(120mg, 0.248mmol) was further separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250mm, mobile phase: MeOH: EtOH ═ 50:50, at 10mL/min, temperature: 30 ℃, wavelength: 214nm) to give the stereoisomers compound 84A (35.5mg, 30% yield) and compound 84B (43.2mg, 36% yield) as yellow solids.

Compound 84A: LC-MS (ESI): r_T＝3.600min，C₁₉H₁₈ClFN₄O₄S₂Calculated mass of 484.0, M/z found value 484.9[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 × 250 mm; mobile phase: MeOH: EtOH ═ 50:50, at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝5.449min)。¹H NMR(400MHz,DMSO-d₆)δ9.73(d,J＝3.6Hz,1H),8.05-8.03(m,2H),7.43-7.40(m,2H),7.20(td,J＝8.4,2.4Hz,1H),5.94(d,J＝3.6Hz,1H),4.55-4.46(m,1H),4.26-4.21(m,2H),4.07(t,J＝8.4Hz,1H),3.99(t,J＝8.4Hz,1H),3.54(s,3H),3.08(s,3H)。

Compound 80: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (cyclobutylsulfonyl) azetidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝2.758min，C₂₂H₂₂ClFN₄O₄S₂Calculated mass of 524.1, M/z found value 524.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝8.206min)；¹H NMR(400MHz,DMSO-d₆)δ9.72(d,J＝2.8Hz,0.95H),9.21(s,0.05H),8.06(d J＝3.2Hz,0.95H),8.04(d J＝3.2Hz,0.95H),8.00(d,J＝3.2Hz,0.05H),7.95(d,J＝3.2Hz,0.05H),7.43-7.38(m,2H),7.23-7.18(m,1H),6.02(s,0.05H),5.94(d,J＝3.2Hz,0.95H),4.51-4.43(m,1H),4.26-4.14(m,3H),4.01(t,J＝8.0Hz,1H),3.94(t,J＝8.0Hz,1H),3.51(d,J＝6.8Hz,3H),2.40-2.27(m,4H),2.05-1.86(m,2H)。

Compound 81: 4- (2-chloro-4-fluoro-phenyl) -6- (1-ethylsulfamoyl-azetidin-3-yl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester

LC-MS(ESI)：R_T＝3.702min，C₂₀H₂₁ClFN₅O₄S₂Calculated mass 513.1, m/z found value 513.9[M+H]⁺. Chiral HPLC (column: Chiralpak IB5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 80:20 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝8.934min)。¹H NMR(400MHz,DMSO-d₆)δ9.71(d,J＝3.2Hz,0.9H),9.25(s,0.1H),8.04(dd,J＝8.0,3.2Hz,1.8H),7.98(dd,J＝11.2,3.2Hz,0.2H),7.44-7.38(m,2H),7.23-7.15(m,2H),6.03(s,0.1H),5.94(d,J＝3.6Hz,0.9H),4.32-4.24(m,1H),4.14-4.06(m,2H),3.92(t,J＝8.4Hz,1H),3.85(t,J＝8.4Hz,1H),3.52(d,J＝7.2Hz,3H),3.12-3.00(m,2H),1.13-1.06(m,3H)。

Compound 82: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (cyclohexylsulfonyl) azetidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝4.108min，C₂₄H₂₆ClFN₄O₄S₂Calculated mass of 552.1, M/z found value 552.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝7.760min)。¹H NMR(400MHz,DMSO-d₆)δ9.71(d,J＝3.2Hz,0.95H),9.25(s,0.05H),8.04(d,J＝3.2Hz,0.95H),8.02(d,J＝3.2Hz,0.95H),7.96(s,0.1H),7.43-7.38(m,2H),7.20(td,J＝10.8,2.4Hz,1H),6.03(s,0.05H),5.94(d,J＝3.2Hz,0.95H),4.47-4.39(m,1H),4.29-4.23(m,2H),4.03(t,J＝8.0Hz,1H),3.97(t,J＝8.0Hz,1H),3.53(s,3H),3.03(tt,J＝11.6,3.6Hz,1H),2.07(d,J＝11.6Hz,2H),1.77(d,J＝12.4Hz,2H),1.62(d,J＝12.8Hz,1H),1.44-1.24(m,4H),1.19-1.08(m,1H)。

Compound 130: 6- (1-benzenesulfonyl-azetidin-3-yl) -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (mixture of 2 stereoisomers)

Compound 130(80mg, 0.147mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak ID 5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 70:30, at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomers compound 130A (17.1mg, 21% yield) and compound 130B (17.3mg, 22% yield) as yellow solids.

Compound 130A: LC-MS (ESI): r_T＝4.231min，C₂₄H₂₀ClFN₄O₄S₂Calculated mass of 546.1, M/z found value 546.9[ M + H]⁺. Chiral HPLC (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝13.425min)；¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝3.6Hz,1H),8.04(d,J＝3.2Hz,1H),8.00(d,J＝3.2Hz,1H),,7.87-7.85(m,2H),7.73-7.69(m,1H),7.67-7.63(m,2H),7.38(dd,J＝8.8,2.0Hz,1H),7.19-7.13(m,2H),5.84(d,J＝3.2Hz,1H),4.21-4.08(m,2H),4.02(t,J＝8.0Hz,1H),3.93(t,J＝7.6Hz,2H),3.48(s,3H)。

Compound 89: trans-methyl 6- (3-acetamido cyclobutyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Compound 89(115mg, 0.249mmol) was further separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the stereoisomer compound 89R (39.6mg, 34% yield) and compound 89S (36.8mg, 32% yield) as yellow solids.

Compound 89R: LC-MS (ESI): r_T＝2.865min，C₂₁H₂₀ClFN₄O₃Calculated mass of S462.1, M/z found value 462.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral HPLC (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 85:15: 0.2; temperature: 30 ℃; wavelength: 230 nm; R_T＝9.512min)。¹H NMR(400MHz,DMSO-d₆)δ9.55(d,J＝3.6Hz,0.9H),8.78(s,0.1H),8.37(d,J＝6.4Hz,0.1H),8.17(d,J＝3.2Hz,0.9H),8.03-8.01(m,1.8H),7.96(s,0.2H),7.44-7.33(m,2H),7.21(td,J＝8.8,2.8Hz,1H),6.00(s,0.2H),5.91(d,J＝3.6Hz,0.8H),4.42-4.48(m,1H),4.33-4.26(m,1H),3.50(s,3H),2.67-2.59(m,1H),2.49-2.44(m,1H),2.29-2.12(m,2H),1.83(s,0.3H),1.80(s,2.7H)。

Compound 116: methyl 4- (2-chloro-3-fluorophenyl) -6- (1- (pyridin-2-ylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 116(140mg, 0.243mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μm20 × 250 mm; mobile phase: MeOH: EtOH: DEA ═ 50:50:0.2 at 8 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the stereoisomers compound 116A (34mg, 24% yield, 100% ee) and compound 116B (23mg, 16% yield, 100% ee) as yellow solids.

Compound 116B: LC-MS (ESI): r_T＝4.343min，C₂₅H₂₃ClFN₅O₄S₂Calculated mass of 575.1, M/z found value 575.9[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 1 ℃; temperature: C; temperature: temperature_T＝13.410min)。¹H NMR(400MHz,DMSO-d₆)δ9.59(d,J＝3.6Hz,0.8H),9.13(s,0.2H),8.84-8.81(m,1H),8.16-8.12(m,1H),8.04-8.00(m,2H),7.97-7.95(m,1H),7.76-7.73(m,1H),7.37-7.33(m,2H),7.19-7.13(m,1H),6.05(s,0.2H),5.95(d,J＝4.0Hz,0.8H),3.93-3.85(m,2H),3.66-3.59(m,1H),3.48(s,2.1H)3.47(s,0.9H),2.79-2.67(m,2H),2.00-1.90(m,1H),1.87-1.73(m,2H),1.61-1.57(m,1H)。

Compound 140: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of diastereomers)

To a solution of methyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 99(300mg, 0.648mmol) in dichloromethane (6mL) was added 2- (trimethylsilyl) ethyl 3- (chlorosulfonyl) -1-methylcyclobutanecarboxylate (293mg, 0.843mmol) and triethylamine (201mg, 1.99mmol) at room temperature. After stirring overnight at 40 ℃ under a nitrogen atmosphere, the reaction mixture was diluted with water (10mL) and extracted twice with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na₂SO_4(s)Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to give the titled compound as a yellow solidCompound 140A (160mg, 90% pure, 31% yield) and 140B (175mg, 90% pure, 34% yield).

Compound 140a (trans):¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝3.2Hz,0.8H),9.13(s,0.2H),7.99-7.90(m,2H),7.35-7.33(m,1H),7.28-7.21(m,1H),7.18-7.16(m,1H),5.99(s,0.2H),5.89(d,J＝3.2Hz,0.8H),4.16-4.12(m,2H),3.97-3.88(m,1H),3.76-3.65(m,3H),3.50(s,3H),2.89-2.72(m,4H),2.29-2.23(m,2H),1.94-1.85(m,1H),1.83-1.69(m,2H),1.63-1.55(m,1H),1.33(s,3H),0.99-0.92(m,2H),0.01(s,9H)。

compound 140b (cis):¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝3.6Hz,0.8H),9.12(s,0.2H),8.00-7.90(m,2H),7.41-7.38(m,1H),7.35-7.28(m,1H),7.20-7.14(m,1H),5.99(s,0.2H),5.89(d,J＝3.6Hz,0.8H),4.15-4.09(m,3H),3.74-3.63(m,3H),3.50(s,3H),2.88-2.79(m,2H),2.68-2.61(m,2H),2.19-2.13(m,2H),1.94-1.69(m,3H),1.65-1.55(m,1H),1.40(s,3H),0.95-0.91(m,2H),0.00(s,9H)。

compound 145: ethyl 6- (1- (((trans) -3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chlorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate: LC-MS (ESI): r_T＝3.573min，C₃₀H₃₇ClN₄O₆S₂Calculated mass of 648.2, M/z found value 649.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; chiral analysis (column: Chiralpak IA 5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA ═ 80:20: 0.2; temperature: 230 ℃; wavelength: 230_T＝8.109min)。

Compound 157A: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((3-methoxy-3-oxopropyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.05min，C₂₄H₂₅ClF₂N₄O₆S₂Calculated mass of 602.1, found value of M/z 603.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.65(d,J＝3.6Hz,0.8H),9.23(s,0.2H),8.02-7.99(m,1.8H),7.94(d,J＝3.2Hz,0.2H),7.47-7.42(m,1H),7.23-7.19(m,1H),6.02(s,0.2H),5.93(d,J＝3.6Hz,0.8H),3.76-3.69(m,3H),3.66(s,3H),3.53(s,3H),3.38-3.35(m,2H),2.93-2.88(m,2H),2.76(t,J＝7.2Hz,2H),2.02-1.96(m,1H),1.85-1.77(m,2H),1.65-1.62(m,1H)。

Compound 158A: methyl 6- (1- ((1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.074min，C₂₃H₂₂ClFN₆O₄S₂Calculated mass of 564.1, M/z found value 564.8[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ13.72(br s,1H),9.58(br s,0.8H),9.18(s,0.2H),8.12-7.93(m,4H),7.39-7.30(m,2H),7.20-7.19(m,1H),6.05(s,0.3H),5.96(s,0.7H),3.74-3.67(m,2.3H),3.55-3.48(m,3.7H),2.28-2.19(m,2H),2.09-2.00(m,1H),1.95-1.86(m,1H),1.80-1.78(m,1H),1.65-1.62(m,1H)。

Compound 161: (trans) -methyl 4- (2-bromo-3, 4-difluorophenyl) -6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 4- (2-bromo-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 160(230mg, 0.464mmol) in dichloromethane (10mL) was added triethylamine (141.0mg, 1.392mmol) and (trans) -tert-butyl 3- (chlorosulfonyl) cyclobutanecarboxylate (153mg, 0.603mmol) at 0 ℃. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 5:1 to 3:1) to give a small polar fraction which was further purified by preparative HPLC (column: gilson X-bright C18(5 μm 19: 150mm) mobile phase a: water (+ 0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 83% -98% (% B)) to give the title compound 161 as a yellow solid (190mg, 57% yield) and large polar fraction 161A as a yellow solid (100mg, 30% yield).

Compound 161, LC-ms (esi): r_T＝3.689min，C₂₉H₃₃BrF₂N₄O₆S₂Calculated mass 714.1, M/z found value 714.8[ M + H [ ]]⁺。

Compound 163: (trans) -Ethyl 6- (-4-carbamoylcyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝4.017min，C₂₃H₂₄ClFN₄O₃Calculated mass of S490.1, M/z found 491.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak OZ-H,5 μm4.6 × 150 mm; mobile phase: Hex: EtOH ═ 70:30, at 1 mL/min; temperature: 35 ℃; wavelength: 254 nm; R; (R); chiral chromatography;)_T＝5.648min)。¹H NMR(400MHz,DMSO-d₆)δ9.37(d,J＝3.6Hz,0.6H),8.83(s,0.4H),7.99-7.97(m,1.6H),7.94(d,J＝3.2Hz,0.4H),7.44-7.40(m,1H),7.37-7.33(m,1H),7.24-7.18(m,2H),6.72(br s,0.4H),6.67(br s,0.6H),6.02(s,0.4H),5.91(d,J＝3.6Hz,0.6H),4.01-3.94(m,2H),3.83-3.78(m,0.4H),3.64-3.55(m,0.6H),2.26-2.15(m,1H),1.91-1.81(m,4H),1.73-1.62(m,2H),1.50-1.36(m,2H),1.10-1.04(m,3H)。

Compound 164: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (morpholinosulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.058min，C₂₄H₂₇ClFN₅O₅S₂Calculated mass of 583.1, M/z found value 584.1[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ8.16(s,0.3H),7.84-7.82(m,1H),7.51(d,J＝3.2Hz,0.7H),7.46-7.45(m,0.3H),7.43(s,0.7H),7.29-7.27(m,0.8H),7.25-7.24(m,0.2H),7.16-7.11(m,1H),6.99-6.89(m,1H),6.19(s,0.3H),6.07(d,J＝2.8Hz,0.7H),4.21-4.13(m,0.3H),3.98-3.85(m,2.7H),3.78-3.75(m,4H),3.61-3.59(m,3H),3.30-3.24(m,4H),3.07-2.95(m,2H),2.25-2.15(m,1H),2.09-1.98(m,1H),1.96-1.78(m,1.4H),1.71-1.67(m,0.6H)。

Compound 165: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((1-methyl-1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.874min，C₂₄H₂₄ClFN₆O₄S₂Calculated mass of 578.1, M/z found value 578.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.3H),7.83(d,J＝3.2Hz,1H),7.75-7.73(m,2H),7.53(d,J＝2.8Hz,0.7H),7.46(d,J＝3.2Hz,0.3H),7.43(s,0.7H),7.28-7.27(m,0.3H),7.26-7.24(m,0.7H),7.15-7.11(m,1H),6.97-6.89(m,1H),6.17(s,0.3H),6.04(d,J＝2.8Hz,0.7H),3.99(s,3H),3.95-3.85(m,2H),3.77-3.69(m,1H),3.55(s,3H),2.44-2.26(m,3H),2.20-2.05(m,1H),2.00-1.87(m,1.4H),1.73-1.69(m,0.6H)。

Compound 166A: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((difluoromethyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Racemic compound 166(70mg, 0.124mmol) was separated by chiral preparative HPLC (column: Chiralpak IG5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 16 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 166B (25mg, 25% yield, 100% stereopurity) and 166A (22mg, 23% yield, 100% stereopurity) as yellow solids.

Compound 166A: LC-MS (ESI): r_T＝2.341min，C₂₁H₁₉ClF₄N₄O₄S₂Calculated mass of 566.1, M/z found value 567.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; temperature: 30 ℃; wavelength: 230 nm; and_T＝8.619min)。¹H NMR(400MHz,DMSO-d₆)δ9.65(s,0.8H),9.35(s,0.2H),8.01(s,1.7H),7.94-7.93(m,0.3H),7.45(q,J＝9.2Hz,1H),7.28-7.12(m,1.7H),7.02-6.99(m,0.3H),6.02(s,0.2H),5.93(s,0.8H),4.02-4.01(m,0.2H),3.91-3.78(m,2.8H),3.58-3.54(m,3H),3.21-3.12(m,2H),2.18-1.64(m,4H)。

compound 190: methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (methylsulfonylamino) -cycloheptyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.016min，C₂₃H₂₆ClFN₄O₄S₂Calculated mass of 540.1, M/z found value 541.0[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.06-8.02(br s,0.4H),7.85-7.81(m,1H),7.50-7.49(m,0.5H),7.46-7.44(m,0.5H),7.40(br s,0.6H),7.30-7.25(m,1H),7.15-7.11(m,1H),6.97-6.98(m,1H),6.17(s,0.4H),6.05-6.03(m,0.6H),4.44-4.25(m,1H),4.22-4.10(m,0.5H),4.03-3.97(m,0.5H),3.80-3.63(m,1H),3.62(s,1.5H),3.60(s,1.5H),3.01(s,1.5H),3.00(s,1.5H),2.28-1.65(m,10H)。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝3.2Hz,0.6H),7.88(d,J＝2.8Hz,0.4H),7.74(d,J＝2.8Hz,0.9H),7.68-7.58(m,0.1H),7.41-7.35(m,1H),7.24-7.20(m,1H),7.07-7.01(m,1H),6.12(d,J＝4.0Hz,0.6H),6.04(d,J＝2.4Hz,0.4H),4.21-4.05(m,0.5H),3.95-3.88(m,0.5H),3.69-3.62(m,0.4H),3.59(s,3H),3.55-3.44(m,0.6H),2.96-2.93(m,3H),2.37-1.44(m,10H)。

Compound 194A: (trans) -Ethyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) -piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (2,4, 6-trifluorophenyl) -1, 4-dihydropyrimidine-5-carboxylate

The reaction mixture was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate ═ 1:10) to give the title compounds 194X (400mg, 19% yield) and 194Y (600mg, 28% yield) as white solids. For 194X: LC-MS (ESI): r_T＝3.540min，C₃₃H₃₅ClF₅N₃O₆Calculated mass of S731.2, found value of M/z 732.3[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.55(s,0.8H),9.45(d,J＝3.2Hz,0.2H),7.57-7.45(m,1H),7.27-7.19(m,3H),5.98(s,0.8H),5.89(d,J＝3.2Hz,0.2H),4.08-3.89(m,4H),3.77-3.62(m,2H),3.08-2.97(m,1H),2.85-2.74(m,2H),2.47-2.42(m,4H),2.00-1.79(m,3H),1.74-1.67(m,1H),1.40(s,9H),1.06-1.03(m,3H)。

Compound 194X was further separated by chiral preparative HPLC (column: Chiralpak OD-H5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.3, at 15 mL/min; temperature: 30 ℃ c; wavelength: 214nm) to give the title compounds 194A (200mg, 33% yield) and 194B (100mg, 17% yield) as colorless solids.

Compound 198A and compound 198B: (trans) -Ethyl 4- (2-bromo-3, 4-difluorophenyl) -6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -Ethyl 4- (2-bromo-3, 4-difluorophenyl) -6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 198A: LC-MS: r_T＝4.589min，C₃₀H₃₅BrF₂N₄O₆S₂728.1, m/z found value: 729.0[ M + 1]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.60(s,0.7H),9.12(s,0.3H),8.00-7.92(m,2H),7.51-7.42(m,1H),7.24-7.14(m,1H),6.02(s,0.2H),5.95(s,0.8H),4.04-3.91(m,3H),3.80-3.67(m,3H),3.16-3.06(m,1H),2.93-2.83(m,2H),2.64-2.55(m,3H),2.04-1.72(m,4H),1.64-1.54(m,1H),1.43(s,9H),1.09-1.05(m,3H)。

Compound 198B: LC-MS: r_T＝4.413min，C₃₀H₃₅BrF₂N₄O₆S₂728.1, m/z found value: 729.0[ M + 1]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.58(s,0.8H),9.12(s,0.2H),8.00-7.93(m,2H),7.54-7.46(m,1H),7.27-7.14(m,1H),6.02(s,0.2H),5.93-5.90(m,0.8H),3.97-3.93(m,3H),3.76-3.65(m,3H),3.11-3.04(m,1H),2.90-2.74(m,2H),2.48-2.35(m,4H),2.01-1.77(m,3H),1.67-1.59(m,1H),1.41(s,9H),1.09-1.05(m,3H)。

Compound 200A: methyl 4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -6- (1- (thiazol-2-ylsulfonyl) piperidin-4-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝3.868min，C₂₃H₂₁ClFN₅O₄S₃Calculated mass of 581.0, found value of M/z 581.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝1.2Hz,0.8H),9.11(s,0.2H),8.25(d,J＝2.0Hz,1H),8.20(d,J＝2.8Hz,1H),8.01-7.95(m,2H),7.42-7.40(m,1H),7.33-7.32(m,1H),7.32-7.20(m,1H),6.00(s,0.2H),5.90(d,J＝3.2Hz,0.8H),3.94-3.87(m,2H),3.67-3.59(m,1H),3.49(s,3H),2.83-2.73(m,2H),1.99-1.87(m,1H),1.81-1.80(m,2H),1.65-1.61(m,1H)。

Compound 201A: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((1-methyl-1H-imidazol-4-yl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.453min，C₂₄H₂₄ClFN₆O₄S₂The calculated mass 578.1 of the mass of the beam,m/z found 578.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.6Hz,0.8H),9.00(s,0.2H),8.03-8.00(m,1.8H),7.94(d,J＝3.2Hz,0.2H),7.86-7.82(m,2H),7.44-7.39(m,1H),7.36-7.29(m,1H),7.23-7.16(m,1H),6.00(s,0.2H),5.90(d,J＝3.6Hz,0.8H),3.82-3.70(m,5H),3.57-3.49(m,1H),3.48(s,3H),2.63-2.55(m,2H),2.07-1.72(m,3H),1.61-1.57(m,1H)。

Compound 204A: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (3- (methyl-sulfonamido) bicyclo [1.1.1]Pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.326min，C₂₁H₁₉ClF₂N₄O₄S₂Calculated mass of 528.1M/z found value 529.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.89(s,0.7H),7.83(d,J＝3.2Hz,0.3H),7.82(d,J＝3.2Hz,0.7H),7.51(d,J＝2.8Hz,0.3H),7.46(d,J＝3.2Hz,0.7H),7.44(br s,0.3H),7.08-7.02(m,2H),6.15(s,0.7H),6.03(d,J＝2.4Hz,0.3H),5.14(br s,0.7H),5.03(br s,0.3H),3.63(s,0.9H),3.60(s,2.1H),3.05(s,0.9H),3.04(s,2.1H),2.61(s,4.2H),2.53(s,1.8H)。

Compound 206B: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (methylsulfonamido) cyclobutyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, (separation conditions: column: Chiralpak IE 5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 60:40 at 10 mL/min; temperature: 30 ℃; wavelength: 214nm), LC-ms (esi): r_T＝3.925min，C₂₀H₂₀ClFN₄O₄S₂Calculated mass of 498.1, M/z found value 498.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝11.912min)。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝3.2Hz,0.9H),8.90(s,0.1H),8.05-8.02(m,1.8H),7.96(d,J＝3.2Hz,0.2H),7.64-7.62(m,0.2H),7.47-7.35(m,2.8H),7.23-7.19(m,1H),6.00(s,0.1H),5.92(d,J＝3.6Hz,0.9H),4.45-4.40(m,0.1H),4.33-4.21(m,1.8H),4.03-3.98(m,0.1H),3.50(s,3H),2.91(s,0.2H),2.87(s,2.8H),2.67-2.61(m,1H),2.48-2.29(m,3H)。

Chemical combinationSubstance 206D: (cis) -methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (methylsulfonamido) cyclobutyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, (separation conditions: column: Chiralpak IA 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 11 mL/min; temperature: 30 ℃; wavelength: 214nm), LC-ms (esi): r_T＝3.312min，C₂₀H₂₀ClFN₄O₄S₂Calculated mass of 498.1, M/z found value 498.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30 ℃_T＝8.762min)。¹H NMR(400MHz,DMSO-d₆)9.54(br s,0.7H),8.83(br s,0.3H),8.04-8.02(m,1.6H),7.97-7.96(m,0.4H),7.53-7.51(m,0.4H),7.46-7.41(m,1.6H),7.33-7.28(m,1H),7.23-7.18(m,1H),5.99(s,0.3H),5.90(d,J＝2.0Hz,0.7H),4.20-4.10(m,0.3H),3.91-3.83(m,0.7H),3.80-3.68(m,1H),3.52(s,2H),3.51(s,1H),2.92(s,1H),2.88(s,2H),2.71-2.68(m,0.4H),2.59-2.58(m,0.6H),2.43-2.33(m,2H),2.28-2.18(m,1H)。

Compound 208B: 3- (N- (3- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) bicyclo [1.1.1]Penta-1-yl) sulfamoyl) benzoic acid, LC-ms (esi): r_T＝4.457min，C₂₇H₂₂ClFN₄O₆S₂Calculated mass of 616.1, M/z found value 616.8[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.38(d,J＝2.8Hz,0.5H),8.98(s,0.5H),8.82(s,0.5H),8.40(s,1H),8.26(s,0.5H),8.21-8.18(m,1H),8.07-8.06(m,1H),7.98-7.92(m,2H),7.78-7.74(m,1H),7.42-7.37(m,1H),7.28-7.23(m,1H),7.20-7.14(m,1H),5.91(s,0.5H),5.81(d,J＝3.2Hz,0.5H),3.48(s,1.5H),3.46(s,1.5H),2.21(s,3H),2.03(s,3H)。

Compounds 209A and 209B: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((4-methyl-4- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclohexyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((4-methyl-4- ((2- (trimethylsilyl) ethoxy) carbonyl) -cyclohexyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester

To a solution of methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 58(300mg, 85% purity, 0.563mmol) in dichloromethane (10mL) was added triethylamine (800mg, 7.906mmol) and 2- (trimethylsilyl) ethyl 4- (chlorosulfonyl) -1-methylcyclohexanecarboxylate (400mg, 90% purity, 1.06mmol, part IV) at 0 ℃. After stirring at 25 ℃ overnight, the mixture was concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 4:1) and preparative thin layer chromatography (petroleum ether: ethyl acetate ═ 4:1) to give 209A (160mg, purity 60%, 23% yield) and 209B (70mg, purity 80%, 13% yield) as yellow solids.

Compound 209A:¹H NMR(400MHz,CDCl₃)δ8.17-8.15(m,0.3H),7.81-7.77(m,1H),7.50-7.48(m,0.7H),7.43-7.41(m,0.4H),7.39-7.35(m,0.6H),7.06-6.93(m,2H),6.16(s,0.4H),6.02(m,0.6H),4.19-4.10(m,2H),4.05-3.72(m,3H),3.58-3.56(m,3H),3.07-2.67(m,3H),2.39-2.13(m,2H),2.09-1.83(m,5H),1.75-1.48(m,5H),1.23-1.20(m,3H),1.00-0.88(m,2H),0.01(s,9H)。

compound 209B:¹H NMR(400MHz,CDCl₃)δ8.14(s,0.4H),7.80-7.77(m,1H),7.50-7.47(m,0.6H),7.42-7.40(m,0.4H),7.37-7.34(m,0.6H),7.02-6.95(m,2H),6.13(s,0.4H),6.00(s,0.6H),4.20-4.11(m,2H),4.03-3.81(m,3H),3.55-3.53(m,3H),3.18-2.80(m,3H),2.36-2.15(m,2H),2.11-1.84(m,4H),1.82-1.55(m,4H),1.19-1.15(m,2H),1.12-1.01(m,3H),0.98-0.91(m,2H),0.01(s,9H)。

compound 213: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((2-methoxy-2-oxoethyl) sulfonyl) pyrrolidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,¹H NMR(400MHz,DMSO-d₆)δ9.68(s,0.9H),9.41-9.37(m,0.1H),8.04-7.98(m,1.8H),7.95-7.93(m,0.2H),7.45-7.43(m,1H),7.40-7.35(m,1H),7.24-7.19(m,1H),6.02(s,0.1H),5.93(s,0.9H),4.48-4.34(m,3H),3.72(s,1.2H),3.71(s,1.8H),3.67-3.56(m,2H),3.54(s,3H),3.51-3.38(m,2H),2.33-2.12(m,1.6H),2.06-1.98(m,0.4H)。

213 of the racemic mixture (400mg, 0.720mmol) was separated by chiral preparative HPLC (first separation conditions: column: Chiralpak IB5 μ M20 × 250 mm; mobile phase: Hex: EtOH ═ 85:15, at 8 mL/min; temperature: 30 ℃; wavelength: 214 nm; second separation conditions: column: ChiralpakID 5 μ M20 mm; mobile phase: Hex: IPA: DEA 98:2:0.2, at 15 mL/min; temperature: 30 ℃; wavelength: 214 nm; column: ChiralpakIF 5 μ M20 × 250 mm; mobile phase: Hex: EtOH ═ 50:50, at 8 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 213X as a yellow solid (40mg, 10% yield, 100% stereopurity), 213Y (45mg, 11% yield), 213% stereopurity (13.7 mg, 13% stereopurity, 13.7 mg, 13% stereopurity).

Compound 213X: LC-MS (ESI): r_T＝3.558min，C₂₂H₂₂ClFN₄O₆S₂Calculated mass of 556.1, found value of M/z 557.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: IPA: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝13.460min)。¹H NMR(400MHz,DMSO-d₆)δ9.65(d,J＝3.2Hz,0.9H),9.37(s,0.1H),8.04-8.01(m,1.8H),7.99(d,J＝3.2Hz,0.1H),7.94(d,J＝2.4Hz,0.1H),7.45-7.42(m,1H),7.40-7.36(m,1H),7.23-7.19(m,1H),6.02(s,0.1H),5.94(d,J＝3.6Hz,0.9H),4.47-4.34(m,3H),3.73(s,3H),3.72-3.65(m,1H),3.63-3.56(m,2H),3.54(s,3H),3.45-3.38(m,1H),2.25-2.16(m,1H),2.06-1.98(m,1H)。

Compound 213M: LC-MS (ESI): r_T＝3.541min，C₂₂H₂₂ClFN₄O₆S₂Calculated mass of 556.1, found value of M/z 557.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IF 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝10.289min)。¹H NMR(400MHz,DMSO-d₆)δ9.68(d,J＝3.2Hz,0.9H),9.40(s,0.1H),8.04-8.02(m,1.8H),7.99(d,J＝2.8Hz,0.1H),7.93(d,J＝2.8Hz,0.1H),7.45-7.42(m,1H),7.39-7.36(m,1H),7.25-7.20(m,1H),6.02(s,0.1H),5.94(d,J＝2.8Hz,0.9H),4.46-4.36(m,3H),3.73(s,3H),3.71-3.58(m,1.4H),3.55(s,3H),3.53-3.49(m,0.6H),3.47-3.40(m,2H),2.33-2.26(m,1H),2.20-2.13(m,1H)。

Compound 215: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((2-methoxyethyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.794min，C₂₃H₂₆ClFN₄O₅S₂Calculated mass of 556.1, M/z found value 556.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.3H),7.83(d,J＝2.8Hz,1H),7.53(d,J＝3.2Hz,0.7H),7.46-7.44(m,1H),7.30-7.28(m,0.8H),7.26(brs,0.2H),7.16-7.12(m,1H),6.99-6.89(m,1H),6.19(s,0.3H),6.07(d,J＝2.4Hz,0.7H),4.20-4.14(m,0.3H),4.00-3.88(m,2.7H),3.83-3.76(m,2H),3.60(s,2H),3.59(s,1H),3.41(s,2H),3.40(s,1H),3.25-3.22(m,2H),3.00-2.88(m,2H),2.31-2.21(m,0.7H),2.13-2.03(m,1H),1.98-1.70(m,2.3H)。

Compound 216: methyl 4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -6- (1- ((2,2, 2-trifluoroethyl) sulfonyl) piperidin-4-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.603min，C₂₂H₂₁ClF₄N₄O₄S₂Calculated mass of 580.1, M/z found to be 581.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.55(s,0.7H),9.24(s,0.3H),8.01-7.93(m,2H),7.44-7.35(m,2H),7.23-7.19(m,1H),6.02-5.93(m,1H),4.56-4.49(m,2H),3.96(br s,0.2H),3.79-3.73(m,2.8H),3.53(s,3H),2.97-2.88(m,2H),2.10-1.81(m,3.2H),1.68-1.65(m,0.8H)。

Compound 222: methyl 6- (1- ((3- (tert-butoxy) -2, 2-dimethyl-3-oxopropyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.790min，C₂₉H₃₆ClFN₄O₆S₂Calculated mass of 654.2, found value of M/z 655.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.16(s,0.3H),7.83-7.81(m,1H),7.52(d,J＝3.2Hz,0.7H),7.44(d,J＝3.2Hz,0.3H),7.42(s,0.7H),7.29-7.28(m,1H),7.16-7.12(m,1H),7.00-6.89(m,1H),6.19(s,0.3H),6.07(d,J＝2.8Hz,0.7H),4.18-4.11(m,0.3H),4.03-3.85(m,2.7H),3.60(s,2H),3.59(s,1H),3.19(s,1.3H),3.18(s,0.7H),2.90-2.79(m,2H),2.32-2.20(m,0.7H),2.16-2.02(m,1H),2.00-1.80(m,1.6H),1.73-1.70(m,0.7H),1.49(s,9H),1.40(s,4H),1.38(s,2H)。

Compounds 231X and 231Y: (trans) -methyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -methyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Intermediate 231X (trans, mixture of enantiomers): LC-MS (ESI): r_T＝3.685min，C₂₉H₃₃ClF₂N₄O₆S₂Calculated mass of 670.2, M/z found value 671.2[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.63(d,J＝3.2Hz,0.8H),9.19(s,0.2H),8.02-7.99(m,1.8H),7.93(d,J＝2.8Hz,0.2H),7.46-7.42(m,1H),7.22-7.18(m,1H),6.02(s,0.2H),5.93(d,J＝3.6Hz,0.8H),4.02-3.97(m,1H),3.76-3.70(m,3H),3.53(s,3H),3.15-3.08(m,1H),2.92-2.83(m,2H),2.57-2.53(m,4H),1.96-1.90(m,1H),1.85-1.73(m,2H),1.62-1.58(m,1H),1.42(s,9H)。

Intermediate 231Y (cis, mixture of enantiomers): LC-MS (ESI): r_T＝3.653min，C₂₉H₃₃ClF₂N₄O₆S₂Calculated mass of 670.2, M/z found value 670.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.63(d,J＝3.6Hz,0.8H),9.20(s,0.2H),8.01-7.99(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.46-7.42(m,1H),7.23-7.19(m,1H),6.02(s,0.2H),5.93(d,J＝3.6Hz,0.8H),3.97-3.93(m,1H),3.75-3.67(m,3H),3.53(s,3H),3.18-3.06(m,1H),2.88-2.80(m,2H),2.46-2.40(m,4H),1.97-1.93(m,1H),1.83-1.74(m,2H),1.62-1.59(m,1H),1.41(s,9H)。

A racemic mixture of (trans) -methyl 6- (1- ((3- (tert-butoxycarbonyl) -cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 231X (280mg, 0.420mmol) was subjected to chiral preparative HPLC (separation conditions: column: Chiralpak IE 5 μm20 250 mm; mobile phase: Hex: EtOH ═ 60:40 at 10 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 231A (80mg, 29% yield, 100% stereopurity) and 231B (100mg, 36% yield, 100% stereopurity) as yellow solids.

Compound 231A: LC-MS (ESI): r_T＝1.93min，C₂₉H₃₃ClF₂N₄O₆S₂Calculated mass of 670.2, M/z found value 671.4[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝9.730min)。¹H NMR(400MHz,CDCl₃)δ8.19(s,0.3H),7.83(d,J＝3.6Hz,1H),7.53(d,J＝2.8Hz,0.6H),7.46(d,J＝3.2Hz,0.4H),7.42(m,0.7H),7.08-7.03(m,2H),6.18(s,0.3H),6.06(d,J＝2.4Hz,0.7H),4.16-3.99(m,0.4H),3.97-3.87(m,3.6H),3.60(s,2H),3.59(s,1H),3.20-3.14(m,1H),2.95-2.90(m,2H),2.82-2.74(m,2H),2.62-2.55(m,2H),2.22-2.14(m,0.6H),2.05-1.92(m,1.1H),1.90-1.66(m,1.3H),1.63-1.58(m,1H),1.47(s,9H)。

Compound 231B: LC-MS (ESI): r_T＝1.93min，C₂₉H₃₃ClF₂N₄O₆S₂Calculated mass of 670.2, M/z found value 671.4[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝12.613min)。¹H NMR(400MHz,CDCl₃)δ8.19(s,0.3H),7.83(d,J＝3.6Hz,1H),7.53(d,J＝2.8Hz,0.6H),7.46(d,J＝3.2Hz,0.4H),7.42(s,0.7H),7.08-7.03(m,2H),6.18(s,0.3H),6.06(d,J＝2.4Hz,0.7H),4.16-4.14(m,0.4H),4.00-3.87(m,3.6H),3.60(s,2H),3.59(s,1H),3.20-3.14(m,1H),2.95-2.90(m,2H),2.82-2.74(m,2H),2.62-2.55(m,2H),2.22-2.14(m,0.6H),2.05-1.77(m,2.4H),1.70-1.58(m,1H),1.47(s,9H)。

A racemic mixture of (cis) -methyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) -sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 231Y (220mg, 0.330mmol) was subjected to chiral preparative HPLC (separation conditions: column: Chiralpak IG5 μm20 250 mm; mobile phase: Hex: EtOH ═ 50:50 at 12 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 231C (97mg, 44% yield, 100% stereopurity) and 231D (107mg, 49% yield, 99.7% stereopurity) as yellow solids.

Compound 231C: LC-MS (ESI): r_T＝1.90min，C₂₉H₃₃ClF₂N₄O₆S₂Calculated mass of 670.2, M/z found value 671.4[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝10.809min)。¹H NMR(400MHz,CDCl₃)δ8.20(s,0.4H),7.84-7.83(m,1H),7.53(d,J＝3.2Hz,0.6H),7.46(d,J＝2.8Hz,0.4H),7.42(d,J＝2.4Hz,0.6H),7.08-7.03(m,2H),6.18(s,0.4H),6.06(d,J＝1.6Hz,0.6H),4.19-4.13(m,0.3H),4.04-3.91(m,2.7H),3.70-3.65(m,1H),3.60(s,2H),3.59(s,1H),3.03-2.90(m,3H),2.79-2.72(m,2H),2.57-2.50(m,2H),2.23-2.18(m,0.4H),2.05-1.97(m,1H),1.89-1.81(m,2H),1.69-1.66(m,0.6H),1.47(s,9H)。

Compound 231D: LC-MS (ESI): r_T＝1.90min，C₂₉H₃₃ClF₂N₄O₆S₂Calculated mass of 670.2, M/z found value 671.4[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝14.521min)。¹H NMR(400MHz,CDCl₃)δ8.21(s,0.4H),7.84-7.83(m,1H),7.53(d,J＝3.2Hz,0.7H),7.46(d,J＝3.2Hz,0.3H),7.42-7.41(m,0.6H),7.08-7.02(m,2H),6.18(s,0.3H),6.06(s,0.6H),4.19-4.13(m,0.3H),4.05-3.89(m,2.7H),3.70-3.63(m,1H),3.60(s,2H),3.59(s,1H),3.03-2.91(m,3H),2.87-2.74(m,2H),2.57-2.51(m,2H),2.23-2.18(m,0.5H),2.05-2.02(m,1H),1.93-1.80(m,2H),1.70-1.66(m,0.5H),1.47(s,9H)。

Compound 237: (trans) -methyl 6- (4- ((N- (tert-butoxycarbonyl) sulfamoyl) amino) -cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,¹H NMR(300MHz,CDCl₃)δ8.13(br s,0.6H),7.83-7.80(m,1H),7.50(d,J＝3.0Hz,0.4H),7.45(d,J＝3.0Hz,0.6H),7.40-7.37(m,0.4H),7.05-6.95(m,2H),6.15(s,0.6H),6.05-6.01(m,0.4H),3.96-3.89(m,0.6H),3.72-3.67(m,0.4H),3.60(s,1.1H),3.58(s,1.9H),3.31-3.23(m,1H),2.31-2.15(m,2H),2.06-1.91(m,2H),1.79-1.57(m,2H),1.50-1.47(m,9H),1.44-1.41(m,2H)。

compounds 240M and 240N: (trans) -methyl 4- (2-bromo-4-fluorophenyl) -6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -methyl 4- (2-bromo-4-fluorophenyl) -6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 240M (mixture of enantiomers): LC-MS (ESI): r_T＝2.650min，C₂₉H₃₄BrFN₄O₆S₂Calculated mass of 696.1, M/z found value 698.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.15(s,0.2H),7.83(d,J＝3.2Hz,1H),7.52-7.44(m,1.8H),7.32(dd,J＝8.4,2.8Hz,1H),7.28-7.25(m,1H),7.02-6.93(m,1H),6.16(s,0.2H),6.03(d,J＝2.4Hz,0.8H),4.20-4.08(m,0.3H),4.04-3.87(m,3.7H),3.60(s,3H),3.22-3.13(m,1H),2.99-2.87(m,2H),2.82-2.72(m,2H),2.63-2.53(m,2H),2.25-2.15(m,0.8H),2.07-1.59(m,3.2H),1.47(s,9H)。

Compound 240N (mixture of enantiomers): LC-MS (ESI): r_T＝2.610min，C₂₉H₃₄BrFN₄O₆S₂Calculated mass of 696.1, M/z found value 698.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.2H),7.83-7.82(m,1H),7.52-7.44(m,1.8H),7.35-7.31(m,1H),7.29-7.21(m,1H),7.02-6.94(m,1H),6.16(s,0.2H),6.03(d,J＝2.4Hz,0.8H),4.21-4.08(m,0.2H),4.05-3.87(m,2.8H),3.73-3.64(m,1H),3.59(s,3H),3.06-2.87(m,3H),2.82-2.71(m,2H),2.59-2.47(m,2H),2.26-2.14(m,0.7H),2.04-1.78(m,2.6H),1.70-1.66(m,0.7H),1.47(s,9H)。

The racemic mixture of (trans) -methyl 4- (2-bromo-4-fluorophenyl) -6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 240M (480mg, 0.69mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak ID 5 μ M20: 250 mm; mobile phase: Hex: IPA: DEA: 50:0.3 at 13 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 240P (140mg, 29% yield, 100% stereopurity) as a yellow solid and 240Q (150mg, 31% yield, 99.2% stereopurity) as a yellow solid.

Compound 240P: LC-MS (ESI): r_T＝3.629min，C₂₉H₃₄BrFN₄O₆S₂Calculated mass of 696.1, M/z found value 699.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: IPA: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝8.996min)。¹H NMR(400MHz,DMSO-d₆)δ9.50(d,J＝3.6Hz,0.8H),9.13(s,0.2H),8.01-7.98(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.58-7.55(m,1H),7.38-7.31(m,1H),7.30-7.21(m,1H),5.99(s,0.2H),5.90(d,J＝3.6Hz,0.8H),4.04-3.95(m,1H),3.80-3.70(m,3H),3.53(s,2.5H),3.52(s,0.5H),3.16-3.08(m,1H),2.92-2.83(m,2H),2.68-2.53(m,4H),2.07-1.88(m,1H),1.87-1.75(m,2H),1.61-1.58(m,1H),1.42(s,9H)。

Compound 240Q: LC-MS (ESI): r_T＝3.794min，C₂₉H₃₄BrFN₄O₆S₂Calculated mass of 696.1, M/z found value 699.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: IPA: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝11.886min)。¹H NMR(400MHz,DMSO-d₆)δ9.50(d,J＝3.6Hz,0.8H),9.12(s,0.2H),8.01-7.98(m,1.8H),7.93(d,J＝3.6Hz,0.2H),7.58-7.55(m,1H),7.38-7.31(m,1H),7.30-7.21(m,1H),5.99(s,0.2H),5.90(d,J＝3.6Hz,0.8H),4.04-3.96(m,1H),3.77-3.70(m,3H),3.53(s,2.5H),3.52(s,0.5H),3.16-3.08(m,1H),2.93-2.83(m,2H),2.66-2.51(m,4H),2.10-1.89(m,1H),1.87-1.75(m,2H),1.61-1.58(m,1H),1.42(d,J＝3.6Hz,9H)。

Compound 242: methyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) -piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazole-2-1, 4-dihydropyrimidine-5-carboxylate,¹H NMR(300MHz,CDCl₃)δ8.18(brs,0.3H),7.84-7.82(m,1H),7.52-7.50(m,0.7H),7.47-7.43(m,1H),7.31-7.28(m,1H),7.15-7.12(m,1H),6.98-6.91(m,1H),6.18(s,0.3H),6.08-6.04(m,0.7H),4.12-3.85(m,4H),3.74-3.66(m,1H),3.59(s,3H),3.37-3.09(m,1H),3.01-2.90(m,2H),2.82-2.73(m,2H),2.60-2.49(m,2H),2.25-2.13(m,1H),2.07-1.98(m,1H),1.91-1.85(m,1H),1.47(s,5H),1.46(s,4H)。

compound 242 was purified by preparative HPLC using C18 column (acetonitrile: water 80% to 88%) to give compounds 242A and 242B

Compound 242a (trans): LC-MS (ESI): r_T＝8.683min，C₂₉H₃₄ClFN₄O₆S₂Calculated mass 652.2, M/z found value 653.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.2Hz,0.9H),9.13(br s,0.1H),8.01-7.98(m,1.8H),7.93-7.92(m,0.2H),7.42(dd,J＝8.8,2.4Hz,1H),7.37-7.31(m,1H),7.23-7.18(m,1H),6.01(s,0.2H),5.92(d,J＝3.2Hz,0.8H),4.03-3.96(m,1H),3.77-3.70(m,3H),3.53-3.52(m,3H),3.15-3.08(m,1H),2.92-2.83(m,2H),2.61-2.53(m,4H),2.07-1.89(m,1.2H),1.86-1.72(m,2H),1.61-1.57(m,0.8H),1.43-1.42(m,9H)。

Compound 242b (cis): LC-MS (ESI): r_T＝1.27min，C₂₉H₃₄ClFN₄O₆S₂Calculated mass 652.2, M/z found value 653.6[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.2Hz,0.8H),9.12(br s,0.2H),8.00(s,1.8H),7.92(m,0.2H),7.42(dd,J＝8.8,2.4Hz,1H),7.38-7.31(m,1H),7.23-7.18(m,1H),6.02(s,0.2H),5.92(d,J＝3.6Hz,0.8H),3.99-3.90(m,1H),3.78-3.67(m,3H),3.53(s,3H),3.12-3.03(m,1H),2.89-2.80(m,2H),2.49-2.48(m,4H),2.08-1.90(m,1.2H),1.87-1.75(m,2H),1.62-1.59(m,0.8H),1.41(s,9H)。

Compound 246: methyl 6- (1- ((1- (tert-butoxycarbonyl) azetidin-3-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.686min，C₂₈H₃₂ClF₂N₅O₆S₂Calculated mass of 671.2, M/z found value 671.8[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.21(s,0.3H),7.86-7.84(m,1H),7.55(s,0.7H),7.49-7.45(m,1H),7.11-7.01(m,2H),6.19(s,0.3H),6.08(s,0.7H),4.35-4.13(m,4.2H),4.09-3.94(m,3.8H),3.61-3.60(m,3H),3.04-2.91(m,2H),2.20-2.16(m,1H),2.06-1.86(m,2H),1.74-1.70(m,1H),1.47(s,9H)。

Compound 249: (trans) -methyl 6- (4- (1- (tert-butoxycarbonyl) azetidine-3-sulfonylamino) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.631min，C₂₉H₃₄ClF₂N₅O₆S₂Calculated mass of 685.2, M/z found value 685.8[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.16(s,0.5H),7.84(d,J＝1.8Hz,1H),7.58-7.53(m,0.5H),7.50-7.46(m,0.5H),7.42(s,0.5H),7.09-7.01(m,2H),6.18(s,0.5H),6.06(s,0.5H),4.39-4.27(m,1H),4.22-4.17(m,4H),4.05-3.90(m,1.5H),3.84-3.67(m,0.5H),3.61(s,1.5H),3.60(s,1.5H),3.54-3.38(m,1H),2.31-1.91(m,4H),1.88-1.65(m,2H),1.58-1.51(m,2H),1.46(s,9H)。

Compound 252: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (3-methoxy-3-oxopropylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.182min，C₂₅H₂₇ClF₂N₄O₆S₂Calculated mass of 616.1, M/z found value 617.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.16(s,0.5H),7.83(d,J＝3.2Hz,1H),7.52(d,J＝3.2Hz,0.5H),7.46(d,J＝2.8Hz,0.5H),7.41(s,0.5H),7.07-6.98(m,2H),6.17(s,0.5H),6.04(d,J＝2.8Hz,0.5H),4.38-4.36(m,0.5H),4.31-4.29(m,0.5H),4.02-3.93(m,0.5H),3.75(s,3H),3.73-3.70(m,0.5H),3.60-3.59(m,3H),3.42-3.37(m,3H),2.89-2.84(m,2H),2.31-1.99(m,4H),1.93-1.72(m,1H),1.64-1.35(m,3H)。

A racemic mixture of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (3-methoxy-3-oxopropylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 252 (200mg,0.320mmol) was separated by chiral preparative SFC (column: chiralpak IA 5 μm20 × 250 mm; mobile phase: CO 2₂45g/min MeOH (DEA) (65: 35: 0.3); column temperature: 39.9 ℃; wavelength: 230nm, back pressure: 100 bar) to yield 252X (80mg, 90% pure, 40% yield, 97.6% stereopure) and 252Y (70mg, 90% pure, 45% yield, 94.2% stereopure) as yellow solids.

Intermediate 252X: LC-MS (ESI): r_T＝2.933min，C₂₅H₂₇ClF₂N₄O₆S₂Calculated mass of 616.1, M/z found value 617.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH: DEA: 65:35:0.2 at 2.999 mL/min; column temperature: 39.9 ℃; wavelength: 230nm, back pressure: 100 bar, R_T＝3.88min)。¹H NMR(400MHz,CDCl₃)δ8.15(s,0.5H),7.84-7.82(m,1H),7.52(d,J＝3.2Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.40(s,0.5H),7.07-6.98(m,2H),6.17(s,0.5H),6.04(d,J＝2.8Hz,0.5H),4.23-4.16(m,1H),4.01-3.93(m,0.5H),3.75(s,3H),3.73-3.69(m,0.5H),3.60-3.59(m,3H),3.44-3.35(m,3H),2.89-2.84(m,2H),2.29-2.14(m,2H),2.12-1.92(m,2H),1.90-1.64(m,2H),1.53-1.35(m,2H)。

Intermediate 252Y: LC-MS (ESI): r_T＝3.842min，C₂₅H₂₇ClF₂N₄O₆S₂Calculated mass of 616.1, M/z found value 617.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH: DEA: 65:35:0.2 at 2.999 mL/min; column temperature: 39.9 ℃; wavelength: 230nm, back pressure: 100 bar, R_T＝4.65min)。¹H NMR(400MHz,CDCl₃)δ8.15(s,0.5H),7.83-7.82(m,1H),7.52(d,J＝3.2Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.40(s,0.5H),7.07-6.98(m,2H),6.17(s,0.5H),6.04(d,J＝2.4Hz,0.5H),4.23-4.16(m,1H),4.01-3.93(m,0.5H),3.75(s,3H),3.73-3.70(m,0.5H),3.60-3.59(m,3H),3.45-3.36(m,3H),2.89-2.84(m,2H),2.29-2.14(m,2H),2.12-1.95(m,2H),1.93-1.64(m,2H),1.55-1.36(m,2H)。

Compound 254: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((1-cyclopropyl-1H-pyrazol-4-yl) sulfonyl) piper-inePyridin-4-yl) -2- (4, 5-dihydrothiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.252min，C₂₆H₂₆ClFN₆O₄S₂Calculated mass of 604.1, M/z found value 604.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.3H),7.83(s,2H),7.72-7.70(m,1H),7.54-7.53(m,0.7H),7.46-7.45(m,0.3H),7.43(s,0.7H),7.30-7.29(m,0.3H),7.25-7.23(m,0.7H),7.15-7.11(m,1H),6.97-6.88(m,1H),6.17(s,0.3H),6.05(s,0.7H),4.01-3.83(m,2H),3.77-3.65(m,2H),3.55(s,3H),2.45-2.27(m,3H),2.20-2.05(m,1H),2.02-1.88(m,1.5H),1.75-1.69(m,0.5H),1.24-1.18(m,2H),1.17-1.09(m,2H)。

Compound 255: methyl 4- (2-chloro-4-fluorophenyl) -6- (-1- (oxetan-3-ylsulfonyl) pyrrolidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.777min，C₂₂H₂₂ClFN₄O₅S₂Calculated mass of 540.1, M/z found value 541.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.63(s,1H),8.02(s,2H),7.44-7.41(m,1H),7.39-7.35(m,1H),7.23-7.18(m,1H),5.94(s,1H),4.97-4.90(m,1H),4.88-4.79(m,4H),4.37-4.28(m,1H),3.63-3.52(m,6H),3.38-3.32(m,1H),2.18-2.07(m,1H),2.05-1.96(m,1H)。

Compound 256A: methyl 4- (2-chloro-4-fluorophenyl) -6- (-1- (propylsulfonyl) pyrrolidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.129min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass 526.1, M/z found 527.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.62(s,1H),8.02(s,2H),7.44-7.41(m,1H),7.39-7.35(m,1H),7.24-7.19(m,1H),5.94(s,1H),4.41-4.33(m,1H),3.63-3.52(m,6H),3.39-3.33(m,1H),3.16-3.12(m,2H),2.23-2.14(m,1H),2.02(br s,1H),1.81-1.71(m,2H),1.01(t,J＝7.2Hz,3H)。

Compound 256D: methyl 4- (2-chloro-4-fluorophenyl) -6- (-1- (propylsulfonyl) pyrrolidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.098min，C₂₂H₂₄ClFN₄O₄S₂Calculated mass 526.1, M/z found 527.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.67(d,J＝2.8Hz,0.9H),9.30(s,0.1H),8.05-8.02(m,1.8H),7.99-7.98(m,0.1H),7.94-7.93(m,0.1H),7.45-7.42(m,1H),7.39-7.36(m,1H),7.24-7.20(m,1H),6.02(s,0.1H),5.93(d,J＝2.8Hz,0.9H),4.61-4.54(m,0.1H),4.42-4.34(m,0.9H),3.62-3.36(m,7H),3.20-3.04(m,2H),2.35-2.26(m,1H),2.18-2.10(m,1H),1.78-1.68(m,2H),1.03-0.95(m,3H)。

Compound 266: methyl 6- (1- (N- (tert-butoxycarbonyl) sulfamoyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.586min，C₂₅H₂₉ClFN₅O₆S₂Calculated mass of 613.1, M/z found value 614.2[ M + H [ ].]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.95(s,1H),9.55(d,J＝3.6Hz,0.8H),9.11(s,0.2H),8.01(s,2H),7.44-7.35(m,2H),7.23-7.19(m,1H),6.02(s,0.2H),5.92(d,J＝3.6Hz,0.8H),3.80-3.62(m,3H),3.52(s,3H),2.90-2.82(m,2H),1.96-1.79(m,3H),1.65-1.62(m,1H),1.44(s,9H)。

Compounds 269A and 269B: (trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) -sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester

Compound 269A:¹H NMR(400MHz,CDCl₃)δ8.10(s,0.4H),7.76(d,J＝3.2Hz,1H),7.47(d,J＝3.2Hz,0.6H),7.39(d,J＝3.2Hz,0.4H),7.29(d,J＝2.4Hz,0.6H),7.02-6.98(m,2H),6.13(s,0.4H),6.02(d,J＝2.8Hz,0.6H),4.19-4.14(m,2H),4.03-3.76(m,6H),2.87-2.80(m,2H),2.70-2.66(m,2H),2.45-2.35(m,2H),2.18-2.09(m,0.5H),1.98-1.58(m,3.5H),1.39(s,2H),1.38(s,1H),1.07-1.03(m,3H),0.98-0.94(m,2H),0.00(s,9H)

compound 269B:¹H NMR(400MHz,CDCl₃)δ8.12(s,0.4H),7.78-7.77(m,1H),7.48(d,J＝2.8Hz,0.6H),7.41(d,J＝3.2Hz,0.4H),7.30(d,J＝2.0Hz,0.6H),7.04-7.01(m,2H),6.15(s,0.4H),6.04(d,J＝2.8Hz,0.6H),4.17-4.13(m,2H),4.01-3.84(m,5H),3.75-3.65(m,1H),2.96-2.78(m,4H),2.20-2.11(m,3H),2.01-1.62(m,3H),1.43(s,2H),1.42(s,1H),1.11-1.04(m,3H),0.99-0.94(m,2H),0.00(s,9H)。

compound 271A and compound 271B: (trans) -ethyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) -cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester

Compound 271A: (trans) -ethyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, intermediate EO8495 — 1034.1 a:¹H NMR(400MHz,CDCl₃)δ8.13(br s,0.2H),7.83(d,J＝2.8Hz,1H),7.52(d,J＝3.2Hz,0.7H),7.45(d,J＝3.2Hz,0.3H),7.36-7.33(m,0.8H),7.31-7.26(m,1H),7.15-7.11(m,1H),6.98-6.89(m,1H),6.20(s,0.3H),6.09(d,J＝2.4Hz,0.7H),4.25-4.21(m,2H),4.03(q,J＝7.2Hz,2H),3.98-3.80(m,4H),2.95-2.73(m,4H),2.51-2.44(m,2H),2.24-2.18(m,0.5H),2.07-2.00(m,1H),1.94-1.85(m,1.5H),1.78-1.66(m,1H),1.46(s,2.5H),1.45(s,0.5H),1.12-1.08(m,3H),0.87-0.86(m,2H),0.07(s,9H)。

compound 271B:¹H NMR(400MHz,CDCl₃)δ8.09(s,0.2H),7.78-7.77(m,1H),7.46(d,J＝2.8Hz,0.7H),7.39(d,J＝3.2Hz,0.3H),7.29(br s,0.8H),7.26-7.22(m,1H),7.10-7.07(m,1H),6.93-6.88(m,1H),6.15(s,0.3H),6.04(d,J＝2.4Hz,0.7H),4.17-4.14(m,2H),4.01-3.85(m,4H),3.73-3.68(m,1H),2.97-2.83(m,4H),2.19-2.11(m,3H),2.00-1.82(m,3H),1.43(s,2.5H),1.42(s,0.5H),1.09-1.03(m,3H),0.99-0.94(m,2H),0.01(s,9H)。

compounds 273A and 273B: (trans) -methyl 4- (2-chloro-3-fluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -methyl 4- (2-chloro-3-fluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester

Compound 273A:¹H NMR(400MHz,CDCl₃)δ8.10(s,0.2H),7.77(d,J＝3.2Hz,1H),7.46(d,J＝3.2Hz,1H),7.38(s,0.8H),7.16-7.11(m,1H),7.10-6.98(m,2H),6.18(s,0.3H),6.05(d,J＝2.8Hz,0.7H),4.18-4.14(m,2H),3.95-3.73(m,4H),3.53(s,2H),3.52(s,1H),2.90-2.82(m,2H),2.76-2.70(m,2H),2.43-2.42(m,2H),2.17-2.10(m,1H)1.98-1.61(m,3H),1.39(s,2H),1.38(s,1H),0.98-0.94(m,2H),0.00(s,9H)

compound 273B:¹H NMR(400MHz,CDCl₃)δ8.13(s,0.2H),7.78-7.77m,1H),7.46(d,J＝3.2Hz,1H),7.40(d,J＝2.8Hz,0.8H),7.21-7.14(m,1H),7.06-7.02(m,2H),6.20(s,0.3H),6.07(d,J＝3.2Hz,0.7H),4.17-4.13(m,2H),3.95-3.85(m,3H),3.73-3.69(m,1H),3.54(s,2H),3.53(s,1H),2.97-2.84(m,4H),2.19-2.12(m,2H),2.00-1.65(m,4H),1.43(s,3H),0.99-0.94(m,2H),0.01(s,9H)

compounds 277C and 277D: (trans) -methyl 4- (2-bromo-3-fluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -methyl 4- (2-bromo-3-fluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester

Compound 277C:¹H NMR(400MHz,CDCl₃)δ8.16(s,0.2H),7.84-7.81(m,1H),7.53-7.49(m,1.7H),7.46-7.45(m,0.2H),7.28-7.27(m,0.8H),7.19-7.00(m,2H),6.24(s,0.2H),6.10(s,0.8H),4.34-4.25(m,2H),4.03-3.80(m,4H),3.59(s,3H),2.96-2.76(m,4H),2.54-2.45(m,2H),2.18-2.09(m,1H),2.03-1.85(m,2H),1.73-1.67(m,1H),1.49-1.40(m,3H),1.05-1.01(m,2H),0.07(s,9H)。

compound 277D:¹H NMR(400MHz,CDCl₃)δ8.12(s,0.2H),7.79-7.75(m,1H),7.49-7.41(m,2H),7.25-7.22(m,0.8H),7.05-6.95(m,2H),6.19(s,0.3H),6.06-6.02(m,0.7H),4.17-4.13(m,2H),3.99-3.66(m,4H),3.53(s,3H),2.98-2.80(m,4H),2.20-2.10(m,3H),1.94-1.60(m,3H),1.43(s,3H),0.99-0.95(m,2H),0.03(s,9H)。

compounds 281C and 281D: (trans) -ethyl 4- (2-bromo-4-fluorophenyl) -6- (1- ((3-methyl-3- (((trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -ethyl 4- (2-bromo-4-fluorophenyl) -6- (1- ((3-methyl-3- (((trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate.

Compound 281C: LC-MS (ESI): r_T＝2.24min，C₃₂H₄₂BrFN₄O₆S₂Calculated mass of Si 768.2, found in M/z 770.8[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.13(s,0.2H),7.83(d,J＝3.2Hz,1H),7.52(d,J＝2.8Hz,0.8H),7.45(d,J＝3.2Hz,0.3H),7.39(d,J＝2.0Hz,0.7H),7.33-7.29(m,2H),7.03-6.94(m,1H),6.18(s,0.2H),6.06(d,J＝2.4Hz,0.8H),4.25-4.20(m,2H),4.06-3.83(m,6H),2.94-2.77(m,4H),2.52-2.46(m,2H),2.24-2.18(m,0.8H),2.08-2.01(m,1H),1.99-1.95(m,0.2H),1.92-1.89(m,1H),1.84-1.77(m,0.3H),1.70-1.66(m,0.7H),1.45(s,3H),1.13-1.08(m,3H),1.05-1.01(m,2H),0.07(s,9H)。

Compound 281D: LC-MS (ESI): r_T＝2.16min，C₃₂H₄₂BrFN₄O₆S₂Calculated mass of Si 768.2, found value of M/z 768.8[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.13(s,0.2H),7.83-7.81(m,1H),7.51(d,J＝3.2Hz,0.8H),7.44(d,J＝3.2Hz,0.3H),7.39(d,J＝2.4Hz,0.7H),7.32-7.28(m,2H),7.02-6.94(m,1H),6.17(s,0.3H),6.05(d,J＝2.4Hz,0.7H),4.22-4.18(m,2.2H),4.05-3.90(m,4.8H),3.77-3.73(m,1H),3.01-2.88(m,4H),2.24-2.16(2.8H),2.07-2.06(m,0.2H),2.01-2.00(m,0.8H),1.98-1.96(m,0.2H),1.92-1.88(m,1H),1.83-1.77(m,0.2H),1.69-1.65(m,0.8H),1.47(s,3H),1.14-1.07(m,3H),1.03-0.99(m,2H),0.04(s,9H)。

Compound 298: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -6-4- (methylsulfonamido) cyclohexyl) -1, 4-dihydropyrimidine-5-carboxylate, LC-MS(ESI)：R_T＝3.182min，C₂₄H₂₃ClF₄N₄O₄Calculated mass of S574.1, M/z found value 575.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.34-8.31(m,1H),7.34-7.29(m,1H),7.07-6.98(m,2H),6.20(s,1H),4.42(d,J＝7.6Hz,1H),3.96-3.90(m,1H),3.60(s,3H),3.48-3.39(m,1H),3.03(s,3H),2.27-2.17(m,3H),2.09-2.06(m,1H),1.94-1.91(m,1H),1.83-1.62(m,2H),1.57-1.45(m,2H)。

The racemic mixture of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -6-4- (methylsulfonamido) cyclohexyl) -1, 4-dihydropyrimidine-5-carboxylate 298 (120mg, 93.5% purity, 0.195mmol) was separated by chiral preparative HPLC (separation conditions: column: chiralpak IC5 μm20 × 250 mm; mobile phase: hex EtOH 50 DEA 50:50:0.3 at 10 mL/min; temperature: 30 ℃; wavelength: 214nm) to yield the title compound 298A (17.3mg, 99.9% pure, 15% yield, 100% stereopure) and 298B (17.3mg, 99.8% pure, 15% yield, 99.7% stereopure) as yellow solids.

Compound 298A: LC-MS (ESI): r_T＝2.652min，C₂₄H₂₃ClF₄N₄O₄Calculated mass of S574.1, found M/z value 575.0[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 50: 0.2; temperature: 230 ℃; wavelength: 230 nm; chiral_T＝7.634min)。¹H NMR(400MHz,DMSO-d₆)δ9.23(s,0.7H),9.15(s,0.3H),8.57(s,1H),8.08-8.03(m,1H),7.48-7.42(m,1H),7.21-7.01(m,2H),6.03(s,0.7H),5.92(s,0.3H),3.85-3.81(m,0.7H),3.51(s,3H),3.20-3.17(m,1H),3.08(br s,0.3H),2.92(s,3H),2.02-1.99(m,2H),1.85-1.71(m,4H),1.36-1.23(m,2H)。

Compound 298B: LC-MS (ESI): r_T＝2.650min，C₂₄H₂₃ClF₄N₄O₄Calculated mass of S574.1, found M/z value 575.0[ M + H [)]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 50: 0.2; temperature: 230 ℃; wavelength: 230 nm; chiral_T＝9.413min)。¹H NMR(400MHz,DMSO-d₆)δ9.23(s,0.7H),9.15(s,0.3H),8.57(s,1H),8.06(t,J＝8.8Hz,1H),7.48-7.42(m,1H),7.22-7.02(m,2H),6.03(s,0.7H),5.92(s,0.3H),3.86-3.81(m,0.7H),3.51(s,3H),3.20-3.18(m,1H),3.08(br s,0.3H),2.92(s,3H),2.03-2.00(m,2H),1.85-1.71(m,4H),1.36-1.26(m,2H)。

Compound 304: methyl 6- (1- ((1, 4-dioxaspiro [4.5] decan-2-ylmethyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 99(434mg, 1.00mmol) in dichloromethane (15mL) were added triethylamine (202mg, 2.00mmol) and 1, 4-dioxaspiro [ 4.5.5 ]]Decyl-2-ylmethanesulfonyl chloride (382mg, 1.5 mmol). After stirring at room temperature for 2 hours, the mixture was diluted with dichloromethane (50mL), washed with water (100mL) and brine (100mL), and filtered over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1 to 3:1) to give a small polar fraction which was further purified by C18 column (acetonitrile: water: 80% to 88%) to give the title compound as a yellow solid (110mg, 20% yield). LC-MS (ESI): r_T＝1.97min，C₂₉H₃₄ClFN₄O₆S₂Calculated mass 652.2, M/z found value 652.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.2H),7.86-7.82(m,1H),7.52(d,J＝3.2Hz,0.8H),7.47-7.42(m,1H),7.31-7.24(m,1H),7.17-7.11(m,1H),6.99-6.89(m,1H),6.19(s,0.3H),6.07(d,J＝2.4Hz,0.7H),4.62-4.52(m,1H),4.21-4.11(m,0.3H),4.04-3.75(m,3.7H),3.62-3.57(m,3H),3.41-3.25(m,2H),3.13-2.88(m,3H),2.31-2.20(m,0.7H),2.13-2.04(m,1H),1.98-1.84(m,1.3H),1.76-1.69(m,1H),1.65-1.60(m,8H),1.45-1.39(m,2H)。

Compound 304(110mg, 0.169mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.3 at 12 mL/min; wavelength: 214nm) to give 304A (45mg, 41% yield, 100% stereopurity) and 304B (45mg, 45% yield, 100% stereopurity) as yellow solids.

Compound 304A: LC-MS (ESI): r_T＝2.00min，C₂₉H₃₄ClFN₄O₆S₂Calculated mass 652.2, M/z found value 652.8[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA ═ 60:40: 0.2; temperature: 230 ℃; wavelength: 230_T＝9.430min)。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.3H),7.85-7.81(m,1H),7.52(d,J＝3.2Hz,0.7H),7.47-7.42(m,1H),7.31-7.24(m,1H),7.17-7.12(m,1H),7.00-6.89(m,1H),6.19(s,0.3H),6.07(d,J＝2.8Hz,0.7H),4.61-4.51(m,1H),4.26-4.14(m,1.3H),4.02-3.79(m,2.7H),3.63-3.57(m,3H),3.35-3.26(m,1H),3.13-2.92(m,4H),2.32-2.21(m,0.7H),2.13-2.02(m,1H),1.99-1.81(m,1.6H),1.76-1.69(m,0.7H),1.65-1.55(m,8H),1.46-1.38(m,2H)。

Compound 304B: LC-MS (ESI): r_T＝2.00min，C₂₉H₃₄ClFN₄O₆S₂Calculated mass 652.2, M/z found value 652.8[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA ═ 60:40: 0.2; temperature: 230 ℃; wavelength: 230_T＝11.231min)。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.3H),7.83(d,J＝2.8Hz,1H),7.52(d,J＝2.8Hz,0.7H),7.47-7.41(m,1H),7.31-7.24(m,1H),7.17-7.11(m,1H),7.00-6.89(m,1H),6.19(s,0.3H),6.07(d,J＝2.8Hz,0.7H),4.62-4.52(m,1H),4.26-4.13(m,1.3H),4.05-3.79(m,2.7H),3.63-3.57(m,3H),3.35-3.25(m,1H),3.12-2.87(m,4H),2.31-2.20(m,0.7H),2.14-2.03(m,1H),1.99-1.82(m,1.6H),1.76-1.69(m,0.7H),1.65-1.56(m,8H),1.46-1.38(m,2H)。

Compounds 308M and 308N: (trans) -methyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (3, 4-difluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -methyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (3, 4-difluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Separation conditions are as follows: silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1 to 2:1) gave small polar fractions which were further purified by C18 column (acetonitrile: water ═ 70% to 75%) to give the title compound 308M as a yellow solid (80mg, 23% yield) and 308N as a yellow solid (70mg, 22% yield).

Intermediate 308M: LC-MS (ESI): r_T＝4.436min，C₃₀H₃₆F₂N₄O₆S₂Calculated mass of 650.2, M/z found value 651.3[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.15(s,0.6H),7.82-7.80(m,1H),7.52(d,J＝3.2Hz,0.4H),7.43(d,J＝3.2Hz,0.6H),7.29-7.27(m,0.4H),7.08-7.05(m,0.7H),6.99-6.94(m,0.3H),6.92-6.87(m,1H),5.93(s,0.6H),5.84(d,J＝2.0Hz,0.4H),4.22-4.14(m,0.5H),4.04-3.77(m,3.5H),3.59(s,1.8H),3.58(s,1.2H),3.22-3.13(m,1H),2.98-2.85(m,2H),2.82-2.71(m,2H),2.62-2.53(m,3.8H),2.42(d,J＝2.4Hz,1.2H),2.20-1.73(m,4H),1.48(s,5H),1.47(s,4H)。

Intermediate 308N: LC-MS (ESI): r_T＝3.620min，C₃₀H₃₆F₂N₄O₆S₂Calculated mass of 650.2, M/z found value 650.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.6H),7.81(d,J＝3.2Hz,1H),7.53(d,J＝2.4Hz,0.4H),7.43(d,J＝3.2Hz,0.6H),7.29-7.28(m,0.4H),7.10-7.05(m,0.7H),7.00-6.94(m,0.3H),6.91-6.87(m,1H),5.93(s,0.6H),5.84(d,J＝2.0Hz,0.4H),4.23-4.15(m,0.5H),4.06-3.90(m,2H),3.84-3.76(m,0.5H),3.72-3.64(m,1H),3.59(s,1.8H),3.58(s,1.2H),3.04-2.86(m,3H),2.81-2.70(m,2H),2.58-2.47(m,4H),2.42(d,J＝2.0Hz,1H),2.18-1.76(m,4H),1.46(s,4H),1.45(s,5H)。

Compound 310: methyl 6- (1- ((3- (tert-butoxycarbonyl) cyclopentyl) sulfonyl) -piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T5.260min and 5.392min, C₃₀H₃₆ClFN₄O₆S₂Calculated mass of 666.2, M/z found value 667.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.6Hz,0.8H),9.15(s,0.2H),8.01-7.98(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.44-7.31(m,2H),7.23-7.17(m,1H),6.02(s,0.2H),5.92(d,J＝3.6Hz,0.8H),4.00-3.91(m,0.2H),3.79-3.69(m,3.8H),3.53(s,2.4H),3.52(s,0.6H),2.95-2.72(m,3H),2.33-1.59(m,10H),1.41-1.40(m,9H)。

The racemic mixture of methyl 6- (1- ((3- (tert-butoxycarbonyl) cyclopentyl) sulfonyl) -piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 310 (500mg, 0.750mmol) was separated by chiral preparative HPLC (column: Chiralpak IB5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 310X (233mg, 47% yield) and 310Y (183mg, 37% yield) as yellow solids.

Intermediate 310X: LC-MS (ESI): r_T＝4.482min，C₃₀H₃₆ClFN₄O₆S₂Calculated mass of 666.2, M/z found value 667.3[ M + H ]]⁺. Chiral analysis (column: Chiralpak IB5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IB5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 85:15: 0.2; temperature: 230 ℃; wavelength: 230nm_T7.745 and 7.932 min).¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.6Hz,0.8H),9.15(s,0.2H),8.01-7.92(m,2H),7.43-7.34(m,2H),7.23-7.18(m,1H),6.02(s,0.2H),5.92(d,J＝3.6Hz,0.8H),4.00-3.93(m,0.2H),3.79-3.72(m,3.8H),3.53(s,2.4H),3.52(s,0.6H),2.96-2.81(m,3H),2.18-1.59(m,10H),1.41-1.40(m,9H)。

Intermediate 310Y: LC-MS (ESI): r_T＝4.285min，C₃₀H₃₆ClFN₄O₆S₂Calculated mass of 666.2, M/z found value 667.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IB5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IB5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 85:15: 0.2; temperature: 230 ℃; wavelength: 230nm_T9.191 and 9.699 min).¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.6Hz,0.8H),9.16(s,0.2H),8.00-7.92(m,2H),7.43-7.31(m,2H),7.23-7.18(m,1H),6.02(s,0.2H),5.92(d,J＝3.6Hz,0.8H),4.00-3.93(m,0.2H),3.79-3.67(m,3.8H),3.53(s,2.4H),3.52(s,0.6H),2.95-2.86(m,2H),2.80-2.72(m,1H),2.33-2.24(m,1H),2.05-1.76(m,8H),1.62-1.56(m,1H),1.41-1.40(m,9H)。

Compound 312: methyl 6- (1- ((4- (tert-butoxycarbonyl) cyclohexyl) sulfonyl) -piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.251min，C₃₁H₃₈ClFN₄O₆S₂Calculated mass of 680.2, M/z found value 681.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(s,0.8H),9.15(s,0.2H),8.01-7.92(m,2H),7.44-7.31(m,2H),7.23-7.17(m,1H),6.02(s,0.2H),5.92(d,J＝3.6Hz,0.8H),4.01-3.93(m,0.2H),3.79-3.72(m,2.8H),3.53(s,2.4H),3.52(s,0.6H),3.22-3.11(m,1H),3.02-2.71(m,2H),2.58-2.54(m,1H),2.23-1.75(m,7.7H),1.64-1.37(m,13.3H)。

The racemic mixture of methyl 6- (1- ((4- (tert-butoxycarbonyl) cyclohexyl) sulfonyl) -piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 312 (160mg, 0.240mmol) was separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.3 at 10 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 312X (40mg, 58% yield, 100% stereopurity) and compound 312Y (45mg, 28% yield, 100% stereopurity) as yellow solids.

Intermediate compound 312x (cis): LC-MS (ESI): r_T＝3.906min，C₃₁H₃₈ClFN₄O₆S₂Calculated mass of 680.2, M/z found value 681.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 50: 0.2; temperature: 230 ℃; wavelength: 230 nm; chiral_T＝6.838min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.2Hz,0.7H),9.15(s,0.3H),8.00(s,1.7H),7.93(s,0.3H),7.43-7.34(m,2H),7.23-7.18(m,1H),6.01(s,0.3H),5.92(d,J＝3.2Hz,0.7H),3.96(br s,0.3H),3.82-3.73(m,2.7H),3.53(s,3H),3.22-3.17(m,1H),2.93(q,J＝12.0Hz,2H),2.55-2.51(m,1H),2.07-1.74(m,7.3H),1.64-1.51(m,4.7H),1.42(s,9H)。

Intermediate compound 312y (cis): LC-MS (ESI): r_T＝5.024min，C₃₁H₃₈ClFN₄O₆S₂Calculated mass of 680.2, M/z found value 681.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 50: 0.2; temperature: 230 ℃; wavelength: 230 nm; chiral_T＝8.891min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.6Hz,0.8H),9.15(s,0.2H),8.00-7.92(m,2H),7.44-7.31(m,2H),7.23-7.17(m,1H),6.02(s,0.2H),5.92(d,J＝3.6Hz,0.8H),4.03-3.93(m,0.2H),3.79-3.72(m,2.8H),3.53(s,2.4H),3.52(s,0.6H),3.17-3.11(m,1H),3.01-2.95(m,2H),2.23-2.16(m,1H),2.09-1.74(m,7H),1.61-1.51(m,1H),1.48-1.33(m,13H)。

Compounds 318M and 318N: (trans) -Ethyl 6- (1- (3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -Ethyl 6- (1- (3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Purification by silica gel column chromatography (petroleum ether: ethyl acetate ═ 6:1 to 3:1) afforded fractions 1 and 2. Fraction 1 was further purified by preparative HPLC (column: Gilson Xfringe C18(5 μ M19 x 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 55% -95% (% B)) to give the title compound 318M as a yellow solid (380mg, 32% yield). Fraction 2 was further purified by preparative HPLC (column: Gilson Xbox C18(5 μm19 x 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 60% -95% (% B)) to give the title compound 318N as a yellow solid (330mg, 28% yield).

Compound 318M: LC-MS (ESI): r_T＝3.959min，C₃₀H₃₆ClFN₄O₆S₂Calculated mass of 666.2, M/z found value 667.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.2Hz,0.8H),9.08(s,0.2H),8.00-7.98(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.40-7.29(m,2H),7.23-7.18(m,1H),6.09(s,0.2H),5.99(d,J＝3.2Hz,0.8H),4.04-3.92(m,3.2H),3.78-3.71(m,2.8H),3.16-3.08(m,1H),2.91-2.83(m,2H),2.61-2.53(m,4H),1.99-1.76(m,3H),1.62-1.59(m,1H),1.43(s,1.8H),1.42(s,7.2H),1.08-1.01(m,3H)。

Compound 318N: LC-MS (ESI): r_T＝3.654min，C₃₀H₃₆ClFN₄O₆S₂Calculated mass of 666.2, M/z found value 667.1[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.93(d,J＝2.8Hz,0.3H),7.88(d,J＝2.8Hz,0.7H),7.75(d,J＝3.2Hz,0.7H),7.73(d,J＝3.6Hz,0.3H),7.32-7.11(m,3H),6.21(s,0.3H),6.14(s,0.7H),4.07-4.00(m,2H),3.97-3.82(m,4H),3.16-3.06(m,1H),3.00-2.89(m,2H),2.68-2.50(m,4H),2.16-1.85(m,3.3H),1.71-1.62(m,0.7H),1.46(s，6.3H),1.45(s,2.7H),1.13-1.09(m,3H)。

The racemic mixture of (trans) -ethyl 6- (1- (3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) -piperidin-4-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 318M (200mg, 0.30mmol) was separated by chiral preparative HPLC (column: chiralpak IE 5 μm20 × 250 mm; mobile phase: hex 50:50 EtOH at 10 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 318X (85mg, 43% yield, 100% stereopurity) and 318Y (80mg, 46% yield, 100% stereopurity) as yellow solids.

Intermediate 318X: LC-MS (ESI): r_T＝3.997min，C₃₀H₃₆ClFN₄O₆S₂Calculated mass of 666.2, M/z found value 667.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254 nm; R_T＝8.184min)。¹H NMR(400MHz,CD₃OD)δ7.89(s,1H),7.74(d,J＝2.8Hz,1H),7.30-7.14(m,3H),6.20(s,0.3H),6.14(s,0.7H),4.06-3.86(m,6H),3.31-3.14(m,1H),3.00-2.90(m,2H),2.73-2.58(m,4H),2.14-1.86(m,3.3H),1.80-1.61(m,0.7H),1.47(s,9H),1.11(t,J＝6.8Hz,3H)。

Intermediate 318Y: LC-MS (ESI): r_T＝3.992min，C₃₀H₃₆ClFN₄O₆S₂Calculated mass of 666.2, M/z found value 667.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 50:50 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝9.519min)。¹H NMR(400MHz,CD₃OD)δ7.93(s,0.2H),7.88(d,J＝2.4Hz,0.8H),7.30-7.14(m,3H),6.21(s,0.2H),6.14(s,0.8H),4.06-3.86(m,6H),3.20-3.14(m,1H),3.00-2.90(m,4H),2.70-2.62(m,4H),2.15-1.79(m,3.2H),1.72-1.65(m,0.8H),1.47(s,9H),1.11(t,J＝7.2Hz,3H)。

Compounds 320A and 320B: (trans) -ethyl 4- (2-chloro-3-fluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) ethyl 4- (2-chloro-3-fluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) -sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester

Separation conditions are as follows: purification by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) gave the title 320A (301mg, according to the formula: v) as a yellow solid¹H NMR purity 95%, 37% yield) and 320B (300mg, according to¹H NMR purity 95%, 37% yield).

Compound 320A:¹H NMR(400MHz,CDCl₃)δ8.15(s,0.3H),7.83(d,J＝3.2Hz,1H),7.52(d,J＝2.8Hz,0.7H),7.45(d,J＝3.2Hz,0.3H),7.39(s,0.7H),7.25-7.17(m,1H),7.14-7.03(m,2H),6.27(s,0.3H),6.15(d,J＝2.8Hz,0.7H),4.25-4.21(m,2H),4.07-4.00(m,2H),3.97-3.80(m,4H),2.95-2.87(m,2H),2.83-2.74(m,2H),2.52-2.44(m,2H),2.25-2.15(m,1H),2.09-2.02(m,1H),1.97-1.68(m,2H),1.48-1.46(m,3H),1.13-1.08(m,3H),1.05-1.01(m,2H),0.07(s,9H)。

compound 320B:¹H NMR(400MHz,CDCl₃)δ8.16(s,0.3H),7.83(d,J＝3.2Hz,1H),7.52(d,J＝3.2Hz,0.7H),7.45(d,J＝2.8Hz,0.3H),7.38(s,0.7H),7.25-7.14(m,1H),7.09-7.03(m,2H),6.27(s,0.3H),6.15(d,J＝2.8Hz,0.7H),4.23-4.19(m,2H),4.07-3.91(m,5H),3.81-3.72(m,1H),3.02-2.86(m,4H),2.25-2.19(m,2H),2.16-1.97(m,2H),1.93-1.67(m,2H),1.48(s,2H),1.47(s,1H),1.13-1.07(m,3H),1.03-1.00(m,2H),0.05(s,9H)。

compounds 322C and 322D: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester

Separation conditions are as follows: silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) gave the title compound 322C (230mg, 90% purity, 22% yield) and the title compound 322D (370mg, 90% purity, 35% yield) as yellow solids.

Compound 322C:¹H NMR(400MHz,CDCl₃)δ8.12(s,0.3H),7.76(d,J＝3.2Hz,1H),7.46(d,J＝3.2Hz,0.7H),7.40(d,J＝3.2Hz,0.3H),7.36(s,0.7H),7.34(s,0.4H),7.02-6.97(m,2H),6.11(s,0.4H),5.99(s,0.6H),4.19-4.17(m,2H),4.06-3.82(m,4H),3.54(s,2.1H),3.52(s,0.9H),2.85-2.80(m,2H),2.76-2.70(m,2H),2.45-2.39(m,2H),2.12-2.03(m,1H),1.98-1.57(m,3H),1.39(s,3H),0.99-0.93(m,2H),0.03(s,9H)。

322D：¹H NMR(400MHz,CDCl₃)δ8.17(s,0.3H),7.75(s,1H),7.48(s,0.7H),7.40(s,0.6H),7.37(s,0.4H),7.01-6.98(m,2H),6.12-6.01(m,1H),4.17-4.10(m,2H),3.95-3.88(m,3H),3.85-3.80(m,1H),3.68(s,3H),2.97-2.84(m,4H),2.19-2.11(m,3H),1.98-1.57(m,3H),1.42(s,3H),0.99-0.94(m,2H),0.03(s,9H)。

compound 324: methyl 6- (1- ((1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.749min，C₂₃H₂₁ClF₂N₆O₄S₂Calculated mass of 582.1, M/z found value 582.8[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ13.77(s,1H),9.63(d,J＝3.6Hz,0.8H),9.23(s,0.2H),8.39(s,1H),8.04-7.99(m,1.8H),7.94(d,J＝3.6Hz,0.2H),7.85(s,1H),7.49-7.40(m,1H),7.23-7.12(m,1H),6.00(s,0.2H),5.91(d,J＝3.6Hz,0.8H),3.80-3.64(m,2.2H),3.56-3.50(m,0.8H),3.48(s,2.4H),3.47(s,0.6H),2.29-2.16(m,2.2H),2.10-1.98(m,1H),1.95-1.84(m,1H),1.82-1.73(m,1H),1.67-1.60(m,0.8H)。

Compounds 328F and 328H: (trans) -Ethyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -Ethyl 6- (1- ((-3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 328F: LC-MS (ESI): r_T＝4.330min，C₃₀H₃₆ClFN₄O₆S₂Calculated mass of 666.2, M/z found value 667.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝15.325min)。¹H NMR(400MHz,DMSO-d₆)δ9.49(s,0.8H),9.07(br s,0.2H),8.00-7.98(m,2H),7.43-7.41(m,1H),7.38-7.34(m,1H),7.23-7.18(m,1H),6.00(br s,0.2H),5.93(s,0.8H),4.02-3.95(m,3H),3.77-3.71(m,3H),3.17-3.08(m,1H),2.91-2.83(m,2H),2.60-2.51(m,4H),1.96-1.93(m,1H),1.84-1.76(m,2H),1.61-1.58(m,1H),1.42(s,9H),1.07(t,J＝7.2Hz,3H)。

Compound 328H: LC-MS (ESI): r_T＝4.029min，C₃₀H₃₆ClFN₄O₆S₂Calculated mass of 666.2, M/z found value 667.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝7.610min)。¹H NMR(400MHz,DMSO-d₆)δ9.50(d,J＝3.6Hz,0.8H),9.06(s,0.2H),8.00-7.98(m,1.8H),7.93-7.92(m,0.2H),7.43-7.40(m,1H),7.38-7.34(m,1H),7.24-7.19(m,1H),6.03(s,0.2H),5.93(d,J＝3.6Hz,0.8H),4.00-3.93(m,3H),3.73-3.67(m,3H),3.10-3.05(m,1H),2.88-2.78(m,2H),2.48-2.40(m,4H),2.04-1.93(m,1H),1.90-1.82(m,2H),1.62-1.57(m,1H),1.41(s,9H),1.09-1.03(m,3H)。

Compounds 330P and 330Q: (trans) -methyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -methyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Separation conditions are as follows: silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1 to 3:1) followed by a C18 column (acetonitrile: water ═ 30% to 90%) gave the title compound 330P (85mg, 98.5% purity, 28% yield) and another crude product which was further purified by preparative HPLC (column: Waters Kinete EVO C18(5 μm,21.2 × 150mm) mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, 40% -80% (% B)) to give 330Q as a yellow solid (75mg, 99.5% purity, 25% yield).

Compound 330P: LC-MS (ESI): r_T＝4.162min，C₂₉H₃₄ClFN₄O₆S₂Calculated mass 652.2, M/z found value 652.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.57(s,0.8H),9.15(s,0.2H),8.04-7.93(m,2H),7.41-7.27(m,2H),7.24-7.15(m,1H),6.07(s,0.2H),5.98(s,0.8H),4.05-3.93(m,1.2H),3.82-3.66(m,2.8H),3.52(s,3H),3.18-3.07(m,1H),2.95-2.81(m,2H),2.63-2.50(m,4H),2.12-2.03(m,0.2H),2.01-1.90(m,1H),1.88-1.70(m,2H),1.65-1.55(m,0.8H),1.42(s,9H)。

Compound 330Q: LC-MS (ESI): r_T＝4.297min，C₂₉H₃₄ClFN₄O₆S₂Calculated mass 652.2, M/z found value 653.3[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.58(d,J＝3.6Hz,0.8H),9.16(s,0.2H),8.01(s,1.6H),7.99(d,J＝2.8Hz,0.2H),7.93(d,J＝2.8Hz,0.2H),7.42-7.29(m,2H),7.24-7.15(m,1H),6.07(s,0.2H),5.98(d,J＝3.6Hz,0.8H),4.01-3.90(m,1.2H),3.79-3.64(m,2.8H),3.53(s,2.4H),3.52(s,0.6H),3.12-3.02(m,1H),2.91-2.78(m,2H),2.48-2.38(m,4H),2.11-2.02(m,0.2H),2.01-1.90(m,1H),1.89-1.71(m,2H),1.66-1.57(m,0.8H),1.41(s,9H)。

Compounds 332M and 332N: (trans) -Ethyl 4- (2-bromo-4-fluorophenyl) -6- (1- (3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -Ethyl 4- (2-bromo-4-fluorophenyl) -6- (1- (3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Separation conditions are as follows: silica gel column chromatography (petroleum ether: ethyl acetate ═ 6:1 to 2:1) followed by further purification by preparative HPLC (column: Gilson X-bridge C18(5 μ M19 × 150mm), flow rate: 15mL/min, mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, gradient: 75% -85% (% B)) afforded the title compound 332M (370mg, 52% yield) and 332N (300mg, 42% yield) as yellow solids.

Compound 332M: LC-MS (ESI): r_T＝3.249min，C₃₀H₃₆BrFN₄O₆S₂Calculated mass of 710.1, M/z found value 711.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.14(s,0.3H),7.82(d,J＝2.8Hz,1H),7.51(d,J＝2.8Hz,0.7H),7.44(d,J＝2.8Hz,0.3H),7.41(s,0.7H),7.33-7.27(m,2H),7.03-6.94(m,1H),6.18(s,0.3H),6.05(d,J＝2.0Hz,0.7H),4.21-4.15(m,0.3H),4.09-3.84(m,5.7H),3.21-3.14(m,1H),2.98-2.87(m,2H),2.82-2.72(m,2H),2.63-2.53(m,2H),2.21-2.18(m,0.7H),2.17-1.77(m,2.6H),1.70(br s,0.7H),1.47(s,9H),1.14-1.08(m,3H)。

Compound 332N: LC-MS (ESI): r_T＝2.896min，C₃₀H₃₆BrFN₄O₆S₂Calculated mass of 710.1, M/z found value 711.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.15(s,0.3H),7.83-7.81(m,1H),7.52(d,J＝3.2Hz,0.7H),7.44(d,J＝3.2Hz,0.3H),7.40(d,J＝2.0Hz,0.7H),7.33-7.28(m,2H),7.03-6.94(m,1H),6.18(s,0.3H),6.06(d,J＝2.4Hz,0.7H),4.21-4.15(m,0.3H),4.08-3.87(m,4.7H),3.74-3.63(m,1H),3.06-2.86(m,3H),2.82-2.70(m,2H),2.58-2.47(m,2H),2.24-2.14(m,0.7H),2.09-1.97(m,1H),1.92-1.78(m,1.3H),1.70-1.63(m,1H),1.46(s,6.3H),1.45(s,2.7H),1.14-1.08(m,3H)。

Rac 332M (300mg, 0.420mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μ M20 × 250 mm; mobile phase: Hex: EtOH ═ 70:30 at 14 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 332X (90mg, 30% yield, 100% stereopurity) and 332Y (75mg, 25% yield, 99.5% stereopurity) as yellow solids.

Compound 332X: LC-MS (ESI): r_T＝4.122min，C₃₀H₃₆BrFN₄O₆S₂Calculated mass of 710.1, M/z found value 711.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝12.685min)。¹H NMR(400MHz,CD₃OD)δ7.93(d,J＝3.2Hz,0.3H),7.89(d,J＝3.2Hz,0.7H),7.74(d,J＝3.2Hz,0.7H),7.73(d,J＝3.2Hz,0.3H),7.43-7.37(m,2H),7.14-7.06(m,1H),6.13(s,0.3H),6.06(s,0.7H),4.14-3.83(m,6H),3.23-3.14(m,1H),3.04-2.89(m,2H),2.74-2.57(m,4H),2.16-1.85(m,3.3H),1.69-1.63(m,0.7H),1.48(s,2.7H),1.47(s,6.3H),1.12(t,J＝7.2Hz,3H)。

Compound 332Y: LC-MS (ESI): r_T＝4.117min，C₃₀H₃₆BrFN₄O₆S₂Calculated mass of 710.1, M/z found value 711.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝15.270min)。¹H NMR(400MHz,CD₃OD)δ7.93(d,J＝2.8Hz,0.3H),7.89(d,J＝3.2Hz,0.7H),7.74(d,J＝3.2Hz,0.7H),7.73(d,J＝3.2Hz,0.3H),7.43-7.37(m,2H),7.13-7.06(m,1H),6.13(s,0.3H),6.06(s,0.7H),4.13-3.85(m,6H),3.22-3.14(m,1H),3.04-2.90(m,2H),2.74-2.56(m,4H),2.16-1.85(m,3.3H),1.69-1.63(m,0.7H),1.48(s,2.7H),1.47(s,6.3H),1.12(t,J＝7.2Hz,3H)。

Compound 334: methyl 6- (1- ((3- ((tert-butyldiphenylsilyl) oxy) cyclobutyl) -sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,¹H NMR(400MHz,CDCl₃)δ8.16-8.14(m,1H),7.82-7.80(m,1H),7.65-7.61(m,4H),7.45-7.36(m,8H),7.16-7.12(m,1H),7.00-6.97(m,1H),6.18(s,0.3H),6.06(s,0.7H),4.67-4.60(m,0.5H),4.16-4.14(m,0.5H),3.98-3.84(m,2.7H),3.79-3.74(m,0.3H),3.60(s,1H),3.59(s,2H),3.12-3.04(m,0.5H),2.92-2.42(m,6H),2.21-2.14(m,0.5H),2.00-1.76(m,2.3H),1.67-1.64(m,0.7H),1.06(s,4.5H),1.04(s,4.5H),0.95-0.80(m,1H)。

compounds 338M and 338N: (trans) -Ethyl 4- (2-bromo-3-fluorophenyl) -6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -Ethyl 4- (2-bromo-3-fluorophenyl) -6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 338M: LC-MS (ESI): r_T＝4.457min，C₃₀H₃₆BrFN₄O₆S₂Calculated mass of 710.1, M/z found value 711.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.2Hz,0.7H),9.08(s,0.3H),8.00-7.92(m,2H),7.44-7.38(m,1H),7.31-7.15(m,2H),6.07(s,0.3H),5.98(d,J＝3.6Hz,0.7H),4.04-3.93(m,3.3H),3.78-3.70(m,2.7H),3.16-3.08(m,1H),2.92-2.82(m,2H),2.67-2.52(m,4H),2.05-1.74(m,3.2H),1.62-1.59(m,0.8H),1.43-1.42(m,9H),1.08-1.01(m,3H)。

Compound 338N: LC-MS (ESI): r_T＝4.103min，C₃₀H₃₆BrFN₄O₆S₂Calculated mass of 710.1, M/z found value 711.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.2Hz,0.7H),9.08(s,0.3H),8.00-7.92(m,2H),7.44-7.38(m,1H),7.31-7.15(m,2H),6.07(s,0.3H),5.98(d,J＝3.6Hz,0.7H),4.04-3.93(m,3.3H),3.78-3.70(m,2.7H),3.16-3.08(m,1H),2.92-2.82(m,2H),2.67-2.52(m,4H),2.05-1.74(m,3.2H),1.62-1.59(m,0.8H),1.42(s,9H),1.08-1.01(m,3H)。

Rac 338M (360mg, 0.510mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak ID 5 μ M20 × 250 mm; mobile phase: Hex: IPA: DEA ═ 50:50:0.3 at 12 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 338A (130mg, 36% yield, 100% stereopurity) and 338B (150mg, 42% yield, 98.1% stereopurity).

Compound 338A: LC-MS (ESI): r_T＝4.684min，C₃₀H₃₆BrFN₄O₆S₂Is calculated byMass 710.1, found M/z value 711.1[ M + H]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: IPA: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝8.521min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝2.4Hz,0.7H),9.09(s,0.3H),8.00-7.93(m,2H),7.44-7.38(m,1H),7.29(t,J＝8.8Hz,1H),7.21-7.15(m,1H),6.07(s,0.3H),5.98(d,J＝3.2Hz,0.7H),4.04-3.95(m,3.3H),3.78-3.71(m,2.7H),3.16-3.08(m,1H),2.91-2.83(m,2H),2.61-2.53(m,4H),2.08-1.77(m,3.3H),1.63-1.58(m,0.7H),1.42(s,9H),1.06(t,J＝6.8Hz,3H)。

Compound 338B: LC-MS (ESI): r_T＝4.684min，C₃₀H₃₆BrFN₄O₆S₂Calculated mass of 710.1, M/z found value 713.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: IPA: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝10.348min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.6Hz,0.7H),9.09(s,0.3H),8.00-7.92(m,2H),7.44-7.37(m,1H),7.32-7.24(m,1H),7.21-7.15(m,1H),6.07(s,0.3H),5.98(d,J＝3.6Hz,0.7H),4.04-3.92(m,3.3H),3.81-3.70(m,2.7H),3.16-3.08(m,1H),2.92-2.82(m,2H),2.61-2.54(m,4H),2.10-1.77(m,3.3H),1.62-1.59(m,0.7H),1.43-1.42(m,9H),1.08-1.01(m,3H)。

Rac 338N (280mg, 0.390mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak ID 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.3 at 12 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 338C (100mg, 36% yield, 100% stereopurity) and 338D (110mg, 39% yield, 97.3% stereopurity) as yellow solids.

Compound 338C: LC-MS (ESI): r_T＝4.576min，C₃₀H₃₆BrFN₄O₆S₂Calculated mass of 710.1, M/z found value 713.1[ M + H [ ]]⁺. Chiral analysis (analysis conditions: column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2, at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis conditions: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40: 0.2; temperature: 30 ℃; wavelength: 230_T＝7.731min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.2Hz,0.7H),9.09(s,0.3H),8.01-7.92(m,2H),7.44-7.37(m,1H),7.31-7.24(m,1H),7.21-7.15(m,1H),6.07(s,0.3H),5.97(d,J＝3.6Hz,0.7H),4.00-3.91(m,3.3H),3.76-3.67(m,2.7H),3.12-3.03(m,1H),2.88-2.80(m,2H),2.48-2.33(m,4H),2.10-1.77(m,3.3H),1.63-1.57(m,0.7H),1.41(s,9H),1.08-1.01(m,3H)。

Compound 338D: LC-MS (ESI): r_T＝4.575min，C₃₀H₃₆BrFN₄O₆S₂Calculated mass of 710.1, M/z found value 711.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak ID 5 μm 4.6: 0.2; temperature: 30 ℃; chiral analysis: C: DEA:. RTM.: 1_T＝9.220min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.2Hz,0.7H),9.09(s,0.3H),8.01-7.92(m,2H),7.44-7.37(m,1H),7.31-7.24(m,1H),7.21-7.15(m,1H),6.07(s,0.3H),5.97(d,J＝3.6Hz,0.7H),4.00-3.91(m,3.3H),3.76-3.67(m,2.7H),3.12-3.03(m,1H),2.88-2.80(m,2H),2.48-2.33(m,4H),2.10-1.77(m,3.3H),1.63-1.57(m,0.7H),1.41(s,9H),1.08-1.01(m,3H)。

Compounds 342X and 342Y: (trans) -Ethyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (3, 4-difluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -Ethyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (3, 4-difluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 342X: LC-MS (ESI): r_T＝3.760min，C₃₁H₃₈F₂N₄O₆S₂Calculated mass of 664.2, M/z found value 665.3[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.11(s,0.6H),7.81-7.80(m,1H),7.52(d,J＝2.8Hz,0.4H),7.43(d,J＝2.8Hz,0.6H),7.09-7.04(m,0.8H),6.99-6.95(m,0.4H),6.92-6.86(m,1.2H),5.94(s,0.6H),5.85(d,J＝2.0Hz,0.4H),4.21-4.15(m,0.5H),4.10-3.76(m,5.5H),3.22-3.13(m,1H),2.97-2.85(m,2H),2.82-2.72(m,2H),2.62-2.53(m,3.7H),2.42(d,J＝1.6Hz,1.3H),2.20-2.01(m,1.5H),1.96-1.73(m,2.2H),1.70-1.67(m,0.3H),1.48(s,9H),1.11(t,J＝7.2Hz,3H)。

Compound 342Y: LC-MS (ESI): r_T＝3.747min，C₃₁H₃₈F₂N₄O₆S₂Calculated mass of 664.2, M/z found value 665.3[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.11(s,0.6H),7.81-7.80(m,1H),7.52(d,J＝3.2Hz,0.4H),7.43(d,J＝3.2Hz,0.6H),7.09-7.03(m,0.8H),6.99-6.94(m,0.4H),6.92-6.86(m,1.2H),5.94(s,0.6H),5.86(d,J＝2.0Hz,0.4H),4.23-4.15(m,0.6H),4.09-3.91(m,4H),3.84-3.77(m,0.4H),3.72-3.63(m,1H),3.06-2.85(m,3H),2.81-2.70(m,2H),2.57-2.48(m,3.8H),2.42(d,J＝2.0Hz,1.2H),2.20-2.01(m,1.5H),1.95-1.76(m,2.2H),1.64-1.61(m,0.3H),1.46(s,9H),1.11(t,J＝7.2Hz,3H)。

Compounds 342M and 342N: (trans) -Ethyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (3, 4-difluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -Ethyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (3, 4-difluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 342M: LC-MS (ESI): r_T＝3.632min，C₃₁H₃₈F₂N₄O₆S₂Calculated mass of 664.2, M/z found value 665.3[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.11(s,0.6H),7.81-7.80(m,1H),7.52(d,J＝2.8Hz,0.4H),7.43(d,J＝2.8Hz,0.6H),7.08-7.04(m,0.8H),6.99-6.93(m,0.4H),6.92-6.86(m,1.2H),5.94(s,0.6H),5.85(d,J＝2.0Hz,0.4H),4.22-4.15(m,0.5H),4.10-3.76(m,5.5H),3.22-3.12(m,1H),2.98-2.85(m,2H),2.82-2.72(m,2H),2.62-2.53(m,3.7H),2.42(d,J＝1.6Hz,1.3H),2.20-2.01(m,1.5H),1.96-1.73(m,2.2H),1.70-1.67(m,0.3H),1.48(s,9H),1.11(t,J＝7.2Hz,3H)。

Compound 342N: LC-MS (ESI): r_T＝2.888min，C₃₁H₃₈F₂N₄O₆S₂Calculated mass of 664.2, M/z found value 665.3[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.13(s,0.6H),7.81-7.80(m,1H),7.52(d,J＝3.2Hz,0.4H),7.43(d,J＝3.2Hz,0.6H),7.09-7.04(m,0.8H),6.99-6.94(m,0.4H),6.92-6.86(m,1.2H),5.94(s,0.6H),5.86(d,J＝2.0Hz,0.4H),4.23-4.15(m,0.6H),4.09-3.91(m,4H),3.85-3.77(m,0.4H),3.72-3.63(m,1H),3.06-2.84(m,3H),2.81-2.70(m,2H),2.57-2.48(m,3.8H),2.42(d,J＝2.4Hz,1.2H),2.20-2.01(m,1.5H),1.95-1.76(m,2.2H),1.69-1.64(m,0.3H),1.46(s,9H),1.11(t,J＝7.2Hz,3H)。

Compounds 315X and 351Y: (trans) -Ethyl 6- (3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -Ethyl 6- (3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 351X: LC-MS (ESI): r_T＝3.273min，C₃₂H₃₅ClF₄N₄O₆Calculated mass of S714.2, M/z found value 715.2[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: IPA 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝10.999min)。¹H NMR(400MHz,CDCl₃)δ8.64(s,0.6H),8.35(d,J＝2.0Hz,0.6H),8.26(d,J＝2.0Hz,0.4H),7.77(s,0.4H),7.33-7.29(m,1H),7.08-6.98(m,2H),6.31(s,0.6H),6.07(d,J＝2.4Hz,0.4H),4.25-4.17(m,0.6H),4.09-3.94(m,3.4H),3.89-3.87(m,2H),3.20-3.15(m,1H),2.98-2.88(m,2H),2.80-2.72(m,2H),2.61-2.53(m,2H),2.22-2.17(m,0.4H),1.97-1.62(m,3.6H),1.48(s,5.4H),1.47(s,3.6H),1.13(t,J＝7.2Hz,3H)。

Compound 351Y: LC-MS (ESI): r_T＝2.469min，C₃₂H₃₅ClF₄N₄O₆Calculated mass of S714.2, M/z found value 715.1[ M + H [ ]]⁺。

Compound 353: ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((4-ethoxycarbonylcyclohexyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.177min，C₃₀H₃₅ClF₂N₄O₆S₂Calculated mass of 684.2, M/z found value 685.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.60(d,J＝3.2Hz,0.7H),9.14(s,0.3H),7.98-7.97(m,1.7H),7.91(d,J＝3.2Hz,0.3H),7.47-7.40(m,1H),7.21-7.14(m,1H),6.01(s,0.2H),5.92(d,J＝3.2Hz,0.8H),4.11-4.01(m,2H),3.98-3.92(m,2H),3.80-3.71(m,3H),3.23-3.11(m,1H),2.98-2.86(m,2H),2.11-1.72(m,8H),1.58-1.36(m,5H),1.19-1.14(m,3H),1.07-1.01(m,3H)。

353 racemic mixture (700mg, 1.02mmol) was separated by chiral preparative HPLC (column: ChiralpakIB 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 15 mL/min; temperature: 30 ℃ c; wavelength: 214nm) to give group 1(360mg) and group 2(230mg) as yellow solids. Group 1(360mg, 0.526mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μ M20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.3 at 12 mL/min; temperature: 30 ℃ c; wavelength: 214nm) to give EO8495_837M (80mg, 11% yield, 100% stereopurity) and EO8495_837N (80mg, 11% yield, 100% stereopurity) as yellow solids. Group 2(230mg, 0.336mmol) was separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.3 at 12 mL/min; temperature: 30 ℃; wavelength: 214nm) to give 353X (90mg, 13% yield, 100% stereopurity) and 353Y (90mg, 13% yield, 100% stereopurity) as yellow solids.

Compound 353M: LC-MS (ESI): r_T＝4.195min，C₃₀H₃₅ClF₂N₄O₆S₂Calculated mass of 684.2, M/z found value 685.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; chiral analysis (column: Chiralpak IE 5 μm 4.6: 0.2; mobile phase: Hex: EtOH: DEA ═ 60:40: 0.2; temperature: 30 ℃; wavelength_T＝17.755min)。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝3.2Hz,0.8H),9.15(s,0.2H),8.02-7.99(m,1.8H),7.93(d,J＝3.6Hz,0.2H),7.49-7.42(m,1H),7.24-7.16(m,1H),6.03(s,0.2H),5.94(d,J＝3.2Hz,0.8H),4.13-4.07(m,2H),4.02-3.94(m,2.3H),3.82-3.72(m,2.7H),3.25-3.17(m,1H),2.99-2.87(m,2H),2.67(br s,1H),2.13-1.74(m,7.4H),1.64-1.52(m,4.6H),1.19(t,J＝7.2Hz,3H),1.09-1.03(m,3H)。

Compound 353N: LC-MS(ESI)：R_T＝4.191min，C₃₀H₃₅ClF₂N₄O₆S₂Calculated mass of 684.2, M/z found value 685.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; chiral analysis (column: Chiralpak IE 5 μm 4.6: 0.2; mobile phase: Hex: EtOH: DEA ═ 60:40: 0.2; temperature: 30 ℃; wavelength_T＝19.587min)。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝3.6Hz,0.8H),9.15(s,0.2H),8.01-7.99(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.49-7.42(m,1H),7.24-7.16(m,1H),6.03(s,0.2H),5.94(d,J＝3.6Hz,0.8H),4.13-4.08(m,2H),4.01-3.94(m,2.3H),3.83-3.72(m,2.7H),3.26-3.17(m,1H),3.00-2.88(m,2H),2.67(br s,1H),2.14-2.02(m,2H),1.98-1.74(m,5H),1.65-1.53(m,5H),1.19(t,J＝7.2Hz,3H),1.09-1.03(m,3H)。

Compound 353X: LC-MS (ESI): r_T＝4.178min，C₃₀H₃₅ClF₂N₄O₆S₂Calculated mass of 684.2, M/z found value 685.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; chiral analysis (column: Chiralpak IC5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA ═ 60:40: 0.2; temperature: 30 ℃; wavelength: 230_T＝13.384min)。¹H NMR(400MHz,DMSO-d₆)δ9.60(d,J＝3.2Hz,0.8H),9.14(s,0.2H),7.99-7.97(m,1.8H),7.92(d,J＝3.6Hz,0.2H),7.47-7.40(m,1H),7.22-7.14(m,1H),6.02(s,0.2H),5.92(d,J＝3.6Hz,0.8H),4.06-4.01(m,2H),3.99-3.92(m,2.2H),3.81-3.71(m,2.8H),3.19-3.11(m,1H),3.00-2.89(m,2H),2.34-2.25(m,1H),2.09-1.73(m,7.2H),1.61-1.54(m,0.8H),1.52-1.36(m,4H),1.16(t,J＝7.2Hz,3H),1.07-1.01(m,3H)。

Compound 353Y: LC-MS (ESI): r_T＝4.180min，C₃₀H₃₅ClF₂N₄O₆S₂Calculated mass of 684.2, M/z found value 685.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; chiral analysis (column: Chiralpak IC5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA ═ 60:40: 0.2; temperature: 30 ℃; wavelength: 230_T＝16.644min)。¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝3.2Hz,0.8H),9.16(s,0.2H),8.01-7.99(m,1.7H),7.94(d,J＝3.2Hz,0.3H),7.49-7.43(m,1H),7.23-7.16(m,1H),6.04(s,0.2H),5.94(d,J＝3.2Hz,0.8H),4.06(q,J＝7.2Hz,2H),4.01-3.94(m,2.3H),3.82-3.73(m,2.7H),3.21-3.13(m,1H),3.00-2.92(m,2H),2.36-2.28(m,1H),2.10-1.74(m,7.2H),1.62-1.59(m,0.8H),1.53-1.38(m,4H),1.18(t,J＝7.2Hz,3H),1.09-1.03(m,3H)。

Compound 355: ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((2-methoxy-2-oxoethyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.127min，C₂₄H₂₅ClF₂N₄O₆S₂Calculated mass of 602.1, M/z found value 602.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.62(br s,0.8H),9.17(br s,0.2H),8.04-7.99(m,1.8H),7.94-7.91(m,0.2H),7.49-7.42(m,1H),7.24-7.17(m,1H),6.04(s,0.2H),5.94-5.91(d,J＝1.6Hz,0.8H),4.33(s,0.5H),4.31(s,1.5H),3.98(q,J＝2.8Hz,2H),3.82-3.67(m,6H),2.97-2.84(m,2H),2.17-2.08(m,0.2H),2.04-1.94(m,1H),1.89-1.80(m,2H),1.70-1.62(m,0.8H),1.10-1.03(m,3H)。

Compound 364: methyl 4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -6- ((R) -1- ((2,2, 2-trifluoroethyl) sulfonyl) pyrrolidin-3-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.458min，C₂₁H₁₉ClF₄N₄O₄S₂Calculated mass of 566.0, M/z found value 566.8[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)9.60-9.38(m,1H),8.04-7.94(m,2H),7.44-7.32(m,2H),7.23-7.20(m,1H),6.03(s,0.1H),5.94(s,0.9H),4.62-4.54(m,2.1H),4.42-4.34(m,0.9H),3.78-3.61(m,3H),3.58(s,3H),3.48-3.42(m,1H),2.24-2.15(m,1H),2.09-1.99(m,1H)。

Compound 365: methyl 4- (2-chloro-4-fluorophenyl) -6- ((R —) -1- ((2-methoxyethyl) sulfonyl) pyrrolidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.246min，C₂₂H₂₄ClFN₄O₅S₂Calculated mass of 542.1, found value of M/z 543.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝3.6Hz,0.9H),9.28(s,0.1H),8.03-7.93(m,2H),7.44-7.41(m,1H),7.39-7.35(m,1H),7.24-7.19(m,1H),6.02(s,0.1H),5.94(d,J＝3.6Hz,0.9H),4.60-4.56(m,0.1H),4.40-4.31(m,0.9H),3.72(t,J＝6.0Hz,2H),3.64-3.50(m,6H),3.48-3.43(m,2H),3.39-3.30(m,4H),2.25-2.16(m,1H),2.03-1.94(m,1H)。

Compounds 366X and 366Y: (trans) -methyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) pyrrolidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -methyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) pyrrolidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 366X: LC-MS (ESI): r_T＝1.92min，C₂₈H₃₂ClFN₄O₆S₂Calculated mass of 638.1, M/z found value 639.8[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.60(s,1H),8.01(d,J＝2.8Hz,1H),7.74-7.66(m,1H),7.43-7.35(m,2H),7.22-7.17(m,1H),5.95(s,1H),4.36-4.32(m,1H),4.14-4.10(m,1H),3.67-3.60(m,2.5H),3.53(s,3H),3.50-3.48(m,0.5H),3.41-3.35(m,1H),3.15-3.09(m,1H),2.66-2.59(m,2H),2.17-2.11(m,1H),2.04-1.95(m,1H),1.37(s,9H),1.27-1.22(m,2H)。

Compound 366Y: LC-MS (ESI): r_T＝1.88min，C₂₈H₃₂ClFN₄O₆S₂Calculated mass of 638.1, M/z found value 638.6[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(s,0.9H),9.25(br s,0.1H),8.03(s,1.5H),7.75-7.69(m,0.5H),7.44-7.36(m,2H),7.23-7.19(m,1H),5.95(s,0.9H),5.79(s,0.1H),4.38-4.33(m,0.8H),4.13-4.01(m,1.2H),3.63-3.48(m,6H),3.27-3.18(m,1H),3.14-3.05(m,1H),2.53(br s,2H),2.22-2.13(m,1H),2.02-1.96(m,1H),1.40(s,9H),1.28-1.15(m,2H)。

Compounds 370B-1 and 370D-1: (trans) -Ethyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -Ethyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound (I)370B-1：LC-MS(ESI)：R_T＝4.718min，C₃₀H₃₅ClF₂N₄O₆S₂Calculated mass of 684.2, M/z found value 685.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.62(s,0.7H),9.13(s,0.3H),8.01-7.94(m,2H),7.49-7.43(m,1H),7.23-7.19(m,1H),6.03(s,0.3H),5.94(s,0.7H),4.04-3.95(m,3.2H),3.78-3.70(m,2.8H),3.16-3.08(m,1H),2.91-2.82(m,2H),2.60-2.52(m,4H),2.02-1.74(m,3H),1.63-1.58(m,1H),1.42(s,9H),1.07(t,d＝6.8Hz,3H)。

Compound 370D-1: LC-MS (ESI): r_T＝2.812min，C₃₀H₃₅ClF₂N₄O₆S₂Calculated mass of 684.2, M/z found value 685.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.3H),7.83(d,J＝3.2Hz,1H),7.53(d,J＝3.2Hz,0.7H),7.45(d,J＝3.6Hz,0.3H),7.35(s,0.7H),7.10-6.99(m,2H),6.20(s,0.3H),6.09(d,J＝2.8Hz,0.7H),4.22-4.15(m,0.3H),4.10-3.87(m,4.7H),3.72-3.63(m,1H),3.06-2.86(m,3H),2.81-2.70(m,2H),2.57-2.47(m,2H),2.24-1.66(m,4H),1.46(s,9H),1.14-1.10(m,3H)。

Compound 389B: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (2-methoxy-2-oxoethylsulfonamide) bicyclo [1.1.1]Pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,¹H NMR(400MHz,DMSO-d₆)9.43(br s,0.3H),8.34-8.32(m,0.7H),8.01-7.98(m,1.5H),7.95-7.94(m,0.5H),7.44-7.40(m,1H),7.35-7.30(m,1H),7.25-7.18(m,1H),5.97(s,0.5H),5.87(s,0.5H),4.20(s,1H),4.15(s,1H),3.72(s,1.2H),3.71(s,1.8H),3.55(s,1.5H),3.53(s,1.5H),2.45(s,2H),2.42(s,1H),2.29(s,2H),2.25(s,1H)。

compound 391B: methyl 6- (3-acetamido-bicyclo [1.1.1]]Pent-1-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.398min，C₂₂H₂₀ClFN₄O₃Calculated mass of S474.1, found value of M/z 475.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.36(d,J＝2.8Hz,0.5H),8.52(s,0.5H),8.39(s,0.5H),8.28(s,0.5H),8.01-7.99(m,1.4H),7.95(d,J＝2.8Hz,0.6H),7.44-7.40(m,1H),7.35-7.30(m,1H),7.25-7.19(m,1H),5.96(s,0.5H),5.86(d,J＝3.6Hz,0.5H),3.55(s,1.5H),3.53(s,1.5H),2.44(s,3.2H),2.28(s,2.8H),1.79(s,1.7H),1.77(s,1.3H)。

Compound 392B: methyl 6- (3- (1, 4-dioxaspiro [4.5]]Dec-2-ylmethylsulfonamido) bicyclo [1.1.1]Pent-1-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝1.86min，C₂₉H₃₂ClFN₄O₆S₂Calculated mass of 650.1, M/z found value 651.5[ M + H ]]⁺。

Compound 396: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -6- (4- (methylsulfonamido) cyclohexyl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.132min，C₂₄H₂₄ClF₃N₄O₄Calculated mass of S556.1, found M/z 557.1[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.18(br s,0.7H),9.07-9.03(m,0.3H),8.59-8.55(m,1H),8.09-8.03(m,1H),7.44-7.39(m,1H),7.36-7.31(m,1H),7.25-7.18(m,1H),7.15-7.09(m,0.7H),7.07-7.02(m,0.3H),6.01(s,0.7H),5.90(d,J＝3.2Hz,0.3H),3.86-3.78(m,0.7H),3.57-3.54(m,0.3H),3.52(s,1H),3.50(s,2H),3.22-3.15(m,0.7H),3.11-3.04(m,0.3H),2.92(s,1H),2.91(s,2H),2.03-1.97(m,2H),1.85-1.79(m,1.8H),1.76-1.71(m,1.8H),1.60-1.53(m,0.4H),1.38-1.27(m,2H)。

Rac 396(140mg, 0.251mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak OD-H5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 85:15:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 396A (25mg, 18% yield, 100% stereopurity) as a yellow solid and 396B (25mg, 18% yield, 97.3% stereopurity) as a yellow solid.

Compound 396A: LC-MS (ESI): r_T＝4.016min，C₂₄H₂₄ClF₃N₄O₄Calculated mass of S556.1, found value of M/z 556.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak OD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 85:15:0.2, at 1.0 mL/min; temperature: 30 ℃; wavelenght:. TM.: 250 mm; chiral analysis; column: Chiralpak OD-H5 μm 4.6: 250 mm; mobile phase: Hex: EtOH: DEALength: 230nm, R_T＝12.683min)。¹H NMR(400MHz,DMSO-d₆)δ9.15(br s,0.7H),9.02(d,J＝3.6Hz,0.3H),8.57-8.55(m,1H),8.08-8.02(m,1H),7.44-7.39(m,1H),7.36-7.31(m,1H),7.24-7.18(m,1H),7.10(d,J＝7.6Hz,0.7H),7.01(d,J＝7.2Hz,0.3H),6.02(s,0.7H),5.91(d,J＝2.8Hz,0.3H),3.84-3.80(m,0.8H),3.56-3.54(m,0.2H),3.52(s,1H),3.50(s,2H),3.21-3.18(m,0.6H),3.10-3.05(m,0.4H),2.92(s,1H),2.91(s,2H),2.04-1.95(m,2H),1.86-1.80(m,1.6H),1.77-1.71(m,2H),1.59-1.54(m,0.4H),1.36-1.27(m,2H)。

Compound 396B: LC-MS (ESI): r_T＝4.016min，C₂₄H₂₄ClF₃N₄O₄Calculated mass of S556.1, found value of M/z 556.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak OD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 85:15:0.2, at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak OD-H5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA ═ 85:15: 0.2; temperature: 30_T＝15.170min)。¹H NMR(400MHz,DMSO-d₆)δ9.16(br s,0.7H),9.02(d,J＝3.2Hz,0.3H),8.57-8.55(m,1H),8.08-8.02(m,1H),7.44-7.39(m,1H),7.35-7.31(m,1H),7.24-7.18(m,1H),7.10(d,J＝7.6Hz,0.7H),7.02(d,J＝7.6Hz,0.3H),6.02(s,0.7H),5.91(d,J＝3.2Hz,0.3H),3.86-3.78(m,0.7H),3.58-3.54(m,0.3H),3.52(s,1H),3.50(s,2H),3.21-3.17(m,0.7H),3.10-3.04(m,0.3H),2.92(s,1H),2.91(s,2H),2.04-1.99(m,2H),1.85-1.80(m,1.7H),1.76-1.71(m,2H),1.58-1.53(m,0.3H),1.36-1.27(m,2H)。

Compound 399: (cis) -methyl 4- (2-chloro-4-fluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -6- (4- (methylsulfonamido) cyclohexyl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.700min，C₂₄H₂₄ClF₃N₄O₄Calculated mass of S556.1, found value of M/z 556.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.19-9.14(m,0.8H),9.08-9.02(m,0.2H),8.65-8.62(m,0.5H),8.58-8.55(m,0.5H),8.11-8.03(m,1H),7.44-7.39(m,1H),7.36-7.31(m,1H),7.25-7.19(m,1H),7.12-7.09(m,0.8H),7.05-7.02(m,0.1H),6.78-6.76(m,0.1H),6.05-6.00(m,0.8H),5.92-5.89(m,0.2H),3.94-3.88(m,0.6H),3.84-3.80(m,0.3H),3.69-3.62(m,0.5H),3.52(s,1H),3.50(s,2H),3.21-3.16(m,0.4H),3.11-3.04(m,0.2H),2.96(s,1.5H),2.92-2.91(s,1.3H),2.90-2.88(m,0.2H),2.07-2.00(m,1H),1.94-1.80(m,3H),1.73-1.51(m,3H),1.36-1.24(m,1H)。

Rac 399(70mg, 0.126mmol) was separated by chiral preparative HPLC (separation conditions: column: chiralpak id 5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 70:30 at 13 mL/min; temperature: 30 ℃; wavelength: 254nm) to give the title compound 399C as a yellow solid (25mg, 36% yield, 100% stereopurity) and 399D as a yellow solid (24mg, 34% yield, 99.4% stereopurity).

Compound 399C: LC-MS (ESI): r_T＝4.040min，C₂₄H₂₄ClF₃N₄O₄Calculated mass of S556.1, found value of M/z 556.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.748min)。¹H NMR(400MHz,DMSO-d₆)δ9.17(br s,0.9H),9.10-9.05(m,0.1H),8.67-8.61(m,0.9H),8.57-8.55(m,0.1H),8.11-8.04(m,1H),7.45-7.40(m,1H),7.39-7.33(m,1H),7.25-7.19(m,1H),7.14-7.07(m,0.9H),6.79-6.76(m,0.1H),6.03(s,0.9H),5.93-5.90(m,0.1H),3.96-3.86(m,1H),3.68-3.62(m,1H),3.51(s,0.4H),3.50(s,2.6H),2.96(s,2.6H),2.89(s,0.4H),1.97-1.80(m,4H),1.68-1.57(m,3H),1.54-1.51(m,1H)。

Compound 399D: LC-MS (ESI): r_T＝4.018min，C₂₄H₂₄ClF₃N₄O₄Calculated mass of S556.1, found value of M/z 556.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝8.621min)。¹H NMR(400MHz,DMSO-d₆)δ9.18(br s,0.7H),9.08-9.03(m,0.3H),8.59-8.54(m,1H),8.09-8.03(m,1H),7.44-7.40(m,1H),7.36-7.31(m,1H),7.25-7.18(m,1H),7.15-7.10(m,0.7H),7.06-7.02(m,0.3H),6.01(s,0.7H),5.92-5.89(m,0.3H),3.86-3.79(m,0.7H),3.57-3.54(m,0.3H),3.51(s,1H),3.50(s,2H),3.20-3.15(m,0.7H),3.09-3.06(m,0.3H),2.92(s,3H),2.02-1.98(m,2H),1.85-1.80(m,1.8H),1.76-1.71(m,2H),1.58-1.55(m,0.2H),1.33-1.24(m,2H)。

Compound 405: methyl 6- (3- (1- (tert-butoxycarbonyl) azetidine-3-sulfonylamino) bicyclo [1.1.1] pent-1-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝1.81min，C₂₈H₃₀ClF₂N₅O₆S₂Calculated mass of 669.1, M/z found 670.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.87-7.81(m,1.7H),7.51-7.46(m,1.3H),7.04-7.02(m,2H),6.15(s,0.7H),6.02(s,0.3H),5.40(s,0.7H),5.23(s,0.3H),4.22-4.17(m,4H),3.99-3.95(m,1H),3.62(s,0.9H),3.59(s,2.1H),2.58(s,4.2H),2.45(s,1.8H),1.45(s,9H)。

Compound 406: methyl 6- (3- (azetidine-3-sulfonylamino) bicyclo [1.1.1] pent-1-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 405 was subjected to de-Boc using TFA to give compound 406, LC-ms (esi): r_T＝3.946min，C₂₃H₂₂ClF₂N₅O₄S₂Calculated mass of 569.1, M/z found value 570.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.88-7.81(m,1.7H),7.52-7.46(m,1.3H),7.10-7.02(m,2H),6.15(s,0.7H),6.02(s,0.3H),4.28-4.16(m,1H),4.10-4.04(m,2H),3.87-3.83(m,2H),3.62(s,0.9H),3.60(s,2.1H),2.57(s,4H),2.48(s,2H)。

Compounds 409P and 409Q: trans-methyl 4- (2-bromo-4-fluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and cis-methyl 4- (2-bromo-4-fluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) -sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester

Compound 409p (trans): LC-MS (ESI): r_T＝3.005min，C₃₁H₄₀BrFN₄O₆S₂Calculated mass of Si 754.1, found value of M/z 754.7[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.84(d,J＝3.2Hz,1H),7.53-7.45(m,1.8H),7.34-7.31(m,1.2H),7.02-6.94(m,1H),6.16(s,0.2H),6.03(d,J＝2.0Hz,0.8H),4.25-4.21(m,2.2H),4.01-3.78(m,3.8H),3.60(s,3H),2.94-2.74(m,4H),2.52-2.46(m,2H),2.29-2.20(m,1H),2.05-2.01(m,1H),1.92-1.88(m,1H),1.71-1.67(m,1H),1.60(s,1H),1.45(m,3H),1.05-1.01(m,2H),0.06(s,9H)。

Compound 409q (cis): LC-MS (ESI): r_T＝2.952min，C₃₁H₄₀BrFN₄O₆S₂Calculated mass of Si 754.1, found value of M/z 754.7[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.12(s,0.2H),7.78(d,J＝2.8Hz,1H),7.47-7.39(m,1.8H),7.28-7.20(m,1H),6.97-6.89(m,1H),6.11(s,0.3H),5.98(d,J＝2.0Hz,0.7H),4.17-4.09(m,2.2H),3.98-3.82(m,2.8H),3.71-3.67(m,1H),3.54(s,3H),2.97-2.81(m,4H),2.19-2.08(m,3H),2.02-1.95(m,1H),1.86-1.83(m,1H),1.64-1.61(m,1H),1.52(s,1H),1.43(s,3H),0.99-0.94(m,2H),0.01(s,9H)。

Compounds 413C and 413D: (trans) -ethyl 4- (2-bromo-3-fluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -ethyl 4- (2-bromo-3-fluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) -sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester

Compound 413c (trans): LC-MS (ESI): r_T＝2.43min，C₃₂H₄₂BrFN₄O₆S₂Calculated mass of Si 768.2, found value of M/z 770.7[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.53(br s,0.8H),9.08(br s,0.2H),8.01-7.97(m,1.9H),7.90-7.83(m,0.1H),7.38(dd,J＝13.6,8.0Hz,1H),7.28-7.24(m,1H),7.17(d,J＝7.6Hz,1H),6.04(br s,0.2H),5.95(br s,0.8H),4.14(t,J＝8.4Hz,2H),3.97-3.89(m,3H),3.73-3.66(m,3H),2.86-2.71(m,4H),2.28-2.22(m,2H),1.80-1.70(m,3H),1.61-1.54(m,1H),1.33(s,3H),1.02(t,J＝6.8Hz,3H),0.94(t,J＝8.4Hz,2H),0.00(s,9H)。

Compound 413d (cis): LC-MS (ESI): r_T＝2.32min，C₃₂H₄₂BrFN₄O₆S₂Calculated mass of Si 768.2, found value of M/z 770.7[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝3.2Hz,0.8H),9.07(br s,0.2H),7.99-7.95(m,1.8H),7.90(d,J＝3.6Hz,0.2H),7.41-7.36(m,1H),7.29-7.22(m,1H),7.18(d,J＝7.6Hz,0.8H),7.13(d,J＝7.6Hz,0.2H),6.04(br s,0.2H),5.94(d,J＝3.6Hz,0.8H),4.15-4.10(m,3H),3.97-3.91(m,2H),3.73-3.63(m,3H),2.87-2.78(m,2H),2.66-2.61(m,2H),2.18-2.13(m,2H),1.94-1.74(m,3H),1.57(d,J＝12.8Hz,1H),1.40(s,3H),1.03(t,J＝6.8Hz,3H),0.93(t,J＝8.4Hz,2H),0.00(s,9H)。

Compound 415: methyl 6- (1- (N- (tert-butoxycarbonyl) sulfamoyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝1.82min，C₂₅H₂₈ClF₂N₅O₆S₂Calculated mass 631.1, M/z found value 632.3[ M + H [ ]]⁺。

Compounds 419A and 419B: (trans) -ethyl 4- (4-fluoro-2-methylphenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -ethyl 4- (4-fluoro-2-methylphenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) -carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester

Compound 419A: LC-MS (ESI): r_T＝2.122min，C₃₃H₄₅FN₄O₆S₂Calculated mass of Si 704.3, found in M/z 705.1[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.09(br s,0.5H),7.81-7.80(m,1H),7.52(d,J＝2.8Hz,0.5H),7.42(d,J＝3.2Hz,0.5H),7.31-7.29(m,0.5H),7.16-7.13(m,0.5H),7.00(s,0.5H),6.90-6.77(m,2H),5.95(s,0.5H),5.86(d,J＝4.8Hz,0.5H),4.25-4.21(m,2.5H),4.03-3.77(m,5.5H),2.95-2.74(m,4H),2.62(s,1.5H),2.52-2.43(m,3.5H),2.15-2.05(m,1.4H),1.96-1.77(m,2H),1.67-1.63(m,0.6H),1.45(d,J＝2.8Hz,3H),1.10(q,J＝7.2Hz,3H),1.06-0.99(m,2H),0.07-0.06(m,9H)。

Compound 419B: LC-MS (ESI): r_T＝2.012min，C₃₃H₄₅FN₄O₆S₂Calculated mass of Si 704.3, found value of M/z 705.2[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ8.10(br s,0.5H),7.80(d,J＝3.2Hz,1H),7.52(d,J＝2.8Hz,0.5H),7.42(d,J＝3.2Hz,0.5H),7.31-7.29(m,0.5H),7.17-7.13(m,0.5H),7.02-6.99(m,0.5H),6.90-6.77(m,2H),5.95(s,0.5H),5.86(d,J＝4.8Hz,0.5H),4.22-4.18(m,2.5H),4.04-3.90(m,4H),3.84-3.71(m,1.5H),3.02-2.83(m,4H),2.62(s,1.5H),2.48(s,1.5H),2.24-2.05(m,3.5H),1.96-1.78(m,2H),1.66-1.64(m,0.5H),1.48(d,J＝2.0Hz,3H),1.10(q,J＝7.2Hz,3H),1.04-0.99(m,2H),0.05(s,9H)。

Compound 421: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (((trans-4- (methoxycarbonyl) cyclohexyl) methyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.13min，C₂₉H₃₄ClFN₄O₆S₂Calculated mass of 652.1, M/z found value 653.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(brs,0.2H),7.87-7.78(m,1H),7.53(d,J＝3.2Hz,0.8H),7.46-7.45(m,1H),7.30-7.26(m,1H),7.16-7.12(m,1H),7.04-6.98(m,1H),6.19(s,0.2H),6.07(d,J＝3.6Hz,0.8H),4.03-3.86(m,3H),3.67(s,3H),3.60-3.59(m,3H),2.94-2.84(m,2H),2.81-2.78(m,2H),2.31-2.20(m,2H),2.16-2.09(m,2H),2.04-1.98(m,3H),1.99-1.80(m,2H),1.74-1.70(m,1H),1.57-1.47(m,2H),1.19-1.09(m,2H)。

Compound 423: ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (((trans-4- (methoxycarbonyl) cyclohexyl) methyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_TCalculated mass 684.2 of C30H35ClF2N4O6S2, M/z found 685.4[ M + H3.28 min [ ]]⁺。¹H NMR(400MHz,CD₃OD)7.95(d,J＝3.2Hz,0.3H),7.91(d,J＝3.2Hz,0.7H),7.78(d,J＝3.2Hz,0.7H),7.91(d,J＝3.2Hz,0.3H),7.30-7.22(m,2H),6.18(s,0.3H),6.11(s,0.7H),4.16-4.01(m,2H),3.98-3.83(m,3H),3.67(s,3H),2.99-2.85(m,4H),2.37-2.27(m,1H),2.20-2.04(m,4H),2.01-1.90(m,4H),1.75-1.70(m,1H),1.55-1.45(m,2H),1.28-1.21(m,2H),116-1.12(m,3H)。

Compounds 428C and 428D: (trans) -ethyl 4- (3-fluoro-2-methylphenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -ethyl 4- (3-fluoro-2-methylphenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) -sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester

Compound 428c (trans): LC-MS (ESI): r_T＝2.06min，C₃₃H₄₅FN₄O₆S₂Calculated mass of Si 704.3, found value of M/z 704.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝3.2Hz,0.3H),7.88(d,J＝3.2Hz,0.7H),7.75-7.72(m,1H),7.18-7.08(m,2H),6.97-6.92(m,1H),5.96(s,0.3H),5.90(s,0.7H),4.26-4.22(m,2H),4.06-3.80(m,6H),3.00-2.79(m,4H),2.50(d,J＝2.0Hz,1H),2.44-2.38(m,4H),2.13-2.01(m,2H),1.90-1.84(m,1.4H),1.68-1.63(m,0.6H),1.43(d,J＝2.4Hz,3H),1.12(t,J＝7.2Hz,3H),1.10-1.00(m,2H),0.07-0.05(m,9H)。

Compound 428d (cis): LC-MS (ESI): r_T＝1.99min，C₃₃H₄₅FN₄O₆S₂Calculated mass of Si 704.3, found value of M/z 704.9[ M + H ]]⁺。¹HNMR(400MHz,CD₃OD)δ7.91-7.88(m,1H),7.76-7.72(m,1H),7.20-7.08(m,2H),6.97-6.91(m,1H),5.96(s,0.3H),5.90(s,0.7H),4.25-4.21(m,2H),4.11-3.79(m,6H),2.99-2.84(m,4H),2.50(d,J＝2.0Hz,1H),2.43(d,J＝1.6Hz,2H),2.27-2.24(m,2H),2.11-1.97(m,2H),1.88-1.85(m,1.4H),1.68-1.64(m,0.6H),1.49(s,3H),1.12(t,J＝7.2Hz,3H),1.05-1.01(m,2H),0.07-0.05(m,9H)。

Compound 437: (cis) -ethyl 4- (2-chloro-4-fluorophenyl) -6- (2, 2-dimethyl-3- (methylsulfonamido) cyclobutyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.161min，C₂₃H₂₆ClFN₄O₄S₂Calculated mass of 540.1, M/z found value 541.2[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.40(d,J＝3.2Hz,0.7H),8.30(s,0.3H),8.04-7.98(m,2H),7.45-7.36(m,2H),7.32-7.25(m,2H),6.08(s,0.3H),5.95(d,J＝3.2Hz,0.7H),4.20-4.15(m,0.3H),3.98(q,J＝7.2Hz,2H),3.84-3.80(m,0.7H),3.62-3.56(m,0.3H),3.50-3.43(m,0.7H),2.94(s,0.9H),2.91(s,2.1H),2.80-2.72(m,0.7H),2.40-2.34(m,0.3H),2.27-2.19(m,0.3H),2.12-2.05(m,0.7H),1.21(s,0.9H),1.18(s,2.1H),1.10-1.04(m,6H)。

Rac 437(200mg, 0.37mmol) was obtained by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 60:40 at 12 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 437A (85mg, 42% yield, 100% stereopurity) and 437B (87mg, 43% yield, 100% stereopurity) as yellow solids.

Compound 437A: LC-MS (ESI): r_T＝3.661min，C₂₃H₂₆ClFN₄O₄S₂Calculated mass of 540.1, M/z found value 540.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.429min)。¹H NMR(400MHz,DMSO-d₆)δ9.39(d,J＝3.2Hz,0.7H),8.30(s,0.3H),8.03-7.98(m,2H),7.45-7.36(m,2H),7.32-7.25(m,2H),6.08(s,0.3H),5.95(d,J＝3.2Hz,0.7H),4.20-4.15(m,0.3H),3.98(q,J＝7.2Hz,2H),3.84-3.79(m,0.7H),3.62-3.56(m,0.3H),3.50-3.43(m,0.7H),2.94(s,0.9H),2.91(s,2.1H),2.79-2.72(m,0.7H),2.40-2.32(m,0.3H),2.27-2.18(m,0.3H),2.12-2.05(m,0.7H),1.21(s,0.9H),1.18(s,2.1H),1.10-1.04(m,6H)。

Compound 437B: LC-MS (ESI): r_T＝3.691min，C₂₃H₂₆ClFN₄O₄S₂Calculated mass of 540.1, M/z found value 540.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝9.756min)。¹H NMR(400MHz,DMSO-d₆)δ9.38(d,J＝3.2Hz,0.7H),8.30(s,0.3H),8.03-7.98(m,2H),7.45-7.36(m,2H),7.32-7.25(m,2H),6.08(s,0.3H),5.95(d,J＝3.2Hz,0.7H),4.20-4.15(m,0.3H),3.98(q,J＝7.2Hz,2H),3.84-3.79(m,0.7H),3.62-3.56(m,0.3H),3.50-3.43(m,0.7H),2.94(s,0.9H),2.91(s,2.1H),2.79-2.72(m,0.7H),2.40-2.33(m,0.3H),2.27-2.18(m,0.3H),2.12-2.05(m,0.7H),1.21(s,0.9H),1.18(s,2.1H),1.10-1.04(m,6H)。

Compounds 438F and 438H: (trans) -methyl 4- (2-bromo-3-fluorophenyl) -6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -methyl 4- (2-bromo-3-fluorophenyl) -6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

And (3) purification conditions: purification by silica gel column chromatography (petroleum ether: ethyl acetate ═ 4:1 to 2:1) and further purification by C18 column (acetonitrile: water ═ 80% to 88%) gave the title compound 438F (450mg, 38% yield, 100% stereopure) and 438H (350mg, 30% yield, 99.5% stereopure) as yellow solids.

Compound 438f (trans): LC-MS (ESI): r_T＝4.235min，C₂₉H₃₄BrFN₄O₆S₂Calculated mass of 696.1, M/z found value 696.8[ M + H ]]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R-_T＝11.290min)。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.2Hz,0.8H),9.16(s,0.2H),8.01-7.98(m,1.7H),7.93(d,J＝3.2Hz,0.3H),7.44-7.37(m,1H),7.29(t,J＝8.4Hz,1H),7.24-7.20(m,0.8H),7.15(d,J＝7.2Hz,0.2H),6.06(s,0.2H),5.97(d,J＝3.6Hz,0.8H),4.04-3.96(m,1H),3.77-3.71(m,3H),3.52(s,2.4H),3.51(s,0.6H),3.16-3.08(m,1H),2.92-2.83(m,2H),2.61-2.54(m,4H),2.06-1.76(m,3H),1.62-1.59(m,1H),1.42(s,9H)。

Compound 438h (cis): LC-MS (ESI): r_T＝4.145min，C₂₉H₃₄BrFN₄O₆S₂Calculated mass of 696.1, M/z found value 696.8[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝9.158min)。¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝2.8Hz,0.8H),9.16(s,0.2H),8.01-7.98(m,1.7H),7.93(d,J＝3.2Hz,0.3H),7.44-7.38(m,1H),7.29(t,J＝8.4Hz,1H),7.24-7.20(m,0.8H),7.14(d,J＝7.6Hz,0.2H),6.06(s,0.2H),5.97(d,J＝3.2Hz,0.8H),3.99-3.91(m,1H),3.76-3.67(m,3H),3.52(s,2.4H),3.51(s,0.6H),3.12-3.03(m,1H),2.89-2.80(m,2H),2.49-2.40(m,4H),2.07-1.76(m,3H),1.63-1.57(m,1H),1.41(s,9H)。

Compound 440B: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (2- (2- (2-methoxyethoxy) ethoxy) ethanesulfonamide) bicyclo [1.1.1]Pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.335min，C₂₇H₃₂ClFN₄O₇S₂Calculated mass of 642.1, M/z found value 643.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.86(s,0.7H),7.83-7.81(m,1H),7.49(d,J＝3.2Hz,0.3H),7.45-7.42(m,1H),7.30-7.28(m,0.5H),7.26-7.24(m,0.5H),7.15-7.11(m,1H),6.97-6.89(m,1H),6.33(s,0.7H),6.15(s,0.7H),6.09(s,0.3H),6.02(d,J＝2.8Hz,0.3H),3.95-3.91(m,2H),3.69-3.66(m,6H),3.63(s,1H),3.60-3.57(m,4H),3.41(s,1H),3.40(s,2H),3.32-3.26(m,2H),2.56(s,4H),2.50(s,2H)。

Compound 443 b: methyl 4- (3-fluoro-2-methylphenyl) -6- (1- (((trans) -4- (methoxycarbonyl) cyclohexyl) methyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝1.86min，C₃₀H₃₇FN₄O₆S₂Calculated mass of 632.2, M/z found value 632.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.59(d,J＝3.2Hz,0.9H),9.17(s,0.1H),8.00-7.92(m,2H),7.22-7.13(m,2H),7.08-6.99(m,1H),5.87(s,0.1H),5.73(d,J＝3.2Hz,0.9H),3.79-3.66(m,3H),3.59(s,3H),3.53(s,0.5H),3.52(s,2.5H),2.94(d,J＝6.4Hz,2H),2.87-2.76(m,2H),2.45(s,0.4H),2.38(s,2.6H),2.30-2.22(m,1H),2.06-1.77(m,8H),1.66-1.62(m,1H),1.36-1.31(m,2H),1.18-1.06(m,2H)

Compounds 447-1C and 447-1D: (trans) -methyl 4- (4-fluoro-2-methylphenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -methyl 4- (4-fluoro-2-methylphenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) -sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester

Compound 447-1c (trans): LC-MS (ESI): r_T＝2.323min，C₃₂H₄₃FN₄O₆S₂Calculated mass of Si 690.2, found value of M/z 691.1[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.92-7.87(m,1H),7.76-7.69(m,1H),7.34-7.30(m,0.7H),7.24-7.21(m,0.3H),6.90-6.78(m,2H),5.90(s,0.3H),5.84(s,0.7H),4.26-4.22(m,2H),4.17-4.06(m,0.4H),3.98-3.78(m,3.6H),3.58(s,3H),3.00-2.79(m,4H),2.60(s,1H),2.52(s,2H),2.46-2.38(m,2H),2.10-1.97(m,2H),1.90-1.83(m,1H),1.65-1.62(m,1H),1.43(s,3H),1.06-0.98(m,2H),0.07(s,9H)。

Compound 447-1d (cis): LC-MS (ESI): r_T＝2.301min，C₃₂H₄₃FN₄O₆S₂Calculated mass of Si 690.2, found value of M/z 691.1[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.92-7.87(m,1H),7.75-7.71(m,1H),7.34-7.31(m,0.7H),7.25-7.21(m,0.3H),6.93-6.83(m,2H),5.90(s,0.3H),5.84(s,0.7H),4.25-4.20(m,2H),4.12-4.02(m,1H),3.95-3.78(m,3H),3.58(s,3H),2.99-2.84(m,4H),2.60(s,1H),2.52(s,2H),2.29-2.22(m,2H),2.11-2.01(m,2H),1.93-1.83(m,1.3H),1.66-1.63(m,0.7H),1.48(s,3H),1.05-1.00(m,2H),0.06(s,9H)。

Compound 449: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (((4- (methoxycarbonyl) -1-methylcyclohexyl) methyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝1.75min，C₃₀H₃₆ClFN₄O₆S₂Calculated mass of 666.2, M/z found value 666.8[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.6Hz,0.8H),9.18(s,0.2H),8.02-7.99(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.44-7.41(m,1H),7.38-7.33(m,1H),7.24-7.20(m,1H),6.02(s,0.2H),5.92(d,J＝2.8Hz,0.8H),3.98-3.93(m,0.2H),3.74-3.66(m,2.8H),3.60(s,3H),3.53(s,2.4H),3.52(s,0.6H),3.01(s,0.9H),2.95(s,1.1H),2.87-2.77(m,2H),2.33-2.24(m,1H),2.02-1.44(m,11H),1.27-1.20(m,1H),1.17(s,1.2H),1.15(m,1.8H)。

Rac 449(100mg, 95% purity, 0.142mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 449a (cis) (40mg, 90% purity, 38% yield) as a yellow solid and 449b (trans) (40mg, 90% purity, 38% yield) as a yellow solid.

Compound 449a (cis): LC-MS (ESI): r_T＝1.67min，C₃₀H₃₆ClFN₄O₆S₂Calculated mass of 666.2, M/z found value 666.8[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of the chiral compound (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 70:30: 0.2; temperature: 30 ℃; wavelength: 230_T＝11.261min)。¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝3.2Hz,0.8H),9.17(s,0.2H),8.01(s,1.6H),7.93(br s,0.4H),7.44-7.35(m,2H),7.24-7.19(m,1H),6.02(s,0.2H),5.92(d,J＝3.6Hz,0.8H),3.96(br s,0.2H),3.72-3.66(m,2.8H),3.59(s,3H),3.53(s,3H),3.01(s,2H),2.90-2.82(m,2H),2.35-2.27(m,1H),2.02-1.96(m,1H),1.91-1.81(m,4H),1.74-1.56(m,5H),1.27-1.21(m,2H),1.17(s,3H)。

Compound 449b (trans): LC-MS (ESI): r_T＝1.66min，C₃₀H₃₆ClFN₄O₆S₂Calculated mass of 666.2, M/z found value 666.8[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; temperature: R-_T＝13.764min)。¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝3.2Hz,0.8H),9.16(s,0.2H),8.02-7.98(m,1.6H),7.93(d,J＝3.2Hz,0.4H),7.44-7.41(m,1H),7.39-7.31(m,1H),7.24-7.19(m,1H),6.02(s,0.2H),5.92(d,J＝3.2Hz,0.8H),3.98-3.92(m,0.2H),3.74-3.66(m,2.8H),3.60(s,3H),3.53(s,2.4H),3.52(s,0.6H),2.95(s,2H),2.85-2.77(m,2H),2.33-2.24(m,1H),2.02-1.95(m,1H),1.90-1.72(m,4H),1.65-1.62(m,3H),1.57-1.44(m,4H),1.15(s,3H)。

Compound 451: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (((4- (methoxycarbonyl) -1-methylcyclohexyl) methyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝1.70min，C₃₀H₃₅ClF₂N₄O₆S₂Calculated mass of 684.2, M/z found value 684.8[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.66(d,J＝3.6Hz,0.8H),9.24(s,0.2H),8.02-7.94(m,2H),7.49-7.43(m,1H),7.23-7.20(m,1H),6.02(s,0.2H),5.93(d,J＝2.8Hz,0.8H),3.96(br s,0.2H),3.76-3.69(m,2.8H),3.60(s,3H),3.53(s,3H),3.01(s,0.8H),2.94(s,1.2H),2.90-2.76(m,2H),2.34-2.24(m,1H),2.02-1.44(m,11H),1.27-1.19(m,1H),1.17-1.15(m,3H)。

Rac 451(90mg, 90% purity, 0.118mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 451A (48mg, 90% purity, 53% yield) as a yellow solid and 451B (40mg, 90% purity, 44% yield) as a yellow solid.

Compound 451a (cis): LC-MS (ESI): r_T＝1.71min，C₃₀H₃₅ClF₂N₄O₆S₂Calculated mass of 684.2, M/z found value 684.8[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; temperature: R-_T＝10.547min)。¹H NMR(400MHz,DMSO-d₆)δ9.65(s,0.8H),9.23(s,0.2H),8.02-7.99(m,1.6H),7.94(d,J＝3.2Hz,0.4H),7.50-7.43(m,1H),7.24-7.16(m,1H),6.03(s,0.2H),5.93(s,0.8H),4.00-3.95(m,0.2H),3.75-3.66(m,2.8H),3.59(s,3H),3.53(s,2.4H),3.52(s,0.6H),3.00(s,2H),2.87-2.82(m,2H),2.34-2.29(m,1H),2.03-1.04(m,10H),1.28-1.21(m,2H),1.07(s,1.8H),1.05(s,1.2H)。

Compound 451b (trans): LC-MS (ESI): r_T＝1.68min，C₃₀H₃₅ClF₂N₄O₆S₂Calculated mass of 684.2, M/z found value 684.8[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; temperature: R-_T＝12.719min)。¹H NMR(400MHz,DMSO-d₆)δ9.65(s,0.8H),9.23(s,0.2H),8.03-7.99(m,1.6H),7.94(d,J＝3.2Hz,0.4H),7.49-7.42(m,1H),7.23-7.15(m,1H),6.02(s,0.2H),5.93(s,0.8H),3.99-3.93(m,0.2H),3.74-3.66(m,2.8H),3.60(s,3H),3.53(s,2.4H),3.52(s,0.6H),2.94(s,2H),2.85-2.77(m,2H),2.30-2.24(m,1H),2.02-1.45(m,12H),1.16(s,1.8H),1.15(s,1.2H)。

Compound 453: (trans) -methyl 4- (2-chloro-3-fluorophenyl) -6- (1- (((4- (methoxycarbonyl) cyclohexyl) methyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝4.0Hz,0.8H),9.19(s,0.2H),8.01-7.99(m,1.8H),7.94(d,J＝3.2Hz,0.2H),7.41-7.32(m,2H),7.23-7.16(m,1H),6.07(s,0.2H),5.98(d,J＝3.2Hz,0.8H),3.77-3.65(m,3H),3.59(s,3H),3.53(s,2.2H),3.52(s,0.8H),2.94(d,J＝6.4Hz,2H),2.86-2.78(m,2H),2.30-2.22(m,1H),1.97-1.78(m,8H),1.66-1.62(m,1H),1.41-1.31(m,2H),1.12-1.08(m,2H)。

compound 455: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (((3- (methoxycarbonyl) bicyclo [ 1.1.1)]Pent-1-yl) methyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.579min，C₂₈H₂₉ClF₂N₄O₆S₂Calculated mass of 654.1, M/z found value 654.7[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.20(s,0.2H),7.84-7.83(m,1H),7.54(d,J＝3.2Hz,0.8H),7.47(d,J＝3.2Hz,0.4H),7.42(d,J＝2.0Hz,0.6H),7.08-7.03(m,2H),6.18(s,0.3H),6.06(d,J＝2.4Hz,0.7H),4.20-4.10(m,0.3H),3.99-3.88(m,2.7H),3.69(s,3H),3.60(s,2H),3.59(s,1H),3.14-3.12(m,2H),2.92-2.85(m,2H),2.28-2.22(m,6H),2.08-2.04(m,2H),1.96-1.90(m,1H),1.73-1.70(m,0.6H),1.56(s,0.4H)。

Compound 458: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((1- (3-hydroxy-3-methylbutyl) -1H-pyrazol-4-yl) sulfonic acidAcyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.150min，C₂₈H₃₂ClFN₆O₅S₂Calculated mass of 650.2, M/z found value 651.2[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.6Hz,0.8H),9.16(s,0.2H),8.40(s,1H),8.02-7.99(m,1.6H),7.93(d,J＝3.2Hz,0.4H),7.80(s,1H),7.42-7.33(m,2H),7.22-7.18(m,1H),6.00(s,0.2H),5.90(d,J＝3.2Hz,0.8H),4.45(s,1H),4.29-4.25(m,2H),3.76-3.65(m,2H),3.55-3.51(m,1H),3.47(s,3H),2.27-2.18(m,2H),2.09-2.01(m,1H),1.95-1.89(m,3H),1.81-1.78(m,1H),1.65-1.62(m,1H),1.11(s,6H)。

Compound 459: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((2- (2- (2-methoxyethoxy) ethoxy) ethyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝4.041min，C₂₇H₃₄ClFN₄O₇S₂Calculated mass of 644.2, M/z found value 645.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.19(s,0.3H),7.83(d,J＝2.8Hz,1H),7.52(d,J＝2.4Hz,0.7H),7.45(d,J＝2.8Hz,1H),7.29-7.28(m,0.7H),7.27(br s,0.3H),7.15-7.13(m,1H),6.97-6.89(m,1H),6.19(s,0.4H),6.07(s,0.7H),4.19-4.12(m,0.4H),3.97-3.87(m,4.6H),3.69-3.65(m,6H),3.60-3.55(m,5H),3.37(d,J＝5.2Hz,3H),3.29-3.26(m,2H),3.03-2.89(m,2H),2.30-2.20(m,0.8H),2.12-1.81(m,3.2H)。

Compound 460: methyl 6- (1- (2,5,8, 11-tetraoxatridec-13-ylsulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.853min，C₂₉H₃₈ClFN₄O₈S₂Calculated mass of 688.2, M/z found value 688.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.19(s,0.3H),7.83(d,J＝3.2Hz,1H),7.53(d,J＝3.2Hz,0.7H),7.45-7.42(m,1H),7.30-7.28(m,0.7H),7.26-7.24(m,0.3H),7.16-7.12(m,1H),6.98-6.89(m,1H),6.19(s,0.3H),6.06(d,J＝2.4Hz,0.7H),4.18-4.11(m,0.3H),3.99-3.87(m,4.7H),3.66-3.62(m,10H),3.60-3.58(m,3H),3.56-3.54(m,2H),3.39(s,2.1H),3.37(s,0.9H),3.29-3.26(m,2H),3.04-2.88(m,2H),2.30-2.20(m,0.7H),2.12-1.80(m,3H),1.73-1.69(m,0.3H)。

Compound 461: ethyl 6- (1- ((1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝1.907min，C₂₄H₂₃ClF₂N₆O₄S₂Calculated mass 596.1, found value M/z 597.0[ M + H]⁺。

Compound 464: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((2- (2 methoxyethoxy) ethyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.921min，C₂₅H₃₀ClFN₄O₆S₂Calculated mass of 600.1, M/z found value 600.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.3H),7.83(d,J＝3.2Hz,1H),7.52(d,J＝3.2Hz,0.7H),7.45(d,J＝2.8Hz,0.3H),7.43-7.41(m,0.7H),7.30-7.27(m,0.7H),7.25-7.24(m,0.3H),7.16-7.12(m,1H),6.97-6.88(m,1H),6.19(s,0.3H),6.06(d,J＝2.4Hz,0.7H),4.20-4.12(m,0.3H),3.99-3.86(m,4.7H),3.68-3.65(m,2H),3.60-3.56(m,5H),3.41(s,2.1H),3.40(s,0.93H),3.30-3.26(m,2H),3.04-2.89(m,2H),2.30-2.19(m,1H),2.12-2.02(m,1H),1.96-1.80(m,1.5H),1.72-1.69(m,0.5H)。

Compound 466: methyl 6- (1- ((1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝1.55min，C₂₃H₂₂ClFN₆O₄S₂Calculated mass of 564.1, M/z found value 565.3[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ13.76(s,1H),9.51(d,J＝3.6Hz,0.8H),9.15(s,0.2H),8.49-8.19(m,1H),8.10-7.76(m,3H),7.42-7.39(m,1H),7.36-7.29(m,1H),7.22-7.17(m,1H),5.99(s,0.2H),5.90(d,J＝3.6Hz,0.8H),3.77-3.67(m,2H),3.55-3.47(m,4H),2.44-2.36(m,0.2H),2.28-2.17(m,2H),2.10-1.99(m,1H),1.95-1.85(m,1H),1.80-1.77(m,1H),1.64-1.61(m,0.8H)。

Compound 467: methyl 4- (2-chloro-4-fluorophenyl)-6- (1- ((2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodecane-12-yl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.14min，C₄₂H₅₀ClFN₄O₇S₂Calculated mass of Si 868.3, found value of M/z 869.7[ M + H ]]⁺。¹HNMR(400MHz,CDCl₃)δ7.83(d,J＝3.2Hz,1H),7.68-7.66(m,4H),7.50(d,J＝2.8Hz,1H),7.44-7.35(m,6H),7.29-7.25(m,1H),7.15-7.12(m,1H),6.95-6.90(m,1H),6.11(s,1H),3.96-3.88(m,5H),3.82(t,J＝5.6Hz,2H),3.69-3.61(m,6H),3.57(s,3H),3.24(t,J＝6.0Hz,2H),2.99-2.88(m,2H),2.13-1.74(m,5H),1.05(s,9H)。

Compound 469: (trans) -methyl 6- (1- ((1- (3- (tert-butoxycarbonyl) cyclobutyl) -1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝2.26min，C₃₂H₃₆ClFN₆O₆S₂Calculated mass of 718.2, M/z found value 718.8[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.19(s,0.3H),7.84(d,J＝2.8Hz,1H),7.81(s,1H),7.79(s,1H),7.55(d,J＝3.2Hz,0.7H),7.46(d,J＝2.8Hz,0.3H),7.45-7.43(m,0.7H),7.30-7.29(m,0.2H),7.26-7.24(m,0.8H),7.16-7.11(m,1H),6.98-6.90(m,1H),6.17(s,0.3H),6.05(d,J＝2.4Hz,0.7H),5.09-4.99(m,1H),4.02-3.70(m,3H),3.55(s,3H),3.18-3.10(m,1H),2.95-2.86(m,2H),2.81-2.71(m,2H),2.46-2.23(m,3H),2.14-1.89(m,2.4H),1.73-1.70(m,0.6H),1.51(s,9H)。

Compound 473: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((2-methoxy-2-oxoethyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate,¹H NMR(400MHz,DMSO-d₆)δ9.64(s,1H),8.03-7.94(m,2H),7.47-7.41(m,1H),7.25-7.16(m,1H),5.94(s,1H),4.34-4.31(m,2H),3.83-3.68(m,6H),3.52(s,3H),2.96-2.87(m,2H),2.04-1.94(m,1H),1.90-1.77(m,2H),1.73-1.62(m,1H)。

compound 475: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((4- (2-ethoxy-2-oxoethyl)

Cyclohexyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

¹H NMR(300MHz,CDCl₃)δ7.84(d,J＝2.1Hz,1H),7.56-7.42(m,1.6H),7.30-7.28(m,0.4H),7.16-7.13(m,1H),6.96-6.92(m,1H),6.10(s,1H),4.17-4.10(m,2.4H),4.04-3.94(m,2.6H),3.60(s,3H),3.09-2.93(m,3H),2.29-2.17(m,5H),1.98-1.89(m,4H),1.82-1.73(m,2H),1.29-1.25(m,5H),1.09-1.05(m,1H),0.93-0.83(m,2H)。

Rac 475(150mg, 94% purity, 0.214mmol) was separated by chiral preparative HPLC (chiralpak ic5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 40:60:0.3 at 11 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 475A (50mg, according to standard procedures) as a yellow solid¹H NMR purity 95%, 33% yield) and 475B (50mg, 92% purity, 32% yield).

Compound 475a (trans): LC-MS (ESI): r_T＝1.91min，C₃₀H₃₆ClFN₄O₆S₂Calculated mass of 666.2, M/z found value 666.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 40:60:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 40:60: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝10.297min)。¹H NMR(300MHz,CDCl₃)δ8.17(s,0.3H),7.83(d,J＝2.1Hz,1H),7.54(d,J＝2.4Hz,0.7H),7.45-7.42(m,1H),7.30-7.29(m,1H),7.15-7.11(m,1H),6.97-6.88(m,1H),6.18(s,0.3H),6.06(d,J＝1.8Hz,0.7H),4.20-4.11(m,2.3H),4.07-3.90(m,2.7H),3.60(s,2H),3.59(s,1H),3.09-2.88(m,3H),2.26-2.18(m,4.3H),2.09-1.78(m,5.7H),1.69-1.60(m,3H),1.26(t,J＝5.4Hz,3H),1.12-1.02(m,2H)。

Compound 475b (cis): LC-MS (ESI): r_T＝1.92min，C₃₀H₃₆ClFN₄O₆S₂Calculated mass of 666.2, M/z found value 666.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 40:60:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 40:60: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝8.298min)。¹H NMR(300MHz,CDCl₃)δ8.17(s,0.3H),7.83-7.81(m,1H),7.52-7.50(m,0.7H),7.45-7.41(m,1H),7.30-7.27(m,0.6H),7.25-7.22(m,0.4H),7.16-7.10(m,1H),6.97-6.87(m,1H),6.18(s,0.3H),6.06(d,J＝2.4Hz,0.7H),4.18-3.87(m,5H),3.59(s,3H),3.09-2.95(m,3H),2.39-2.36(m,2H),2.29-2.11(m,2H),2.02-1.98(m,1H),1.95-1.69(m,8.6H),1.66-1.63(m,1.4H),1.25(t,J＝7.2Hz,3H)。

Compound 477: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((4- (2-ethoxy-2-oxoethyl) cyclohexyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝1.93min，C₃₀H₃₅ClF₂N₄O₆S₂Calculated mass of 684.2, M/z found value 684.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.83(d,J＝3.2Hz,1H),7.55-7.46(m,1H),7.06-7.02(m,2H),6.18(s,0.4H),6.06(s,0.6H),4.16-3.93(m,5H),3.60(s,3H),3.09-2.89(m,3H),2.38-2.17(m,6H),2.01-1.74(m,8H),1.28-1.24(m,5H)。

Rac 477(140mg, 95% purity, 0.194mmol) was separated by chiral preparative HPLC (chiralpak ic5 μm 30 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.3 at 25 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 477A (50mg, according to standard methods in reference to the description) as a yellow solid¹H NMR purity 95%, 36% yield) and 477B (30mg, according to¹H NMR purity 95%, 21% yield).

Compound 477a (trans): LC-MS (ESI): r_T＝1.94min，C₃₀H₃₅ClF₂N₄O₆S₂Calculated mass of 684.2, M/z found value 684.8[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1.0 mL/min; temp.:30 ℃; wavelength: 230nm, R_T＝10.735min)。¹H NMR(400MHz,CDCl₃)δ8.22(s,0.4H),7.84-7.82(m,1H),7.55(d,J＝2.8Hz,0.6H),7.46-7.43(m,1H),7.08-7.00(m,2H),6.17(s,0.4H),6.06(d,J＝2.8Hz,0.6H),4.19-4.13(m,2.3H),4.06-3.90(m,2.7H),3.60(s,1.8H),3.59(s,1.2H),3.08-2.88(m,3H),2.25-2.14(m,4.7H),2.04-1.77(m,6H),1.69-1.66(m,2.3H),1.26(t,J＝7.2Hz,3H),1.11-1.01(m,2H)。

Compound 477b (cis): LC-MS (ESI): r_T＝1.95min，C₃₀H₃₅ClF₂N₄O₆S₂Calculated mass of 684.2, M/z found value 684.8[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1.0 mL/min; temp.:30 ℃; wavelength: 230nm, R_T＝8.605min)。¹H NMR(400MHz,CDCl₃)δ8.19(s,0.3H),7.83(d,J＝3.2Hz,1H),7.53-7.52(m,0.7H),7.46(d,J＝3.2Hz,0.4H),7.41(s,0.6H),7.08-7.00(m,2H),6.18(s,0.4H),6.06(d,J＝2.8Hz,0.6H),4.22-3.89(m,5H),3.60(s,1.8H),3.59(s,1.2H),3.08-2.97(m,3H),2.39-2.36(m,2H),2.25-2.15(m,2H),2.08-1.99(m,1H),1.96-1.78(m,8H),1.73-1.61(m,2H),1.26(t,J＝7.2Hz,3H)。

Compound 479: ethyl 6- (1- (((3- (tert-butoxycarbonyl) cyclobutyl) methyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

LC-MS(ESI)：R_T＝2.02min，C₃₁H₃₇ClF₂N₄O₆S₂Calculated mass of 698.2, M/z found value 699.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.4H),7.83(d,J＝3.2Hz,1H),7.53(d,J＝3.2Hz,0.6H),7.45(d,J＝3.2Hz,0.4H),7.36(s,0.6H),7.11-6.98(m,2H),6.20(s,0.4H),6.09(d,J＝2.4Hz,0.6H),4.22-3.86(m,5H),3.11-2.74(m,6H),2.58-2.44(m,2H),2.30-2.06(m,3.6H),1.97-1.77(m,1.8H),1.75-1.67(0.6H),1.50-1.41(m,9H),1.26(t,J＝7.2Hz,0.4H),1.12(t,J＝7.2Hz,3H)。

Rac 479(750mg, 1.07mmol) was separated by chiral preparative HPLC (first separation conditions: column: Chiralpak ID 5 μ M20 × 250 mm; mobile phase: Hex: EtOH: DEA 80:20:0.3 at 15 mL/min; wavelength 214 nm; second separation conditions: column: Superchiral S-IC 5 μ M21: 250 mm; mobile phase: Hex: EtOH 95:5 at 20 mL/min; wavelength 254 nm; third separation conditions: column: Superchiral S-IC 5 μ M21: 250 mm; mobile phase: Hex: EtOH 95:5 at 20 mL/min; wavelength 254nm) to give the title compound 479M (170mg, 99.8% purity, 23% yield, 100% stereopure 479N) (60mg, 98.5% purity, 120% yield, 99.9% stereopure P) as a yellow solid (170mg, 99.8% purity, 23% yield, 100% stereopure 479N (60mg, 98.5% purity, 120% yield, 99.9% yield, 100% stereopure P) and stereopure P (100mg, 100% stereopure P), 99.8% purity, 8% yield, 100% stereopurity).

Compound 479M: LC-MS (ESI): r_T＝3.331min，C₃₁H₃₇ClF₂N₄O₆S₂Calculated mass of 698.2, M/z found value 699.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak ID 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 80:20: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝12.253min)。¹H NMR(400MHz,DMSO-d₆)δ9.63(d,J＝3.6Hz,0.8H),9.14(s,0.2H),8.04-7.99(m,1.8H),7.94(d,J＝3.2Hz,0.2H),7.49-7.43(m,1H),7.24-7.17(m,1H),6.03(s,0.2H),5.94(d,J＝3.2Hz,0.8H),4.01-3.94(m,2.2H),3.75-3.66(m,2.8H),3.16(d,J＝7.2Hz,2H),3.02-2.93(m,1H),2.85-2.77(m,2H),2.67-2.59(m,1H),2.35-2.28(m,2H),2.10-1.93(m,3H),1.90-1.77(m,2.2H),1.65-1.62(m,0.8H),1.39(s,9H),1.10-1.03(m,3H)。

Compound 479N: LC-MS (ESI): r_T＝3.318min，C₃₁H₃₇ClF₂N₄O₆S₂Calculated mass of 698.2, M/z found value 699.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak ID 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 80:20: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝12.963min)。¹H NMR(400MHz,DMSO-d₆)δ9.63(d,J＝3.2Hz,0.8H),9.14(s,0.2H),8.01-7.99(m,1.8H),7.94(d,J＝2.8Hz,0.2H),7.49-7.43(m,1H),7.24-7.17(m,1H),6.04(s,0.2H),5.94(d,J＝3.6Hz,0.8H),4.01-3.94(m,2.2H),3.75-3.66(m,2.8H),3.25(d,J＝7.6Hz,2H),3.09-3.01(m,1H),2.86-2.73(m,3H),2.33-2.27(m,2H),2.15-2.08(m,2H),2.04-1.97(m,1H),1.95-1.78(m,2.2H),1.65-1.62(m,0.8H),1.41(s,9H),1.10-1.03(m,3H)。

Compound 479P: LC-MS (ESI): r_T＝3.318min，C₃₁H₃₇ClF₂N₄O₆S₂Calculated mass of 698.2, M/z found value 699.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃;wavelength: 230nm, R_T＝15.188min)。¹H NMR(400MHz,DMSO-d₆)δ9.63(d,J＝3.2Hz,0.8H),9.14(s,0.2H),8.01-7.99(m,1.8H),7.94(d,J＝2.8Hz,0.2H),7.49-7.43(m,1H),7.24-7.17(m,1H),6.04(s,0.2H),5.94(d,J＝3.6Hz,0.8H),4.01-3.94(m,2.2H),3.75-3.66(m,2.8H),3.16(d,J＝7.6Hz,2H),3.02-2.93(m,1H),2.85-2.77(m,2H),2.67-2.59(m,1H),2.35-2.28(m,2H),2.11-1.93(m,3H),1.90-1.77(m,2.2H),1.65-1.62(m,0.8H),1.39(s,9H),1.10-1.03(m,3H)。

Compound 479Q: LC-MS (ESI): r_T＝3.313min，C₃₁H₃₇ClF₂N₄O₆S₂Calculated mass of 698.2, M/z found value 699.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak ID 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 80:20: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝15.206min)。¹H NMR(400MHz,DMSO-d₆)δ9.63(d,J＝2.8Hz,0.8H),9.14(s,0.2H),8.01-7.99(m,1.8H),7.94(d,J＝3.2Hz,0.2H),7.49-7.43(m,1H),7.24-7.17(m,1H),6.04(s,0.2H),5.94(d,J＝2.0Hz,0.8H),4.01-3.94(m,2.2H),3.75-3.66(m,2.8H),3.25(d,J＝7.2Hz,2H),3.08-3.01(m,1H),2.86-2.73(m,3H),2.33-2.27(m,2H),2.15-2.05(m,2H),2.02-1.94(m,1H),1.90-1.77(m,2.2H),1.65-1.62(m,0.8H),1.41(s,9H),1.10-1.03(m,3H)。

Compounds 481A and 481B: ethyl 6- (1- ((3- (2- (tert-butoxy) -2-oxoethyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

And (3) purification conditions: silica gel column chromatography (petrol: ethyl acetate 4:1 to 2:1) gave the product as a yellow solid (210mg, 88% yield) which was isolated by chiral preparative SFC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: CO₂IPA, DEA 60:40:0.3 at 50 g/min; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100 bar) to give 481A (65.8mg, 31% yield, 100% stereopure) and 481B (64.8mg, 31% yield, 100% stereopure) as yellow solids.

Compound 481A: LC-MS (ESI): r_T＝3.997min，C₃₁H₃₇ClF₂N₄O₆S₂Calculated mass of 698.2, M/z found value 699.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: CO)₂IPA, DEA 60:40:0.2, at 3.0 g/min; column temperature: 40 ℃; wavelength: 280nm, R_T＝5.40min)。¹H NMR(400MHz,CD₃OD)δ7.93(d,J＝3.2Hz,0.3H),7.89(d,J＝3.6Hz,0.7H),7.76(d,J＝3.2Hz,0.7H),7.73(d,J＝3.6Hz,0.3H),7.27-7.19(m,2H),6.15(s,0.3H),6.08(s,0.7H),4.11-3.98(m,3.4H),3.95-3.82(m,2.6H),2.98-2.88(m,2H),2.82-2.74(m,1H),2.70-2.61(m,2H),2.48(d,J＝7.6Hz,2H),2.22-1.85(m,5.3H),1.70-1.65(m,0.7H),1.44-1.43(m,9H),1.14-1.10(m,3H)。

Compound 481B: LC-MS (ESI): r_T＝3.986min，C₃₁H₃₇ClF₂N₄O₆S₂Calculated mass of 698.2, M/z found value 699.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: CO)₂IPA, DEA 60:40:0.2, at 3.0 g/min; column temperature: 40 ℃; wavelength: 280nm, R_T＝4.28min)。¹H NMR(400MHz,DMSO-d6)δ9.62(d,J＝3.2Hz,0.7H),9.12(s,0.3H),8.01-8.00(m,2H),7.51-7.43(m,1H),7.24-7.17(m,1H),6.03(s,0.3H),5.93(d,J＝3.2Hz,0.7H),4.01-3.89(m,3H),3.76-3.64(m,3H),2.88-2.77(m,2H),2.44-2.41(m,1H),2.34(d,J＝7.2Hz,2H),2.07-1.57(m,8H),1.40-1.39(m,9H),1.09-1.03(m,3H)。

Compound 483: methyl 6- (1- ((2- (2- ((tert-butyldiphenylsilyl) oxy) ethoxy) ethyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

¹H NMR(400MHz,CDCl₃)δ8.16(s,0.3H),7.82-7.81(m,1H),7.69-7.67(m,4H),7.48(d,J＝3.2Hz,0.7H),7.44-7.34(m,7H),7.30-7.27(m,0.6H),7.25-7.23(m,0.4H),7.16-7.12(m,1H),6.97-6.88(m,1H),6.19(s,0.3H),6.06(d,J＝2.4Hz,0.7H),4.10-4.05(m,0.3H),3.99-3.82(m,6.7H),3.63-3.60(m,2H),3.57-3.56(m,3H),3.22-3.18(m,2H),2.95-2.84(m,2H),2.29-2.19(m,0.7H),2.11-1.99(m,1H),1.92-1.89(m,1.2H),1.83-1.77(m,0.4H),1.71-1.67(m,0.7H),1.58(s,9H)。

Section IV: hydrolysis of labile esters of the principal dihydropyrimidines of the formula I

Compound 105: 3- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) propionic acid

The method S comprises the following steps: to methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3-methoxy-3-oxopropyl) sulfonyl) at 0 deg.C

To a solution of piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 104(63mg, 0.11mmol) in tetrahydrofuran (2mL) was added a solution of lithium hydroxide monohydrate (13.4mg, 0.33mmol) in water (3 mL). After stirring at room temperature for 2 hours, the mixture was acidified to pH 3 with 1N aqueous hydrochloric acid (5 mL). The resulting mixture was extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (30mg, 49% yield). LC-MS (ESI): r_T＝3.040min，C₂₃H₂₄ClFN₄O₆S₂Calculated mass of 570.1, M/z found value 571.1[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; temperature: R-_T＝11.155min)。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.95(m,2H),7.41(dd,J＝8.8,2.4Hz,1H),7.38-7.34(m,1H),7.23-7.18(m,1H),5.94(s,1H),3.75-3.66(m,3H),3.54(s,3H),3.23(t,J＝3.6Hz,2H),2.88(q,J＝12.4Hz,2H),2.50-2.46(m,2H),2.06-2.94(m,1H),1.86-1.75(m,2H),1.70-1.56(m,1H)。

Compound 92: 2- (trans-2- (6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclopropyl) acetic acid

The method T comprises the following steps: a mixture of compound 91H (46mg, 0.09mmol) in 4M hydrochloric acid in 1, 4-dioxane (4mL) was stirred at room temperature for 2 hours. It was then concentrated to give a residue which was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate ═ 1:1) to give the title compound as a yellow solid (14.0mg, 34% yield). LC-MS (ESI): r_T＝3.904min，C₂₁H₁₉ClFN₃O₄Calculated mass of S463.1, found value of M/z 463.9[ M + H]⁺. Chiral HPLC (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: IPA: TFA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; and_T＝7.771min)。¹H NMR(400MHz,DMSO-d₆)δ9.44(d,J＝3.6Hz,1H),7.99-7.96(m,2H),7.44-7.36(m,2H),7.20-7.15(m,1H),5.90(d,J＝2.0Hz,1H),4.02-3.94(m,2H),3.13-3.07(m,1H),2.37-2.32(m,3H),1.92-1.82(m,1H),1.08(t,J＝7.2Hz,3H),0.78-0.71(m,1H)。

compound 141: (trans) -3- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutane-1-carboxylic acid

The method U comprises the following steps: to a solution of (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 140A (160mg, 0.202mmol) in dichloromethane (8mL) was added trifluoroacetic acid (4mL) at room temperature. After stirring at room temperature under a nitrogen atmosphere for 2 hours, the reaction mixture was diluted with water (20mL) and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO_4(s)Dried, filtered and concentrated. The residue was purified by C18 column (acetonitrile: water ═ 60% to 80%) to give the title compound as a yellow solid (125mg, 98% yield). LC-MS (ESI): r_T＝3.476min，C₂₆H₂₈ClFN₄O₆S₂Calculated mass of 610.1, M/z found value 610.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.58(s,1H),9.55(d,J＝3.2Hz,0.8H),9.15(s,0.2H),8.01-7.98(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.45-7.41(m,1H),7.37-7.30(m,1H),7.24-7.17(m,1H),6.01(s,0.2H),5.91(d,J＝3.2Hz,0.8H),4.00-3.92(m,1H),3.79-3.65(m,3H),3.53(s,2.4H),3.52(s,0.6H),2.91-2.82(m,2H),2.79-2.68(m,2H),2.29-2.20(m,2H),2.08-1.71(m,3H),1.62-1.55(m,1H),1.35(s,3H)。

Compound 270A: (trans) -3- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid

Method W: to a solution of (trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((3-methyl-3- ((2- (trimethylsilyl) ethoxy) carbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 269A (180mg, 90% purity, 0.218mmol) in tetrahydrofuran (5mL) was added 1M tetrabutylammonium fluoride in tetrahydrofuran (5mL, 5.0 mmol). After stirring at room temperature for 2 hours, the reaction was quenched with water (5mL) and concentrated to give a residue, which was diluted with water (5mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed three times with water (10mL) and Na₂SO_4(s)Drying and concentration gave the crude product which was purified by preparative HPLC (column: Gilson Xbox C18(5 μm19 x 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 10% -80% (% B)) to give the desired product as a yellow solid (125mg, 99.7% purity, 89% yield). LC-MS (ESI): r_T＝3.401min，C₂₇H₂₉ClF₂N₄O₆S₂Calculated mass of 642.1M/z found value 643.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.01-7.94(m,2H),7.45(q,J＝8.4Hz,1H),7.23-7.15(m,1H),6.04(s,0.2H),5.93(s,0.8H),4.02-3.89(m,3H),3.75-3.64(m,3H),2.92-2.80(m,2H),2.74-2.64(m,2H),2.25-2.18(m,2H),2.02-1.70(m,3H),1.64-1.56(m,1H),1.33(s,3H),1.07(t,J＝7.2Hz,3H)。

Similarly using a similar procedure (method S or method T, method U or method W), the following acids can be prepared:

compound 107: 2- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) acetic acid

LC-MS(ESI)：R_T＝3.307min，C₂₂H₂₂ClFN₄O₆S₂Calculated mass of 556.1, M/z found value 556.9[ M + H [ ]]⁺. Chiral HPLC (Chiralpak IB5 μm4.6 × 250mm, mobile phase: Hex: EtOH: TFA: 70:30:0.2,at 1.0mL/min, temperature: 30 ℃, wavelength: 230nm, R_T＝8.254min)；¹H NMR(400MHz,DMSO-d₆)δ8.00(s,1.7H),7.92(s,0.3H),7.41(dd,J＝8.8,2.8Hz,1H),7.38-7.34(m,1H),7.23-7.18(m,1H),6.01(s,0.2H),5.92(s,0.8H),3.95-3.88(m,2H),3.80-3.64(m,3H),3.53(s,3H),2.97-2.88(m,2H),2.04-1.91(m,1H),1.90-1.77(m,2H),1.62(d,J＝11.2Hz,1H)。

Compound 7: 2- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydro-pyrimidin-4-yl) piperidin-1-yl) sulfonyl) -2-methylpropionic acid

LC-MS(ESI)：R_T＝3.967min，C₂₄H₂₆ClFN₄O₆S₂Calculated mass 584.1, M/z found value 584.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: IPA: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; temperature: 1_T＝10.158min)。¹H NMR(400MHz,DMSO-d₆(+D₂O))δ7.98(dd,J＝12.4,3.2Hz,2H),7.41(dd,J＝8.4,2.8Hz,1H),7.34(dd,J＝9.2,6.0Hz,1H),7.22-7.17(m,1H),5.93(s,1H),3.85-3.82(m,3H),3.52(s,3H),3.06-2.98(m,2H),2.01-1.92(m,1H),1.88-1.80(m,1H),1.75(d,J＝12Hz,1H),1.60(d,J＝12.4Hz,1H),1.51(s,6H)。

Compound 114: 3- ((4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydro-pyrimidin-4-yl) piperidin-1-yl) sulfonyl) propionic acid

LC-MS(ESI)：R_T＝2.524min，C₂₃H₂₄ClFN₄O₆S₂Calculated mass of 570.1, M/z found value 571.1[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IF 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; and_T＝11.664min)。¹H NMR(400MHz,DMSO-d₆)δ9.62(brs,1H),8.00(s,2H),7.41-7.31(m,2H),7.21(d,J＝7.2Hz,1H),5.99(s,1H),3.80-3.68(m,3H),3.53(s,3H),3.31(t,J＝7.2Hz,2H),2.95-2.86(m,2H),2.67(t,J＝7.2Hz,2H),2.05-1.61(m,4H)。

compound 17: trans-4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexanecarboxylic acid

LC-MS(ESI)：R_T＝3.326min，C₂₂H₂₁ClFN₃O₄Calculated mass of S477.1, M/z found mass 477.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 0 ℃; chiral HPLC (column: Chiralpak IE 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: TFA: 85:15: 0.2; temperature: 230 ℃_T＝11.064min)。¹H NMR(400MHz,DMSO-d₆)δ9.45(brs,0.6H),8.94(br s,0.4H),7.99-7.93(m,2H),7.39-7.29(m,2H),7.19-7.17(m,1H),6.06(br s,0.4H),5.97(br s,0.6H),3.87-3.77(m,0.4H),3.64-3.56(m,0.6H),3.52(s,3H),2.42-2.37(m,0.4H),2.35-2.21(m,0.6H),2.05-1.97(m,2H),1.86-1.76(m,2H),1.73-1.62(m,2H),1.44-1.36(m,2H)。

Compound 19: trans-4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexanecarboxylic acid

LC-MS(ESI)：R_T＝3.958min，C₂₂H₂₁ClFN₃O₄Calculated mass of S477.1, found value of M/z 478.1[ M + H]⁺. Chiral HPLC (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: IPA: TFA: DEA ═ 85:15:0.1:0.1, at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; wavelength: 230 nm; time: 250 mm; solvent concentration: solvent concentration_T＝9.501min)。¹H NMR(400MHz,DMSO-d₆)δ12.03(br s,1H),9.40(d,J＝2.8Hz,0.6H),8.92(s,0.4H),7.99-7.98(m,1.6H),7.94-7.93(m,0.4H),7.45-7.39(m,1H),7.36-7.30(m,1H),7.23-7.18(m,1H),6.01(s,0.4H),5.91(d,J＝3.2Hz,0.6H),3.89-3.75(m,0.4H),3.64-3.56(m,0.6H),3.53(s,3H),2.44-2.32(m,0.4H),2.25-2.17(m,0.6H),2.09-1.97(m,2H),1.88-1.58(m,4H),1.49-1.34(m,2H)。

Compound 21: trans-4- (6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexanecarboxylic acid

LC-MS(ESI)：R_T＝4.156min，C₂₃H₂₃ClFN₃O₄Calculated mass of S491.1, M/z found value 491.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: IPA: DEA: TFA ═ 85:15:0.1:0.1, 1.0mLMin; temperature: 30 ℃; wavelength: 230nm, 100% ee, R_T＝8.533min)。¹H NMR(400MHz,DMSO-d₆)δ8.88(br s,0.2H),7.99(d,J＝3.6Hz,1.8H),7.94(d,J＝3.2Hz,0.2H),7.44-7.41(m,1H),7.36-7.33(m,1H),7.24-7.19(m,1H),6.02(s,0.4H),5.91(s,0.6H),4.00-3.93(m,2H),3.86-3.77(m,0.4H),3.61-3.54(m,0.6H),2.40-2.33(m,0.4H),2.25-2.18(m,0.6H),2.04-1.74(m,6H),1.47-1.32(m,2H),1.10-1.03(m,3H)。

Compound 23: trans-4- (6- (2-chloro-3-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexanecarboxylic acid

LC-MS(ESI)：R_T＝3.542min，C₂₃H₂₃ClFN₃O₄Calculated mass of S, M/z found value 492.2[ M + H]⁺. Chiral HPLC (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: IPA: TFA: DEA ═ 90:10:0.1:0.1, at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; wavelength: 230 nm; time: 250 mm; solvent concentration: solvent concentration_T＝12.746min)。¹H NMR(400MHz,DMSO-d₆)δ9.49(brs,0.5H),8.88(s,0.5H),8.00-7.93(m,2H),7.39-7.31(m,2H),7.21-7.17(m,1H),6.07(s,0.4H),5.96(s,0.6H),4.00-3.93(m,2H),3.84-3.78(m,0.5H),3.59-3.55(m,0.5H),2.34-2.28(m,0.5H),2.18-2.15(m,0.5H),2.03-1.96(m,2H),1.86-1.63(m,4H),1.40-1.35(m,2H),1.09-1.02(m,3H)。

Compound 25: cis-3- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexanecarboxylic acid

LC-MS(ESI)：R_T＝4.541min，C₂₂H₂₁ClFN₃O₄Calculated mass of S477.1, M/z found 477.9[ M + H ]]⁺. Chiral HPLC (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; and_T＝7.090min)。¹H NMR(400MHz,DMSO-d₆)δ9.12(br s,0.3H),8.00-7.98(m,1.6H),7.94(d,J＝2.8Hz,0.4H),7.40-7.29(m,2H),7.21-7.15(m,1H),6.06(s,0.4H),5.97(s,0.6H),3.97-3.89(m,0.4H),3.71-3.63(m,0.6H),3.52-3.51(m,3H),2.35-2.24(m,1H),1.93-1.81(m,3H),1.78-1.67(m,3H),1.45-1.25(m,2H)。

compound 29: 2- (trans-4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) acetic acid

LC-MS(ESI)：R_T＝3.930min，C₂₃H₂₃ClFN₃O₄Calculated mass of S491.1, M/z found value 491.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; temperature: 30 ℃; temperature: pH: 0.2; pH_T＝9.625min)。¹H NMR(400MHz,DMSO-d₆)δ11.81(brs,1H),9.46(br s,0.4H),8.97(s,0.6H),7.99-7.97(m,1.6H),7.93(d,J＝3.2Hz,0.4H),7.39-7.28(m,2H),7.21-7.15(m,1H),6.06(s,0.4H),5.96(s,0.6H),3.87-3.53(m,1H),3.51-3.50(m,3H),2.14(d,J＝6.8Hz,2H),1.88-1.55(m,7H),1.15-1.03(m,2H)。

Compound 72C: 3- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclopentanecarboxylic acid

LC-MS(ESI)：R_T＝3.434min，C₂₀H₁₇ClFN₃O₄Calculated mass of S463.1, found value of M/z 463.9[ M + H]⁺. Chiral HPLC (column: Chiralcel OJ-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: TFA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.639min)。¹H NMR(400MHz,CD₃OD)δ7.93(d,J＝2.8Hz,1H),7.78(d,J＝3.2Hz,1H),7.38(dd,J＝8.4,6.0Hz,1H),7.25(dd,J＝8.4,2.8Hz,1H),7.07(td,J＝8.4,2.4Hz,1H),6.08(s,1H),4.44-4.35(m,1H),3.59(s,3H),3.18-3.10(m,1H),2.29-2.16(m,3H),2.05-1.81(m,3H)。

Compound 72F: 3- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclopentanecarboxylic acid

LC-MS(ESI)：R_T＝3.875min，C₂₁H₁₉ClFN₃O₄Calculated mass of S463.1, found value of M/z 463.9[ M + H]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; and_T＝5.240min)。¹H NMR(400MHz,DMSO-d₆)δ12.02(s,1H),9.45(d,J＝3.6Hz,0.8H),8.99(s,0.2H),7.99(q,J＝3.2Hz,1.8H),7.93(d,J＝3.2Hz,0.2H),7.44-7.40(m,1H),7.35-7.30(m,1H),7.24-7.17(m,1H),6.01(s,0.2H),5.92(d,J＝3.6Hz,0.8H),4.35-4.28(m,0.2H),4.24-4.16(m,0.8H),3.52(s,2.4H),3.51(s,0.6),3.06-2.97(m,1H),2.16-1.77(m,6H)。

compound 77: 3- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclopentanecarboxylic acid

LC-MS(ESI)：R_T＝3.607min，C₂₁H₁₉ClFN₃O₄Calculated mass of S463.1, found value of M/z 463.9[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.09(br s,1H),9.75-9.45(m,1H),8.01-7.91(m,2H),7.41-7.30(m,2H),7.23-7.13(m,1H),6.06(s,0.3H),5.97-5.95(m,0.7H),4.52-4.34(m.0.3H),4.30-4.07(m.0.7H),3.52(s,3H),3.43-3.23(m,1H),3.08-2.96(m,0.4H),2.91-2.68(m,0.6H),2.22-1.99(m,3H),1.94-1.74(m,2H)。

Compound 86: 6- (3-carboxy-cyclobutyl) -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester

LC-MS(ESI)：R_T＝4.042min，C₂₀H₁₇ClFN₃O₄Calculated mass of S449.1, M/z found value 449.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; and_T＝5.654min)。¹H NMR(400MHz,CDCl₃)δ8.31(s,0.2H),7.85(d,J＝2.8Hz,0.8H),7.83(d,J＝3.2Hz,0.2H),7.53-7.50(m,1.6H),7.46(d,J＝3.6Hz,0.2H),7.30-7.27(m,1H),7.14(dd,J＝8.4,2.4Hz,1H),6.97-6.89(m,1H),6.18(s,0.2H),6.06(d,J＝2.8Hz,0.8H),4.75-4.69(m,0.2H),4.64-4.56(m,0.8H),3.61(s,2.5H),3.59(s,0.5H),3.47-3.39(m,0.8H),3.28-3.20(m,0.2H),2.85-2.69(m,2H),2.67-2.60(m,1.7H),2.54-2.51(m,0.3H)。

compound 93: 2- (trans-2- (6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclopropyl) acetic acid

LC-MS(ESI)：R_T＝3.309min，C₂₁H₁₉ClFN₃O₄Calculated mass of S463.1, found value of M/z 463.9[ M + H]⁺. Chiral HPLC (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; and_T＝10.898min)。¹H NMR(400MHz,DMSO-d₆)δ9.48(s,J＝3.2Hz,1H),8.00-7.96(m,2H),7.40(dd,J＝7.2,2.4Hz,1H),7.34-7.30(m,1H),7.24-7.19(m,1H),5.92(d,J＝3.6Hz,1H),3.98(q,J＝7.2Hz,2H),3.11-3.05(m,1H),2.37-2.28(m,2H),1.70-1.61(m,1H),1.46-1.39(m,1H),1.07(t,J＝7.2Hz,3H),0.84-0.74(m,1H)。

compound 95: 4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cycloheptanecarboxylic acid

LC-MS(ESI)：R_T＝3.860min，C₂₃H₂₃ClFN₃O₄Calculated mass of S491.1, M/z found value 491.9[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.91(br s,1H),7.74-7.73(m,1H),7.41-7.36(m,1H),7.23-7.21(m,1H),7.06-7.02(m,1H),6.11-6.05(m,1H),4.11(br s,0.6H),3.93(br s,0.4H),3.59(s,3H),2.55(br s,1H),2.22-1.47(m,10H)。

Compound 95A: LC-MS (ESI): r_T＝3.623min，C₂₃H₂₃ClFN₃O₄Calculated mass of S491.1, M/z found value 491.9[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.91(s,1H),7.73(d,J＝3.2Hz,1H),7.40-7.37(m,1H),7.22-7.20(m,1H),7.07-7.03(m,1H),6.11(s,0.6H),6.05(s,0.4H),4.11(br s,0.6H),3.93(br s,0.4H),3.59(s,3H),2.64(s,1H),2.19-1.74(m,9H),1.61-1.46(m,1H)。

Compound 95C: LC-MS (ESI): r_T＝2.621min，C₂₃H₂₃ClFN₃O₄Calculated mass of S491.1, M/z found value 492.2[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.92(s,1H),7.74(d,J＝3.2Hz,1H),7.41-7.37(m,1H),7.23-7.21(m,1H),7.07-7.02(m,1H),6.11(s,0.6H),6.05(s,0.4H),,4.11(br s,0.6H),3.93(br s,0.4H),3.59(s,3H),2.61(br s,1H),2.22-1.75(m,10H)。

Compound 95E: LC-MS (ESI): r_T＝3.530min，C₂₃H₂₃ClFN₃O₄Calculated mass of S491.1, M/z found value 492.2[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.92-7.89(m,1H),7.74(d,J＝3.2Hz,1H),7.39-7.36(m,1H),7.23-7.21(m,1H),7.06-7.01(m,1H),6.12(s,0.6H),6.04(s,0.4H),,4.12(brs,0.6H),3.94(br s,0.4H),3.59(s,3H),2.55(br s,1H),2.17-1.71(m,10H)。

Compound 142: (cis) -3- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutane-1-carboxylic acid

LC-MS(ESI)：R_T＝3.345min，C₂₆H₂₈ClFN₄O₆S₂Calculated mass of 610.1, M/z found value 610.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d6)δ9.55(s,0.8H),9.15(s,0.2H),8.03-8.00(m,1.8H),7.93(s,0.2H),7.45-7.41(m,1H),7.38-7.34(m,1H),7.24-7.19(m,1H),6.02(s,0.2H),5.92(s,0.8H),4.14-4.05(m,1H),3.78-3.63(m,3H),3.53(s,3H),2.90-2.80(m,2H),2.70-2.63(m,2H),2.17-2.07(m,2H),2.00-1.71(m,3H),1.63-1.55(m,1H),1.40(s,3H)。

Compound 146: (trans) -3- ((4- (6- (2-chlorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutane-1-carboxylic acid: LC-MS (ESI): r_T＝4.575min，C₂₆H₂₉ClN₄O₆S₂Calculated mass of 592.1, M/z found value 592.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.99-7.97(m,1.8H),7.92(d,J＝2.8Hz,0.2H),7.44-7.42(m,1H),7.36-7.26(m,3H),6.07(s,0.2H),5.96(s,0.8H),4.02-3.95(m,3.2H),3.78-3.71(m,2.8H),3.13-3.10(m,1H),2.91-2.82(m,2H),2.57-2.51(m,4H),2.06-1.94(m,1H),1.89-1.76(m,2.2H),1.61-1.58(m,0.8H),1.08-1.02(m,3H)。

Compound 148A: (trans) -4- (6- (2-bromophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexane-1-carboxylic acid, LC-ms (esi): r_T＝3.561min，C₂₃H₂₄BrN₃O₄Calculated mass of S517.1, m/z found value520.1[M+H]⁺. Chiral analysis (column: Chiralpak OJ-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: TFA ═ 85:15:0.2, at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝8.374min)。¹H NMR(400MHz,DMSO-d₆)δ12.01(br s,1H),9.23(s,0.6H),8.83(s,0.4H),7.99-7.97(m,1.5H),7.92(d,J＝3.2Hz,0.5H),7.61(d,J＝8.4Hz,1H),7.38-7.32(m,2H),7.22-7.16(m,1H),6.03(s,0.4H),5.91(d,J＝2.8Hz,0.6H),4.01-3.92(m,2H),3.87-3.79(m,0.5H),3.61-3.56(m,0.5H),2.42-2.35(m,0.5H),2.25-2.19(m,0.5H),2.04-1.97(m,2H),1.91-1.64(m,4H),1.47-1.37(m,2H),1.10-1.02(m,3H)。

Compound 150A: (trans) -4- (6- (2-bromo-3-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexane-1-carboxylic acid, LC-ms (esi): r_T＝3.634min，C₂₃H₂₃BrFN₃O₄Calculated mass of S535.1, found M/z 538.1[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.87(s,1H),7.99(d,J＝4.0Hz,1.5H),7.93(d,J＝3.2Hz,0.5H),7.44-7.38(m,1H),7.31-7.24(m,1H),7.20-7.15(m,1H),6.60(s,0.5H),5.96(s,0.5H),3.99-3.94(m,2H),3.89-3.79(m,0.5H),3.62-3.55(m,0.5H),2.41-2.34(m,0.5H),2.25-2.19(m,0.5H),2.05-1.98(m,2H),1.91-1.63(m,4H),1.47-1.33(m,2H),1.09-1.01(m,3H)。

Compound 152A: LC-MS (ESI): r_T＝3.382min，C₂₂H₂₁BrFN₃O₄Calculated mass of S521.0, M/z found value 524.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IE 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: TFA: 85:15: 0.2; temperature: 230 ℃; wavelength: 230 nm; R_T＝10.792min)。¹H NMR(400MHz,CDCl₃)δ8.11(s,0.7H),7.83(d,J＝2.8Hz,1H),7.51(s,0.3H),7.49(d,J＝3.2Hz,0.5H),7.45(d,J＝3.2Hz,0.5H),7.24-7.18(m,1H),7.12(d,J＝7.6Hz,1H),7.07-6.99(m,1H),6.25(s,0.5H),6.09(d,J＝2.8Hz,0.5H),4.07-4.01(m,0.5H),3.83-3.75(m,0.5H),3.61(s,1H),3.59(s,2H),2.50-2.43(m,1H),2.27-2.12(m,2.5H),2.06-1.93(m,1.5H),1.81-1.50(m,4H)。

Compound 154A: LC-MS (ESI): r_T＝3.726min，C₂₄H₂₅F₂N₃O₄Calculated mass of S489.2, M/z found 490.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.04(s,1H),9.49(d,J＝2.8Hz,0.7H),8.88(s,0.3H),7.98(d,J＝3.2Hz,1.7H),7.92(d,J＝3.2Hz,0.3H),7.26-7.17(m,1H),7.10-7.07(m,0.7H),7.00-6.95(m,0.3H),5.81(s,0.3H),5.68(d,J＝3.2Hz,0.7H),3.97(q,J＝7.2Hz,2H),3.86-3.79(m,0.3H),3.61-3.52(m,0.7H),2.50(s,1H),2.45(s,2H),2.39-2.32(m,0.3H),2.25-2.18(m,0.7H),2.08-1.59(m,6H),1.49-1.30(m,2H),1.07(t,J＝6.8Hz,3H)。

Compound 156A: LC-MS (ESI): r_T＝3.467min，C₂₃H₂₃BrFN₃O₄Calculated mass of S535.1, found M/z 536.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; chiral analysis (column: Chiralpak IE 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: TFA: 90:10: 0.2; temperature: 230 ℃; wavelength: R:_T＝12.600min)。¹H NMR(400MHz,DMSO-d₆)δ11.99(br s,1H),9.31(d,J＝3.2Hz,0.6H),8.85(s,0.4H),7.99-7.97(m,1.6H),7.93(d,J＝3.2Hz,0.4H),7.56(dd,J＝8.4,2.0Hz,1H),7.36-7.31(m,1H),7.28-7.22(m,1H),5.99(s,0.4H),5.89(d,J＝3.6Hz,0.6H),4.01-3.93(m,2H),3.85-3.78(m,0.4H),3.61-3.54(m,0.6H),2.42-2.32(m,0.4H),2.26-2.19(m,0.6),2.04-1.97(m,2H),1.90-1.61(m,4H),1.47-1.36(m,2H),1.11-1.04(m,3H)。

compound 162 trans-3- ((4- (-6- (2-bromo-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid: LC-MS (ESI): r_T＝4.127min，C₂₅H₂₅BrF₂N₄O₆S₂Calculated mass 658.0, M/z found value 658.8[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.91(s,1H),7.75(s,1H),7.29-7.19(m,2H),6.12-6.07(m,1H),4.10-3.87(m,4H),3.58(s,3H),3.26-3.20(m,1H),3.02-2.92(m,2H),2.77-2.64(m,4H),2.14-1.69(m,4H)。

Compound 195A: (trans) -3- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5-ethoxycarbonyl-2- (2,4, 6-trifluorophenyl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-MS (ES)I)：R_T＝4.267min，C₂₉H₂₇ClF₅N₃O₆Calculated mass of S675.1, M/z found 676.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralcel OZ-H5 μm4.6 x 150mm, Phase: Hex: EtOH ═ 90:10, at 1.0mL/min, temperature: 35 ℃ C., wavelength: 254nm, R_T＝7.778min)。¹H NMR(400MHz,DMSO-d₆)δ9.56(s,1H),7.59-7.47(m,1H),7.27-7.17(m,3H),5.97(s,0.8H),5.88(s,0.2H),4.01-3.92(m,4H),3.81-3.66(m,2H),3.12-3.08(m,1H),2.86-2.79(m,2H),2.58-2.53(m,4H),1.97-1.53(m,4H),1.06-1.03(m,3H)。

Compound 199A: (trans) -3- ((4- (6- (2-bromo-3, 4-difluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.993min，C₂₆H₂₇BrF₂N₄O₆S₂Calculated mass of 672.1, M/z found value 673.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝13.117min)。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.98(m,1.8H),7.93-7.92(m,0.2H),7.52-7.45(m,1H),7.23-7.14(m,1H),6.02(s,0.2H),5.93(s,0.8H),4.02-3.95(m,3H),3.78-3.71(m,3H),3.17-3.11(m,1H),2.91-2.81(m,2H),2.58-2.54(m,4H),2.04-1.83(m,3H),1.62-1.60(m,0.8H),1.47-1.42(m,0.2H),1.09-1.05(m,3H)。

Compound 199B: (trans) -3- ((4- (6- (2-bromo-3, 4-difluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝4.002min，C₂₆H₂₇BrF₂N₄O₆S₂Calculated mass of 672.1, M/z found value 673.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝11.811min)。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.98(m,1.8H),7.95-7.92(m,0.2H),7.52-7.45(m,1H),7.25-7.17(m,1H),6.02(s,0.2H),5.93(s,0.8H),4.02-3.96(m,3H),3.77-3.71(m,3H),3.16-3.10(m,1H),2.91-2.82(m,2H),2.57-2.53(m,4H),2.03-1.74(m,3H),1.63-1.58(m,0.8H),1.48-1.42(m,0.2H),1.07-1.05(m,3H)。

Compound 210A: (trans) -4- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclohexanecarboxylic acid, LC-ms (esi): r_T＝3.66min，C₂₈H₃₁ClF₂N₄O₆S₂Calculated mass of 657.1M/z found value 656.1[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.97-7.89(m,1H),7.76-7.75(m,1H),7.28-7.17(m,2H),6.14(s,0.3H),6.07(s,0.7H),4.21-4.10(m,0.3H),4.02-3.85(m,2.7H),3.59(s,3H),3.14-2.99(m,3H),2.18-1.95(m,4H),1.90-1.63(m,8H),1.25(s,3H)。

Compound 210B: (cis) -4- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclohexanecarboxylic acid, LC-ms (esi): r_T＝3.65min，C₂₈H₃₁ClF₂N₄O₆S₂Calculated mass of 657.1M/z found value 656.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.97-7.88(m,1H),7.79-7.72(m,1H),7.27-7.18(m,2H),6.13(s,0.3H),6.07(s,0.7H),4.22-4.11(m,0.3H),3.99-3.83(m,2.7H),3.59(s,3H),3.14-2.95(m,3H),2.32-2.29(m,2H),2.18-1.96(m,4H),1.90-1.61(m,4H),1.28-1.21(m,2H),1.17(s,3H)。

Compound 212M: (trans) -4- (-6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) tetrahydrofuran-2-carboxylic acid

LC-MS(ESI)：R_T＝2.910min，C₂₀H₁₇ClFN₃O₅Calculated mass of S465.1, M/z found value 466.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.85(d,J＝2.0Hz,1H),7.52(d,J＝2.8Hz,1H),7.24-7.22(m,1H),7.12-7.07(m,2H),6.24(brs,0.1H),6.17(s,0.9H),4.90-4.87(m,1H),4.63-4.61(m,1H),4.51-4.49(m,1H),4.24-4.22(m,1H),3.61(s,3H),2.80-2.79(m,1H),2.28-2.26(m,1H)。

Compound 214A: 2- (((-3- (-6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) pyrrolidin-1-yl) sulfonyl) acetic acid, LC-ms (esi): r_T＝3.127min，C₂₁H₂₀ClFN₄O₆S₂Calculated mass of 542.1, M/z found value 543.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; chiral analysis of chiral molecules: chiral molecules, chiral_T＝13.322min)。¹H NMR(400MHz,DMSO-d₆)δ8.01(s,2H),7.44-7.41(m,1H),7.39-7.35(m,1H),7.25-7.20(m,1H),5.94(s,1H),4.41-4.29(m,1H),3.87(s,2H),3.70-3.58(m,2H),3.54(s,3H),3.51-3.39(m,2H),2.26-2.13(m,1H),2.05-1.92(m,1H)。

Compound 214C: 2- (((-3- (-6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) pyrrolidin-1-yl) sulfonyl) acetic acid, LC-ms (esi): r_T＝2.914min，C₂₁H₂₀ClFN₄O₆S₂Calculated mass of 542.1, M/z found value 543.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak OD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: TFA ═ 70:30:0.2, at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak OD-H5 μm 4.6: 250 mm; mobile phase: Hex: EtOH: TFA ═ 70:30: 0.2; temperature_T＝7.997min)。¹H NMR(400MHz,DMSO-d₆)δ8.01(s,2H),7.44-7.41(m,1H),7.38-7.35(m,1H),7.24-7.19(m,1H),5.94(s,1H),4.42-4.30(m,1H),3.87(s,2H),3.63-3.54(m,5H),3.47-3.40(m,2H),2.33-2.24(m,1H),2.19-2.08(m,1H)。

Compound 223: 3- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -2, 2-dimethylpropanoic acid, LC-ms (esi): r_T＝3.326min，C₂₅H₂₈ClFN₄O₆S₂Calculated mass of 598.1, M/z found value 599.2[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.89(brs,1H),7.75(d,J＝2.8Hz,1H),7.41-7.37(m,1H),7.24-7.22(m,1H),7.07-7.03(m,1H),6.14-6.07(m,1H),4.09(br s,0.3H),3.89-3.82(m,2.7H),3.59(s,3H),3.36(s,2H),2.94-2.84(m,2H),2.21-1.89(m,3.3H),1.72-1.68(m,0.7H),1.39(s,6H)。

Compound 225: (trans) -4- (6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexanecarboxylic acid

¹H NMR(400MHz,DMSO-d₆)δ8.93(br s,1H),7.99(s,1.5H),7.93(d,J＝2.8Hz,0.5H),7.57-7.55(m,1H),7.37-7.33(m,1H),7.29-7.22(m,1H),5.98(s,0.5H),5.88(s,0.5H),3.87-3.76(m,0.5H),3.65-3.58(m,0.5H),3.53(s,1.6H),3.51(s,1.4H),2.41-2.34(m,0.5H),2.25-2.16(m,0.5H),2.09-1.97(m,2H),1.89-1.74(m,3H),1.67-1.58(m,1H),1.50-1.34(m,2H)。

Compound 227A: (trans) -4- (-6- (3, 4-difluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexanecarboxylic acid, LC-ms (esi): r_T＝3.615min，C₂₃H₂₃F₂N₃O₄Calculated mass of S475.1, found value of M/z 475.9[ M + H]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝7.364min)。¹HNMR(400MHz,DMSO-d₆)δ7.99-7.97(m,1.7H),7.92(d,J＝2.8Hz,0.3H),7.26-7.17(m,1H),7.11-7.06(m,0.7H),6.98-6.95(m,0.3H),5.81(s,0.3H),5.68(s,0.7H),3.85(br s,0.3H),3.62-3.57(m,0.7H),3.52(s,3H),2.44-2.38(m,3H),2.30-2.16(m,1H),2.06-1.96(m,2H),1.90-1.62(m,4H),1.46-1.33(m,2H)。

Compound 229B: (trans) -4- (6- (2-bromo-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexane-carboxylic acid, LC-ms (esi): r_T＝3.510min，C₂₂H₂₀BrF₂N₃O₄Calculated mass of S539.0, M/z found value 542.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 80:20: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝5.689min)。¹H NMR(400MHz,DMSO-d₆)δ11.97(s,1H),9.51(s,0.4H),8.98(s,0.6H),8.00-7.99(m,1.5H),7.94-7.93(m,0.5H),7.52-7.44(m,1H),7.22-7.12(m,1H),6.00(s,0.5H),5.91(s,0.5H),3.88-3.80(m,0.5H),3.65-3.51(m,3.5H),2.41-2.33(m,0.5H),2.25-2.19(m,0.5H),2.06-2.01(m,2H),1.97-1.61(m,4H),1.49-1.36(m,2H)。

Compound 230: 3- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) propionic acid

LC-MS(ESI)：R_T＝3.864min，C₂₃H₂₃ClF₂N₄O₆S₂Calculated mass 588.1, M/z found mass 588.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆+ one drop D₂O)δ8.01-7.99(m,1.8H),7.93-7.92(m,0.2H),7.48-7.42(m,1H),7.23-7.19(m,1H),6.02(s,0.2H),5.94(s,0.8H),3.77-3.68(m,3H),3.54(s,3H),3.30-3.27(m,2H),2.94-2.84(m,2H),2.63-2.59(m,2H),2.04-1.94(m,1H),1.89-1.77(m,2.2H),1.66-1.61(m,0.8H)。

Compound 232B: (trans) -3- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.944min，C₂₅H₂₅ClF₂N₄O₆S₂Calculated mass of 614.1, M/z found mass 615.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.01-7.92(m,2H),7.49-7.41(m,1H),7.22-7.18(m,1H),6.01(s,0.2H),5.92(s,0.8H),4.00-3.97(m,1H),3.76-3.70(m,3H),3.53(s,3H),3.11-3.04(m,1H),2.91-2.83(m,2H),2.56-2.51(m,4H),1.98-1.91(m,1H),1.86-1.72(m,2H),1.61-1.57(m,1H)。

Compound 232D: (cis) -3- ((4- (-6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.164min，C₂₅H₂₅ClF₂N₄O₆S₂Calculated mass of 614.1, M/z found mass 615.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.32(s,1H),8.01-7.95(m,2H),7.48-7.42(m,1H),7.22-7.18(m,1H),5.93(s,1H),3.95-3.91(m,1H),3.73-3.67(m,3H),3.53(s,3H),3.06-3.01(m,1H),2.88-2.80(m,2H),2.48-2.41(m,4H),1.99-1.92(m,1H),1.83-1.74(m,2.1H),1.62-1.59(m,0.9H)。

Compound 232X: (trans) -3- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.939min，C₂₅H₂₅ClF₂N₄O₆S₂Calculated mass of 614.1, M/z found mass 615.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.63(s,1H),8.01-7.97(m,2H),7.48-7.41(m,1H),7.22-7.18(m,1H),5.94(s,1H),4.03-3.99(m,1H),3.77-3.71(m,3H),3.53(s,3H),3.17-3.14(m,1H),2.92-2.84(m,2H),2.59-2.55(m,4H),2.07-1.96(m,1.2H),1.91-1.72(m,2H),1.64-1.59(m,0.8H)。

Compound 241B: (trans) -3- ((4- (-6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.329min，C₂₅H₂₆BrFN₄O₆S₂Calculated mass of 640.1, M/z found value 643.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.01-7.98(m,1.8H),7.93(d,J＝2.8Hz,0.2H),7.58-7.55(m,1H),7.38-7.30(m,1H),7.28-7.21(m,1H),5.99(s,0.2H),5.89(s,0.8H),4.04-3.95(m,1H),3.77-3.70(m,3H),3.53(s,2.5H),3.52(s,0.5H),3.18-3.10(m,1H),2.88(q,J＝14.0Hz,2H),2.59-2.53(m,4H),2.10-1.84(m,1H),1.82-1.75(m,2H),1.61-1.57(m,1H)。

Compound 258: 3- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) bicyclo [1.1.1]Pentane-1-carboxylic acid, LC-ms (esi): r_T＝2.821min，C₂₁H₁₇ClFN₃O₄Calculated mass of S461.1, found value of M/z 462.1[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.01-7.99(m,1.4H),7.95(d,J＝2.8Hz,0.6H),7.44-7.42(m,1H),7.32-7.30(m,1H),7.24-7.20(m,1H),5.97(s,0.5H),5.87(s,0.5H),3.56(s,1.5H),3.55(s,1.5H),2.34(s,3H),2.26(s,3H)。

Compound 258B: 3- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) bicyclo [1.1.1]Pentane-1-carboxylic acid, LC-ms (esi): r_T＝3.399min，C₂₁H₁₇ClFN₃O₄Calculated mass of S461.1, found value of M/z 461.9[ M + H [)]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝6.227min)。¹H NMR(400MHz,DMSO-d₆)δ8.01-7.99(m,1.4H),7.95-7.92(m,0.6H),7.44-7.42(m,1H),7.35-7.28(m,1H),7.24-7.20(m,1H),5.97(s,0.5H),5.87(s,0.5H),3.56(s,1.5H),3.55(s,1.5H),2.36(s,3H),2.26(s,3H)。

Compounds 265E and 265H: (cis) -5- (-6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) tetrahydro-2H-pyran-2-carboxylic acid

Compound 265E: LC-MS (ESI): r_T＝3.412min，C₂₂H₂₁ClFN₃O₅Calculated mass of S493.1, M/z found 494.0[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R-_T＝12.672min)。¹H NMR(400MHz,DMSO-d₆)δ9.57(br s,1H),8.00(s,2H),7.43(dd,J＝8.8,2.4Hz,1H),7.38-7.34(m,1H),7.24-7.20(m,1H),5.96(s,1H),4.03-4.01(m,1H),3.98(q,J＝7.2Hz,2H),3.88-3.78(m,3H),2.06-1.97(m,2H),1.83-1.76(m,1H),1.59-1.50(m,1H),1.07(t,J＝7.2Hz,3H)。¹H NMR(400MHz,DMSO-d₆+D₂O)δ8.02-8.01(m,1H),7.97-7.95(m,1H),7.44-7.36(m,2H),7.24-7.19(m,1H),5.98(s,1H),4.05-3.98(m,4H),3.92-3.85(m,2H),2.07-2.00(m,2H),1.86-1.80(m,1H),1.60-1.51(m,1H),1.07(t,J＝7.2Hz,3H)。

Compound 265H: LC-MS (ESI): r_T＝3.153min，C₂₂H₂₁ClFN₃O₅Calculated mass of S493.1, M/z found value 493.9[ M + H [ ]]⁺. Chiral SFC (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: CO₂ACN: TFA 60:40:0.2 at 2.999 g/min; column temperature: 40.1 ℃; wavelength: 214nm, back pressure: 100 bar; r_T＝6.19min)。¹H NMR(400MHz,DMSO-d₆)δ9.58(br s,1H),8.00(s,2H),7.43(dd,J＝8.8,2.8Hz,1H),7.37(dd,J＝8.8,6.0Hz,1H),7.25-7.20(m,1H),5.95(s,1H),3.98(q,J＝7.2Hz,2H),3.90-3.82(m,3H),3.75-3.70(m,1H),2.15-2.09(m,1H),2.04-1.97(m,2H),1.62-1.53(m,1H),1.07(t,J＝6.8Hz,3H)。¹H NMR(400MHz,DMSO-d₆+D₂O)δ8.01(d,J＝3.2Hz,1H),7.96(d,J＝3.2Hz,1H),7.43(dd,J＝8.8,2.4Hz,1H),7.37(dd,J＝8.8,6.0Hz,1H),7.25-7.20(m,1H),5.98(s,1H),3.99(q,J＝6.8Hz,2H),3.92-3.86(m,3H),3.77-3.72(m,1H),2.17-2.12(m,1H),2.07-1.99(m,2H),1.64-1.54(m,1H),1.07(t,J＝6.8Hz,3H)。

270B: (cis) -3- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.425min，C₂₇H₂₉ClF₂N₄O₆S₂Calculated mass of 642.1M/z found value 643.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.71(br s,1H),8.00(s,2H),7.46(q,J＝8.4Hz,1H),7.23-7.19(m,1H),5.94(s,1H),4.10-4.06(m,1H),3.97(q,J＝7.2Hz,2H),3.74-3.67(m,3H),2.84(q,J＝10.4Hz,2H),2.67-2.62(m,2H),2.13-2.08(m,2H),2.01-1.82(m,1H),1.85-1.78(m,2H),1.74-1.61(m,1H),1.39(s,3H),1.07(t,J＝7.2Hz,3H)。

Compound 272A: (trans) -3- ((4- (6- (2-chloro-4-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.339min，C₂₇H₃₀ClFN₄O₆S₂Calculated mass of 624.1M/z found value 625.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.01-7.93(m,2H),7.42(dd,J＝8.8,2.8Hz,1H),7.36(dd,J＝8.8,6.0Hz,1H),7.26-7.18(m,1H),6.02(s,0.2H),5.92(s,0.8H),3.98-3.94(m,3H),3.76-3.72(m,3H),2.86-2.78(m,2H),2.75-2.72(m,2H),2.26-2.20(m,2H),2.04-1.77(m,3H),1.60-1.55(m,1H),1.33(s,3H),1.07(t,J＝7.2Hz,3H)。

Compound 272B: (cis) -3- ((4- (6- (2-chloro-4-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.321min，C₂₇H₃₀ClFN₄O6S₂Calculated mass of 624.1M/z found value 625.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.43(br s,1H),8.01-8.00(m,2H),7.42-7.38(m,1H),7.38-7.35(m,1H),7.24-7.19(m,1H),5.93(s,1H),4.10-4.06(m,1H),3.97(q,J＝7.2Hz,2H),3.74-3.71(m,3H),2.89-2.80(m,2H),2.67-2.62(m,2H),2.13-2.08(m,2H),1.99-1.92(m,1H),1.88-1.76(m,2H),1.61-1.53(m,1H),1.39(s,3H),1.07(t,J＝6.8Hz,3H)。

Compound 274A: (trans) -3- ((4- (-6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.165min，C₂₆H₂₈ClFN₄O₆S₂Calculated mass of 610.1M/z found value 611.2[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.42(br s,1H),8.01-7.99(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.38-7.31(m,2H),7.22-7.20(m,1H),6.07(s,0.2H),5.97(s,0.8H),3.97-3.93(m,1H),3.76-3.68(m,3H),3.52(s,2H),3.51(s,1H),2.90-2.81(m,2H),2.79-2.73(m,2H),2.27-2.22(m,2H),2.06-1.72(m,3H),1.62-1.53(m,1H),1.34(s,3H)。

Compound 274B: (cis) -3- ((4- (-6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.142min，C₂₆H₂₈ClFN₄O₆S₂Calculated mass of 610.1M/z found value 611.2[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.78(br s,1H),8.03-7.92(m,2H),7.39-7.34(m,2H),7.22-7.20(m,1H),6.07(s,0,2H),5.97(s,0.8H),4.21-4.06(m,1H),3.81-3.62(m,3H),3.52(s,3H),2.94-2.80(m,2H),2.68-2.62(m,2H),2.16-2.10(m,2H),1.99-1.90(m,1H),1.82-1.70(m,2H),1.65-1.52(m,1H),1.40(s,3H)

Compound 278C: (trans) -3- ((4- (6- (2-bromo-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.742min，C₂₆H₂₈BrFN₄O₆S₂Calculated mass of 654.1, M/z found value 654.8[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.60(s,1H),9.60(s,0.8H),9.18(s,0.2H),8.03-7.95(m,1.7H),7.95-7.91(m,0.2H),7.44-7.37(m,1H),7.33-7.26(m,1H),7.22-7.13(m,1H),6.05(s,0.2H),5.96(s,0.8H),3.99-3.92(m,1H),3.80-3.65(m,3H),3.55-3.50(m,3H),2.94-2.70(m,4H),2.31-2.18(m,2H),2.18-2.09(m,1H),2.07-1.71(m,3.2H),1.63-1.55(m,0.8H),1.35(s,3H)。

Compound 278D: (cis) -3- ((4- (6- (2-bromo-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.662min，C₂₆H₂₈BrFN₄O₆S₂Calculated mass of 654.1, M/z found value 654.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(s,0.8H),9.20-9.18(m,0.2H),8.05-7.98(m,2H),7.45-7.39(m,1H),7.31-7.24(m,1H),7.19-7.15(m,1H),6.07-5.54(m,1H),4.19-4.09(m,1H),3.79-3.65(m,3H),3.55-3.50(m,3H),2.93-2.80(m,2H),2.71-2.62(m,2H),2.18-2.13(m,2H),2.04-1.74(m,3.2H),1.65-1.57(m,0.8H),1.41(s,3H)。

Compound 282C: (trans) -3- ((4- (-6- (2-bromo-4-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝2.852min，C₂₇H₃₀BrFN₄O₆S₂Calculated mass of 668.1, M/z found value 670.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.99(s,1.8H),7.93(s,0.2H),7.57(dd,J＝8.4,2.4Hz,1H),7.37-7.34(m,1H),7.28-7.24(m,1H),5.99(s,0.2H),5.90(s,0.8H),4.00-3.85(m,3.2H),3.75-3.68(m,2.8H),2.87-2.79(m,2H),2.73-2.67(m,2H),2.19-2.13(m,2H),2.00-1.76(m,3.2H),1.60-1.57(m,0.8H),1.28(s,3H),1.08(t,J＝7.2Hz,3H)。

Compound 282D: (cis) -3- ((4- (6- (2-bromo-4-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝2.746min，C₂₇H₃₀BrFN₄O₆S₂Calculated mass of 668.1, M/z found value 670.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.82(br s,1H),8.01-7.99(m,2H),7.57(dd,J＝8.8,2.8Hz,1H),7.38-7.34(m,1H),7.29-7.24(m,1H),5.99(s,0.2H),5.91(s,0.8H),4.08-3.95(m,3.2H),3.74-3.67(m,2.8H),2.89-2.80(m,2H),2.66-2.61(m,2H),2.10-1.78(m,5.2H),1.61-1.59(m,0.8H),1.37(s,3H),1.08(t,J＝6.8Hz,3H)。

Compound 285A: trans-3- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutane-carboxylic acid, LC-ms (esi): r_T＝8.027min，C₂₅H₂₆ClFN₄O₆S₂Calculated mass 596.1, found value M/z 596.9[ M + H]⁺. Chiral HPLC (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; temperature: R-_T＝8.190min)；¹H NMR(400MHz,DMSO-d₆)δ12.39(br s,1H),9.51(d,J＝3.6Hz,0.8H),9.12(s,0.2H),7.99(dd,J＝8.8,3.2Hz,1.8H),7.93(d,J＝3.2Hz,0.2H),7.44-7.40(m,1H),7.37-7.31(m,1H),7.23-7.18(m,1H),6.01(s,0.2H),5.92(d,J＝3.2Hz,0.8H),4.05-3.97(m,1H),3.77-3.70(m,3H),3.53(s,3H),3.19-3.11(m,1H),2.93-2.83(m,2H),2.59-2.54(m,4H),2.06-1.91(m,1H),1.90-1.73(m,2.2H),1.60-1.57(m,0.8H)。

Compound 289A: (trans) -4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexanecarboxylic acid, LC-ms (esi): r_T＝3.915min，C₂₂H₂₀ClF₂N₃O₄Calculated mass of S495.1, M/z found value 495.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.90(m,2H),7.48-7.41(m,1H),7.18(br s,1H),6.02(s,0.5H),5.93(s,0.5H),3.82-3.59(m,1H),3.53(s,3H),2.34-2.21(m,1H),2.05-1.99(m,2H),1.86-1.64(m,4H),1.48-1.34(m,2H)。

Compound 293C: (trans) -1- ((4- ((R) -6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -sulfonyl) pyrrolidine-3-carboxylic acid, chiral componentAnalysis (column: Chiralpak IG5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: TFA: 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R); pH; (R);)_T＝9.720min)。LC-MS(ESI)：R_T＝2.674min，C₂₆H₂₇ClF₂N₄O₆S₂Calculated mass 628.1, M/z found value 629.1[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.90(s,1H),7.75(d,J＝2.8Hz,1H),7.23-7.20(m,2H),6.10(s,1H),4.05-3.74(m,1H),3.66-3.64(m,2H),3.60(s,3H),3.52-3.49(m,2H),3.27-3.25(m,1H),3.20-3.16(m,1H),2.36-2.31(m,2H),2.28-2.20(m,2H),2.12-1.96(m,2H),1.87-1.64(m,4H)。

Compound 302A: (trans) -4- (-6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cycloheptanecarboxylic acid, purified by C18 column (acetonitrile: water (+ 0.1% ammonium bicarbonate) ═ 5% to 80%) to give the title compound as a yellow solid (95mg, 97.4% purity, 86% yield, 95.2% stereopurity). LC-MS (ESI): r_T＝3.673min，C₂₄H₂₄ClF₂N₃O₄Calculated mass of S523.1, M/z found value 523.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝7.999min)。¹H NMR(400MHz,CD₃OD)δ7.92(br s,1H),7.74(d,J＝2.8Hz,1H),7.26-7.19(m,2H),6.13(s,0.7H),6.06(s,0.3H),4.19-4.10(m,0.7H),4.04(q,J＝7.2Hz,2H),3.98-3.90(m,0.3H),2.67-2.54(m,1H),2.20-1.88(m,7H),1.81-1.70(m,2H),1.59-1.48(m,1H),1.14(t,J＝7.2Hz,3H)。

Compound 302C: (cis) -4- (-6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cycloheptanecarboxylic acid, purified by C18 column (acetonitrile: water (+ 0.1% ammonium bicarbonate) ═ 5% to 80%) to give the title compound as a yellow solid (90mg, 97.5% purity, 82% yield, 100% stereopurity). LC-MS (ESI): r_T＝3.679min，C₂₄H₂₄ClF₂N₃O₄Calculated mass of S523.1, M/z found value 523.9[ M + H [ ]]⁺. Chiral HPLC (column): chiralpak IA 5 μm4.6 × 250 mm; mobile phase: hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝5.465min)。¹H NMR(400MHz,CD₃OD)δ7.92(s,0.7H),7.89(s,0.3H),7.74(d,J＝3.2Hz,1H),7.26-7.19(m,2H),6.12(s,0.7H),6.06(s,0.3H),4.19-4.10(m,0.7H),4.04(q,J＝7.2Hz,2H),3.97-3.91(m,0.3H),2.65-2.53(m,1H),2.25-2.14(m,1H),2.11-1.93(m,3H),1.90-1.69(m,6H),1.14(t,J＝7.2Hz,3H)。

Compound 302E: (cis) -4- (-6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cycloheptanecarboxylic acid, purified by C18 column (acetonitrile: water (+ 0.1% ammonium bicarbonate) ═ 5% to 80%) to give the title compound as a yellow solid (72mg, 98.1% purity, 81% yield, 98.9% stereopurity). LC-MS (ESI): r_T＝3.844min，C₂₄H₂₄ClF₂N₃O₄Calculated mass of S523.1, M/z found value 523.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝10.165min)。¹H NMR(400MHz,CD₃OD)δ7.92(br s,0.7H),7.89(br s,0.3H),7.74(d,J＝3.2Hz,1H),7.26-7.18(m,2H),6.13(s,0.7H),6.06(s,0.3H),4.19-4.10(m,0.7H),4.04(q,J＝7.2Hz,2H),3.98-3.92(m,0.3H),2.68-2.61(m,0.7H),2.59-2.53(m,0.3H),2.17-1.87(m,7H),1.85-1.69(m,2H),1.63-1.53(m,1H),1.14(t,J＝7.2Hz,3H)。

Compound 302F: (trans) -4- (-6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cycloheptanecarboxylic acid, purified by C18 column (acetonitrile: water (+ 0.1% ammonium bicarbonate) ═ 5% to 80%) to give the title compound as a yellow solid (78mg, 98.4% purity, 87% yield, 100% stereopurity). LC-MS (ESI): r_T＝3.810min，C₂₄H₂₄ClF₂N₃O₄Calculated mass of S523.1, M/z found value 523.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝8.067min)。¹H NMR(400MHz,CD₃OD)δ7.95-7.87(m,1H),7.74(d,J＝2.8Hz,1H),7.26-7.18(m,2H),6.13(s,0.7H),6.06(s,0.3H),4.18-4.10(m,0.7H),4.04(q,J＝7.2Hz,2H),3.98-3.90(m,0.3H),2.62-2.49(br s,1H),2.21-2.11(m,1H),2.10-1.95(m,2.5H),1.93-1.76(m,5.5H),1.75-1.65(m,1H),1.14(t,J＝7.2Hz,3H)。

Compound 309C: (trans) -3- ((4- (6- (3, 4-difluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.189min，C₂₆H₂₈F₂N₄O₆S₂Calculated mass of 594.1, M/z found value 595.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.97(m,1.9H),7.92(s,0.1H),7.25-7.18(m,1H),7.12-7.08(m,1H),5.81(s,0.1H),5.69(s,0.9H),4.00-3.96(m,1H),3.78-3.69(m,3H),3.52(s,3H),3.09-3.04(m,1H),2.91-2.82(m,2H),2.56-2.51(m,4H),2.43(s,3H),2.00-1.91(m,1H),1.84-1.72(m,2H),1.60-1.57(m,1H)。

Compound 311A: (trans) -3- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -cyclopentanecarboxylic acid and LC-ms (esi): r_T＝3.395min，C₂₆H₂₈ClFN₄O₆S₂Calculated mass of 610.1, M/z found value 611.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.93(m,2H),7.43-7.35(m,2H),7.23-7.19(m,1H),6.02(s,0.3H),5.92(s,0.7H),4.00-3.93(m,0.3H),3.80-3.72(m,3.7H),3.53(s,3H),2.96-2.82(m,3H),2.24-2.19(m,1H),2.17-2.10(m,2H),2.06-1.99(m,2H),1.96-1.83(m,2H),1.79-1.59(m,3H)。

Compound 311B: (cis) -3- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -cyclopentanecarboxylic acid, LC-ms (esi): r_T＝3.340min，C₂₆H₂₈ClFN₄O₆S₂Calculated mass of 610.1, M/z found value 611.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.99(s,2H),7.43-7.34(m,2H),7.23-7.18(m,1H),6.02(s,0.3H),5.93(s,0.7H),4.02-3.91(m,0.3H),3.79-3.66(m,3.7H),3.53(s,3H),2.95-2.86(m,2H),2.79-2.70(m,1H),2.32-2.25(m,1H),2.03-1.59(m,9H)。

Compound 313A: (cis) -4- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -cyclohexanecarboxylic acid, LC-ms (esi): r_T＝3.669min，C₂₇H₃₀ClFN₄O₆S₂Calculated mass of 624.1, M/z found value 625.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.99(d,J＝3.2Hz,1H),7.94(d,J＝2.4Hz,0.7H),7.88(br s,0.3H),7.42-7.34(m,2H),7.22-7.17(m,1H),6.02(s,0.3H),5.94(s,0.7H),3.82-3.74(m,3H),3.54(s,3H),3.20(br s,1H),2.95(q,J＝12.0Hz,2H),2.59(s,1H),2.11(br s,2H),1.97-1.78(m,5H),1.59-1.54(m,5H)。

Compound 313B: (trans) -4- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -cyclohexanecarboxylic acid, LC-ms (esi): r_T＝2.353min，C₂₇H₃₀ClFN₄O₆S₂Calculated mass of 624.1, M/z found value 625.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.93(m,2H),7.43-7.31(m,2H),7.23-7.18(m,1H),6.02(s,0.3H),5.92(s,0.7H),4.01-3.94(m,0.3H),3.79-3.72(m,2.7H),3.53(s,3H),3.18-3.12(m,1H),2.97(q,J＝12.0Hz,2H),2.24-2.18(m,1H),2.09-1.71(m,7.3H),1.61-1.35(m,4.7H)。

Compound 319B: (trans) -3- ((4- (6- (2-chloro-3-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.410min，C₂₆H₂₈ClFN₄O₆S₂Calculated mass of 610.1, M/z found value 611.1[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.91(s,1H),7.75(d,J＝2.8Hz,1H),7.34-7.14(m,3H),6.16(s,1H),4.07-4.02(m,3H),3.96-3.87(m 3H),3.28-3.22(m,1H),3.03-2.93(m,2H),2.80-2.65(m,4H),2.16-1.66(m,4H),1.12(t,J＝7.2Hz,3H)。

Compound 321A: (tran)s) -3- ((4- (6- (2-chloro-3-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.435min，C₂₇H₃₀ClFN₄O₆S₂Calculated mass of 624.1, M/z found value 625.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.60(s,0.8H),9.11(s,0.2H),8.01-7.99(m,1.8H),7.94(d,J＝3.2Hz,0.2H),7.40-7.32(m,2H),7.23-7.18(m,1H),6.08(s,0.2H),5.98(d,J＝2.4Hz,0.8H),4.00-3.93(m,3H),3.77-3.69(m,3H),2.89-2.81(m,2H),2.79-2.73(m,2H),2.27-2.22(m,2H),2.00-1.87(m,1H),1.81-1.74(m,2H),1.61-1.58(m,1H),1.34(s,3H),1.08-1.03(m,

Compound 321B: (cis) -3- ((4- (6- (2-chloro-3-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.422min，C₂₇H₃₀ClFN₄O₆S₂Calculated mass of 624.1, M/z found value 625.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.60(s,0.8H),9.11(s,0.2H),8.03-8.00(m,1.8H),7.94(s,0.2H),7.41-7.32(m,2H),7.23-7.21(m,1H),6.09(s,0.2H),5.98(s,0.8H),4.14-4.05(m,1H),3.97(q,J＝6.8Hz,2H),3.77-3.66(m,3H),2.89-2.81(m,2H),2.69-2.64(m,2H),2.14-2.09(m,2H),1.99-1.90(m,1H),1.86-1.75(m,2H),1.62-1.59(m,1H),1.40(s,3H),1.06(t,J＝7.2Hz,3H)。

Compound 323C: trans-methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((3- (methoxycarbonyl) -3-methylcyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, purified by preparative HPLC (column: gilson Xbridge C18(5 μm19 x 150mm), mobile phase A: water (+ 0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 10% -80% (% B)) to give the title compound as a yellow solid (125mg, 98% purity, 69% yield, 100% ee). LC-MS (ESI): r_T＝3.270min，C₂₆H₂₇ClF₂N₄O₆S₂Calculated mass 628.1, M/z found value 629.0[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak)IC5 μm4.6 x 250 mm; mobile phase: hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; RT — 9.816 min).¹H NMR(400MHz,DMSO-d₆)δ8.01-7.94(m,2H),7.49-7.42(m,1H),7.22-7.16(m,1H),6.01(s,0.2H),5.92(s,0.8H),3.95-3.87(m,1H),3.76-3.64(m,3H),3.53(s,3H),2.89-2.81(m,2H),2.78-2.72(m,2H),2.25-2.18(m,2H),2.00-1.81(m,1H),1.81-1.69(m,2H),1.61-1.56(m,1H),1.33(s,3H)。

Compound 323D: cis-methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((3- (methoxycarbonyl) -3-methylcyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, purified by preparative HPLC (column: gilson xbridge C18(5 μm19 x 150mm), mobile phase a: water (+ 0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 10% -80% (% B)) to give the title compound as a yellow solid (125mg, 99% purity, 43% yield). LC-MS (ESI): r_T＝3.243min，C₂₆H₂₇ClF₂N₄O₆S₂Calculated mass 628.1, M/z found value 629.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.01-8.00(m,2H),7.50-7.42(m,1H),7.24-7.14(m,1H),5.93(s,1H),4.13-4.01(m,1H),3.82-3.61(m,3H),3.53(s,3H),2.89-2.81(m,2H),2.70-2.62(m,2H),2.16-2.08(m,2H),2.01-1.94(m,1H),1.85-1.74(m,2H),1.74-1.61(m,1H),1.39(s,3H)。

Compound 329B: (trans) -3- ((4- (6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutane-carboxylic acid was purified by preparative HPLC (column: Xbridge C18(5 μm 10. multidot.190 mm) mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 30% -70% (% B)) to give the title compound as a yellow solid (58mg, 63% yield, 100% stereopurity). LC-MS (ESI): r_T＝3.553min，C₂₆H₂₈ClFN₄O₆S₂Calculated Mass 610.1, M/z found Mass 611.1[ M + H]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: TFA ═ 80:20:0.2 at 1.0 mL/min; temperature:30 ℃; wavelength: 230nm, R_T＝11.296min)。¹H NMR(400MHz,DMSO-d₆)δ7.99-7.92(m,2H),7.43-7.40(m,1H),7.38-7.34(m,1H),7.23-7.19(m,1H),6.03(br s,0.2H),5.93(s,0.8H),4.00-3.92(m,3H),3.74-3.67(m,3H),3.07-3.00(m,1H),2.88-2.79(m,2H),2.46-2.44(m,4H),1.97-1.91(m,1H),1.83-1.76(m,2H),1.63-1.57(m,1H),1.07(t,J＝7.2Hz,3H)。

Compound 331C: (trans) -3- ((4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutane-carboxylic acid, LC-ms (esi): r_T＝3.780min，C₂₅H₂₆ClFN₄O₆S₂Calculated mass 596.1, found value M/z 596.9[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.16(s,1H),9.58(d,J＝3.2Hz,0.8H),9.15(s,0.2H),8.01-7.98(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.40-7.31(m,2H),7.22-7.16(m,1H),6.07(s,0.2H),5.97(d,J＝3.2Hz,0.8H),4.05-3.97(m,1H),3.77-3.71(m,3H),3.52(s,2.4H),3.51(s,0.6H),3.17-3.13(m,1H),2.93-2.84(m,2H),2.59-2.55(m,4H),1.97-1.90(m,1H),1.82-1.74(m,2.2H),1.61-1.58(m,0.8H)。

Compound 333B: (trans) -3- ((4- (6- (2-bromo-4-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutane-1-carboxylic acid, LC-ms (esi): r_T＝3.702min，C₂₆H₂₈BrFN₄O₆S₂Calculated mass of 654.1M/z found value 655.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; temperature: 30 ℃; chiral analysis of chiral molecules: 4.6: (1.0 mL/min; chiral molecules: 250 mm; chiral molecules: 1:5_T＝13.060min)。¹H NMR(400MHz,CD₃OD)δ7.91(br s,1H),7.76(d,J＝2.8Hz,1H),7.43-7.39(m,2H),7.14-7.10(m,1H),6.09(s,1H),4.05(q,J＝7.2Hz,2H),3.96-3.89(m,4H),3.26-3.22(m,1H),3.03-2.93(m,2H),2.80-2.68(m,4H),2.15-1.61(m,4H),1.14(t,J＝7.2Hz,3H)。

Compound 339B: (trans) -3- ((4- (6- (2-bromo-3-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.933min，C₂₆H₂₈BrFN₄O₆S₂Calculated mass of 654.1, M/z found value 655.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(s,0.7H),9.07(s,0.3H),8.00-7.92(m,2H),7.44-7.37(m,1H),7.31-7.15(m,2H),6.07(s,0.3H),5.97(s,0.7H),4.03-3.93(m,3H),3.78-3.71(m,3H),3.15-3.12(m,1H),2.92-2.83(m,2H),2.58-2.53(m,4H),2.06-1.58(m,4H),1.08-1.01(m,3H)。

Compound 339D: (cis) -3- ((4- (6- (2-bromo-3-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝4.011min，C₂₆H₂₈BrFN₄O₆S₂Calculated mass of 654.1, M/z found value 655.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(s,0.7H),9.09(s,0.3H),8.00(s,1.7H),7.93(s,0.3H),7.44-7.39(m,1H),7.29(d,J＝7.6Hz,1H),7.24-7.15(m,1H),6.07(s,0.3H),5.97(s,0.7H),4.00-3.91(m,3.3H),3.77-3.67(m,2.7H),3.11-3.02(m,1H),2.88-2.80(m,2H),2.48-2.33(m,4H),2.04-1.78(m,3.3H),1.62-1.59(m,0.7H),1.08-1.01(m,3H)。

Compound 343A: (trans) -3- ((4- (6- (3, 4-difluoro-2-methylphenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝4.142min，C₂₇H₃₀F₂N₄O₆S₂Calculated mass of 608.2, found M/z value 609.2[ M + H [)]⁺。¹H NMR(400MHz,CD₃OD)δ7.89(s,1H),7.73(d,J＝2.8Hz,1H),7.17-6.99(m,2H),5.86(s,1H),4.07-3.79(m,6H),3.26-3.17(m,1H),3.04-2.90(m,2H),2.77-2.63(m,4H),2.56-2.41(m,3H),2.16-1.80(m,3.3H),1.70-1.61(m,0.7H),1.12(t,J＝7.2Hz,3H)。

Compound 343C: (trans) -3- ((4- (6- (3, 4-difluoro-2-methylphenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.310min，C₂₇H₃₀F₂N₄O₆S₂Calculated mass 608.2, m/z found value609.2[M+H]⁺。¹H NMR(400MHz,CD₃OD)δ7.89(d,J＝2.4Hz,1H),7.73(d,J＝3.2Hz,1H),7.17-6.99(m,2H),5.86(s,1H),4.07-3.77(m,6H),3.27-3.20(m,1H),3.03-2.91(m,2H),2.77-2.64(m,4H),2.48(s,3H),2.15-1.79(m,3.3H),1.74-1.59(m,0.7H),1.12(t,J＝7.2Hz,3H)。

343D: (cis) -3- ((4- (6- (3, 4-difluoro-2-methylphenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutane-carboxylic acid, LC-ms (esi): r_T＝4.133min，C₂₇H₃₀F₂N₄O₆S₂Calculated mass of 608.2, found M/z value 609.2[ M + H [)]⁺。¹H NMR(400MHz,CD₃OD)δ7.89(d,J＝2.0Hz,1H),7.73(d,J＝2.8Hz,1H),7.15-6.98(m,2H),5.86(s,1H),4.07-3.78(m,6H),3.21-3.13(m,1H),2.99-2.89(m,2H),2.72-2.54(m,4H),2.49(s,3H),2.18-1.57(m,4H),1.12(t,J＝7.2Hz,3H)。

Compound 345A: (trans) - (R X) -4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexanecarboxylic acid was purified by preparative HPLC (column: Gilson X-bridged C18(5 μm 19. about.150 mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 25% -70% (% B)) to give the title compound as a yellow solid (110mg, 66% yield, 100% stereopurity). LC-MS (ESI): r_T＝3.766min，C₂₃H₂₂ClF₂N₃O₄Calculated mass of S509.1, M/z found 510.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IE 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: TFA: 85:15: 0.2; temperature: 230 ℃; wavelength: 230 nm; R_T＝8.775min)。¹H NMR(400MHz,DMSO-d₆)δ8.91(br s,1H),8.03-7.98(m,1.5H),7.94(d,J＝3.2Hz,,0.5H),7.49-7.42(m,1H),7.20-7.16(m,1H),6.02(s,0.4H),5.92(s,0.6H),4.00-3.94(m,2H),3.86-3.80(m,0.5H),3.60-3.57(m,0.5H),2.39-2.33(m,0.5H),2.24-2.17(m,0.5H),2.05-1.97(m,2H),1.87-1.63(m,4H),1.43-1.35(m,2H),1.10-1.03(m,3H)。

Compound 347B: (trans) -4- (6- (2-bromo-3, 4-difluorophenyl)) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexanecarboxylic acid, purified by preparative HPLC (column: gilson X-bright C18(5 μm19 × 150mm), mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 30% -70% (% B)) to give the title compound as a yellow solid (6.5mg, 3% yield). LC-MS (ESI): r_T＝3.672min，C₂₃H₂₂BrF₂N₃O₄Calculated mass of S553.1, found M/z value 556.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.45(s,0.5H),8.90(s,0.5H),7.99(d,J＝2.4Hz,1.5H),7.93(s,0.5H),7.53-7.45(m,1H),7.21-7.12(m,1H),6.00(s,0.5H),5.91(s,0.5H),4.02-3.95(m,2H),3.86-3.80(m,0.5H),3.64-3.45(m,0.5H),2.40-2.34(m,0.5H),2.26-2.20(m,0.5H),2.04-1.94(m,2H),1.89-1.64(m,4H),1.50-1.35(m,2H),1.08-1.05(m,3H)。

Compound 352B: (trans) -3- (4-6- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -5-ethoxycarbonyl-3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.229min，C₂₈H₂₇ClF₄N₄O₆Calculated mass of S658.1, M/z found value 658.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 85:15: 0.2; temperature: 230 ℃; R:. sup._T＝18.175min)。¹H NMR(400MHz,CD₃OD)δ8.43(s,1H),7.71-7.67(m,1H),7.24-7.22(m,2H),6.15(s,1H),4.12-3.97(m,4H),3.94-3.88(m,2H),3.24-3.17(m,1H),3.00-2.92(m,2H),2.74-2.58(m,4H),2.03-1.79(m,4H),1.13(t,J＝7.2Hz,3H)。

Compound 354B: (cis) -4- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclohexane-carboxylic acid, LC-ms (esi): r_T＝3.622min，C₂₈H₃₁ClF₂N₄O₆S₂Calculated mass of 656.1, M/z found value 656.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.89(brs,1H),7.75(s,1H),7.28-7.21(m,2H),6.17(s,0.3H),6.09(s,0.7H),4.19-4.11(m,0.3H),4.07-4.02(m,2H),3.99-3.85(m,2.7H),3.15-2.98(m,3H),2.46(br s,1H),2.32-2.29(m,2H),2.13-1.52(m,10H),1.14-1.11(m,3H)。

Compound 354C: (trans) -4- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclohexane-carboxylic acid, LC-ms (esi): r_T＝3.909min，C₂₈H₃₁ClF₂N₄O₆S₂Calculated mass of 656.1, M/z found value 656.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.94-7.89(m,1H),7.75(br s,1H),7.23-7.22(m,2H),6.15(s,0.3H),6.09(s,0.7H),,4.21-4.11(m,0.4H),4.09-4.01(m,2H),3.99-3.84(m,2.6H),3.15-2.99(m,3H),2.33-1.84(m,8.3H),1.69-1.46(m,4.7H),1.14-1.11(m,3H)。

Compound 363E: (trans) -6- (-6- (2-chloro-4-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) tetrahydro-2H-pyran-3-carboxylic acid, LC-ms (esi): r_T＝2.392min，C₂₂H₂₁ClFN₃O₅Calculated mass of S493.1, M/z found 494.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝5.908min)。¹HNMR(400MHz,CDCl₃)δ9.30(br s,1H),8.00(s,1H),7.69(br s,1H),7.47-7.44(m,1H),7.15(dd,J＝8.8,2.4Hz,1H),6.99-6.95(m,1H),6.29(s,1H),5.28(d,J＝10.4Hz,1H),4.46-4.42(m,1H),4.11-4.02(m,2H),3.74-3.68(m,1H),2.87-2.78(m,1H),2.32-2.29(m,1H),2.21-2.18(m,1H),1.99-1.88(m,1H),1.60-1.50(m,1H),1.15(t,J＝7.2Hz,3H)。

Compound 363H: (trans) -6- (6- (2-chloro-4-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) tetrahydro-2H-pyran-3-carboxylic acid, LC-ms (esi): r_T＝2.623min，C₂₂H₂₁ClFN₃O₅Calculated mass of S493.1, M/z found value 493.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝6.854min)。¹HNMR(400MHz,CDCl₃)δ9.18(br s,1H),7.98-7.96(m,1H),7.64-7.42(m,2H),7.14(d,J＝6.4Hz,1H),6.99-6.95(m,1H),6.30-6.29(m,1H),5.25(br s,1H),4.43(br s,1H),4.06(brs,2H),3.71-3.68(m,1H),2.84-2.81(m,1H),2.30(br s,2H),2.04-1.96(m,1H),1.73(brs,1H),1.17(s,3H)。

Compound 367A: (trans) -3- ((3- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) pyrrolidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝2.980min，C₂₄H₂₄ClFN₄O₆S₂Calculated mass of 582.1, M/z found value 582.8[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.89(d,J＝2.8Hz,1H),7.77(d,J＝2.8Hz,1H),7.40-7.37(m,1H),7.24-7.21(m,1H),7.10-7.05(m,1H),6.09(s,1H),4.56-4.46(m,1H),4.20-4.12(m,1H),3.76-3.66(m,3H),3.60(s,3H),3.50-3.44(m,1H),3.24-3.16(m,1H),2.81-2.73(m,2H),2.69-2.62(m,2H),2.31-2.20(m,1H),2.14-2.03(m,1H)。

Compound 367B: (cis) -3- ((3- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) pyrrolidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.627min，C₂₄H₂₄ClFN₄O₆S₂Calculated mass of 582.1, M/z found value 582.9[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.90(d,J＝2.8Hz,1H),7.77(d,J＝3.2Hz,1H),7.40-7.36(m,1H),7.24-7.21(m,1H),7.10-7.05(m,1H),6.10(s,1H),4.52(s,1H),4.08-4.00(m,1H),3.75-3.64(m,3H),3.60(s,3H),3.48-3.42(m,1H),3.15-3.05(m,1H),2.77-2.69(m,2H),2.60-2.53(m,2H),2.33-2.23(m,1H),2.16-2.03(m,1H)。

Compound 410C: trans-3- ((4- (6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid

LC-MS(ESI)：R_T＝3.397min，C₂₆H₂₈BrFN₄O₆S₂Calculated mass of 654.1, M/z found value 655.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak)IA 250mm 4.6mm 5 um; mobile phase: hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝10.874min)。¹H NMR(400MHz,DMSO-d₆)δ8.00(s,1.8H),7.93(m,0.2H),7.56(dd,J＝8.4,2.4Hz,1H),7.36-7.27(m,1H),7.26-7.23(m,1H),5.98(s,0.2H),5.89(s,0.8H),3.96-3.87(m,1.3H),3.75-3.67(m,2.7H),3.53(s,3H),2.90-2.81(m,2H),2.76-2.71(m,2H),2.23-2.18(m,2H),2.05-1.91(m,1H),1.84-1.74(m,2.2H),1.60-1.57(m,0.8H),1.31(s,3H)。

Compound 410D: cis-3- ((4- (6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid

LC-MS(ESI)：R_T＝3.727min，C₂₆H₂₈BrFN₄O₆S₂Calculated mass of 654.1, M/z found value 654.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 250 mm. times.4.6 mm 5 um; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; temperature: 30 ℃; chiral analysis of chiral molecules_T＝10.417min)。¹H NMR(400MHz,DMSO-d₆)δ9.25(brs,1H),8.02-8.00(m,2H),7.57(dd,J＝8.8,2.8Hz,1H),7.38-7.35(m,1H),7.28-7.26(m,1H),5.98(br s,0.2H),5.90(s,0.8H),4.13-4.04(m,1H),3.96-3.87(m,0.3H),3.73-3.71(m,2.7H),3.53(s,3H),2.90-2.81(m,2H),2.67-2.62(m,2H),2.14-2.09(m,2H),1.97-1.94(m,1H),1.81-1.78(m,2.2H),1.60-1.58(m,0.8H),1.39(s,3H)。

Compound 414C: (trans) -3- ((4- (6- (2-bromo-3-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.458min，C₂₇H₃₀BrFN₄O₆S₂Calculated mass of 668.1, M/z found value 671.0[ M + H [)]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝9.867min)。¹H NMR(400MHz,DMSO-d₆)δ10.04(br s,1H),8.01-7.99(m,1.8H),7.93(br s,0.2H),7.42(dd,J＝13.6,8.0Hz,1H),7.29(t,J＝8.4Hz,1H),7.21(d,J＝7.6Hz,1H),6.07(br s,0.2H),5.98(s,0.8H),4.14-4.05(m,1H),3.97(dd,J＝13.2,6.4Hz,2H),3.74-3.67(m,3H),2.89-2.81(m,2H),2.68-2.63(m,2H),2.12(t,J＝10.4Hz,2H),2.01-1.77(m,3H),1.62-1.59(m,1H),1.40(s,3H),1.06(t,J＝6.8Hz,3H)。

Compound 414D: (cis) -3- ((4- (6- (2-bromo-3-fluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.458min，C₂₇H₃₀BrFN₄O₆S₂Calculated mass of 668.1, M/z found value 671.0[ M + H [)]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝15.337min)。¹H NMR(400MHz,DMSO-d₆)9.10(br s,1H),8.02-8.00(m,1.8H),7.93(br s,0.2H),7.41(dd,J＝14.0,8.0Hz,1H),7.30(t,J＝8.4Hz,1H),7.21(d,J＝7.6Hz,1H),6.07(s,0.2H),5.98(s,0.8H),4.15-4.07(m,1H),4.00-3.95(m,2H),3.77-3.67(m,3H),2.89-2.81(m,2H),2.68-2.63(m,2H),2.13(t,J＝10.4Hz,2H),2.01-1.77(m,3H),1.61(d,J＝14.0Hz,1H),1.40(s,3H),1.06(t,J＝7.2Hz,3H)。

Compound 420A: (trans) -3- ((4- (5-ethoxycarbonyl-6- (4-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝2.813min，C₂₈H₃₃FN₄O₆S₂Calculated mass of 604.2, M/z found value 605.0[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.88(br s,1H),7.73(s,1H),7.33-7.30(m,1H),6.91-6.83(m,2H),5.85(br s,1H),4.06-3.82(m,6H),2.97-2.81(m,4H),2.59-2.53(m,3H),2.39-2.34(m,2H),2.07-1.84(m,3.4H),1.66-1.64(m,0.6H),1.41(s,3H),1.11(t,J＝7.2Hz,3H)。

Compound 422: trans-4- (((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) methyl) cyclohexane-1-carboxylic acid.

LC-MS(ESI)：R_T＝2.83min，C₂₈H₃₂ClFN₄O₆S₂Calculated mass of 638.1, M/z found value of 639.2[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ8.06-8.05(m,1H),7.97-7.96(m,1H),7.48-7.45(m,1H),7.31(dd,J＝2.6,J＝8.6Hz,1H),7.15-7.10(m,1H),6.19(s,1H),4.04-3.79(m,3H),3.64(s,3H),2,98-2.85(m,4H),2.31-2.22(m,1H),2.19-1.91(m,8H),1.84-1.83(m,1H),1.56-1.41(m,2H),1.28-1.14(m,2H)。

Compound 424: trans-4- (((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) methyl) cyclohexane-1-carboxylic acid

LC-MS(ESI)：R_T＝2.99min，C₂₉H₃₃ClF₂N₄O₆S₂Calculated mass of 670.1, M/z found value 670.5[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.44-11.8(brs,0.3H),9.64(s,0.8H),9.14(s,0.2H),8.09-7.91(m,2H),7.51-7.42(m,1H),7.26-7.16(m,1H),6.04(m,0.2H),5.94(s,0.8H),4.04-3.91(m,2H),3.78-3.61(m,3H),2.95-2.94(d,J＝6.4Hz,2H),2.86-2.77(m,2H),2.18-2.08(m,1H),2.03-1.77(m,8H),1.66-1.63(m,1H),1.40-1.22(m,2H),1.18-0.97(m,5H)。

Compound 425: trans-4- (((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) methyl) cyclohexane-1-carboxylic acid

LC-MS(ESI)：R_T＝2.89min，C₂₈H₃₁ClF₂N₄O₆S₂Calculated mass of 656.1, M/z found value 656.5[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.68-9.20(brs,1H),8.04-7.94(m,2H),7.50-7.40(m,1H),7.27-7.14(m,1H),6.03(s,0.2H),5.94(s,0.8H),3.78-3.62(m,3H),3.53(s,3H),2.94(d,J＝6.4Hz,2H),2.86-2.79(m,2H),2.15-2.08(m,1H),2.03-1.76(m,8H),1.71-1.60(m,1H),1.39-1.21(m,2H),1.20-0.94(m,2H)。

Compound 429C: (trans) -3- ((4- (-5-ethoxycarbonyl-6- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.097min，C₂₈H₃₃FN₄O₆S₂Calculated mass of 604.2, M/z found value 605.0[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.88(s,1H),7.73(d,J＝2.8Hz,1H),7.16-7.11(m,2H),6.96-6.91(m,1H),5.90(s,1H),4.06-3.84(m,6H),2.99-2.81(m,4H),2.43-2.36(m,5H),2.10-1.84(m,3.4H),1.66-1.61(m,0.6H),1.42(s,3H),1.11(t,J＝7.2Hz,3H)。

Compound 429D: (cis) -3- ((4- (-5-ethoxycarbonyl-6- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.025min，C₂₈H₃₃FN₄O₆S₂Calculated mass of 604.2, M/z found value 605.0[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.88(d,J＝2.4Hz,1H),7.73(d,J＝3.2Hz,1H),7.14-7.10(m,2H),6.96-6.91(m,1H),5.91(s,1H),4.06-3.86(m,6H),2.99-2.83(m,4H),2.44(s,3H),2.24-2.19(m,2H),2.08-1.86(m,3.4H),1.70-1.64(m,0.6H),1.48(s,3H),1.11(t,J＝7.2Hz,3H)。

Compound 439B: (trans) -3- ((4- (6- (2-bromo-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.082min，C₂₅H₂₆BrFN₄O₆S₂Calculated mass of 640.1, M/z found value 640.8[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; chiral analysis of chiral molecules: chiral molecules, chiral_T＝17.633min)。¹H NMR(400MHz,DMSO-d₆)δ8.00(s,1.8H),7.93(s,0.2H),7.43-7.38(m,1H),7.29(t,J＝8.4Hz,1H),7.21(d,J＝7.2Hz,0.8H),7.15(d,J＝7.2Hz,0.2H),6.06(s,0.2H),5.97(s,0.8H),4.03-3.95(m,1H),3.77-3.71(m,3H),3.52(s,3H),3.14-3.06(m,1H),2.92-2.83(m,2H),2.57-2.53(m,4H),2.08-1.75(m,3.2H),1.61-1.59(m,0.8H)。

Compound 439D: (cis) -3- ((4- (6- (2-bromo-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.213min，C₂₅H₂₆BrFN₄O₆S₂Calculated mass of 640.1, M/z found value 643.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of chiral molecules (column: Chiralpak IE 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: TFA: 60:40: 0.2; temperature: 230 ℃; wavelength: 230_T＝13.828min)。¹H NMR(400MHz,DMSO-d₆)δ8.00(s,1.8H),7.93(br s,0.2H),7.43-7.38(m,1H),7.28(t,J＝8.8Hz,1H),7.20(d,J＝7.2Hz,1H),6.05(br s,0.2H),5.97(s,0.8H),3.98-3.89(m,1H),3.74-3.67(m,3H),3.52(s,3H),3.09-3.00(m,1H),2.89-2.80(m,2H),2.51-2.44(m,4H),2.01-1.76(m,3.2H),1.62-1.59(m,0.8H)。

Compound 444 b: (trans) -4- (((4- (6- (3-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) methyl) cyclohexanecarboxylic acid, LC-ms (esi): r_T＝4.233min，C₂₉H₃₅FN₄O₆S₂Calculated mass of 618.2, M/z found value 619.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.97(m,1.8H),7.92-7.91(m,0.2H),7.23-7.13(m,1.9H),7.07-6.99(m,1.1H),5.87(s,0.1H),5.74(s,0.9H),4.03-3.95(m,0.2H),3.77-3.66(m,2.8H),3.53(s,0.5H),3.52(s,2.5H),2.93(d,J＝6.4Hz,2H),2.87-2.78(m,2H),2.45(br s,0.4H),2.39(s,2.6H),2.18-1.77(m,9.2H),1.65-1.61(m,0.8H),1.38-1.28(m,2H),1.17-1.06(m,2H)。

Compound 447C: (trans) -3- ((4- (6- (4-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝2.727min，C₂₇H₃₁FN₄O₆S₂Calculated mass of 590.2, M/z found value 591.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.56(br s,1H),8.01-7.99(m,1.9H),7.91(d,J＝3.2Hz,0.1H),7.28-7.24(m,1H),7.02-6.95(m,2H),5.80(s,0.1H),5.67(s,0.9H),3.95-3.87(m,1H),3.75-3.68(m,3H),3.51(s,3H),2.87-2.78(m,2H),2.75-2.70(m,2H),2.51(s,3H),2.21-2.16(m,2H),2.01-1.92(m,1H),1.85-1.72(m,2H),1.59-1.56(m,1H),1.31(s,3H)。

Compound 447D: (cis) -3- ((4- (6- (4-fluoro)-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1-methylcyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.919min，C₂₇H₃₁FN₄O₆S₂Calculated mass of 590.2, M/z found value 591.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.99(m,2H),7.28-7.25(m,1H),7.01-6.95(m,2H),5.68(s,1H),4.08-3.99(m,1H),3.74-3.66(m,3H),3.52(s,3H),2.89-2.80(m,2H),2.68-2.63(m,2H),2.50(s,3H),2.08-2.03(m,2H),1.98-1.92(m,1H),1.87-1.73(m,2H),1.60-1.57(m,1H),1.37(s,3H)。

Compound 450A: (cis) -4- (((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) methyl) -4-methylcyclohexanecarboxylic acid, LC-ms (esi): r_T＝4.473min，C₂₉H₃₄ClFN₄O₆S₂Calculated mass 652.2, M/z found value 653.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; chiral analysis of the chiral structure of the protein_T＝12.154min)。¹H NMR(400MHz,DMSO-d₆)δ8.01-7.99(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.42(dd,J＝8.8,2,8Hz,1H),7.39-7.31(m,1H),7.22(td,J＝8.8,2.8Hz,1H),6.02(s,0.2H),5.92(s,0.8H),3.99-3.93(m,0.2H),3.73-3.66(m,2.8H),3.53(s,2.1H),3.52(s,0.9H),3.00(s,2H),2.90-2.82(m,2H),2.22-2.14(m,1H),2.05-1.96(m,1H),1.90-1.81(m,4H),1.72-1.53(m,5H),1.25-1.19(m,2H),1.17(s,3H)。

Compound 450B: (trans) -4- (((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) methyl) -4-methylcyclohexanecarboxylic acid, LC-ms (esi): r_T＝4.402min，C₂₉H₃₄ClFN₄O₆S₂Calculated mass 652.2, M/z found value 652.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; chiral analysis of the chiral structure of the protein_T＝14.009min)。¹H NMR(400MHz,DMSO-d₆)δ8.01(s,1.6H),7.93(br s,0.4H),7.43(dd,J＝8.8,2.4Hz,1H),7.38-7.35(m,1H),7.22(td,J＝8.8,2.8Hz,1H),6.01(br s,0.2H),5.92(s,0.8H),3.95(br s,0.2H),3.74-3.67(m,2.8H),3.53(s,3H),2.94(s,2H),2.85-2.77(m,2H),2.15-2.08(m,1H),2.03-1.97(m,1H),1.90-1.79(m,2H),1.73-1.62(m,5H),1.57-1.40(m,4H),1.15(s,3H)。

Compound 452A: (cis) -4- (((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) methyl) -4-methylcyclohexanecarboxylic acid, LC-ms (esi): r_T＝3.659min，C₂₉H₃₃ClF₂N₄O₆S₂Calculated mass of 670.2, found value of M/z 671.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.02(s,1.6H),7.94(s,0.4H),7.50-7.43(m,1H),7.23-7.16(m,1H),6.02(s,0.2H),5.93(s,0.8H),4.01-3.94(m,0.2H),3.76-3.66(m,2.8H),3.53(s,3H),3.00(s,2H),2.91-2.83(m,2H),2.21-2.14(m,1H),2.02-1.97(m,1H),1.90-1.77(m,4H),1.71-1.53(m,5H),1.25-1.19(m,2H),1.16(s,3H)。

Compound 452B: (trans) -4- (((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) methyl) -4-methylcyclohexanecarboxylic acid, LC-ms (esi): r_T＝3.603min，C₂₉H₃₃ClF₂N₄O₆S₂Calculated mass of 670.2, M/z found value 670.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.00(br s,1H),9.66(br s,0.8H),9.26(s,0.2H),8.03-7.99(m,1.7H),7.94(d,J＝3.2Hz,0.3H),7.50-7.43(m,1H),7.23-7.15(m,1H),6.02(s,0.2H),5.93(s,0.8H),4.00-3.94(m,0.2H),3.73-3.66(m,2.8H),3.53(s,3H),2.94(s,2H),2.85-2.76(m,2H),2.18-2.13(m,1H),2.02-1.96(m,1H),1.90-1.71(m,4H),1.65-1.62(m,3H),1.55-1.43(m,4H),1.15(s,3H)。

Compound 454: (trans) -4- (((4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) methyl) -cyclohexanecarboxylic acid, LC-ms (esi): r_T＝3.612min，C₂₈H₃₂ClFN₄O₆S₂Meter (2)Mass 639.2[ M + H ] calculated for mass 638.1, M/z]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.67(br s,0.8H),9.21(br s,0.2H),8.01-7.99(m,1.7H),7.94(d,J＝3.2Hz,0.3H),7.41-7.32(m,2H),7.23-7.16(m，1H),6.07(s,0.2H),5.98(s,0.8H),4.00-3.94(m,0.3H),3.77-3.67(m,2.7H),3.53(s,3H),2.94(d,J＝6.4Hz,2H),2.86-2.78(m,2H),2.16-2.09(m,1H),2.00-1.78(m,8H),1.66-1.62(m,1H),1.39-1.28(m,2H),1.16-1.07(m,2H)

Compound 456: 3- (((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) methyl) bicyclo [1.1.1]Pentane-1-carboxylic acid, LC-ms (esi): r_T＝3.237min，C₂₇H₂₇ClF₂N₄O₆S₂Calculated mass of 640.1, M/z found value 641.2[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.35(br s,1H),9.67(s,0.8H),9.25(s,0.2H),8.02-7.99(m,1.8H),7.94(d,J＝2.8Hz,0.2H),7.49-7.42(m,1H),7.23-7.14(m,1H),6.02(s,0.2H),5.93(d,J＝1.6Hz,0.8H),3.98-3.92(m,0.2H),3.75-3.66(m,2.8H),3.53(s,2.5H),3.52(s,0.5H),3.35-3.32(m,2H),2.87-2.75(m,2H),2.07(s,6H),2.06-2.00(m,1H),1.94-1.76(m,2.2H),1.64-1.61(m,0.8H)。

Compound 470: (trans) -3- (4- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1H-pyrazol-1-yl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝2.100min，C₂₈H₂₈ClFN₆O₆S₂Calculated mass 662.1, M/z found value 662.9[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)8.26(s,1H),7.94(br s,1H),7.87(s,1H),7.76(d,J＝2.4Hz,1H),7.39-7.35(m,1H),7.24-7.21(m,1H),7.06-7.01(m,1H),6.05(br s,1H),5.19-5.11(m,1H),3.94-3.78(m,2H),3.76-3.61(m,1H),3.54(s,3H),3.25-3.15(m,1H),2.95-2.85(m,2H),2.81-2.72(m,2H),2.45-2.34(m,2H),2.24-1.84(m,3.4H),1.77-1.63(m,0.6H)。

Compound 476A: (trans) -2- (4- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclohexyl) acetic acid, LC-MS (ESI)：R_T＝3.658min，C₂₈H₃₂ClFN₄O₆S₂Calculated mass of 638.1, M/z found value 639.0[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.90(d,J＝3.2Hz,1H),7.77(d,J＝3.2Hz,1H),7.39(dd,J＝8.8,6.0Hz,1H),7.23(dd,J＝8.8,2.8Hz,1H),7.08-7.03(m,1H),6.09(s,1H),4.01-3.88(m,3H),3.59(s,3H),3.09-3.00(m,3H),2.18-2.15(m,2H),2.10-2.06(m,3H),1.98-1.87(m,4H),1.82-1.68(m,2H),1.64-1.54(m,2H),1.11-1.07(m,2H)。

Compound 476B: (cis) -2- (4- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclohexyl) acetic acid, LC-ms (esi): r_T＝3.647min，C₂₈H₃₂ClFN₄O₆S₂Calculated mass of 638.1, M/z found value 639.0[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.90(d,J＝3.2Hz,1H),7.75(d,J＝2.8Hz,1H),7.39(dd,J＝8.8,6.0Hz,1H),7.23(dd,J＝8.8,2.4Hz,1H),7.08-7.03(m,1H),6.09(s,1H),4.00-3.89(m,3H),3.59(s,3H),3.16-3.13(m,1H),3.10-3.00(m,2H),2.25-2.23(m,2H),2.18-1.89(m,8H),1.81-1.71(m,3H),1.67-1.59(m,2H)。

Compound 476: 2- (4- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclohexyl) acetic acid, LC-ms (esi): r_T＝4.253min，C₂₈H₃₁ClF₂N₄O₆S₂Calculated mass of 656.1, M/z found value 656.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.07(br s,0.4H),9.65(br s,0.4H),9.26(br s,0.2H),8.01-7.99(m,1.8H),7.94-7.93(m,0.2H),7.49-7.42(m,1H),7.23-7.14(m,1H),6.02(s,0.2H),5.92(s,0.8H),4.02-3.96(m,0.2H),3.79-3.72(m,2.8H),3.53(s,3H),3.22-3.16(m,0.4H),3.10-3.04(m,0.6H),3.00-2.91(m,2H),2.25(d,J＝7.6Hz,0.8H),2.11(d,J＝6.8Hz,1.2H),2.07-2.01(m,2H),1.98-1.91(m,1H),1.84-1.59(m,7H),1.47-1.40(m,1H),1.31-1.26(m,0.6H),1.11-1.02(m,1H),0.88-0.84(m,0.4H)。

Compound 478: 2- (4- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl)) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclohexyl) acetic acid, LC-ms (esi): r_T＝4.253min，C₂₈H₃₁ClF₂N₄O₆S₂Calculated mass of 656.1, M/z found value 656.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.07(br s,0.4H),9.65(br s,0.4H),9.26(br s,0.2H),8.01-7.99(m,1.8H),7.94-7.93(m,0.2H),7.49-7.42(m,1H),7.23-7.14(m,1H),6.02(s,0.2H),5.92(s,0.8H),4.02-3.96(m,0.2H),3.79-3.72(m,2.8H),3.53(s,3H),3.22-3.16(m,0.4H),3.10-3.04(m,0.6H),3.00-2.91(m,2H),2.25(d,J＝7.6Hz,0.8H),2.11(d,J＝6.8Hz,1.2H),2.07-2.01(m,2H),1.98-1.91(m,1H),1.84-1.59(m,7H),1.47-1.40(m,1H),1.31-1.26(m,0.6H),1.11-1.02(m,1H),0.88-0.84(m,0.4H)。

Compound 478A: (trans) -2- (4- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclohexyl) acetic acid, LC-ms (esi): r_T＝3.397min，C₂₈H₃₁ClF₂N₄O₆S₂Calculated mass of 656.1, M/z found value 656.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.08(s,1H),9.66(d,J＝2.8Hz,0.8H),9.27(s,0.2H),8.01-7.99(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.49-7.42(m,1H),7.23-7.14(m,1H),6.02(s,0.2H),5.92(d,J＝3.2Hz,0.8H),4.02-3.96(m,0.2H),3.79-3.72(m,2.8H),3.53(s,3H),3.10-3.04(m,1H),3.00-2.92(m,2H),2.12-2.04(m,4H),1.98-1.91(m,1H),1.84-1.57(m,6H),1.48-1.39(m,2H),1.11-1.01(m,2H)。

Compound 480B: 3- (((4- (6- (2-chloro-3, 4-difluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) methyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.418min，C₂₇H₂₉ClF₂N₄O₆S₂Calculated mass of 642.1, M/z found value 642.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; temperature: 30 ℃; chiral analysis of the chiral compound (column: Chiralpak IA 5 μm 4.6: 0.2; chiral compound(s): 1.0 mL/min; chiral compound(s): chiral compound_T＝11.747min)。¹H NMR(400MHz,DMSO-d₆+ one drop D₂O)δ8.00(d,J＝3.2Hz,1H),7.97(d,J＝3.2Hz,0.8H),7.91(d,J＝3.2Hz,0.2H),7.49-7.42(m,1H),7.24-7.19(m,1H),6.04(s,0.2H),5.95(s,0.8H),4.01-3.95(m,2.2H),3.76-3.67(m,2.8H),3.17(d,J＝7.2Hz,2H),3.05-2.96(m,1H),2.85-2.77(m,2H),2.68-2.60(m,1H),2.38-2.32(m,2H),2.05-1.97(m,3H),1.90-1.78(m,2.2H),1.65-1.62(m,0.8H),1.10-1.04(m,3H)。

Compound 480Y: 3- (((4- (6- (2-chloro-3, 4-difluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) methyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.388min，C₂₇H₂₉ClF₂N₄O₆S₂Calculated mass of 642.1, M/z found value 642.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; temperature: 30 ℃; chiral analysis of the chiral compound (chiral compound)_T＝13.820min)。¹H NMR(400MHz,DMSO-d₆+ one drop D₂O)δ8.00(d,J＝3.2Hz,1H),7.96(d,J＝3.2Hz,0.8H),7.90(d,J＝3.2Hz,0.2H),7.49-7.42(m,1H),7.24-7.19(m,1H),6.04(s,0.2H),5.95(s,0.8H),4.01-3.95(m,2.2H),3.76-3.66(m,2.8H),3.26(d,J＝7.2Hz,2H),3.12-3.04(m,1H),2.86-2.76(m,3H),2.37-2.31(m,2H),2.18-2.11(m,2H),2.05-1.96(m,1H),1.91-1.79(m,2.2H),1.66-1.63(m,0.8H),1.10-1.04(m,3H)。

Compound 482A: 2- (3- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutyl) acetic acid, LC-ms (esi): r_T＝3.832min，C₂₇H₂₉ClF₂N₄O₆S₂Calculated mass of 642.1, M/z found value 642.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.96-7.89(m,1H),7.76(s,1H),7.27-7.19(m,2H),6.16(br s,0.3H),6.08(s,0.7H),4.14-3.98(m,3.4H),3.95-3.85(m,2.6H),2.99-2.89(m,2H),2.86-2.77(m,1H),2.72-2.65(m,2H),2.54(d,J＝7.6Hz,2H),2.23-1.81(m,5.3H),1.71-1.63(m,0.7H),1.12(t,J＝7.2Hz,3H)。

Compound 482B: 2- (3- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydro-carbonyl)Pyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutyl) acetic acid, LC-ms (esi): r_T＝3.831min，C₂₇H₂₉ClF₂N₄O₆S₂Calculated mass of 642.1, M/z found value 642.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.94-7.90(m,1H),7.76(br s,1H),7.28-7.22(m,2H),6.16-6.09(m,1H),4.12-4.02(m,3.4H),3.95-3.83(m,2.6H),2.98-2.89(m,2H),2.76-2.86(m,1H),2.60-2.53(m,2H),2.46(d,J＝7.6Hz,2H),2.22-1.82(m,5.3H),1.70-1.65(m,0.7H),1.13(t,J＝7.2Hz,3H)。

Compound 370B: (trans) -3- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝2.546min，C₂₆H₂₇ClFN₄O₆S₂Calculated mass 628.1, M/z found value 629.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.25(br s,1H),9.61(s,0.8H),9.11(s,0.2H),8.01-7.93(m,2H),7.49-7.42(m,1H),7.23-7.17(m,1H),6.03(s,0.2H),5.93(s,0.8H),4.05-3.94(m,3.2H),3.78-3.70(m,2.8H),3.19-3.11(m,1H),2.92-2.82(m,2H),2.59-2.53(m,4H),2.07-1.59(m,4H),1.09-1.03(m,3H)。

Compound 370D: (cis) -3- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5-ethoxycarbonyl-2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) cyclobutanecarboxylic acid, LC-ms (esi): r_T＝3.478min，C₂₆H₂₇ClF₂N₄O₆S₂Calculated mass 628.1, M/z found value 629.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.93(m,2H),7.49-7.42(m,1H),7.22-7.19(m,1H),6.03(s,0.2H),5.94(s,0.8H),4.00-3.91(m,3H),3.74-3.68(m,3H),3.11-3.02(m,1H),2.88-2.79(m,2H),2.47-2.42(m,4H),1.97-1.60(m,4H),1.07(t,J＝7.2Hz,3H)。

Section V: heterotransformations of primary dihydropyrimidines of the general formula I

Compound 131: methyl 6- (1- (2- (tert-butoxy) -2-oxoethyl) piperidin-3-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

To a solution of methyl 6- (1- (tert-butoxycarbonyl) piperidin-3-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 30(315mg, 0.59mmol) in methanol (10mL) at room temperature was added 4M hydrochloric acid in methanol (10mL, 40 mmol). After stirring at room temperature for 20 min, the mixture was concentrated to leave a residue (355mg crude), which was dissolved in N, N-dimethylformamide (15 mL). To the above solution were added tert-butyl 2-bromoacetate (115mg, 0.59mmol) and triethylamine (149mg, 1.48 mmol). After stirring at room temperature overnight, the reaction mixture was poured into water (30mL) and extracted three times with ethyl acetate (30 mL). The combined organic layers were washed with water (40mL) and brine (40mL) and washed with Na₂SO_4(s)Drying and then concentration gave a residue which was purified by: c18 column (acetonitrile: water 65% to 85% and preparative HPLC (column: xbridge C185 μm19 × 150mm, mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 20mL/min, gradient: 60% -90% (% B)) gave two fractions a (83mg, 26% yield, mixture of 2 stereoisomers) and B (43mg, 13% yield, mixture of 2 stereoisomers) as yellow solids.

Fraction B (43mg, 0.08mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak ID 5 μ M20 × 250 mm; mobile phase: Hex: IPA ═ 70:30 at 13 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the stereoisomer compound 131M (24.0mg, 56% yield) and compound 131N (18.0mg, 42% yield).

Compound 131N: LC-MS (ESI): r_T＝4.354min，C₂₆H₃₀ClFN₄O₄Calculated mass of S548.2, M/z found value 549.0[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: IPA 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.639min)。¹H NMR(400MHz,DMSO-d₆)δ11.9(s,0.9H),9.51(s,0.1H),7.99(s,0.3H),7.88(d,J＝3.2Hz,0.85H),7.87(d,J＝3.2Hz,0.85H),7.41-7.27(m,2H),7.20-7.15(m,1H),6.10(s,0.9H),5.97(d,J＝2.8Hz,0.1H),4.00(s,0.9H),3.81(s,0.1H),3.53-3.48(m,3H),3.38-3.30(m,2H),3.31-3.29(m,1H),3.12(d,J＝12.8Hz,1H),3.02(d,J＝10.4Hz,0.9H),2.87-2.81(m,0.1H),2.73(dd,J＝11.6,3.2Hz,1H),1.93-1.83(m,1H),1.82-1.70(m,3H),1.42-1.37(m,9H)。

Compound 132: trans-Ethyl 4- (2-chloro-4-fluorophenyl) -6- (4- (methylcarbamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

A solution of trans-ethyl 4- (2-chloro-4-fluorophenyl) -6- (4- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 20(100mg, 0.20mmol) in methylamine (in alcohol) (10mL) was stirred in a sealed tube at 45 ℃ overnight. After cooling to room temperature, the mixture was concentrated to give a residue which was purified by C18 column (acetonitrile: water ═ 45% to 55%) to give the title compound as a yellow solid (70mg, 70% yield).

Compound 132(250mg, 0.500mmol) was further separated by SFC (column: Chiralpak IC5 μm20 x 250 mm; mobile phase: CO)₂EtOH 60:40 at 45 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar) to give the stereoisomers compound 132A (92mg, 37% yield) and compound 132B (96mg, 38% yield) as yellow solids.

Compound 132A: LC-MS (ESI): r_T＝3.670min，C₂₄H₂₆ClFN₄O₃Calculated mass of S504.1, M/z found 505.0[ M + H [ ]]⁺. SFC analysis conditions: (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 60:40, at 3.0 mL/min; column temperature: 40 ℃; wavelength: 214nm, back pressure 100 bar, R_T＝2.66min)。¹H NMR(400MHz,CDCl₃)δ8.08(br s,0.5H),7.83-7.80(m,1H),7.48(d,J＝3.2Hz,0.5H),7.44(d,J＝2.8Hz,0.5H),7.34-7.28(m,1.5H),7.14-7.11(m,1H),6.96-6.88(m,1H),6.20(s,0.5H),6.06(d,J＝2.0Hz,0.5H),5.49(br s,1H),4.06(q,J＝7.2Hz,2H),4.02-3.97(m,0.5H),3.80-3.73(m,0.5H),2.84(d,J＝4.4Hz,3H),2.26-1.91(m,5H),1.80-1.64(m,2.8H),1.58-1.46(m,1.2H),1.14(t,J＝7.2Hz,3H)。

Compound 135:

compound 133: 1-tert-butyl 5-methyl 6- (2-chloro-4-fluorophenyl) -4- (cis-4- (methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate

To a solution of methyl 4- (2-chloro-4-fluorophenyl) -6- (cis-4- (methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 128(70mg, 0.133mmol) in tetrahydrofuran (5mL) was added 4-dimethylaminopyridine (20mg, 0.160mmol) and di-tert-butyl dicarbonate (35mg, 0.160mmol) at room temperature. The mixture was stirred at 60 ℃ overnight under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue which was purified by preparative TLC (petroleum ether: ethyl acetate ═ 1:1) to give the title compound as a yellow solid (60mg, 72% yield). LC-MS (ESI): r_T＝2.590min，C₂₇H₃₂ClFN₄O₆S₂Calculated mass of 626.1, M/z found value 626.7[ M + H ]]⁺。¹HNMR(400MHz,CDCl₃)δ7.89(d,J＝3.2Hz,1H),7.50(d,J＝3.2Hz,1H),7.12(dd,J＝8.4,2.4Hz,1H),7.07-7.03(m,1H),6.79(td,J＝8.4,2.4Hz,1H),6.70(s,1H),4.96(d,J＝7.6Hz,1H),3.84-3.82(m,1H),3.71(s,3H),3.69-3.65(m,1H),3.03(s,3H),2.02-1.74(m,7H),1.56-1.52(m,1H),1.24(s,9H)。

Compound 134: 1-tert-butyl 5-methyl 4- (trans-4- (N- (2- (tert-butoxy) -2-oxoethyl) methylsulfonylamino) cyclohexyl) -6- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate

To a solution of 1-tert-butyl 5-methyl 6- (2-chloro-4-fluorophenyl) -4- ((cis) -4- (methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate compound 133(60mg, 0.0958mmol) in tetrahydrofuran (5mL) at 0 ℃ under a nitrogen atmosphere was added 60 wt% sodium hydride in mineral oil (11mg, 0.287 mmol). After stirring at room temperature for 30 minutes, tert-butyl 2-bromoacetate (3) was added dropwise at 0 deg.C7mg, 0.192 mmol). Stirring overnight at room temperature under a nitrogen atmosphere, and then adding 1M aqueous hydrochloric acid solution dropwise to the mixture to adjust the pH to 4-5. The separated aqueous solution was extracted three times with ethyl acetate (20 mL). The combined organic layers were washed twice with brine (20mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (petroleum ether: ethyl acetate ═ 3:1) to give the title compound as a yellow solid (35mg, 49% yield).

A mixture of compound 134 (790mg, 1.07mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC5 μm 30 × 250 mm; mobile phase: Hex: EtOH ═ 80:20 at 20 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 134A (210mg, 27% yield) and compound 134B (280mg, 35% yield).

Compound 134B: LC-MS (ESI): r_T＝2.26min，C₃₃H₄₂ClFN₄O₈S₂Calculated mass of 740.2, M/z found value 741.2[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 80:20 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝11.705min)。¹H NMR(400MHz,CDCl₃)δ7.91(d,J＝3.2Hz,0.8H),7.89(d,J＝3.2Hz,0.2H),7.50-7.48(m,1H),7.14-7.10(m,1H),7.07-7.02(m,1H),6.78(td,J＝8.0,2.4Hz,1H),6.69(s,0.2H),6.68(s,0.8H),4.17(d,J＝18.4Hz,0.8H),4.09(d,J＝18.4Hz,0.8H),3.97-3.96(m,0.4H),3.92-3.88(m,1H),3.79-3.74(m,1H),3.71(s,0.7H),3.70(s,2.3H),3.15(s,0.7H),3.11(s,2.3H),2.24-2.19(m,1.5H),2.14-2.05(m,1.5H),1.98-1.81(m,4.7H),1.71-1.67(m,0.3H),1.48(s,2H),1.39(s,7H),1.25(s,7H),1.23(s,2H)。

Compound 135: 2- (N- (cis-4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) methanesulfonamido) acetic acid

1-tert-butyl 5-methyl 4- ((cis) -4- (N- (2- (tert-butoxy) -2-oxoethyl) methanesulfonamido) cyclohexyl) -6- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate compound 134B (280mg, 0.378mmol) was added to 1MA solution of hydrochloric acid (in dichloromethane) (10mL, 10mmol) was stirred at room temperature overnight. The reaction mixture was then concentrated to give a residue which was purified by preparative HPLC (column: waters2-Atlantis T35 μm19 x 150mm, flow rate: 15mL/min, mobile phase A: water (0.1% hydrochloric acid), mobile phase B: acetonitrile, gradient: 20% -85% (% B)) to give the title compound as a yellow solid (30mg, 14% yield, 90.3% ee). LC-MS (ESI): r_T＝3.334min，C₂₄H₂₆ClFN₄O₆S₂Calculated mass 584.1, M/z found value 584.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R); C; (R);)_T＝8.969min)。¹H NMR (400MHz, one drop in DMSO-d)₆D in (1)₂O)δ8.02-7.99(m,2H),7.44-7.41(m,1H),7.36-7.32(m,1H),7.23-7.18(m,1H),5.95(s,1H),3.97(s,2H),3.72-3.63(m,2H),3.52(s,3H),3.07(s,3H),2.02-1.92(m,1H),1.89-1.76(m,4H),1.68-1.65(m,1H),1.59-1.47(m,2H)。

Compound 139:

compound 136: methyl 4- (2-chloro-4-fluorophenyl) -6- (trans-4- ((2-ethoxy-2-oxoethyl) amino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (trans-4-aminocyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 125(800mg, 1.78mmol) in dichloromethane (20mL) was added ethyl 2-oxoacetate (363mg, 50 wt% in toluene, 1.78mmol) at room temperature. After stirring overnight at room temperature under a nitrogen atmosphere, sodium cyanoborohydride (336mg, 5.34mmol) was added. The mixture was stirred at room temperature for an additional 2 hours, then quenched with saturated aqueous sodium bicarbonate (30 mL). The separated aqueous solution was extracted three times with dichloromethane (30 mL). The combined organic layers were washed twice with brine (20mL) and Na₂SO_4(s)Dried and filtered. Concentrating the filtrate under reduced pressure to obtain residueThe residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate: ammonium hydroxide ═ 10:1:0.02) to give a residue, which was further purified by C18 (acetonitrile: water (+ 0.1% trifluoroacetic acid) ═ 5% to 95%) to give the title compound (200mg, 21% yield) as a yellow solid. LC-MS (ESI): r_T＝2.03min，C₂₅H₂₈ClFN₄O₄Calculated mass of S534.2, found value of M/z 535.2[ M + H [)]⁺。¹H NMR(300MHz,CDCl₃)δ8.11(br s,0.6H),7.82-7.80(m,1H),7.46(dd,J＝13.2,3.0Hz,1H),7.40(br s,0.4H),7.30-7.28(m,1H),7.14-7.11(m,1H),6.95-6.86(m,1H),6.17(s,0.6H),6.03(d,J＝2.4Hz,0.4H),4.21(q,J＝7.2Hz,2H),3.95(t,J＝12.0Hz,0.6H),3.71(br s,0.4H),3.60-3.59(m,3H),3.48-3.47(m,2H),2.60-2.52(m,1H),2.11-1.90(m,4H),1.79-1.71(m,1H),1.60-1.40(m,4H),1.30(t,J＝7.2Hz,3H)。

Compound 137: methyl 4- (2-chloro-4-fluorophenyl) -6- (trans-4- (N- (2-ethoxy-2-oxoethyl) methyl-sulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To methyl 4- (2-chloro-4-fluorophenyl) -6- (trans-4- ((2-ethoxy-2-oxoethyl) amino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of compound 136(200mg, 0.374mmol) in dichloromethane (10mL) were added triethylamine (113mg, 1.12mmol) and methanesulfonyl chloride (43mg, 0.374 mmol). After stirring overnight at room temperature under a nitrogen atmosphere, the mixture was quenched with saturated aqueous sodium bicarbonate (20 mL). The separated aqueous solution was then extracted three times with dichloromethane (20 mL). The combined organic layers were washed twice with brine (20mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (dichloromethane: methanol ═ 20:1) to give the title compound as a yellow solid (85mg, 37% yield). LC-MS (ESI): r_T＝4.211min，C₂₆H₃₀ClFN₄O₆S₂Calculated mass of 612.1, M/z found value 612.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.44(d,J＝4.0Hz,0.6H),9.04(s,0.4H),7.99(s,1H),7.98-7.93(m,1H),7.44-7.40(m,1H),7.35-7.29(m,1H),7.23-7.17(m,1H),5.99(s,0.4H),5.90(d,J＝3.6Hz,0.6H),4.13(q,J＝7.2Hz,2H),4.06(s,2H),3.87-3.78(m,1H),3.67-3.60(m,0.6H),3.55(s,0.4H),3.52-3.510(m,3H),3.09-3.07(m,3H),2.08-2.02(m,0.4H),1.93-1.70(m,5H),1.63-1.50(m,2.6H),1.22(t,J＝7.2Hz,3H)。

Compound 138: 1-tert-butyl 5-methyl 6- (2-chloro-4-fluorophenyl) -4- (trans-4- (N- (2-ethoxy-2-oxoethyl) -methyl-sulfonylamino) -cyclohexyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate (mixture of 2 stereoisomers)

To a solution of methyl 4- (2-chloro-4-fluorophenyl) -6- (trans-4- (N- (2-ethoxy-2-oxoethyl) methanesulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 137(240mg, 0.392mmol) in tetrahydrofuran (5mL) at room temperature were added 4-dimethylaminopyridine (57mg, 0.47mmol) and di-tert-butyl dicarbonate (103mg, 0.470 mmol). The mixture was stirred at 60 ℃ overnight under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue which was purified by C18 (acetonitrile: water ═ 30% to 85%) to give the title compound as a yellow solid (200mg, 72% yield).

Compound 138(200mg, 0.281mmol) was further separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC 5um 20mm 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 15 mL/min; temperature: 30 ℃ c; wavelength: 214nm) to give the stereoisomers compound 138A (88mg, 44% yield) and compound 138B (85mg, 43% yield).

Compound 138B: LC-MS (ESI): r_T＝2.20min，C₃₁H₃₈ClFN₄O₈S₂Calculated mass of 712.2, M/z found value 713.1[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IC 5um4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 210nm, 100% ee, Rt ═ 21.183 min).¹H NMR(400MHz,CDCl₃)δ7.89(d,J＝3.2Hz,1H),7.50(d,J＝3.2Hz,1H),7.11(dd,J＝8.6,2.6Hz,1H),7.05-7.02(m,1H),6.78(td,J＝8.4,2.4Hz,1H),6.69(s,1H),4.20(q,J＝7.2Hz,2H),4.11(d,J＝18.8Hz,1H),4.04(d,J＝18.4Hz,1H),3.83-3.77(m,1H),3.71(s,3H),3.59-3.53(m,1H),3.15(s,3H),2.06-1.87(m,5H),1.71-1.68(m,1H),1.54-1.46(m,2H),1.31(t,J＝7.2Hz,3H),1.23(s,9H)。

Compound 139:

2- (N- (trans-4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) methanesulfonamido) acetic acid

A solution of 1-tert-butyl 5-methyl 6- (2-chloro-4-fluorophenyl) -4- (trans-4- (N- (2-ethoxy-2-oxoethyl) methylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate compound 138B (85mg, 0.119mmol) in 1M hydrochloric acid (in dichloromethane) (5mL, 5mmol) at room temperature. After stirring at room temperature for 5 hours under a nitrogen atmosphere, the reaction mixture was concentrated to give a residue, which was dissolved in tetrahydrofuran (2mL) and water (2mL), and lithium hydroxide (50mg, 1.19mmol) was added at room temperature. After stirring overnight at room temperature under a nitrogen atmosphere, a 1N hydrochloride aqueous solution was added dropwise to the mixture to adjust the pH to 3 to 4. The separated aqueous solution was extracted three times with ethyl acetate (20 mL). The combined organic layers were washed twice with brine (20mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by C18 (acetonitrile: water ═ 5% to 95%) to give the title compound as a yellow solid (30mg, 43% yield). LC-MS (ESI): r_T＝3.822min，C₂₄H₂₆ClFN₄O₆S₂Calculated mass 584.1, M/z found value 584.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IG 5um4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; and_T＝9.786min)。¹H NMR(400MHz,DMSO-d₆)δ12.73(brs,1H),9.46(d,J＝3.2Hz,0.6H),9.06(s,0.4H),7.99-7.94(m,2H),7.46-7.41(m,1H),7.35-7.29(m,1H),7.25-7.17(m,1H),5.99(s,0.4H),5.89(d,J＝3.2Hz,0.6H),3.97(s,2H),3.84-3.79(m,1H),3.64-3.58(m,1H),3.52-3.51(m,3H),3.10-3.08(m,3H),1.92-1.70(m,5H),1.63-1.46(m,3H)。

compound 474: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((2-hydroxyethyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((2-methoxy-2-oxoethyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 473(45mg, 0.076mmol) in tetrahydrofuran (2mL) was added lithium borohydride (5.0mg, 0.23mmol) at 0 ℃, and the mixture was stirred at 0 ℃ for 1 hour. The mixture was concentrated at room temperature under reduced pressure to give a residue which was purified by preparative HPLC (column: gilson X-bridgeC18(5 μm 19X 150mm) mobile phase a: water (+ 0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 40% -70% (% B)) to give the title compound 474 as a yellow solid (21mg, 49% yield). LC-MS (ESI): r_T＝4.021min，C₂₂H₂₃ClFN₄O₅S₂Calculated mass of 560.1, M/z found value 561.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.62(s,0.8H),9.21(s,0.2H),7.99-7.93(m,2H),7.48-7.41(m,1H),7.23-7.14(m,1H),6.02(s,0.2H),5.93(s,0.8H),5.05-5.00(m,1H),4.02-3.92(m,0.3H),3.80-3.65(m,4.7H),3.58(s,3H),3.24-3.19(m,2H),2.94-2.84(m,2H),2.12-1.76(m,3.2H),1.65-1.62(m,0.8H)。

Compound 158: methyl 4- (2-chloro-3-fluorophenyl) -6- (1- ((1- (oxazol-2-ylmethyl) -1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (1- ((1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 158A (80.0mg, 0.142mmol) in N, N-dimethylformamide (2mL) was added potassium carbonate (39.0mg, 0.284mmol) and sodium iodide (21.0mg, 0.142 mmol). 2-, (N, N-dimethylformamide (1mL) after stirring at room temperature for 5 minutesChloromethyl) oxazole (15.0mg, 0.123 mmol). After stirring at room temperature overnight, the reaction mixture was poured into water (10mL) and extracted twice with ethyl acetate (10 mL). The combined organic layers were washed twice with water (10mL), twice with brine (10mL), and over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: waters Kinet EVO C18(5 μm 21.2X 150mm) mobile phase A: water (+ 0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 30% -80% (% B)) to give the title compound as a yellow solid (25mg, 27% yield). LC-MS (ESI): r_T＝4.318min，C₂₇H₂₅ClFN₇O₅S₂Calculated mass of 645.1, M/z found value 646.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.19(s,0.3H),7.95(d,J＝2.8Hz,1H),7.84-7.79(m,2H),7.71(s,1H),7.53(d,J＝3.2Hz,0.7H),7.46-7.45(m,1H),7.24-7.02(m,4H),6.23(s,0.3H),6.10(d,J＝2.8Hz,0.7H),5.50(s,2H),4.03-3.85(m,2.3H),3.77-3.72(m,0.7H),3.56-3.55(m,3H),2.48-1.91(m,5.3H),1.73-1.70(m,0.7H)。

Compound 173: methyl 4- (2-chloro-4-fluorophenyl) -6- ((cis) -3- (hydroxymethyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 4- (2-chloro-4-fluorophenyl) -6- ((cis) -3- (methoxycarbonyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 172(100mg, 0.200mmol) in tetrahydrofuran (3mL) was added lithium borohydride (22mg, 1.0mmol) at room temperature. After stirring overnight at room temperature, the suspension was quenched with water (20mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was separated by preparative HPLC (column: gilson X-bridge C18(5 μm 19. multidot.150 mm), mobile phase A: water (+ 0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 1: acetonitrile5mL/min, gradient: 35% -90% (% B)) to give the title compound as a yellow solid (90mg, 96% yield). LC-MS (ESI): r_T＝3.055min，C₂₂H₂₃ClFN₃O₃Calculated mass of S463.1, found value of M/z 464.2[ M + H [)]⁺.¹H NMR(400MHz,CDCl₃)δ8.15(s,0.6H),7.82(d,J＝2.8Hz,1H),7.49(d,J＝3.6Hz,0.3H),7.44(d,J＝3.6Hz,0.7H),7.40(br s,0.4H),7.33-7.29(m,1H),7.15-7.11(m,1H),6.96-6.87(m,1H),6.18(d,J＝1.6Hz,0.7H),6.04(d,J＝2.4Hz,0.3H),4.08-4.01(m,0.7H),3.86-3.79(m,0.3H),3.61-3.53(m,5H),2.12-1.62(m,5H),1.58-1.02(m,5H)。

Compounds 173A and 173C: methyl 4- (2-chloro-4-fluorophenyl) -6- ((cis) -3- (hydroxymethyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Racemic compound 173(300mg, 0.650mmol) was separated by chiral preparative HPLC (first separation (column: Chiralpak IC5 μm 50 × 250 mm; mobile phase: Hex: IPA: DEA ═ 85:15:0.1 at 60 mL/min; temperature: 30 ℃; wavelength: 254nm) and second separation (column: Chiralpak IC5 μm 50:250mm; mobile phase: Hex: EtOH ═ 90:10:0.1 at 60 mL/min; temperature: 30 ℃; wavelength: 254nm)) followed by purification via a C18 column (acetonitrile: water ═ 40% to 95%) to give the title compound 173A (42.0mg, 14% yield, 96.2% stereopurity), 173B (38.4mg, 13% stereopurity, 94.0% stereopurity), 173C (38.7mg, 13% yield, 100% stereopurity, and 173D (100% stereopurity, 9.9% stereopurity, 100% stereopurity).

Compound 173A: LC-MS (ESI): r_T＝4.063min，C₂₂H₂₃ClFN₃O₃Calculated mass of S463.1, found value of M/z 463.9[ M + H]⁺. Chiral HPLC (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 90:10:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝11.411min)。¹H NMR(400MHz,CDCl₃)δ8.15(s,0.7H),7.83-7.81(m,1H),7.48(d,J＝3.2Hz,0.3H),7.44(d,J＝3.6Hz,0.7H),7.39(br s,0.3H),7.33-7.29(m,1H),7.15-7.11(m,1H),6.97-6.89(m,1H),6.19(s,0.7H),6.05(d,J＝2.4Hz,0.3H),4.07-4.00(m,0.7H),3.85-3.79(m,0.3H),3.61-3.53(m,5H),2.12-2.09(m,1H),1.99-1.76(m,4H),1.67-1.60(m,1H),1.55-1.46(m,1H),1.41-1.34(m,1H),1.30-1.21(m,1H),1.13-1.05(m,1H)。

Compound 173C: LC-MS (ESI): r_T＝4.044min，C₂₂H₂₃ClFN₃O₃Calculated mass of S463.1, found value of M/z 463.9[ M + H]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: IPA: DEA: 90:10:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝15.756min)。¹H NMR(400MHz,CDCl₃)δ8.14(s,0.6H),7.82-7.81(m,1H),7.48(d,J＝2.8Hz,0.3H),7.44(d,J＝2.8Hz,0.7H),7.39(br s,0.4H),7.32-7.29(m,1H),7.15-7.11(m,1H),6.95-6.87(m,1H),6.18(s,0.7H),6.04(d,J＝2.8Hz,0.3H),4.08-4.01(m,0.7H),3.86-3.79(m,0.3H),3.61(s,0.9H),3.59(s,2.1H),3.58-3.50(m,2H),2.05-1.98(m,2H),1.90-1.70(m,3H),1.55-1.41(m,2H),1.36-1.27(m,1H),1.21-1.03(m,2H)。

Compound 180B: (cis) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (N- (2-hydroxyethyl) methylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydro-pyrimidine-5-carboxylate

Compound 177: (cis) -1-tert-butyl 5-methyl 6- (2-chloro-4-fluorophenyl) -4- (4- (methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate

To a solution of (cis) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (methylsulfonylamino) -cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 128(1.40g, 2.66mmol) in tetrahydrofuran (14mL) was added N, N-dimethylpyridin-4-amine (389mg, 3.19mmol) and di-tert-butyl dicarbonate (696mg, 3.19mmol) at room temperature. After stirring at 60 ℃ overnight, the mixture was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: tetrahydrofuran ═ 10:1:1 to 5:1:1) to give the title compound (1.30g, 78% yield) as a yellow solid.¹HNMR(300MHz,CDCl₃)δ7.89(d,J＝2.4Hz,1H),7.49(d,J＝2.1Hz,1H),7.14-7.10(m,1H),7.07-7.02(m,1H),6.83-6.75(m,1H),6.71-6.69(m,1H),5.01-4.93(m,1H),3.86-3.78(m,1H),3.71(s,3H),3.68-3.57(m,1H),3.02(s,3H),2.02-1.74(m,7H),1.57-1.51(m,1H),1.23(s,9H)。

Compound 178: (cis) -1-tert-butyl 5-methyl 4- (4- (N- (2- (tert-butoxy) -2-oxoethyl) methylsulfonylamino) cyclohexyl) -6- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate

To a solution of (cis) -1-tert-butyl 5-methyl 6- (2-chloro-4-fluorophenyl) -4- (4- (methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate 177(1.0g, 1.60mmol) in tetrahydrofuran (10mL) at 0 deg.C was added 60% wt sodium hydride in mineral oil (192mg, 4.80 mmol). After stirring at room temperature for 30 minutes, tert-butyl 2-bromoacetate (623mg, 3.19mmol) was added at 0 ℃. After stirring at room temperature overnight, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (20mL) and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: tetrahydrofuran ═ 10:1:1 to 5:1:1) to give the title compound (430mg, 36% yield) as a yellow solid.¹H NMR(300MHz,CDCl₃)δ7.92-7.88(m,1H),7.51-7.47(m,1H),7.15-7.09(m,1H),7.07-7.01(m,1H),6.82-6.74(m,1H),6.70-6.67(m,1H),4.20-4.05(m,1.6H),3.98-3.95(m,0.6H),3.94-3.89(m,0.8H),3.80-3.76(m,0.5H),3.71(s,1H),3.69(s,2H),3.62-3.52(m,0.5H),3.15(s,1H),3.11(s,2H),2.24-2.17(m,1H),2.14-2.00(m,2H),1.95-1.75(m,4H),1.71-1.59(m,1H),1.48(s,3H),1.38(s,6H),1.24(s,6H),1.22(s,3H)。

Intermediate 179: (cis) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (N- (2-methoxy-2-oxoethyl) methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of 1M hydrochloride in methanol (10mL, 10mmol) was added (cis) -1-tert-butyl 5-methyl 4- (4- (N- (2- (tert-butoxy) -2-oxoethyl) methylsulfonamido) -cyclohexyl) -6- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate 178(430mg, 0.580 mmol). At room temperatureAfter stirring overnight, the mixture was concentrated under reduced pressure to give a residue, which was dissolved in dichloromethane (20mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The separated aqueous phase was extracted three times with dichloromethane (20 mL). The combined organic layers were washed twice with brine (20mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: tetrahydrofuran ═ 20:1:1) to give the title compound (340mg, 98% yield) as a yellow solid.¹H NMR(300MHz,CDCl₃)δ7.85-7.80(m,1H),7.47-7.45(m,1H),7.32-7.29(m,1H),7.19-7.15(m,1H),7.06-7.01(m,1H),6.96-6.89(m,1H),6.19-6.15(m,0.3H),6.08-6.01(m,0.7H),4.10(s,2H),3.99-3.95(m,1H),3.89-3.85(m,1H),3.72(s,3H),3.58(s,3H),3.14(s,3H),2.09-2.00(m,5H),1.78-1.58(m,3H)。

Compound 180: (cis) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (N- (2-hydroxy-ethyl) methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (cis) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (N- (2-methoxy-2-oxoethyl) methylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 179(320mg, 0.534mmol) in tetrahydrofuran (5mL) was added lithium tetrahydroborate (71mg, 3.21mmol) at 0 ℃. After stirring at 30 ℃ for 2 hours under a nitrogen atmosphere, the reaction mixture was slowly quenched with 1M aqueous hydrochloride solution (20mL) and extracted three times with dichloromethane (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Gilson X-bridge C18(5 μm 19X 150mm), mobile phase A: water (0.2% ammonium acetate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 30% -70% (% B)) to give the title compound as a yellow solid (110mg, 36% yield). LC-MS (ESI): r_T＝4.007min，C₂₄H₂₈ClFN₄O₅S₂Calculated mass of 570.1, M/z found value 571.1[ M + H ]]⁺。

Compound 180B: (cis) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (N- (2-hydroxy-ethyl) methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Rac (cis) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (N- (2-hydroxyethyl) -methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 180(110mg, 0.193mmol) was separated by chiral preparative HPLC (first separation condition: column: Chiralpak IA 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3, at 22 mL/min; temperature: 30 ℃; wavelength: 230 nm; second separation condition: column: Chiralpak AD-H5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA: 85:15:0.3, at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 180A (15mg, 14% yield, 100% stereopure) and 180B as a yellow solid (30mg, 27% yield, 100% stereopure).

Compound 180B: LC-MS (ESI): r_T＝3.946min，C₂₄H₂₈ClFN₄O₅S₂Calculated mass of 570.1, found M/z value of 570.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IA 5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30 ℃; wavelength: 230_T＝7.725min)。¹H NMR(400MHz,DMSO-d₆)δ9.43(br s,0.6H),9.10(br s,0.4H),8.01-7.97(m,1.5H),7.95-7.92(m,0.5H),7.44-7.40(m,1H),7.36-7.30(m,1H),7.24-7.17(m,1H),6.00(s,0.4H),5.91(s,0.6H),4.79-4.73(m,1H),3.86-3.74(m,1H),3.59-3.55(m,1H),3.53(s,1.7H),3.51(s,1.3H),3.50-3.47(m,2H),3.17(t,J＝7.2Hz,2H),2.97(s,1.7H),2.96(s,1H),2.95(s,0.3H),2.11-2.03(m,0.4H),1.92-1.73(m,5H),1.66-1.56(m,2.6H)。

Compound 182A: (trans) methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (2-methoxyethylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 181A: (trans) -1-tert-butyl 5-methyl 4- (4- ((tert-butoxycarbonyl) amino) -cyclohexyl) -6- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate

To a solution of (trans) -methyl 6- (4- ((tert-butoxycarbonyl) amino) cyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 14(500mg, 0.910mmol) in dichloromethane (5mL) at room temperature was added di-tert-butyl dicarbonate (398mg, 1.82mmol) and triethylamine (184mg, 1.82 mmol). After stirring for 30 min, N-dimethylpyridin-4-amine (222mg, 1.82mmol) was added. The mixture was then stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue obtained was purified by silica gel column chromatography (ethyl acetate: petroleum ether ═ 1:5) to give a yellow solid (400mg) which was isolated by chiral preparative SFC (column: Chiralpak IE 5 μm20 × 250 mm; mobile phase: CO₂IPA 75:25 at 50 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar) to yield 181A (80mg, 14% yield, 99.4% stereopure) and 181B (90mg, 15% yield, 96.9% stereopure) as yellow solids.

Compound 181A: chiral analysis (column: Chiralpak IE 5 μm4.6 x 250mm, mobile phase: CO₂IPA 75:25 at 3.0 g/min; column temperature: 39.6 ℃; wavelength: 230nm, back pressure: 100 bar, R_T＝2.89min)。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.99(m,1H),7.47(dd,J＝9.2,2.4Hz,1H),7.14(td,J＝8.0,2.0Hz,1H),7.05-7.01(m,1H),6.83(d,J＝8.4Hz,1H),6.55(s,1H),3.66(s,3H),3.45-3.40(m,1H),3.31-3.24(m,1H),1.94-1.82(m,3H),1.88-1.60(m,2H),1.54-1.50(m,1H),1.40(s,9H),1.32-1.24(m,2H),1.15(s,9H)。

Compound 182A: (trans) methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (2-methoxyethylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of 4N hydrochloride in methanol (5mL) was added (trans) -1-tert-butyl 5-methyl 4- (4- ((tert-butoxycarbonyl) amino) cyclohexyl) -6- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate 181A (100mg, 0.154mmol) at room temperature. After stirring overnight, the reaction mixture was concentrated to give a residue, which was dissolved in tetrahydrofuran (10 mL). To the solution was added triethylamine (92mg, 0.912mmol) at 0 ℃. Stirring at room temperature for 30 minutesAfter the clock. 2-Methoxyethanesulfonyl chloride (96mg, 0.610mmol) was added and the mixture was stirred at 0 ℃ for 2 hours. It was then concentrated to give a residue which was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate ═ 1:1) to give the title compound as a yellow solid (22mg, 25% yield, 98.2% stereopurity). LC-MS (ESI): r_T＝4.004min，C₂₄H₂₈ClFN₄O₅S₂Calculated mass of 570.1, found M/z value of 570.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝17.095min)。¹H NMR(400MHz,DMSO-d₆)δ9.46(d,J＝3.2Hz,0.6H),9.00(s,0.4H),8.00-7.98(m,1.6H),7.94-7.93(m,0.4H),7.44-7.41(m,1H),7.35-7.29(m,1H),7.24-7.14(m,2H),6.00(s,0.4H),5.90(d,J＝3.6Hz,0.6H),3.83-3.76(m,0.4H),3.69-3.65(m,2H),3.58-3.55(m,0.6H),3.52(s,1.8H),3.50(s,1.2H),3.31-3.28(m,5.4H),3.16-3.08(m,0.6H),2.05-1.96(m,2.4H),1.88-1.66(m,3H),1.60-1.57(m,0.6H),1.38-1.22(m,2H)。

Compound 185B: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((2-hydroxyethyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((2-methoxy-2-oxoethyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 106(140mg, 0.250mmol) in tetrahydrofuran (40mL) was added lithium borohydride (27.0mg, 1.25mmol) at 0 ℃. After stirring at room temperature for 6 hours, water (30mL) was added to the mixture, and the mixture was extracted three times with ethyl acetate (30 mL). The separated organic layer was washed with brine (30mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated to give a residue which was purified by preparative HPLC (column: gilson, x-bridge C18(5 μm 19. multidot.150 mm, mobile phase A: water (+ 0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 30% -80% (% B)) to give the title compound 185 as a yellow solid (60mg, 45% yield). LC-MS (ESI): r_T＝3.962min，C₂₂H₂₄ClFN₄O₅S₂Calculated mass of 542.1, found value of M/z 543.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.20(s,0.2H),7.84-7.81(m,1H),7.52(d,J＝3.2Hz,0.8H),7.46-7.44(m,1H),7.30-7.27(m,0.8H),7.26-7.25(m,0.2H),7.16-7.12(m,1H),6.98-6.89(m,1H),6.19(s,0.2H),6.07(d,J＝2.8Hz,0.8H),4.23-4.15(m,0.2H),4.12-4.01(m,2H),3.93-3.89(m,2.8H),3.60(s,2H),3.59(s,1H),3.22-3.19(m,2H),3.02-2.90(m,2H),2.79-2.73(m,1H),2.31-2.28(m,0.8H),2.21-2.03(m,1H),1.97-1.85(m,1.2H),1.83-1.72(m,1H)。

Racemic compound 185(127mg, 0.200mmol) was separated by chiral preparative HPLC (column: chiralpak ia 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 25 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 185A (51.6mg, 41% yield, 100% stereopurity) and compound 185B (59.2mg, 47% yield, 98.4% stereopurity) as yellow solids.

Compound 185A: LC-MS (ESI): r_T＝3.954min，C₂₂H₂₄ClFN₄O₅S₂Calculated mass of 542.1, M/z found value 543.1[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; temperature: 30 ℃; wavelength: 230 nm; R-_T＝7.832min)。¹H NMR(400MHz,CDCl₃)δ8.16(s,0.2H),7.89-7.77(m,1H),7.54(d,J＝12.0Hz,0.8H),7.49(d,J＝7.6Hz,0.2H),7.44(br s,0.8H),7.32-7.25(m,0.6H),7.25-7.23(m,0.4H),7.19-7.14(m,1H),7.01-6.87(m,1H),6.19(s,0.2H),6.07(d,J＝2.4Hz,0.8H),4.28-4.16(m,0.2H),4.16-4.06(m,2H),4.05-3.87(m,2.8H),3.60(s,2H),3.59(s,1H),3.25-3.19(m,2H),3.07-2.87(m,2H),2.80-2.67(m,1H),2.36-2.18(m,0.7H),2.16-2.10(m,1H),1.99-1.81(m,1.3H),1.76-1.68(m,1H)。

Compound 185B LC-MS (ESI): r_T＝3.951min，C₂₂H₂₄ClFN₄O₅S₂Calculated mass of 542.1, M/z found value 543.1[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; temperature: 30 ℃; wavelength: 230 nm; R-_T＝11.235min)。¹H NMR(400MHz,CDCl₃)δ8.19(br s,0.2H),7.88-7.78(m,1H),7.54(d,J＝14.0Hz,0.8H),7.48(d,J＝15.2Hz,0.2H),7.39(br s,0.8H),7.32-7.30(m,0.7H),7.25-7.23(m,0.3H),7.19-7.13(m,1H),7.03-6.85(m,1H),6.19(s,0.2H),6.07(d,J＝2.8Hz,0.8H),4.27-4.17(m,0.2H),4.17-4.07(m,2H),4.02-3.87(m,2.8H),3.60(s,2H),3.59(s,1H),3.27-3.13(m,2H),3.02-2.83(m,2H),2.78-2.67(m,1H),2.35-2.16(m,0.7H),2.11-2.04(m,1H),2.00-1.88(m,1.3H),1.80-1.67(m,1H)。

Compound 186A: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (propyl-sulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

A solution of (trans) -1-tert-butyl 5-methyl 4- (4- ((tert-butoxycarbonyl) amino) cyclohexyl) -6- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate 181A (100mg, 0.154mmol) in 4M hydrochloride (in ethyl acetate) (5mL, 20mmol) was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure to give a residue, which was dissolved in dichloromethane (5 mL). To the solution were added triethylamine (78mg, 0.770mmol) and propane-1-sulfonyl chloride (26mg, 0.185 mmol). After stirring at room temperature for 2 hours, the mixture was quenched with saturated aqueous sodium bicarbonate (20mL) and extracted three times with dichloromethane (20 mL). The combined organic layers were washed twice with brine (20mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate ═ 3:2) to give the title compound (40mg, 47% yield, 98.1% stereopurity) as a yellow solid. LC-MS (ESI): r_T＝3.988min，C₂₄H₂₈ClFN₄O₄S₂Calculated mass of 554.1, found value of M/z 554.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IA 5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30 ℃; wavelength: 230_T＝8.095min)。¹H NMR(400MHz,DMSO-d₆)δ9.45(br s,0.6H),9.01(br s,0.4H),7.99-7.97(m,1.5H),7.94-7.93(m,0.5H),7.44-7.40(m,1H),7.35-7.29(m,1H),7.23-7.18(m,1H),7.12-7.08(m,1H),6.00(s,0.4H),5.90(d,J＝3.6Hz,0.6H),3.82-3.77(m,0.4H),3.57-3.56(m,0.6H),3.51(s,1.6H),3.50(s,1.4H),3.30-3.24(m,0.4H),3.10-3.07(m,0.6H),3.02-2.96(m,2H),1.99-1.94(m,2H),1.86-1.78(m,2H),1.72-1.66(m,3H),1.64-1.56(m,1H),1.39-1.30(m,2H),1.01-0.97(m,3H)。

Compound 187B: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (2-hydroxyethylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 181B-1: (trans) -methyl 6- (4-aminocyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -1-tert-butyl 5-methyl 4- (4- ((tert-butoxycarbonyl) amino) cyclohexyl) -6- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate compound 181B (200mg, 0.31mmol) in dichloromethane (8mL) was added trifluoroacetic acid (5mL) under a nitrogen atmosphere. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to give a residue, which was basified to pH 8 with saturated aqueous sodium carbonate solution. The aqueous phase was then extracted three times with ethyl acetate (10 mL). The combined organic layers were passed over anhydrous Na₂SO_4(s)Drying, filtration and concentration gave the desired compound 181B-1 as a yellow solid (140mg, 99% yield). LC-MS (ESI): r_T＝2.159min，C₂₁H₂₂ClFN₄O₂Calculated mass of S448.1, M/z found value 449.1[ M + H [ ]]⁺。

Compound 187B-1: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (2-methoxy-2-oxoethylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 6- (4-aminocyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 181B-1(100mg, 0.23mmol) and triethylamine (47mg, 0.46mmol) in dichloromethane (6mL) under a nitrogen atmosphere was added methyl 2- (chlorosulfonyl) acetate (48mg, 0.27 mmol). After stirring at room temperature for 2 hours, the mixture was concentrated to give a residue, which was purified by C18 column (acetonitrile: water ═ 40% to 80%) to give the title compound 187B-1(100mg, 75% yield) as a yellow solid. LC-MS (ESI): r_T＝4.022min，C₂₄H₂₆ClFN₄O₆S₂Calculated mass 584.1, M/z found value 584.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.12(s,0.4H),7.83-7.82(m,1H),7.51(d,J＝2.8Hz,0.6H),7.45(d,J＝2.8Hz,0.4H),7.41(s,0.6H),7.31-7.24(m,1H),7.15-7.11(m,1H),6.96-6.88(m,1H),6.18(s,0.4H),6.04(d,J＝2.4Hz,0.6H),4.75-4.70(m,1H),4.07-4.06(m,2H),4.01-3.94(m,0.4H),3.83(s,3H),3.78-3.70(m,0.6H),3.60(s,1.8H),3.59(s,1.2H),3.44-3.39(m,1H),2.32-2.17(m,2H),2.13-1.93(m,2H),1.90-1.67(m,1.5H),1.57-1.40(m,2.5H)。

Compound 187B: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (2-hydroxyethylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (2-methoxy-2-oxoethylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 187B-1(100mg, 0.17mmol) in tetrahydrofuran (10mL) under a nitrogen atmosphere was added lithium borohydride (20mg, 0.85 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by C18 column (acetonitrile: water 35% to 80%) to give the title compound 187B as a pale yellow solid (51mg, 55% yield). LC-MS (ESI): r_T＝3.626min，C₂₃H₂₆ClFN₄O₅S₂Calculated mass of 556.1, M/z found value 556.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.12(s,0.4H),7.83-7.82(m,1H),7.51(d,J＝2.8Hz,0.6H),7.45(d,J＝3.2Hz,0.4H),7.41(s,0.6H),7.29-7.23(m,1H),7.15-7.11(m,1H),6.96-6.87(m,1H),6.18(s,0.4H),6.04(d,J＝2.4Hz,0.6H),4.34-4.27(m,1H),4.12-4.08(m,2H),4.01-3.94(m,0.4H),3.78-3.70(m,0.6H),3.60(s,1.8H),3.59(s,1.2H),3.48-3.40(m,1H),3.33-3.29(m,2H),2.67(t,J＝6.0Hz,0.6H),2.58(t,J＝6.0Hz,0.4H),2.32-2.15(m,2H),2.13-1.96(m,2H),1.93-1.60(m,2H),1.55-1.37(m,2H)。

Compound 205: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (S-methylsulfonimidoyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 205P: methyl 6- (1- (N- (tert-butyldimethylsilyl) -S-methylsulfonylimino) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a stirred solution of triphenylphosphine dichloride (2.40g, 7.20mmol) in dry chloroform (10mL) under a nitrogen atmosphere was added triethylamine (1.00g, 9.90mmol) at 0 ℃. After stirring at room temperature for 10 min, the reaction mixture was cooled to 0 ℃ and a solution of N- (tert-butyldimethylsilyl) -methanesulfonamide (1.40g, 6.60mmol) in dry chloroform (3mL) was added. After stirring at 0 ℃ for 20 minutes, a solution of methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 99(300mg, 0.660mmol) in chloroform (2mL) was added. After stirring at 0 ℃ for 30 minutes, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane: 10:1: 1). 205P1(60mg, 9% yield) and 205P2(40mg, 14% yield) were obtained as yellow solids.

Compound 205P 1: LC-MS (ESI): r_T＝2.864min，C₂₇H₃₆ClF₂N₅O₃S₂Calculated mass of SiAmount 643.2, M/z found value 644.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.21(s,0.4H),7.83(d,J＝3.2Hz,1H),7.53(d,J＝2.8Hz,0.6H),7.46(d,J＝3.2Hz,0.4H),7.40(br s,0.6H),7.09-7.02(m,2H),6.19(s,0.4H),6.06(d,J＝2.4Hz,0.6H),4.12-3.86(m,3H),3.61(s,1.6H),3.59(s,1.4H),2.76(s,1.6H),2.75(s,1.4H),2.68-2.63(m,2H),2.31-2.22(m,0.6H),2.07-1.98(m,1.4H),1.93-1.86(m,1H),1.77-1.71(m,1H),0.93(s,5H),0.92(s,4H),0.16-0.11(m,6H)。

Compound 205P 2: LC-MS (ESI): r_T＝2.848min，C₂₇H₃₆ClF₂N₅O₃S₂Calculated mass of Si 643.2, found value of M/z 644.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.21(s,0.4H),7.83(d,J＝3.2Hz,1H),7.53(d,J＝3.2Hz,0.6H),7.46(d,J＝2.8Hz,0.4H),7.41(d,J＝1.6Hz,0.6H),7.08-6.99(m,2H),6.19(s,0.4H),6.07(d,J＝2.8Hz,0.6H),4.13-3.83(m,3H),3.61(s,1.6H),3.59(s,1.4H),2.76(s,1.6H),2.75(s,1.4H),2.73-2.63(m,2H),2.29-2.19(m,0.5H),2.14-2.04(m,1H),2.04-1.95(m,1H),1.91-1.81(m,1H),1.73-1.70(m,0.5H),0.94(s,5H),0.93(s,4H),0.17-0.14(m,6H)。

Compound 205: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (S-methylsulfonimidoyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of 205P2(40mg, 0.060mmol) in methanol (2mL) was added 2M aqueous hydrochloride (0.5mL) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in water (10 mL). The mixture was adjusted to pH 9-10 with 28% ammonia solution (0.5mL) and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: xbridge C18 HILIC (5 μm 10 × 190mm) mobile phase a: water, mobile phase B: acetonitrile, UV: 214nm, flow rate: 50mL/min, gradient: 20% -95% (% B)) to give compound 205A as a yellow solid (20.8mg, 65% yield). LC-MS (ESI): r_T＝3.418min，C₂₁H₂₂ClF₂N₅O₃S₂Calculated mass of 529.1, M/z found value 529.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm 4.6. multidot.250)mm; mobile phase: CO 2₂MeOH 60:40 at 2.999 g/min; column temperature: 39.3 ℃; wavelength: 214nm, back pressure: 100 bar, R_T6.14min and 6.84 min).¹H NMR(400MHz,CDCl₃)δ8.19(s,0.4H),7.84-7.83(m,1H),7.53(d,J＝3.2Hz,0.6H),7.47(d,J＝3.2Hz,0.4H),7.43(br s,0.6H),7.09-7.02(m,2H),6.19(s,0.4H),6.07(d,J＝2.4Hz,0.6H),4.14-4.03(m,2.4H),3.92-3.86(m,0.6H),3.61(s,1.8H),3.59(s,1.2H),2.86(s,1.8H),2.84(s,1.2H),2.81-2.74(m,2H),2.31-2.20(m,0.7H),2.17-2.00(m,2.3H),1.95-1.74(m,2H)。

Compound 205B was prepared from 205P1 in analogy to 205A,¹H NMR(400MHz,CDCl₃)δ8.19(s,0.4H),7.84-7.82(m,1H),7.53(d,J＝3.2Hz,0.6H),7.47(d,J＝3.6Hz,0.4H),7.43(d,J＝1.6Hz,0.6H),7.08-7.01(m,2H),6.19(s,0.4H),6.07(d,J＝2.8Hz,0.6H),4.17-4.00(m,2.3H),3.93-3.86(m,0.7H),3.61(s,1.9H),3.59(s,1.1H),2.86(s,1.9H),2.84(s,1.1H),2.83-2.73(m,2H),2.28-2.22(m,0.7H),2.17-2.06(m,2H),2.02-1.94(m,1H),1.89-1.80(m,0.7H),1.75-1.72(m,0.6H)。

compound 207C: methyl 4- (2-chloro-4-fluorophenyl) -6- (-1-methylpyrrolidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 4- (2-chloro-4-fluorophenyl) -6- (pyrrolidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 64(220mg, 0.524mmol) and paraformaldehyde (157mg, 5.23mmol) in methanol (8mL) was added sodium cyanoborohydride (494mL, 7.87 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to give a residue which was purified by preparative HPLC (column: gilson C185 μm19 x 150mm, flow rate: 20ml/min, mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, gradient: 15% -60% (% B)) to give the title compound as a yellow solid (90mg, 40% yield). LC-MS (ESI): r_T＝3.328min，C₂₀H₂₀ClFN₄O₂Calculated mass of S434.1, found value of M/z 435.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.59(s,0.5H),10.55(s,0.5H),7.97(d,J＝2.8Hz,1H),7.91(s,1H),7.44-7.34(m,2H),7.22-7.15(m,1H),6.00(s,0.5H),5.96(s,0.5H),4.52(s,1H),3.51(s,1.5H),3.50(s,1.5H),3.17-2.93(m,2H),2.44(s,1.5H),2.42(s,1.5H),2.33-1.71(m,4H)。

207 (90mg, 0.21mmol) were separated by chiral preparative HPLC (column: Chiralpak IE 5 μm20 × 250mm, Mobile Phase: Hex: EtOH: DEA ═ 90:10:0.3 at 15mL/min, temperature: 30 ℃ and wavelength: 230nm) to give the title compounds 207C (6.3mg, 7% yield, 97.0% de), 207D (9.3mg, 10% yield, 98.2% de) and a mixture of 207A and 207B.

Compound 207C: LC-MS (ESI): r_T＝3.329min，C₂₀H₂₀ClFN₄O₂Calculated mass of S434.1, found value of M/z 434.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 1 ℃; temperature: C; temperature: temperature_T＝9.672min)。¹H NMR(400MHz,CDCl₃)δ10.61(s,1H),7.81(d,J＝2.8Hz,1H),7.39(d,J＝3.2Hz,1H),7.33(dd,J＝8.8,6.4Hz,1H),7.12(dd,J＝8.8,2.8Hz,1H),6.92-6.88(m,1H),6.13(s,1H),4.67-4.63(m,1H),3.59(s,3H),3.21(t,J＝8.8Hz,1H),3.09(d,J＝10.0Hz,1H),2.50(s,3H),2.46-2.35(m,2H),2.15(q,J＝8.8Hz,1H),1.87-1.79(m,1H)。

Compound 219: methyl 4- (2-chloro-3-fluorophenyl) -6- (5- (hydroxymethyl) -tetrahydrofuran-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 4- (2-chloro-3-fluorophenyl) -6- (5- (ethoxycarbonyl) -tetrahydrofuran-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 211M (1.33g, 2.70mmol) in tetrahydrofuran (45mL) was added lithium borohydride (297mg, 13.5mmol) at 0 ℃ under a nitrogen atmosphere. After stirring at 0 ℃ for 3h, the reaction mixture was quenched with water (25mL) and 0.6M aqueous hydrochloride (6mL) and extracted three times with ethyl acetate (40 mL). The combined organic layers were washed with water (20mL)Twice over Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by preparative HPLC (column: Waters X-bridge C18(5 μm 19X 150mm) mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 30% -80% (% B)) to give the title compound 219 as a yellow solid (960mg, 79% yield). LC-MS (ESI): r_T＝3.126min，C₂₀H₁₉ClFN₃O₄Calculated mass of S451.1, M/z found value 451.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.65-9.62(m,0.3H),9.61-9.56(m,0.3H),9.24(s,0.1H),9.16(s,0.1H),9.11(s,0.1H),9.04(s,0.1H),8.01(s,1H),7.97-7.91(m,1H),7.41-7.33(m,2H),7.27-7.16(m,1H),6.09-6.05(m,0.4H),6.00-5.96(m,0.6H),5.03-4.86(m,0.2H),4.74-4.59(m,0.8H),4.43-4.33(m,0.5H),4.21-4.11(m,0.5H),4.04-3.97(m,1H),3.90-3.76(m,1H),3.68-3.64(m,0.4H),3.60-3.57(m,0.6H),3.53-3.52(m,2H),3.51-3.46(m,1H),3.43-3.41(m,1H),2.40-2.33(m,0.4H),2.23-2.13(m,0.6H),2.03-1.87(m,0.7H),1.78-1.68(m,0.3H)。

Rac 219(1.00g, 2.20mmol) was separated by chiral preparative HPLC (column: Chiralpak AD-H5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 219D (19.7mg, 2% yield, 100% stereopurity), 219F (19.9mg, 2% yield, 100% stereopurity), 219H (19.5mg, 2% yield, 100% stereopurity) and a mixture of five isomers (600mg, 60% yield). The mixture (600mg, 1.33mmol) was separated by chiral preparative HPLC (column: Chiralpak OD-H5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 219B (19.6mg, 2% yield, 100% stereopurity), fraction 1(230mg, 23% yield) and fraction 2(170mg, 17% yield). Fraction 1(230mg, 0.51mmol) was further separated by chiral SFC (column: Chiralpak IG5 μm20 × 250 mm; mobile phase: CO)₂50g/min MeOH (DEA) (75: 25: 0.3); column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar) to yield the title compound 219A (19.5mg, 2% yield, 100% stereopure) and 219C (19.2mg, 2% yield, 100%% stereopure). Fraction 2(170mg, 0.38mmol) was further separated by chiral SFC (column: Chiralpak IG5 μm20 × 250 mm; mobile phase: CO)₂IPA, DEA 70:30:0.3 at 50 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar) to yield the title compound 219E (19.7mg, 2% yield, 100% stereopurity) and 219G (20.0mg, 2% yield, 100% stereopurity).

Compound 219A: LC-MS (ESI): r_T＝3.308min，C₂₀H₁₉ClFN₃O₄Calculated mass of S451.1, M/z found 452.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak OD-H5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak OD-H5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA ═ 90:10: 0.2; temperature: 30_T＝10.908min)。¹H NMR(400MHz,DMSO-d₆)δ9.63(d,J＝3.6Hz,0.7H),9.04(s,0.3H),8.03-8.00(m,1.6H),7.94(d,J＝3.2Hz,0.4H),7.41-7.29(m,2H),7.24-7.22(m,1H),6.09(s,0.3H),5.96(d,J＝4.0Hz,0.7H),4.87-4.84(m,0.3H),4.70-4.67(m,0.7H),4.65-4.60(m,0.3H),4.44-4.36(m,0.7H),4.32-4.26(m,0.3H),4.18-4.13(m,0.7H),4.04-3.96(m,1H),3.89-3.85(m,0.3H),3.68-3.65(m,0.7H),3.53(s,2H),3.51(s,1H),3.45-3.42(m,2H),2.41-2.34(m,0.7H),2.23-2.20(m,0.6H),1.92-1.85(m,0.7H)。

Compound 219C: LC-MS (ESI): r_T＝3.319min，C₂₀H₁₉ClFN₃O₄Calculated mass of S451.1, M/z found 452.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak AD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2, at 0.5 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝4.358min)。¹H NMR(400MHz,DMSO-d₆)δ9.61-9.56(m,0.7H),9.13-9.08(m,0.3H),8.01(s,1.6H),7.95(s,0.4H),7.41-7.26(m,2.3H),7.18(d,J＝7.2Hz,0.7H),6.06(s,0.4H),5.90(d,J＝2.8Hz,0.6H),4.89-4.76(m,0.3H),4.70-4.54(m,0.7H),4.41-4.31(m,0.7H),4.26-4.22(m,0.3H),4.21-4.10(m,1.6H),3.97-3.89(m,0.4H),3.82-3.78(m,0.7H),3.52(s,3H),3.43(s,1.3H),3.42(s,1H),2.28-2.15(m,1H),2.09-2.00(m,0.4H),1.80-1.71(m,0.6H)。¹H NMR(400MHz,CD₃OD +0.6 mhz cl in water (1 drop)) δ 8.00(d, J ═ 3.2Hz,1H),7.90(d, J ═ 2.8Hz,1H),7.34-7.31(m,1H),7.28-7.26(m,1H),7.22-7.17(m,1H),6.22(s,1H),4.70-4.60(m,1H),4.41-4.38(m,1H),4.18-4.11(m,2H),3.65-3.58(m,5H),2.30-2.25(m,1H),2.15-2.10(m,1H)。

Compound 219E: LC-MS (ESI): r_T＝2.601min，C₂₀H₁₉ClFN₃O₄Calculated mass of S451.1, M/z found value 451.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak AD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak AD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30_T＝5.603min)。¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝3.6Hz,0.5H),9.24(s,0.5H),8.01(s,1H),7.96(d,J＝3.2Hz,0.5H),7.91(d,J＝2.8Hz,0.5H),7.41-7.29(m,2H),7.21(d,J＝7.6Hz,1H),6.06(s,0.5H),5.97(d,J＝3.2Hz,0.5H),5.04(t,J＝5.2Hz,0.5H),4.73-4.67(m,1H),4.45-4.36(m,0.5H),4.04-3.97(m,1.5H),3.89-3.80(m,1.5H),3.76-3.68(m,0.5H),3.63-3.56(m,1H),3.54(s,1.5H),3.51(s,1.5H),3.50-3.46(m,0.5H),2.47-2.44(m,0.5H),2.18-2.09(m,1H),1.97-1.91(m,0.5H)。

Compound 219H: LC-MS (ESI): r_T＝3.051min，C₂₀H₁₉ClFN₃O₄Calculated mass of S451.1, M/z found value 451.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak AD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak AD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30_T＝14.702min)。¹H NMR(400MHz,DMSO-d₆)δ9.62-9.57(m,0.5H),9.16(s,0.5H),8.01(s,1H),7.96(d,J＝2.8Hz,0.5H),7.92(d,J＝3.2Hz,0.5H),7.40-7.30(m,2H),7.28-7.16(m,1H),6.09-6.05(m,0.5H),5.99-5.95(m,0.5H),4.91(t,J＝5.2Hz,0.5H),4.68-4.66(m,1H),4.42-4.33(m,0.5H),4.21-4.18(m,0.5H),4.03-3.94(m,1.5H),3.93-3.79(m,1H),3.62-3.55(m,1.4H),3.53(s,1.4H),3.52(s,1.6H),3.48-3.44(m,0.6H),2.46-2.40(m,0.6H),2.01(t,J＝8.4Hz,1H),1.74-1.67(m,0.4H)。¹H NMR(400MHz,CD₃OD +0.6M aqueous HCl (1 drop)) δ 8.23-8.19(M,2H),7.45-7.40(M,2.2H),7.35-7.31(M,0.8H),6.35-6.33(M,1H),4.73-4.69(M,1H),4.26-4.19(M,2H),4.07-4.03(M,1H),3.97-3.93(M,1H),3.81(d, J ═ 4.0Hz,0.6H),3.78(d, J ═ 3.6Hz,0.4H),3.67(s,0.3H),3.64(s,2.7H),2.55-2.47(m,1H),2.14-2.11(m,1H)。

Compound 221: (cis) -methyl 4- (2-chloro-3-fluorophenyl) -6- (4- (hydroxymethyl) tetrahydrofuran-2-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (cis) -methyl 6- (4- (((tert-butyldiphenylsilyl) oxy) methyl) -tetrahydrofuran-2-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 220(2.20g, 3.19mmol) in tetrahydrofuran (25mL) was added tetrabutylammonium fluoride trihydrate (3.03g, 9.60mmol) at room temperature under a nitrogen atmosphere. Stirred at 60 ℃ overnight under nitrogen. It was then cooled to room temperature and concentrated under reduced pressure to give a residue which was purified by C18 column (acetonitrile: water ═ 5% to 95%) to give the title compound as a yellow solid (1.13g, 78% yield). LC-MS (ESI): r_T3.277 and 3.326min, C₂₀H₁₉ClFN₃O₄Calculated mass of S451.1, M/z found 452.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ9.13(s,0.5H),9.06(s,0.5H),7.83(dd,J＝10.0,3.2Hz,1H),7.43(d,J＝3.2Hz,1H),7.23-7.02(m,3H),6.27(s,0.5H),6.22(s,0.5H),5.62-5.53(m,1H),4.14-4.02(m,2H),4.01-3.71(m,0.3H),3.70-3.66(m,1.7H),3.63-3.62(m,1H),3.58(s,3H),2.91-2.86(m,1H),2.71-2.66(m,1H),1.68-1.65(m,0.5H),1.56-1.53(m,0.5H)。

The racemic mixture of 221 (1.13g, 2.50mmol) was separated by chiral preparative HPLC (column: chiralpak ie 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2 at 15 mL/min; temperature: 30 ℃ c; wavelength: 214nm) to give 221D (251mg, 22% yield, 100% stereopurity) and fraction 1(800 mg). Fraction 1(800mg, 1.77mmol) was further separated by chiral preparative HPLC (column: Chiralpak IG5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 80:20 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give 221A (161mg, 14% yield, 100% stereopurity) and fraction 2(444 mg). Fraction 2(444mg, 0.984mmol) was further separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: IPA ═ 80:20 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give 221B (182mg, 16% yield, 100% stereopurity) and 221C (181mg, 16% yield, 96.9% stereopurity).

Compound 221D: LC-MS (ESI): r_T＝3.123min，C₂₀H₁₉ClFN₃O₄Calculated mass of S451.1, M/z found value 451.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of chiral structure (column: Chiralpak IE 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 80:20: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝11.164min)。¹H NMR(400MHz,CD₃OD)δ7.91(d,J＝3.2Hz,1H),7.73(d,J＝2.8Hz,1H),7.29-7.26(m,1H),7.20-7.11(m,2H),6.22(s,1H),5.55-5.51(m,1H),4.05-4.03(m,2H),3.61-3.58(m,5H),2.84-2.81(m,1H),2.65-2.61(m,1H),1.72-1.69(m,1H)。

Compounds 243A and 243B: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3- (methoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (cis) -methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3- (methoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 242(670mg, 1.03mmol) in 3M hydrochloride (in methanol) (10mL, 30mmol) was added. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure to give a residue, which was dissolved in dichloromethane (20 mL). To the above solution was added saturated aqueous sodium bicarbonate (20mL) and extracted three times with dichloromethane (20 mL). The combined organic layers were washed twice with brine (20mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (petroleum ether: ethyl acetate ═ 2:1) to give the title compound 243A (200 m) as a yellow solidg, 32% yield) and 243B as a yellow solid (180mg, 29% yield).

Compound 243A:¹H NMR(300MHz,DMSO-d₆)δ9.52-9.51(m,0.8H),9.12(br s,0.2H),8.04-7.98(m,1.8H),7.94-7.92(m,0.2H),7.43-7.33(m,2H),7.24-7.15(m,1H),6.01(s,0.2H),5.92(d,J＝3.3Hz,0.8H),4.08-4.00(m,1H),3.78-3.69(m,3H),3.65(s,3H),3.53(s,3H),3.29-3.21(m,1H),2.93-2.82(m,2H),2.62-2.57(m,4H),1.97-1.73(m,3H),1.64-1.54(m,1H)。

compound 243B:¹H NMR(300MHz,DMSO-d₆)δ9.55-9.49(m,0.8H),9.12(br s,0.2H),8.00-7.89(m,2H),7.43-7.33(m,2H),7.24-7.17(m,1H),6.01(s,0.2H),5.94-5.90(m,0.8H),4.05-3.94(m,1H),3.74-3.67(m,3H),3.63(s,3H),3.53(s,3H),3.24-3.16(m,1H),2.90-2.79(m,2H),2.59-2.53(m,4H),2.02-1.75(m,3H),1.65-1.55(m,1H)。

compound 244X: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3- (2-hydroxyprop-2-yl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3- (methoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 243A (281mg, 0.46mmol) in tetrahydrofuran (6mL) was added dropwise 3.0M methylmagnesium chloride in tetrahydrofuran (1.2mL, 3.6mmol) at-78 ℃. After stirring at room temperature overnight, the reaction mixture was quenched with saturated aqueous ammonium chloride (20mL) and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (petroleum ether: ethyl acetate: 3:2) to give the impure title compound which was further purified by preparative HPLC (column: Xbridge C18(5 μm 10 × 190mm), mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 15mL/min, gradient: 40% -75% (% B)) to give the title compound as a yellow solidThe title compound (220mg, 78% yield). LC-MS (ESI): r_T＝4.313min，C₂₇H₃₂ClFN₄O₅S₂Calculated mass of 610.2, M/z found value 611.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.6Hz,0.8H),9.10(br s,0.2H),8.01-7.98(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.44-7.40(m,1H),7.37-7.31(m,1H),7.23-7.17(m,1H),6.01(s,0.2H),5.92(d,J＝4.0Hz,0.8H),4.36(s,1H),3.97-3.90(m,0.2H),3.78-3.71(m,3.8H),3.53(s,2.3H),3.52(s,0.7H),2.88-2.79(m,2H),2.40-2.26(m,5H),2.02-1.91(m,1H),1.83-1.74(m,2H),1.63-1.55(m,1H),1.02(s,6H)。

244X racemic mixture (200mg, 0.327mmol) was separated by chiral preparative SFC (separation conditions: column: Chiralpak IF 5 μm20 × 250 mm; mobile phase: CO:. sup.₂MeOH 60:40 at 50 g/min; column temperature: 39.8 ℃; wavelength: 214 nm; back pressure: 100 bar) to yield 244A as a yellow solid (70mg, 35% yield, 100% stereopurity) and 244B as a yellow solid (75mg, 38% yield, 100% stereopurity).

Compound 244A: LC-MS (ESI): r_T＝4.342min，C₂₇H₃₂ClFN₄O₅S₂Calculated mass of 610.2, M/z found value 611.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IF 5 μm4.6 x 250 mm; mobile phase: CO)₂EtOH 60:40 at 2.999 g/min; column temperature: 40.1 ℃; wavelength: 230nm, back pressure: 100 bar, R_T＝4.95min)。¹H NMR(400MHz,DMSO-d₆)δ9.48(br s,0.8H),9.16-9.03(m,0.2H),8.06-7.90(m,2H),7.43-7.40(m,1H),7.37-7.31(m,1H),7.23-7.18(m,1H),6.02-5.97(m,0.2H),5.92(s,0.8H),4.35(s,1H),3.96-3.89(m,0.2H),3.78-3.69(m,3.8H),3.52(s,3H),2.89-2.80(m,2H),2.40-2.26(m,5H),2.00-1.92(m,1H),1.85-1.74(m,2H),1.64-1.55(m,1H),1.02(s,6H)。

Compound 244B: LC-MS (ESI): r_T＝4.308min，C₂₇H₃₂ClFN₄O₅S₂Calculated mass of 610.2, M/z found value 611.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IF 5 μm4.6 x 250 mm; mobile phase: CO)₂EtOH 60:40 at 2.999 g/min;column temperature: 40 ℃; wavelength: 230nm, back pressure: 100 bar, R_T＝6.15min)。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.6Hz,0.8H),9.09(br s,0.2H),8.01-7.98(m,1.8H),7.94-7.91(m,0.2H),7.44-7.40(m,1H),7.38-7.31(m,1H),7.23-7.18(m,1H),6.01(s,0.2H),5.92(d,J＝3.6Hz,0.8H),4.35(s,1H),3.99-3.91(m,0.2H),3.78-3.71(m,3.8H),3.53(s,2.3H),3.52(s,0.7H),2.88-2.80(m,2H),2.40-2.25(m,5H),2.02-1.91(m,1H),1.86-1.74(m,2H),1.63-1.55(m,1H),1.02(s,6H)。

Compound 244Y: (cis) -methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3- (2-hydroxypropan-2-yl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (cis) -methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3- (methoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 243B (200mg, 0.327mmol) in tetrahydrofuran (4mL) at-78 ℃ was added 3.0M methylmagnesium chloride in tetrahydrofuran (0.9mL, 2.7mmol) dropwise. After stirring at room temperature overnight, the reaction mixture was quenched with saturated aqueous ammonium chloride (20mL) and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to dryness under reduced pressure to give a residue which was purified by preparative TLC (petroleum ether: ethyl acetate 1:1) to give the impure title compound which was further purified by preparative HPLC (column: xbridge C185 μm 10 × 190mm, flow rate: 15mL/min, mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, gradient: 40% -75% (% B)) to give the title compound as a yellow solid (130mg, 65% yield). LC-MS (ESI): r_T＝4.314min，C₂₇H₃₂ClFN₄O₅S₂Calculated mass of 610.2, M/z found value 611.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.6Hz,0.8H),9.08(br s,0.2H),8.01-7.98(m,1.8H),7.93(d,J＝2.8Hz,0.2H),7.44-7.40(m,1H),7.38-7.31(m,1H),7.23-7.17(m,1H),6.02(s,0.2H),5.92(d,J＝3.2Hz,0.8H),4.28(s,0.2H),4.26(s,0.8H),3.98-3.91(m,0.2H),3.77-3.68(m,3.8H),3.53(s,2.3H),3.52(s,0.7H),2.89-2.81(m,2H),2.33-2.27(m,2H),2.24-2.20(m,1H),2.12-2.06(m,2H),2.00-1.91(m,1H),1.87-1.74(m,2H),1.63-1.54(m,1H),0.98(s,6H)。

A racemic mixture of 244Y (110mg, 0.180mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.3 at 9 mL/min; temperature: 30 ℃ C; wavelength: 230nm) to give the title compound 244C (43mg, 39% yield, 100% stereopurity) as a yellow solid and 244D (42mg, 38% yield, 100% stereopurity) as a yellow solid.

Compound 244C: LC-MS (ESI): r_T＝4.328min，C₂₇H₃₂ClFN₄O₅S₂Calculated mass of 610.2, M/z found value 611.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of chiral molecules: 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: 50: 0.2; temperature: 230 ℃_T＝10.291min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.2Hz,0.8H),9.09(br s,0.2H),8.01-7.98(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.44-7.40(m,1H),7.37-7.31(m,1H),7.23-7.17(m,1H),6.01(s,0.2H),5.92(d,J＝2.8Hz,0.8H),4.29(s,0.2H),4.26(s,0.8H),3.97-3.91(m,0.2H),3.77-3.67(m,3.8H),3.53(s,2.3H),3.52(s,0.7H),2.89-2.80(m,2H),2.33-2.26(m,2H),2.24-2.20(m,1H),2.12-2.06(m,2H),2.01-1.91(m,1H),1.86-1.74(m,2H),1.62-1.55(m,1H),0.98(s,6H)。

Compound 244D: LC-MS (ESI): r_T＝4.328min，C₂₇H₃₂ClFN₄O₅S₂Calculated mass of 610.2, M/z found value 611.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of chiral molecules: 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: 50: 0.2; temperature: 230 ℃_T＝10.635min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.2Hz,0.8H),9.09(br s,0.2H),8.03-7.98(m,1.8H),7.93(d,J＝3.6Hz,0.2H),7.44-7.40(m,1H),7.38-7.31(m,1H),7.23-7.17(m,1H),6.02(s,0.2H),5.92(d,J＝3.2Hz,0.8H),4.29(s,0.3H),4.26(s,0.7H),3.98-3.92(m,0.2H),3.77-3.67(m,3.8H),3.53(s,3H),2.89-2.80(m,2H),2.33-2.27(m,2H),2.24-2.20(m,1H),2.12-2.06(m,2H),2.01-1.91(m,1H),1.86-1.74(m,2H),1.63-1.55(m,1H),0.98(s,6H)。

Compound 245: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- ((R) -2-hydroxy-3-methoxypropyl) methylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 236-a: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (((R) -2-hydroxy-3-methoxypropyl) amino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 6- (4-aminocyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 236(200mg, 0.430mmol) in methanol (4mL) was added (R) -2- (methoxymethyl) oxirane (40mg, 0.470 mmol). After stirring at 90 ℃ for 2 hours in a microwave reactor, the reaction mixture was cooled to room temperature, diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by C18 column (acetonitrile: water 40% to 80%) to give the title compound as a yellow solid (200mg, 84% yield). LC-MS (ESI): r_T＝2.161min，C₂₅H₂₉ClF₂N₄O₄Calculated mass of S554.2, M/z found value 554.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.15(s,0.5H),7.83-7.81(m,1H),7.50(d,J＝3.2Hz,0.5H),7.45(d,J＝3.2Hz,0.5H),7.39(s,0.5H),7.09-6.98(m,2H),6.17(s,0.6H),6.04(s,0.4H),4.20-4.13(m,0.5H),4.00-3.93(m,1H),3.81-3.71(m,0.5H),3.61-3.59(m,3H),3.50-3.41(m,2H),3.40(s,3H),3.12-3.09(m,1H),2.96-2.88(m,2H),2.28-1.99(m,4H),1.84-1.39(m,4H)。

Compound 236-B: (trans) -methyl 6- (4- ((tert-butoxycarbonyl) ((R) -2-hydroxy-3-methoxypropyl) amino) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (((R) -2-hydroxy-3-methoxypropyl) amino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 236-a (150mg, 0.270mmol) in dichloromethane (8mL) under a nitrogen atmosphere was added di-tert-butyl dicarbonate (177mg, 0.810mmol) and triethylamine (90mg, 0.810 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (40mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (180mg, 99% yield). LC-MS (ESI): r_T＝2.517min，C₃₀H₃₇ClF₂N₄O₆Calculated mass of S654.2, found value of M/z 655.0[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.6H),7.83(d,J＝3.2Hz,1H),7.51(d,J＝2.8Hz,0.4H),7.45(d,J＝2.8Hz,0.6H),7.39(s,0.4H),7.07-6.98(m,2H),6.17(s,0.7H),6.04(s,0.3H),3.99-3.83(m,2H),3.61-3.59(m,3H),3.41-3.24(m,8H),2.14-1.70(m,8H),1.52(s,9H)。

Compound 236-C: (trans) -methyl 6- (4- (((R) -2-acetoxy-3-methoxypropyl) -amino) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 6- (4- ((tert-butoxycarbonyl) ((R) -2-hydroxy-3-methoxypropyl) amino) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1,4 dihydropyrimidine-5-carboxylate 236-B (130mg, 0.200mmol) in dichloromethane (10mL) was added acetic anhydride (61mg, 0.600mmol), 4-dimethylaminopyridine (24mg, 0.200mmol), and triethylamine (60mg, 0.600mmol) under a nitrogen atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with 1M aqueous hydrochloride (10mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure,crude compound (150mg) was obtained as a colorless oil, which was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (5ml) was added to the above solution under a nitrogen atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the crude compound as a colorless oil (140mg, 99% yield). LC-MS (ESI): r_T＝2.402min，C₂₇H₃₁ClF₂N₄O₅Calculated mass of S596.2, found value of M/z 596.8[ M + H]⁺。

Compound 236-D: (trans) -methyl 6- (4- (N- ((R) -2-acetoxy-3-methoxypropyl) methylsulfonamido) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 6- (4- (((R) -2-acetoxy-3-methoxypropyl) amino) -cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 236-C (140mg, 0.230mmol) in dichloromethane (10mL) was added methanesulfonyl chloride (40mg, 0.350mmol) and triethylamine (70mg, 0.700mmol) under a nitrogen atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by C18 column (acetonitrile: water 40% to 80%) to give the title compound as a yellow solid (75mg, 50% yield). LC-MS (ESI): r_T＝1.837min，C₂₈H₃₃ClF₂N₄O₇S₂Calculated mass of 674.1, M/z found value 674.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.16(s,0.5H),7.84-7.83(m,1H),7.56-7.41(m,1.5H),7.05(br s,2H),6.17(s,0.5H),6.05(s,0.5H),4.00-3.90(m,1H),3.61-3.50(m,6H),3.38(s,3H),3.14(s,3H),2.93(s,3H),2.12(s,3H),2.05-1.72(m,8H)。

Compound 245M: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- ((R) -2-hydroxy-3-methoxypropyl) methylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 6- (4- (N- ((R) -2-acetoxy-3-methoxypropyl) methanesulfonamido) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 236-D (110mg, 0.160mmol) in methanol (8mL) was added potassium carbonate (44mg, 0.320mmol) under a nitrogen atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a residue which was purified by C18 column (acetonitrile: water 40% to 80%) to give the title compound as a yellow solid (40mg, 41% yield). LC-MS (ESI): r_T＝1.739min，C₂₆H₃₁ClF₂N₄O₆S₂Calculated mass of 632.1, M/z found value 632.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.5H),7.83(d,J＝4.0Hz,1H),7.53(d,J＝2.8Hz,0.5H),7.46(d,J＝2.8Hz,0.5H),7.39(s,0.5H),7.08-6.99(m,2H),6.17(s,0.5H),6.04(d,J＝2.8Hz,0.5H),4.00-3.94(m,1.5H),3.85-3.70(m,1.5H),3.61-3.59(m,3H),3.46-3.38(m,5H),3.34-3.31(m,2H),2.98-2.96(m,3.5H),2.89-2.85(m,0.5H),2.15-1.94(m,4H),1.90-1.64(m,4H)。

Rac 245M (80mg, 0.13mmol) was separated by chiral preparative HPLC (column: Chiralpak IA 5 μ M20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 25 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 245A (40mg, 50% yield, 100% stereopurity) and 245B (40mg, 50% yield, 100% stereopurity) as yellow solids.

Compound 245A: LC-MS (ESI): r_T＝2.135min，C₂₆H₃₁ClF₂N₄O₆S₂Calculated mass of 632.1, M/z found value 632.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of the chiral structure of the_T＝8.105min)。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.5H),7.83(d,J＝3.2Hz,1H),7.52(d,J＝3.2Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.41(s,0.5H),7.07-6.98(m,2H),6.17(s,0.5H),6.04(d,J＝2.8Hz,0.5H),4.01-3.93(m,1.5H),3.85-3.68(m,1.5H),3.61-3.59(m,3H),3.46-3.41(m,5H),3.42-3.31(m,2H),2.98-2.96(m,3.5H),2.88-2.87(m,0.5H),2.16-1.96(m,4H),1.92-1.67(m,4H)。

Compound 245B: LC-MS (ESI): r_T＝2.123min，C₂₆H₃₁ClF₂N₄O₆S₂Calculated mass of 632.1, M/z found value 632.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IG5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of the chiral structure of the_T＝10.000min)。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.5H),7.83(d,J＝3.2Hz,1H),7.52(d,J＝3.2Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.40(s,0.5H),7.07-6.98(m,2H),6.17(s,0.5H),6.04(d,J＝2.8Hz,0.5H),4.01-3.93(m,1.5H),3.85-3.69(m,1.5H),3.61-3.59(m,3H),3.46-3.39(m,5H),3.34-3.24(m,2H),3.01-2.98(m,3.5H),2.90-2.89(m,0.5H),2.16-1.93(m,4H),1.90-1.63(m,4H)。

Compound 236-E: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (((S) -2-hydroxy-3-methoxypropyl) amino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 6- (4-aminocyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 236(200mg, 0.430mmol) in methanol (4mL) was added (S) -2- (methoxymethyl) oxirane (42mg, 0.470 mmol). After stirring at 85 ℃ for 2 hours in a microwave reactor, the reaction mixture was cooled to room temperature, diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by C18 column (acetonitrile: water 40% to 80%) to give a yellow solidTitle compound of body (170mg, 71% yield). LC-MS (ESI): r_T＝2.169min，C₂₅H₂₉ClF₂N₄O₄Calculated mass of S554.2, M/z found value 554.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.15(s,0.5H),7.83-7.81(m,1H),7.50(d,J＝3.2Hz,0.5H),7.45(d,J＝3.2Hz,0.5H),7.39(s,0.5H),7.08-6.98(m,2H),6.17(s,0.6H),6.04(s,0.4H),4.21-4.14(m,0.5H),3.98-3.93(m,1H),3.80-3.72(m,0.5H),3.61-3.59(m,3H),3.50-3.41(m,2H),3.40(s,3H),3.13-3.08(m,1H),2.97-2.88(m,2H),2.33-1.98(m,4H),1.82-1.42(m,4H)。

Compound 236-F: (trans) -methyl 6- (4- ((tert-butoxycarbonyl) ((S) -2-hydroxy-3-methoxypropyl) amino) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (((S) -2-hydroxy-3-methoxypropyl) amino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 236-E (170mg, 0.300mmol) in dichloromethane (10mL) was added di-tert-butyl pyrocarbonate (200mg, 0.920mmol) and triethylamine (93mg, 0.920mmol) under a nitrogen atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (40mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (200mg, 99% yield). LC-MS (ESI): r_T＝1.945min，C₃₀H₃₇ClF₂N₄O₆Calculated mass of S654.2, found value of M/z 654.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.6H),7.83-7.82(m,1H),7.51(d,J＝2.8Hz,0.4H),7.45(d,J＝2.8Hz,0.6H),7.39(s,0.4H),7.07-6.98(m,2H),6.17(s,0.7H),6.04(s,0.3H),3.99-3.83(m,2H),3.61-3.59(m,3H),3.41-3.24(m,8H),2.14-1.70(m,8H),1.51(s,9H)。

Compounds 236-G: (trans) -methyl 6- (4- (((S) -2-acetoxy-3-methoxypropyl) (tert-butoxycarbonyl) amino) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 6- (4- ((tert-butoxycarbonyl) ((S) -2-hydroxy-3-methoxypropyl) amino) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1,4 dihydropyrimidine-5-carboxylate 236-F (200mg, 0.310mmol) in dichloromethane (10mL) was added acetic anhydride (94mg, 0.930mmol), 4-dimethylaminopyridine (40mg, 0.310mmol) and triethylamine (83mg, 0.930mmol) under a nitrogen atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with 1M aqueous hydrochloride (10mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the crude compound as a colorless oil (220mg, 99% yield). LC-MS (ESI): r_T＝2.121min，C₃₂H₃₉ClF₂N₄O₇Calculated mass of S696.2, M/z found value 696.9[ M + H [ ]]⁺。

Compound 236-H: (trans) -methyl 6- (4- (N- ((S) -2-acetoxy-3-methoxypropyl) methylsulfonamido) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 6- (4- (((S) -2-acetoxy-3-methoxypropyl) (tert-butoxycarbonyl) amino) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 236-G (220mg, 0.310mmol) in dichloromethane (10mL) was added trifluoroacetic acid (5mL) under a nitrogen atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give crude compound (230mg), which was dissolved in dichloromethane (10 mL). To the above solution were added methanesulfonyl chloride (53mg, 0.470mmol) and triethylamine (90mg, 0.900 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was passed through a C18 column (acetonitrile: water 40% to80%) to yield the title compound as a yellow solid (150mg, 75% yield). LC-MS (ESI): r_T＝1.855min，C₂₈H₃₃ClF₂N₄O₇S₂Calculated mass of 674.1, M/z found value 674.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.16(s,0.5H),7.84-7.83(m,1H),7.56-7.41(m,1.5H),7.05(br s,2H),6.17(s,0.5H),6.05(s,0.5H),4.00-3.90(m,1H),3.61-3.50(m,6H),3.38(s,3H),3.14(s,3H),2.93(s,3H),2.12(s,3H),2.05-1.72(m,8H)。

Compound 245N: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- ((S) -2-hydroxy-3-methoxypropyl) methylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 6- (4- (N- ((S) -2-acetoxy-3-methoxypropyl) methanesulfonamido) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 236-H (150mg, 0.220mmol) in methanol (5mL) was added potassium carbonate (60mg, 0.440mmol) under a nitrogen atmosphere. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a residue which was purified by C18 column (acetonitrile: water 40% to 80%) to give the title compound as a yellow solid (85mg, 60% yield). LC-MS (ESI): r_T＝2.456min，C₂₆H₃₁ClF₂N₄O₆S₂Calculated mass of 632.1, M/z found value 632.8[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.5H),7.84-7.83(m,1H),7.53(d,J＝3.2Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.41(s,0.5H),7.06-6.98(m,2H),6.17(s,0.5H),6.04(d,J＝2.8Hz,0.5H),4.03-3.91(m,1.5H),3.80-3.68(m,1.5H),3.65-3.59(m,3H),3.51-3.41(m,5H),3.34-3.31(m,2H),3.04-2.98(m,3.5H),2.92-2.86(m,0.5H),2.18-1.91(m,4H),1.80-1.65(m,4H)。

Rac 245N (150mg, 0.240mmol) was separated by chiral preparative HPLC (column: Chiralpak IA 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 25 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 245C (75mg, 50% yield, 100% stereopurity) and 245D (75mg, 50% yield, 99.7% stereopurity) as yellow solids.

Compound 245C: LC-MS (ESI): r_T＝2.124min，C₂₆H₃₁ClF₂N₄O₆S₂Calculated mass of 632.1, M/z found value 632.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IA 5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA ═ 60:40: 0.2; temperature: 230 ℃; wavelength: 230_T＝5.708min)。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.5H),7.83(d,J＝2.8Hz,1H),7.52(d,J＝3.2Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.40(s,0.5H),7.07-6.98(m,2H),6.17(s,0.5H),6.04(d,J＝2.4Hz,0.5H),4.02-3.92(m,1.5H),3.86-3.69(m,1.5H),3.61-3.59(m,3H),3.46-3.39(m,5H),3.34-3.30(m,2H),2.99-2.98(m,3.5H),2.90-2.89(m,0.5H),2.17-1.96(m,4H),1.90-1.63(m,4H)。

Compound 245D: LC-MS (ESI): r_T＝2.103min，C₂₆H₃₁ClF₂N₄O₆S₂Calculated mass of 632.1, M/z found value 632.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IA 5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA ═ 60:40: 0.2; temperature: 230 ℃; wavelength: 230_T＝6.282min)。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.5H),7.83(d,J＝2.8Hz,1H),7.52(d,J＝2.8Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.40(s,0.5H),7.07-6.98(m,2H),6.17(s,0.5H),6.04(d,J＝2.4Hz,0.5H),4.02-3.94(m,1.5H),3.85-3.70(m,1.5H),3.61-3.59(m,3H),3.48-3.38(m,5H),3.34-3.31(m,2H),2.98-2.96(m,3.5H),2.87-2.86(m,0.5H),2.16-1.92(m,4H),1.89-1.63(m,4H)。

Compound 248: methyl 6- (1- ((1- (2- (tert-butoxy) ethyl) azetidin-3-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (1- (azetidin-3-ylsulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 247(150mg, crude, 0.250mmol (as quantified by 246)), potassium carbonate (100mg, 0.780mmol) and sodium iodide (30mg, 0.200mmol) in N, N-dimethylformamide (9mL) was added a solution of 2- (tert-butoxy) ethyl 4-methylbenzenesulfonate (100mg, 0.390mmol) in N, N-dimethylformamide (1 mL). After stirring at room temperature for 3 days, the mixture was diluted in water (30mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed three times with brine (10mL) and Na₂SO_4(s)Drying, filtration and concentration under reduced pressure gave a residue which was purified by preparative TLC (petroleum ether: ethyl acetate ═ 1:1) to give the title compound 248(10mg, 6% yield) as a yellow solid. LC-MS (ESI): r_T＝9.582min，C₂₉H₃₆ClF₂N₅O₅S₂Calculated mass of 671.2, M/z found value 672.3[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.19(s,0.5H),7.83(dd,J＝3.2,1.2Hz,1H),7.53(d,J＝2.8Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.42(br s,0.5H),7.10-6.99(m,2H),6.18(s,0.4H),6.06(d,J＝2.4Hz,0.6H),4.20-4.13(m,0.3H),4.04-3.87(m,3.7H),3.78-3.69(m,2H),3.60-3.58(m,3H),3.56-3.52(m,2H),3.38(t,J＝5.2Hz,2H),2.96-2.83(m,2H),2.68(q,J＝5.6Hz,2H),2.24-1.67(m,4H),1.17(s,9H)。

Compound 251: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1-methylazetidine-3-sulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 6- (4- (azetidine-3-sulfonylamino) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 250(210mg, 0.340mmol) and formaldehyde (1.5mL) in methanol (10mL) was added acetic acid (5 drops) at room temperature under a nitrogen atmosphere. After stirring at room temperature for 1 hour,sodium cyanoborohydride (90mg, 1.36mmol) was added to the mixture, and stirred at room temperature for 3 hours. The mixture was then quenched with water (10mL), concentrated under reduced pressure to remove methanol, and extracted three times with dichloromethane (10 mL). The combined organic layers were washed with brine (20mL) and Na₂SO_4(s)Drying, filtration and concentration under reduced pressure gave a residue which was purified by C18 column (acetonitrile: water 5% to 100%) to give the title compound as a yellow solid (130mg, 60% yield). LC-MS (ESI): r_T＝1.677min，C₂₅H₂₈ClF₂N₅O₄S₂Calculated mass of 599.1, M/z found value 599.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.14(s,0.5H),7.84-7.82(m,1H),7.52(d,J＝3.2Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.39(s,0.5H),7.07-6.98(m,2H),6.17(s,0.5H),6.04(d,J＝2.4Hz,0.5H),4.09(s,1H),4.01-3.92(m,1.5H),3.77-3.69(m,0.5H),3.68-3.63(m,2H),3.60(s,1.5H),3.58(s,1.5H),3.49-3.43(m,2H),3.39-3.36(m,1H),2.38(d,J＝1.6Hz,3H),2.25-1.90(m,4.3H),1.85-1.66(m,1.7H),1.53-1.36(m,2H)。

Rac 251(130mg, 0.220mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.3 at 10 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 251A (30mg, 23% yield, 100% stereopurity) as a yellow solid and 251B (30mg, 31% yield, 99.6% stereopurity) as a yellow solid.

Compound 251A: LC-MS (ESI): r_T＝8.952min，C₂₅H₂₈ClF₂N₅O₄S₂Calculated mass of 599.1, M/z found 600.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of chiral molecules: 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: 50: 0.2; temperature: 230 ℃_T＝10.756min)。¹H NMR(400MHz,CDCl₃)δ8.14(s,0.5H),7.83-7.82(m,1H),7.52(d,J＝3.2Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.39(s,0.5H),7.07-6.98(m,2H),6.17(s,0.5H),6.04(d,J＝2.4Hz,0.5H),4.15-4.08(m,1H),4.02-3.92(m,1.5H),3.77-3.71(m,0.5H),3.66(q,J＝7.6Hz,2H),3.60(s,1.5H),3.58(s,1.5H),3.48-3.43(m,2H),3.42-3.34(m,1H),2.38(d,J＝2.4Hz,3H),2.25-1.90(m,4.4H),1.84-1.66(m,1.6H),1.59-1.34(m,2H)。

Compound 251B: LC-MS (ESI): r_T＝3.687min，C₂₅H₂₈ClF₂N₅O₄S₂Calculated mass of 599.1, M/z found 600.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of chiral molecules: 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: 50: 0.2; temperature: 230 ℃_T＝14.460min)。¹H NMR(400MHz,CDCl₃)δ8.14(s,0.5H),7.83(t,J＝2.4Hz,1H),7.52(d,J＝3.2Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.39(s,0.5H),7.09-6.98(m,2H),6.17(s,0.5H),6.04(d,J＝2.4Hz,0.5H),4.11-4.05(m,1H),4.01-3.91(m,1.6H),3.78-3.71(m,0.4H),3.65(q,J＝8.0Hz,2H),3.60(s,1.5H),3.58(s,1.5H),3.49-3.43(m,2H),3.40-3.34(m,1H),2.38(d,J＝1.2Hz,3H),2.25-1.94(m,4H),1.91-1.78(m,0.8H),1.73-1.62(m,1.2H),1.56-1.33(m,2H)。

Compound 253B: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (3-hydroxypropylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (3-methoxy-3-oxopropylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 252Y (100mg, 0.160mmol) in tetrahydrofuran (8mL) under a nitrogen atmosphere was added lithium borohydride (15mg, 0.640 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by C18 column (acetonitrile: water 35% to 80%) to give the title compound as a pale yellow solid (50mg, 53% yield). LC-MS (ESI): r_T＝3.941min，C₂₄H₂₇ClF₂N₄O₅S₂Calculated mass of 588.1, M/z found value 588.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.15(s,0.5H),7.83-7.82(m,1H),7.52(d,J＝3.2Hz,0.5H),7.45(d,J＝3.2Hz,0.5H),7.40(s,0.5H),7.07-6.98(m,2H),6.17(s,0.5H),6.04(d,J＝2.4Hz,0.5H),4.31-4.29(m,0.5H),4.24-4.22(m,0.5H),4.01-3.94(m,0.5H),3.84-3.82(m,2H),3.76-3.69(m,0.5H),3.60-3.59(m,3H),3.45-3.37(m,1H),3.24-3.20(m,2H),2.31-2.17(m,2H),2.14-1.83(m,4H),1.82-1.65(m,2H),1.55-1.39(m,2H)。

Compound 268: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (N- (2-methoxyethyl) -sulfamoyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 267: methyl 6- (1- (N- (tert-butoxycarbonyl) -N- (2-methoxyethyl) -sulfamoyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (1- (N- (tert-butoxycarbonyl) sulfamoyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 266(307mg, 0.500mmol), 2-methoxyethanol (49mg, 0.65mmol), and triphenylphosphine (460mg, 1.75mmol) in tetrahydrofuran (10mL) was added 1.9M diisopropyl azodicarboxylate (0.9mL, 1.75mmol) in tetrahydrofuran at 0 ℃. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure to give a residue which was purified by C18 column (acetonitrile: water ═ 60% to 80%) to give the title compound as a yellow solid (170mg, 50% yield). LC-MS (ESI): r_T＝2.776min，C₂₈H₃₅ClFN₅O₇S₂Calculated mass of 671.2, M/z found value 672.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.55(d,J＝3.6Hz,0.8H),9.15(s,0.2H),8.01-7.93(m,2H),7.44-7.31(m,2H),7.23-7.19(m,1H),6.02(s,0.2H),5.92(d,J＝3.6Hz,0.8H),3.96-3.78(m,4H),3.74-3.67(m,1H),3.53(s,3H),3.49(t,J＝6.0Hz,2H),3.27(s,3H),2.98-2.87(m,2H),2.03-1.76(m,3H),1.64-1.61(m,1H),1.49(s,9H)。

Compound 268: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (N- (2-methoxyethyl) -sulfamoyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (1- (N- (tert-butoxycarbonyl) -N- (2-methoxyethyl) sulfamoyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 267(160mg, 0.238mmol) in dichloromethane (10mL) at 0 ℃ was added trifluoroacetic acid (10 mL). After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure, basified with saturated aqueous sodium carbonate solution to pH 7-8, and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed twice with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by C18 column (acetonitrile: water 65% to 85%) to give the title compound as a yellow solid (120mg, 88% yield). LC-MS (ESI): r_T＝3.148min，C₂₃H₂₇ClFN₅O₅S₂Calculated mass of 571.1, M/z found value 571.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝2.4Hz,0.8H),9.03(s,0.2H),8.01-7.99(m,1.8H),7.94-7.93(m,0.2H),7.43(dd,J＝8.8,2.4Hz,1H),7.38-7.29(m,2H),7.21-7.19(m,1H),6.02(s,0.2H),5.92(d,J＝3.6Hz,0.8H),3.70-3.60(m,3H),3.53(s,3H),3.41(t,J＝5.6Hz,2H),3.28(s,3H),3.09(q,J＝6.0Hz,2H),2.73-2.65(m,2H),2.04-1.96(m,1H),1.88-1.76(m,2H),1.63-1.60(m,1H)。

Rac 268(100mg, 0.175mmol) was separated by chiral preparative HPLC (column: Chiralpak IA 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 10 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 268A (17.5mg, 17.5% yield, 100% stereopurity) and 268B (15.3mg, 15.3% yield, 96.8% stereopurity) as yellow solids.

Compound 268A: LC-MS (ESI): r_T＝3.652min，C₂₃H₂₇ClFN₅O₅S₂Calculated mass of 571.1, M/z found value 571.9[ M + H ]]⁺. Chiral moietyAnalysis (column: Chiralpak IA 5 μm4.6 × 250mm, mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝11.598min)。¹H NMR(400MHz,DMSO-d₆)δ9.55(s,0.8H),9.04(s,0.2H),8.00-7.95(m,2H),7.44-7.42(m,1H),7.37-7.31(m,2H),7.23-7.18(m,1H),6.01-5.92(m,1H),3.68-3.65(m,3H),3.53(s,3H),3.42-3.40(m,2H),3.28(s,3H),3.12-3.09(m,2H),2.71-2.68(m,2H),2.03-2.00(m,1H),1.89-1.76(m,2H),1.63-1.60(m,1H)。

Compound 268B: LC-MS (ESI): r_T＝3.652min，C₂₃H₂₇ClFN₅O₅S₂Calculated mass of 571.1, M/z found value 571.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of the chiral structure of the chiral_T＝13.014min)。¹H NMR(400MHz,DMSO-d₆)δ9.54(s,0.8H),9.03(s,0.2H),8.00-7.94(m,2H),7.44-7.42(m,1H),7.34-7.31(m,2H),7.23-7.19(m,1H),6.01-5.92(m,1H),3.68-3.65(m,3H),3.53(s,3H),3.42-3.40(m,2H),3.28(s,3H),3.09(q,J＝6.0Hz,2H),2.71-2.68(m,2H),2.02-1.99(m,1H),1.89-1.76(m,2H),1.63-1.61(m,1H)。

Compound 284: methyl 4- (2-chloro-3-fluorophenyl) -6- (-5-oxopyrrolidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

A solution of compound 283N (530mg, 0.94mmol) in trifluoroacetic acid (22mL) was stirred at 50 ℃ under a nitrogen atmosphere overnight. The mixture was concentrated to give a residue, which was diluted with dichloromethane (10mL) and washed with saturated aqueous sodium bicarbonate (5 mL). Subjecting the organic layer to Na₂SO_4(s)Dried and filtered. The filtrate was concentrated to give a residue, which was diluted with 4.4M ammonia in methanol (20mL) and stirred at 30 ℃ under a nitrogen atmosphere overnight. It was then concentrated to give a residue which was purified by C18 column (acetonitrile: water 5% to 100%) to give the title compound as a yellow solid (210mg, 41%Yield). LC-MS (ESI): r_T＝2.135min，C₁₉H₁₆ClFN₄O₃Calculated mass of S434.1, found value of M/z 435.1[ M + H [)]⁺。¹HNMR(400MHz,CDCl₃)δ7.83(d,J＝2.8Hz,1H),7.55-7.52(m,2H),7.27-7.20(m,1H),7.12-7.07(m,2H),6.26-6.12(m,1H),5.8-5.76(m,1H),4.97-4.84(m,1H),3.81(t,J＝8.4Hz,0.3H),3.73-3.62(m,0.7H),3.61(s,3H),3.53-3.49(m,1H),3.07-3.01(m,0.7H),2.90-2.84(m,0.3H),2.65-2.59(m,0.8H),2.50-2.44(m,0.2H)。

A racemic mixture of compound 284N (210mg, 0.48mmol) was separated by chiral preparative HPLC (first separation conditions: column: Chiralpak IA 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 13 mL/min; temperature: 30 ℃; wavelength: 230 nm; second separation conditions: column: Chiralpak IB5 μm20 ═ 250 mm; mobile phase: Hex: IPA: DEA ═ 80:20:0.3 at 16 mL/min; temperature: 30 ℃; wavelength: 214 nm; third separation conditions: column: Chiralpak AD-H5 μm 20:250mm; mobile phase: Hex: EtOH ═ 60:40 at 13 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound C as a yellow solid (22.6mg, 284% yield, 31.31% and 284.94% stereopure (22.6mg, 14% yield, 22.4% stereogenic yield).

Compound 284C: LC-MS (ESI): r_T＝3.562min，C₁₉H₁₆ClFN₄O₃Calculated mass of S434.1, found value of M/z 435.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝12.940min)。¹H NMR(400MHz,CDCl₃)δ8.35(s,0.1H),7.84-7.80(m,0.9H),7.54-7.52(m,1.9H),7.46(s,0.1H),7.27-7.22(m,1H),7.13-7.09(m,2H),6.26(s,0.1H),6.13(d,J＝2.0Hz,0.9H),5.95(s,0.1H),5.65(s,0.9H),5.18(s,0.1H),4.96-4.89(m,0.9H),3.83-3.75(m,0.2H),3.68-3.63(m,3.8H),3.53-3.49(m,1H),3.07-3.01(m,0.9H),2.90-2.83(m,0.1H),2.65-2.59(m,1H)。

Compound 284D: LC-MS (ESI): r_T＝3.567min，C₁₉H₁₆ClFN₄O₃Calculated mass of S434.1, found value of m/z 435.1[M+H]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝15.428min)。¹H NMR(400MHz,CDCl₃)δ8.35(s,0.1H),7.84-7.80(m,0.9H),7.52(d,J＝3.6Hz,1.9H),7.46(d,J＝2.8Hz,0.1H),7.27-7.20(m,1H),7.11(t,J＝7.2Hz,2H),6.26(s,0.1H),6.13(d,J＝2.4Hz,0.9H),5.85(s,0.1H),5.58(s,0.9H),5.18(s,0.1H),4.96-4.89(m,0.9H),3.83-3.78(m,0.2H),3.68-3.61(m,3.8H),3.51(t,J＝7.2Hz,1H),3.07-3.01(m,1H),2.65-2.59(m,1H)。

Compound 287: methyl 4- (2-chloro-4-fluorophenyl) -6- ((trans) -4- (methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 286: methyl 6- ((trans) -4- (N' - (tert-butyldimethylsilyl) -methylsulfinamido) cyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a stirred solution of triphenylphosphine dichloride (2.0g, 6.0mmol) in dry chloroform (10mL) under a nitrogen atmosphere was added triethylamine (827mg, 8.20mmol) at 0 deg.C. After stirring at room temperature for 10 min, the reaction mixture was cooled to 0 ℃ and a solution of N- (tert-butyldimethylsilyl) -methanesulfonamide (1.15g, 5.50mmol) in dry chloroform (3mL) was added. The reaction mixture was stirred at 0 ℃ for 20 minutes, after which time a solution of methyl 6- ((trans) -4-aminocyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 125(300mg, 0.53mmol) in chloroform (2mL) was added. After stirring at 0 ℃ for 30 min, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound (55mg, 16% yield) as a yellow solid.¹H NMR(400MHz,CDCl₃)δ8.13(s,0.4H),7.83-7.82(m,1H),7.51(d,J＝2.8Hz,0.5H),7.45(d,J＝2.8Hz,0.5H),7.40(br s,0.6H),7.29-7.28(m,1H),7.15-7.11(m,1H),6.96-6.88(m,1H),6.18(s,0.4H),6.04(d,J＝2.8Hz,0.6H),3.98-3.92(m,0.5H),3.84-3.81(m,1H),3.75-3.70(m,0.5H),3.60(s,1.6H),3.59(s,1.4H),3.41-3.31(m,1H),3.01(s,1.6H),3.00(s,1.4H),2.32-2.19(m,1.5H),2.15-2.11(m,1H),2.09-1.97(m,1.5H),1.91-1.84(m,0.7H),1.78-1.62(m,1.3H),1.55-1.35(m,2H),0.93(s,5H),0.92(s,4H),0.14-0.12(m,6H)。

Compound 287: methyl 4- (2-chloro-4-fluorophenyl) -6- ((trans) -4- (methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- ((trans) -4- (N' - (tert-butyldimethylsilyl) methylsulfinamido) cyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 286(50mg, 0.080mmol) in methanol (2mL) at room temperature was added 2M aqueous hydrochloride solution (1 mL). After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in water (10 mL). The mixture was adjusted to pH 9-10 with 28% ammonia solution (1mL) and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: xbridge C18 HILIC (5 μm 10 × 190mm) mobile phase a: water, mobile phase B: acetonitrile, UV: 214nm, flow rate: 50mL/min, gradient: 20% -95% (% B)) to give the title compound 287 as a yellow solid (25.0mg, 74% yield). LC-MS (ESI): r_T＝3.364min，C₂₂H₂₅ClFN₅O₃S₂Calculated mass of 525.1, M/z found value 526.2[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.14(s,0.4H),7.83-7.82(m,1H),7.52(d,J＝3.2Hz,0.6H),7.46(d,J＝3.2Hz,0.4H),7.43(br s,0.6H),7.30-7.25(m,1H),7.15-7.12(m,1H),6.95-6.88(m,1H),6.18(s,0.4H),6.04(d,J＝2.8Hz,0.6H),4.00-3.94(m,0.4H),3.76-3.71(m,0.6H),3.60(s,1.6H),3.59(s,1.4H),3.43-3.38(m,1H),3.10(s,1.6H),3.09(s,1.4H),2.23-2.09(m,2H),2.05-1.80(m,2H),1.74-1.55(m,2H),1.48-1.41(m,2H)。

A racemic mixture of compound 287 (220mg, 0.344mmol) was separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.3 at 12mL/min, temperature: 30 ℃; wavelength: 230nm) to give group 1(70mg) and group 2(30 mg).

Group 1(70mg, 0.13mmol) was separated by chiral preparative HPLC (column: Chiralpak AD-H5 μm20 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 15mL/min, temperature: 30 ℃; wavelength: 214nm) to give the title compounds 287A (20.4mg, 29% yield, 100% ee) and 287B (19.2mg, 27% yield, 100% ee) as yellow solids. Group 2(30mg, 0.060mmol) was separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.3, at 10mL/min, temperature: 30 ℃ C; wavelength: 230nm) to give the title compounds 287C (11.0mg, 37% yield, 100% ee) and 287D (9.8mg, 33% yield, 97.2% ee) as yellow solids.

Compound 287A: LC-MS (ESI): r_T＝2.522min，C₂₂H₂₅ClFN₅O₃S₂Calculated mass of 525.1, M/z found value 525.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; time: 0.2; time: 0.C; time: 1.0mL/min_T＝10.044min)。¹H NMR(400MHz,CDCl₃)δ8.13(s,0.4H),7.83-7.82(m,1H),7.51(d,J＝2.8Hz,0.6H),7.45(d,J＝3.2Hz,0.4H),7.41(d,J＝1.6Hz,0.6H),7.29-7.27(m,0.7H),7.26-7.25(m,0.3H),7.15-7.11(m,1H),6.96-6.88(m,1H),6.18(s,0.4H),6.04(d,J＝2.8Hz,0.6H),4.01-3.94(m,0.4H),3.76-3.71(m,0.6H),3.60(s,1.6H),3.59(s,1.4H),3.43-3.38(m,1H),3.10(s,1.6H),3.09(s,1.4H),2.23-2.16(m,2H),2.09-1.97(m,2H),1.96-1.69(m,2H),1.62-1.35(m,2H)。

Compound 287B: LC-MS (ESI): r_T＝2.876min，C₂₂H₂₅ClFN₅O₃S₂Calculated mass of 525.1, M/z found value 525.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; time: 0.2; time: 0.C; time: 1.0mL/min_T＝10.327min)。¹H NMR(400MHz,CDCl₃)δ8.13(s,0.4H),7.83-7.82(m,1H),7.51(d,J＝2.8Hz,0.6H),7.45(d,J＝3.6Hz,0.4H),7.41(br s,0.6H),7.29-7.28(m,0.6H),7.26-7.25(m,0.4H),7.15-7.11(m,1H),6.95-6.88(m,1H),6.18(s,0.4H),6.04(d,J＝2.4Hz,0.6H),4.01-3.95(m,0.4H),3.76-3.72(m,0.6H),3.60(s,1.6H),3.59(s,1.4H),3.43-3.38(m,1H),3.10(s,1.6H),3.09(s,1.4H),2.26-2.09(m,2.3H),2.05-1.96(m,1.7H),1.93-1.86(m,0.9H),1.78-1.66(m,1.1H),1.55-1.37(m,2H)。

Compound 287C: LC-MS (ESI): r_T＝2.556min，C₂₂H₂₅ClFN₅O₃S₂Calculated mass of 525.1, found value of M/z 526.1[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; time: 0.2; time: 0.C; time: 1.0mL/min_T＝13.442min)。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝3.6Hz,0.5H),7.88(d,J＝3.2Hz,0.5H),7.75-7.73(m,1H),7.39-7.35(m,1H),7.24-7.20(m,1H),7.07-7.00(m,1H),6.13(s,0.5H),6.05(s,0.5H),3.96-3.89(m,0.5H),3.72-3.66(m,0.5H),3.58(s,3H),3.40-3.31(m,1H),3.04(s,3H),2.19-2.13(m,2H),2.03-1.99(m,1H),1.92-1.87(m,1.5H),1.80-1.77(m,0.8H),1.73-1.67(m,0.7H),1.51-1.42(m,2H)。

Compound 287D: LC-MS (ESI): r_T＝2.558min，C₂₂H₂₅ClFN₅O₃S₂Calculated mass of 525.1, M/z found value 526.2[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; time: 0.2; time: 0.C; time: 1.0mL/min_T＝15.164min)。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝2.8Hz,0.5H),7.88(d,J＝3.2Hz,0.5H),7.75-7.73(m,1H),7.39-7.35(m,1H),7.24-7.20(m,1H),7.07-7.00(m,1H),6.13(s,0.5H),6.05(s,0.5H),3.96-3.90(m,0.5H),3.71-3.65(m,0.5H),3.59(s,3H),3.40-3.35(m,0.7H),3.30-3.27(m,0.3H),3.04(s,3H),2.21-2.11(m,2H),2.08-1.96(m,1H),1.93-1.86(m,1.5H),1.83-1.77(m,0.8H),1.72-1.67(m,0.7H),1.53-1.41(m,2H)。

Compound 291: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (2-hydroxyethyl) sulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (2-ethoxy-2-oxoethyl) sulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 290S (308mg, 0.500mmol) in tetrahydrofuran (20mL) was added lithium borohydride (33mg, 1.50mmol) at 0 ℃. After stirring at 25 ℃ for 6 hours under a nitrogen atmosphere, the mixture was diluted with ethyl acetate (200mL) and brine (100 mL). Separating the organic layer over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1 to 2:1) to give the title compound (140mg, 78% yield) as a pale yellow solid. LC-MS (ESI): r_T＝3.357min，C₂₃H₂₅ClF₂N₄O₅S₂Calculated mass of 574.1, M/z found value 575.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝3.2Hz,0.6H),8.98(s,0.4H),8.00-7.99(m,1.6H),7.95-7.94(m,0.4H),7.49-7.41(m,1H),7.21-7.14(m,1H),7.06(t,J＝6.0Hz,0.4H),6.98(t,J＝6.0Hz,0.6H),6.01(s,0.4H),5.92(d,J＝3.6Hz,0.6H),4.77-4.71(m,1H),3.89-3.81(m,0.4H),3.61-3.56(m,0.6H),3.53(s,1.8H),3.52(s,1.2H),3.48-3.42(m,2H),3.19-3.13(m,0.4H),3.06-3.00(m,2.6H),2.21-2.14(m,2H),1.99-1.94(m,1H),1.87-1.77(m,2H),1.73-1.69(m,1H),1.55-1.45(m,2H)。

The racemic mixture of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (2-hydroxyethyl) sulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 291 (140mg, 0.243mmol) was separated by chiral preparative SFC (separation conditions: column: Chiralpak IA 5 μm20 × 250 mm; mobile phase: CO:. sup.₂MeOH 70:30 at 45 g/min; column temperature: 40.2 ℃; wavelength: 214nm, back pressure: 100 bar) to yield the title compound 291C (43.2mg, 20% yield, 98.3% stereopurity) and 291D (38.5mg, 18% yield, 94.4% stereopurity) as yellow solids.

Compound 291C: LC-MS (ESI): r_T＝4.541min，C₂₃H₂₅ClF₂N₄O₅S₂Calculated mass of 574.1, M/z found value 575.0[ M + H ]]⁺. Chiral moietyAnalysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 2.999 g/min; column temperature: 40.2 ℃; wavelength: 214nm, back pressure: 100 bar, R_T＝3.96min)。¹H NMR(400MHz,DMSO-d₆)δ9.57(br s,0.6H),8.98(br s,0.4H),8.00-7.99(m,1.6H),7.95(d,J＝3.2Hz,0.4H),7.49-7.41(m,1H),7.21-7.15(m,1H),7.06(t,J＝6.0Hz,0.4H),6.98(t,J＝6.0Hz,0.6H),6.01(s,0.4H),5.92(s,0.6H),4.77-4.71(m,1H),3.89-3.82(m,0.4H),3.60-3.56(m,0.6H),3.53(s,1.8H),3.52(s,1.2H),3.48-3.42(m,2H),3.19-3.13(m,0.4H),3.06-2.99(m,2.6H),2.22-2.14(m,2H),1.99-1.94(m,1H),1.87-1.81(m,2H),1.73-1.70(m,1H),1.53-1.45(m,2H)。

Compound 291D: LC-MS (ESI): r_T＝4.535min，C₂₃H₂₅ClF₂N₄O₅S₂Calculated mass of 574.1, M/z found value 575.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 2.999 g/min; column temperature: 40.1 ℃; wavelength: 214nm, back pressure: 100 bar, R_T＝4.82min)。¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝4.0Hz,0.6H),8.98(br s,0.4H),8.00-7.99(m,1.6H),7.94(d,J＝3.2Hz,0.4H),7.49-7.41(m,1H),7.21-7.14(m,1H),7.06(d,J＝6.0Hz,0.4H),6.98(d,J＝6.0Hz,0.6H),6.01(s,0.4H),5.92(d,J＝3.2Hz,0.6H),4.77-4.71(m,1H),3.89-3.82(m,0.4H),3.61-3.58(m,0.6H),3.53(s,1.8H),3.52(s,1.2H),3.48-3.43(m,2H),3.19-3.13(m,0.4H),3.06-2.99(m,2.6H),2.21-2.14(m,2H),1.99-1.94(m,1H),1.88-1.78(m,2H),1.73-1.70(m,1H),1.55-1.43(m,2H)。

Compound 295: methyl 4- (2-chloro-4-fluorophenyl) -6- (3-hydroxycyclobutyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (3- ((tert-butyldiphenylsilyl) oxy) cyclobutyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 294(100mg, 0.15mmol) in tetrahydrofuran (5mL) at 0 deg.C was added1M tetrabutylammonium fluoride in tetrahydrofuran (0.17mL, 0.17 mmol). After stirring at room temperature for 16 h, the mixture was diluted with ethyl acetate (50mL), washed with water (50mL) and brine (50mL), and washed with Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by C18 column (acetonitrile: water (+ 0.1% ammonium bicarbonate) ═ 35% to 65%) to give the title compound as a yellow solid (33.2mg, 52% yield). LC-MS (ESI): r_T＝3.828min，C₁₉H₁₇ClFN₃O₃Calculated mass of S421.1, found value of M/z 422.0[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.50-9.46(m,0.6H),8.99(m,0.4H),8.02-8.00(m,1.6H),7.96-7.95(m,0.4H),7.43-7.39(m,1H),7.33-7.29(m,1H),7.24-7.17(m,1H),6.00(s,0.4H),5.90-5.89(m,0.5H),5.42-5.40(m,0.4H),5.07-5.05(m,0.5H),4.98-4.97(m,0.1H),4.56-4.51(m,0.1H),4.26-4.22(m,0.1H),4.12-3.98(m,1.2H),3.78-3.69(m,0.6H),3.51(s,3H),2.67-2.61(m,0.5H),2.42-2.36(m,0.7H),2.29-2.22(m,2H),2.08-1.93(m,0.8H)。

Compound 303: methyl 6- (1-carbamoylpiperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 99(100mg, 0.230mmol) in dichloromethane (2mL) was added isocyanatotrimethylsilane (200mg, 1.80mmol) at room temperature under a nitrogen atmosphere. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Gilson X-bridge C18(5 μm 19X 150mm), mobile phase A: water (+ 0.1% trifluoroacetic acid), mobile phase B: acetonitrile, UV: 214nm, flow rate: 20mL/min, gradient: 40% -60% (% B)) to give the title compound as a yellow solid (30mg, 27% yield). LC-MS (ESI): r_T＝4.233min，C₂₁H₂₁ClFN₅O₃Calculated mass of S477.1, M/z found value 478.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.47(d,J＝3.2Hz,0.7H),9.10(s,0.3H),8.00-7.98(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.44-7.31(m,2H),7.24-7.17(m,1H),6.01-5.91(m,3H),4.16-3.98(m,2.3H),3.79-3.72(m,0.7H),3.53(s,2H),3.52(s,1H),2.76-2.64(m,2H),1.96-1.59(m,3.3H),1.49-1.46(m,0.7H)。

Compound 305: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((2,3-di hydroxypropyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To methyl 6- (1- ((1, 4-dioxaspiro [4.5 ]) at 0 deg.C]Decan-2-ylmethyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 304A (45mg, 0.070mmol) was added dropwise to a solution of trifluoroacetic acid (1mL) in dichloromethane (2 mL). After stirring at room temperature for 1 hour, the mixture was washed three times with saturated aqueous sodium bicarbonate solution (10mL), and then with water (10 mL). The separated organic layer was concentrated under reduced pressure to give a residue which was purified by C18 column (acetonitrile: water (0.1% ammonium bicarbonate) ═ 5% to 80%) to give the title compound 305A as a yellow solid (10mg, 25% yield, 100% stereopure). LC-MS (ESI): r_T＝3.984min，C₂₃H₂₆ClFN₄O₆S₂Calculated mass of 572.1, M/z found value 573.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R); C; (R);)_T＝12.191min)。¹H NMR(400MHz,DMSO-d₆)δ9.56(s,0.8H),9.19(s,0.2H),8.04-7.98(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.46-7.40(m,1H),7.38-7.31(m,1H),7.25-7.18(m,1H),6.02(s,0.2H),5.92(s,0.8H),5.16-5.12(m,1H),4.88-4.82(m,1H),3.98-3.86(m,1.2H),3.77-3.64(m,2.8H),3.55(s,2.1H),3.53(s,0.9H),3.43-3.38(m,1H),3.32-3.20(m,2H),3.06-2.82(m,3H),2.16-2.07(m,0.2H),2.05-1.92(m,1H),1.90-1.73(m,2H),1.66-1.59(m,0.8H)。

Similar conditions were used to convert compound 304B to compound 305B.

Compound 305B: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((2, 3-dihydropropyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate, LC-ms (esi): r_T＝3.640min，C₂₃H₂₆ClFN₄O₆S₂Calculated mass of 572.1, M/z found value 573.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R); C; (R);)_T＝15.002min)。¹H NMR(400MHz,DMSO-d₆)δ9.53(s,0.8H),9.16(s,0.2H),8.04-7.96(m,1.8H),7.95-7.91(m,0.2H),7.46-7.40(m,1H),7.38-7.30(m,1H),7.25-7.16(m,1H),6.02(s,0.2H),5.92(d,J＝3.2Hz,0.8H),5.12(br s,1H),4.83(br s,1H),3.99-3.86(m,1.2H),3.79-3.61(m,2.8H),3.53(s,3H),3.44-3.39(m,1H),3.29-3.21(m,2H),3.07-2.93(m,2H),2.88-2.77(m,1H),2.17-2.06(m,0.2H),2.04-1.93(m,1H),1.90-1.73(m,2H),1.67-1.58(m,0.8H)。

Compound 315: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (2-hydroxyethyl) methylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 6- (4- (N- (2- ((tert-butyldimethylsilyl) oxy) ethyl) methylsulfonamido) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 314(200mg, 0.280mmol) in dry tetrahydrofuran (10mL) at 0 ℃ under a nitrogen atmosphere was added 1M tetrabutylammonium fluoride in tetrahydrofuran (1mL, 1.0 mmol). After stirring at room temperature for 1 hour, the mixture was quenched with water (20mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by C18 column (acetonitrile: water 45% to 60%) to give the title compound as a yellow solid (150mg, 90% yield). LC-MS (ESI)：R_T＝3.550min，C₂₄H₂₇ClF₂N₄O₅S₂Calculated mass of 588.1, M/z found value 588.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.16(s,0.5H),7.83(d,J＝3.2Hz,1H),7.53(d,J＝3.2Hz,0.5H),7.46(d,J＝2.8Hz,0.5H),7.40(s,0.5H),7.07-6.99(m,2H),6.17(s,0.5H),6.04(d,J＝2.8Hz,0.5H),3.99-3.94(m,0.5H),3.89-3.85(m,1H),3.83-3.78(m,2H),3.75-3.69(m,0.5H),3.60(s,1.5H),3.59(s,1.5H),3.41-3.37(m,2H),2.97(s,3H),2.35(t,J＝5.6Hz,0.5H),2.26-2.24(m,0.5H),2.16-1.84(m,5H),1.78-1.61(m,3H)。

Racemic compound 315(150mg, 0.230mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA 5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 70:30, at 25 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 315C (13.8mg, 9% yield, 100% stereopurity) and 315D (11.1mg, 7% yield, 99.0% stereopurity) as yellow solids.

Compound 315C: LC-MS (ESI): r_T＝3.302min，C₂₄H₂₇ClF₂N₄O₅S₂Calculated mass of 588.1, M/z found value 589.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.533min)。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.5H),7.83(d,J＝2.8Hz,1H),7.53(d,J＝2.8Hz,0.5H),7.46(d,J＝2.8Hz,0.5H),7.40(s,0.5H),7.07-6.98(m,2H),6.17(s,0.5H),6.04(d,J＝2.4Hz,0.5H),4.00-3.94(m,0.5H),3.87-3.69(m,3.5H),3.60(s,1.5H),3.59(s,1.5H),3.40-3.37(m,2H),2.97(s,3H),2.37(d,J＝6.0Hz,0.5H),2.30-2.27(m,0.5H),2.15-1.87(m,5H),1.80-1.64(m,3H)。

Compound 315D: LC-MS (ESI): r_T＝4.127min，C₂₄H₂₇ClF₂N₄O₅S₂Calculated mass of 588.1, M/z found value 589.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝8.328min)。¹H NMR(400MHz,CDCl₃)δ8.16(s,0.5H),7.83(d,J＝2.8Hz,1H),7.53(d,J＝3.2Hz,0.5H),7.46(d,J＝2.8Hz,0.5H),7.40(s,0.5H),7.06-6.98(m,2H),6.17(s,0.5H),6.04(d,J＝3.2Hz,0.5H),3.99-3.94(m,0.5H),3.88-3.70(m,3.5H),3.60(s,1.5H),3.59(s,1.5H),3.40-3.37(m,2H),2.97(s,3H),2.36(d,J＝6.0Hz,0.5H),2.29-2.25(m,0.5H),2.16-1.93(m,4.5H),1.80-1.64(m,3.5H)。

Compound 325: methyl 4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -6- (1- ((1- (3,3, 3-trifluoro-2-hydroxypropyl) -1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (1- ((1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 324(80mg, 0.14mmol) and 2- (trifluoromethyl) ethylene oxide (18mg, 0.17mmol) in acetonitrile (2mL) was added cesium carbonate (22mg, 0.069 mmol). After stirring at room temperature under a nitrogen atmosphere for 5 hours, the mixture was quenched by addition of water (20mL) and then extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with water (15mL), brine (15mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: gilson X-bridge C18(5 μm 19X 150mm) mobile phase a: water (+ 0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 70% -80% (% B)) to give the title compound as a yellow solid (36mg, 99.3% purity, 38% yield). LC-MS (ESI): r_T＝3.915min，C₂₆H₂₄ClF₅N₆O₅S₂Calculated mass of 694.1, M/z found value 695.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.65(d,J＝3.2Hz,0.8H),9.25(s,0.2H),8.43(s,0.2H),8.41(s,0.8H),8.05-7.99(m,1.8H),7.94(d,J＝3.2Hz,0.2H),7.91(s,0.2H),7.90(s,0.8H),7.49-7.39(m,1H),7.23-7.12(m,1H),6.80(d,J＝6.4Hz,1H),6.01(s,0.2H),5.91(d,J＝3.2Hz,0.8H),4.57-4.45(m,2H),4.41-4.32(m,1H),3.80-3.64(m,2.2H),3.58-3.50(m,0.8H),3.48(s,2.4H),3.47(s,0.6H),2.21-2.16(m,2.2H),2.12-2.01(m,1H),1.98-1.85(m,1H),1.84-1.75(m,1H),1.69-1.61(m,0.8H)。

Compound 335: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3-hydroxycyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (1- ((3- ((tert-butyldiphenylsilyl) oxy) cyclobutyl) -sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 334(260mg, 0.320mmol) in tetrahydrofuran (5mL) at 0 ℃ was added 1M tetrabutylammonium fluoride in tetrahydrofuran (1mL, 1.0 mmol). After stirring at room temperature for 2 hours, the mixture was diluted in ethyl acetate (150mL), washed with water (50mL) and brine (50mL), and washed with Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by C18 column (acetonitrile: water (0.1% ammonium bicarbonate) ═ 5% to 80%) to give the title compound (200mg, purity 90%, 99% yield) as a yellow solid. LC-MS (ESI): r_T＝1.61min，C₂₄H₂₆ClFN₄O₅S₂Calculated mass of (568.1), M/z found value 569.3[ M + H [ ]]⁺。

Rac 335(200mg, 90% purity, 0.316mmol) was separated by chiral preparative HPLC (column: Chiralpak IC5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 335A (cis isomer) (55.0mg, 31% yield, 100% stereopurity) and 335B (50.0mg, 28% yield, 100% stereopurity) as a yellow solid.

Compound 335A (cis isomer): LC-MS (ESI): r_T＝4.005min，C₂₄H₂₆ClFN₄O₅S₂Calculated mass of (568.1), M/z found value 569.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: hex EtOH DEA 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝7.531min)。¹H NMR(400MHz,DMSO-d₆)δ9.49(br s,0.8H),9.12(br s,0.2H),8.00-7.99(m,1.8H),7.93-7.92(m,0.2H),7.43-7.40(m,1H),7.38-7.31(m,1H),7.23-7.18(m,1H),6.05(s,0.2H),5.92(s,0.8H),5.37-5.34(m,1H),4.38-4.30(m,1H),3.96-3.94(m,0.2H),3.92-3.85(m,1H),3.78-3.68(m,2.8H),3.53(s,2.4H),3.52(s,0.6H),2.89-2.80(m,2H),2.60-2.54(m,2H),2.31-2.24(m,2H),2.07-2.04(m,0.2H),2.00-1.74(m,3H),1.61-1.57(m,0.8H)。

Compound 335B (trans isomer): LC-MS (ESI): r_T＝3.920min，C₂₄H₂₆ClFN₄O₅S₂Calculated mass of (568.1), M/z found value 569.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IC5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IC5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA ═ 60:40: 0.2; temperature: 230 ℃; wavelength: 230_T＝10.464min)。¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝3.2Hz,0.8H),9.14(s,0.2H),8.02-7.99(m,1.8H),7.93-7.92(m,0.2H),7.44-7.41(m,1H),7.38-7.31(m,1H),7.23-7.17(m,1H),6.01(s,0.2H),5.92(d,J＝3.6Hz,0.8H),5.46-5.44(m,1H),4.07-3.98(m,1H),3.94-3.90(m,0.2H),3.75-3.65(m,2.8H),3.53(s,2.4H),3.52(s,0.6H),3.50-3.43(m,1H),2.86-2.76(m,2H),2.59-2.51(m,2H),2.18-2.14(m,2H),2.11-1.75(m,3.2H),1.62-1.59(m,0.8H)。

Compound 348: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (1-hydroxyethyl) bicyclo [1.1.1] pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 348 — 1: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (methoxy (methyl) carbamoyl) bicyclo [1.1.1] pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To 3- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) bicyclo [1.1.1] at room temperature]Pentane-1-carboxylic acid 258(380mg, 90% purity, 0.74)0mmol), 1-hydroxybenzotriazole (150mg, 1.11mmol) and N- ((ethylimino) methylene) -N, N-dimethylpropane-1, 3-diamine hydrochloride (213mg, 1.11mmol) to a solution in N, N-dimethylformamide (10mL) were added ethyldiisopropylamine (287mg, 2.22mmol) and N, O-dimethylhydroxylamine hydrochloride (108mg, 1.11 mmol). After stirring at room temperature overnight, the mixture was quenched with water (40mL) and extracted three times with ethyl acetate (40 mL). The combined organic layers were washed with 1M aqueous hydrochloric acid (30mL), water (30mL), brine (30mL), and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (340mg, according to¹Purity of H NMR 90%, 82% yield). LC-MS (ESI): r_T＝1.54min，C₂₃H₂₂ClFN₄O₄Calculated mass of S504.1, M/z found 505.5[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.90(s,0.7H),7.82(d,J＝3.2Hz,1H),7.49-7.40(m,1.3H),7.30-7.28(m,1H),7.14-7.11(m,1H),6.97-6.89(m,1H),6.16(s,0.7H),6.04(s,0.3H),3.73(s,3H),3.61(s,3H),3.23(s,3H),2.61(s,6H)。

Compound 348_ 2: methyl 6- (3-acetylbicyclo [1.1.1] pent-1-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (methoxy (methyl) carbamoyl) bicyclo [1.1.1] at 0 deg.C]Pentan-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 348-1 (340mg, 90% purity, 0.606mmol) in tetrahydrofuran (8mL) was added 2M methylmagnesium bromide in tetrahydrofuran (1.5mL, 3.00mmol) dropwise. After stirring at 0 ℃ for 3 hours, the mixture was quenched with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by C18 column (acetonitrile: water ═ 60% to 90%) to give the title compound (185mg, according to the formula: r) as a yellow solid¹Purity of H NMR 90%, 60% yield). LC-MS (ESI): r_T＝1.61min，C₂₂H₁₉ClFN₃O₃Calculated mass of S459.1, found value of m/z 460.4[M+H]⁺。¹H NMR(400MHz,CDCl₃)δ7.89(s,0.7H),7.83-7.81(m,1H),7.50(d,J＝3.2Hz,0.4H),7.45(d,J＝3.2Hz,0.6H),7.42(s,0.3H),7.31-7.28(m,1H),7.15-7.12(m,1H),6.98-6.90(m,1H),6.17(s,0.6H),6.03(d,J＝2.8Hz,0.4H),3.64(s,1.1H),3.61(s,1.9H),2.54(s,3.8H),2.48(s,2.2H),2.20(s,3H)。

Rac 348-2 (180mg, 90% purity, 0.352mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IG5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 85:15:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 348-2A (78mg, according to standard: 230nm) as a yellow solid¹H NMR purity 90%, 43% yield, 100% stereopure) and 348-2B (76mg, according to¹H NMR purity 90%, 42% yield, 100% stereopure).

Compound 348_ 2A: LC-MS (ESI): r _T＝1.58min，C₂₂H₁₉ClFN₃O₃Calculated mass of S459.1, M/z found 460.4[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IG 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 85:15: 0.2; temperature: 230 ℃; wavelength_T＝10.906min)。¹H NMR(400MHz,DMSO-d₆)δ9.44(d,J＝3.2Hz,0.6H),8.34(s,0.4H),8.01-7.99(m,1.6H),7.96-7.95(m,0.4H),7.46-7.41(m,1H),7.35-7.31(m,1H),7.25-7.20(m,1H),5.98(s,0.4H),5.88(d,J＝2.8Hz,0.6H),3.56(s,1.8H),3.55(s,1.2H),2.45(s,2.5H),2.30(s,3.5H),2.15(s,1.2H),2.13(s,1.8H)。

Compound 348_ 2B: LC-MS (ESI): r_T＝1.58min，C₂₂H₁₉ClFN₃O₃Calculated mass of S459.1, M/z found value 460.3[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak IG 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 85:15: 0.2; temperature: 230 ℃; wavelength_T＝12.902min)。¹H NMR(400MHz,DMSO-d₆)δ9.44(d,J＝3.2Hz,0.6H),8.34(s,0.4H),8.01-7.99(m,1.6H),7.96-7.95(m,0.4H),7.45-7.40(m,1H),7.35-7.31(m,1H),7.25-7.19(m,1H),5.98(s,0.4H),5.88(d,J＝3.6Hz,0.6H),3.56(s,1.8H),3.55(s,1.2H),2.45(s,2.5H),2.30(s,3.5H),2.15(s,1.3H),2.13(s,1.7H)。

Compound 348B: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (1-hydroxyethyl) bicyclo [1.1.1] pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To methyl 6- (3-acetylbicyclo [1.1.1] at 0 deg.C]Pent-1-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 348-2B (70mg, 90% purity, 0.14mmol) to a solution in methanol (0.8mL) and tetrahydrofuran (1.6mL) was added sodium borohydride (11mg, 0.27 mmol). The reaction mixture was stirred at 0 ℃ for 2 hours. Water (10mL) was slowly added to the mixture, which was concentrated to give a residue, which was extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: water X-bridge C18(5 μm 19X 150mm), mobile phase a: water (+ 0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 30% -95% (% B)) to give the title compound as a yellow solid (20mg, 99.2% purity, 31% yield). LC-MS (ESI): r_T＝3.347min，C₂₂H₂₁ClFN₃O₃Calculated mass of S461.1, found value of M/z 462.1[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ7.92(s,0.8H),7.82-7.80(m,1H),7.48(d,J＝3.2Hz,0.2H),7.44(d,J＝3.2Hz,0.8H),7.40(s,0.2H),7.33-7.28(m,1H),7.14-7.11(m,1H),6.97-6.89(m,1H),6.16(s,0.8H),6.01(d,J＝2.8Hz,0.2H),3.95-3.87(m,1H),3.63(s,0.5H),3.60(s,2.5H),2.24-2.09(m,6H),1.34(d,J＝3.2Hz,1H),1.19(d,J＝6.4Hz,3H)。

Compound 356: ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((2-hydroxyethyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((2-methoxy-2-oxoethyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) at 0 ℃ under a nitrogen atmosphere) To a solution of 355(320mg, 99% pure, 0.525mmol) of (E) -1, 4-dihydropyrimidine-5-carboxylate in tetrahydrofuran (5mL) was added lithium tetrahydroborate (70mg, 96% pure, 3.1 mmol). After stirring at room temperature for 30 minutes, the reaction mixture was slowly quenched with saturated aqueous sodium bicarbonate (20mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO_4(s)Drying, filtration and concentration under reduced pressure gave a residue which was purified by silica gel column chromatography (dichloromethane: methanol 200:1 to 100:1) to give the title compound (250mg, purity 99.7%, 80% yield) as a yellow solid. LC-MS (ESI): r_T＝3.809min，C₂₃H₂₅ClF₂N₄O₅S₂Calculated mass of 574.1, M/z found value 574.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.62(br s,0.8H),9.16(br s,0.2H),8.06-7.97(m,1.8H),7.95-7.92(m,0.2H),7.49-7.43(m,1H),7.23-7.17(m,1H),6.03(s,0.2H),5.94(s,0.8H),5.34-5.31(m,0.1H),5.06-5.02(m,0.9H),3.98(q,J＝6.8Hz,2H),3.79-3.65(m,5H),3.24-3.19(m,2H),2.92-2.83(m,2H),2.16-2.08(m,0.2H),2.03-1.94(m,1H),1.87-1.78(m,2H),1.68-1.59(m,0.8H),1.09-1.03(m,3H)。

Rac 356(240mg, 0.405mmol) was separated by chiral preparative HPLC (column: Chiralpak ID 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 356A (80mg, 99.9% purity, 34% yield, 100% stereopurity) and 356B (65mg, 99.0% purity, 28% yield, 98.1% stereopurity) as yellow solids.

Compound 356A: LC-MS (ESI): r_T＝3.846min，C₂₃H₂₅ClF₂N₄O₅S₂Calculated mass of 574.1, M/z found value 574.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak ID 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 70:30: 0.2; temperature: 30 ℃; wavelength: 230nm_T＝9.363min)。¹H NMR(400MHz,DMSO-d₆)δ9.40(br s,1H),8.00-7.96(m,2H),7.48-7.42(m,1H),7.26-7.19(m,1H),5.96(s,1H),5.02(br s,1H),3.97(q,J＝7.2Hz,2H),3.79-3.67(m,5H),3.21(t,J＝6.4Hz,2H),2.92-2.84(m,2H),2.05-1.97(m,1H),1.88-1.79(m,2H),1.71-1.62(m,1H),1.07(t,J＝7.2Hz,3H)。

Compound 356B: LC-MS (ESI): r_T＝3.847min，C₂₃H₂₅ClF₂N₄O₅S₂Calculated mass of 574.1, M/z found value 574.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak ID 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 70:30: 0.2; temperature: 30 ℃; wavelength: 230nm_T＝11.939min)。¹H NMR(400MHz,DMSO-d₆)δ8.74(br s,1H),8.04-7.94(m,2H),7.49-7.42(m,1H),7.22-7.17(m,1H),5.96(s,1H),5.03(br s,1H),3.97(q,J＝6.8Hz,2H),3.77-3.67(m,5H),3.21(t,J＝6.0Hz,2H),2.92-2.84(m,2H),2.04-1.96(m,1H),1.87-1.79(m,2H),1.69-1.62(m,1H),1.07(t,J＝6.8Hz,3H)。

Compound 357A: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3- (hydroxymethyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 6- (1- ((3- (tert-butoxycarbonyl) cyclobutyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 242A (210mg, 0.322mmol) in tetrahydrofuran (15mL) was added lithium borohydride (21mg, 0.966mmol) at 0 ℃. After stirring at room temperature for 6 hours, the mixture was quenched with water (40mL) at 0 ℃, concentrated under reduced pressure, and extracted twice with ethyl acetate (40 mL). The combined organic layers were passed over Na₂SO_4(s)Drying and concentration gave a residue which was purified by C18 column (acetonitrile: water 50% to 58%) to give the title compound as a yellow solid (50mg, 22% yield, 99.9% stereopure). LC-MS (ESI): r_T＝3.848min，C₂₅H₂₈ClFN₄O₅S₂Calculated mass of 582.1, M/z found value 582.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG 5 μ M4.6 x 250 mm; mobile phase: CO2: MeOH at 2.999g/min 70: 30; column temperature: 39.9 ℃; wavelength: 230nm, back pressure: 100 bar, R_T＝3.79min)。¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝3.6Hz,0.8H),9.12(s,0.2H),8.01-7.93(m,2H),7.45-7.41(m,1H),7.38-7.31(m,1H),7.23-7.18(m,1H),6.01(s,0.2H),5.92(d,J＝3.2Hz,0.8H),4.66(t,J＝4.8Hz,1H),4.03-3.95(m,1H),3.76-3.69(m,3H),3.53(s,2.4H),3.52(s,0.6H),3.47(s,2H),2.87-2.79(m,2H),2.40-2.33(m,3H),2.14-1.74(m,5.2H),1.61-1.58(m,0.8H)。

Compound 357B: (cis) -methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3- (hydroxymethyl) cyclobutyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 357B was prepared similarly to compound 357A from compound 242B, LC-ms (esi): r_T＝3.635min，C₂₅H₂₈ClFN₄O₅S₂Calculated mass of 582.1, M/z found value 583.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG 5 μm4.6 x 250 mm; mobile phase: CO2: MeOH 70:30 at 2.999 g/min; column temperature: 39.9 ℃ C.; wavelength: 230nm, back pressure: 100 bar, R: 100 bar; chiral analysis: Chiralpak IG 5 μm 4.6: 250 mm; mobile phase: CO2: MeOH: 70: 30; column temperature: 39.9 ℃ C.; wavelength_T＝3.79min)。¹H NMR(400MHz,DMSO-d₆)δ8.01-7.93(m,2H),7.45-7.31(m,2H),7.24-7.18(m,1H),6.01(s,0.2H),5.92(s,0.8H),4.61(t,J＝5.6Hz,1H),3.95-3.86(m,1.2H),3.77-3.66(m,2.8H),3.53(s,2.4H),3.52(s,0.6H),3.40-3.35(m,2H),2.87-2.79(m,2H),2.42-2.25(m,3H),2.12-1.74(m,5H),1.62-1.57(m,1H)。

Compound 358B: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (3-hydroxy-3-methylbutyl) sulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (3-methoxy-3-oxopropyl) sulfamoyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 252Y (60mg, 97.2 μmol) in tetrahydrofuran (4mL) was added 3.0M methylmagnesium chloride in tetrahydrofuran (1.6mL, 4.8mmol) dropwise at-78 ℃.After stirring at room temperature overnight, the reaction mixture was quenched with saturated aqueous ammonium chloride (20mL) and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (dichloromethane: methanol 20:1) to give an impure compound which was further purified by preparative HPLC (column: X-bridge C18(5 μm 19X 150mm), mobile phase a: water (+ 0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 45% -70% (% B)) to give the title compound as a yellow solid (25mg, 36% yield, 99.0% stereopurity). LC-MS (ESI): r_T＝3.690min，C₂₆H₃₁ClF₂N₄O₅S₂Calculated mass of 616.1, M/z found value 617.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of chiral molecules: 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: 50: 0.2; temperature: 230 ℃_T＝9.331min)。¹H NMR(400MHz,DMSO-d₆)δ9.55(d,J＝2.8Hz,0.6H),8.98(br s,0.4H),8.07-7.98(m,1.6H),7.94(d,J＝2.8Hz,0.4H),7.48-7.41(m,1H),7.21-7.15(m,1H),6.92(t,J＝6.4Hz,0.4H),6.85(t,J＝5.6Hz,0.6H),6.01(s,0.4H),5.92(d,J＝3.2Hz,0.6H),4.34(s,0.4H),4.32(s,0.6H),3.90-3.82(m,0.4H),3.62-3.58(m,0.6H),3.53(s,1.8H),3.52(s,1.2H),3.18-3.12(m,0.5H),3.08-3.04(m,2H),2.99-2.95(m,0.5H),2.22-2.12(m,2H),2.01-1.82(m,3H),1.75-1.70(m,1H),1.61-1.56(m,2H),1.53-1.43(m,2H),1.10(s,6H)。

Compound 360C: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((1- ((R) -2-hydroxypropyl) -1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To methyl 6- (1- ((1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 466(100mg, 0.177mmol) and (R) -2-methyloxirane (103mg, 1.77 mmol)mmol) to a solution in acetonitrile (2mL) was added cesium carbonate (29mg, 0.089 mmol). After stirring at room temperature under a nitrogen atmosphere for 16 hours, the mixture was diluted with water (20mL) and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with water (15mL), brine (15mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Gilson X-bridge C18(5 μm 19X 150mm) mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 50% -55% (% B)) to give the title compound as a yellow solid (45.0mg, 95.1% purity, 41% yield). LC-MS (ESI): r_T＝2.611min，C₂₆H₂₈ClFN₆O₅S₂Calculated mass of 622.1, M/z found value 622.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.6Hz,0.8H),9.15(s,0.2H),8.28(s,0.2H),8.27(s,0.8H),8.04-7.98(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.83(s,0.2H),7.82(s,0.8H),7.44-7.38(m,1H),7.37-7.29(m,1H),7.24-7.16(m,1H),6.00(s,0.2H),5.90(d,J＝3.2Hz,0.8H),4.99(d,J＝4.4Hz,1H),4.17-3.98(m,3H),3.79-3.63(m,2.2H),3.58-3.50(m,0.8H),3.48(s,2.4H),3.47(s,0.6H),2.30-2.17(m,2.2H),2.11-2.00(m,1H),1.97-1.87(m,1H),1.84-1.75(m,1H),1.68-1.60(m,0.8H),1.05(d,J＝6.0Hz,3H)。

Compound 360D: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((1- ((S) -2-hydroxypropyl) -1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 360D was prepared from compound 466 in analogy to compound 360C, by preparative HPLC purification (column: gilson x-bridge C18(5 μm 19 x 150mm) mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 50% -55% (% B)) to give the title compound as a yellow solid (65.0mg, 98.2% purity, 59% yield). LC-MS (ESI): r_T＝2.557min，C₂₆H₂₈ClFN₆O₅S₂Calculated mass of 622.1, M/z found value 622.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.6Hz,0.8H),9.15(s,0.2H),8.28(s,0.2H),8.27(s,0.8H),8.04-7.98(m,1.8H),7.92(d,J＝2.8Hz,0.2H),7.83(s,0.2H),7.82(s,0.8H),7.44-7.38(m,1H),7.37-7.30(m,1H),7.23-7.16(m,1H),6.00(s,0.2H),5.90(d,J＝3.6Hz,0.8H),4.99(d,J＝4.8Hz,1H),4.17-3.98(m,3H),3.79-3.63(m,2.2H),3.57-3.50(m,0.8H),3.48(s,2.4H),3.47(s,0.6H),2.30-2.17(m,2.2H),2.12-1.99(m,1H),1.97-1.85(m,1H),1.84-1.75(m,1H),1.68-1.60(m,0.8H),1.05(d,J＝6.0Hz,3H)。

Compound 376: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (N- ((R) -2, 3-dihydroxypropyl) methylsulfonamido) bicyclo [1.1.1] pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 374: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- ((((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) amino) bicyclo [1.1.1] pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To methyl 6- (3-aminobicyclo [1.1.1] at room temperature]To a solution of pentan-1-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 373(250mg, 0.579mmol) in methanol (8mL) was added (R) -2, 2-dimethyl-1, 3-dioxolane-4-carbaldehyde (113mg, 0.859 mmol). After stirring at room temperature for 1.5 h, sodium cyanoborohydride (73mg, 1.16mmol) was allowed to stand at room temperature. After stirring at room temperature overnight, the reaction mixture was poured into water (10mL) and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed twice with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: X-bright C18(5 μm 19X 150mm) mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 60% -90% (% B)) to give the title compound as a yellow solid (150mg, 48% yield).¹H NMR(300MHz,CDCl₃)δ7.88-7.80(m,2H),7.49-7.40(m,1.3H),7.33-7.28(m,0.7H),7.14-7.11(m,1H),6.95-6.89(m,1H),6.16(s,0.9H),6.04(s,0.1H),4.29-4.21(m,1H),4.09-4.04(m,1H),3.72-3.67(m,1H),3.63-3.60(m,3H),2.81-2.77(m,2H),2.30-2.24(m,7H),1.44(s,3H),1.37(s,3H)。

Compound 375: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (N- (((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) methylsulfonamido) bicyclo [1.1.1] pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To methyl 4- (2-chloro-4-fluorophenyl) -6- (3- ((((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) amino) bicyclo [1.1.1] methyl at 0 deg.C]To a solution of pentan-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 374(150mg, 0.275mmol) in dichloromethane (5mL) was added methanesulfonyl chloride (38mg, 0.330mmol) and triethylamine (83mg, 0.825 mmol). After stirring at room temperature for 2 hours, the mixture was diluted with water (10mL) and extracted twice with dichloromethane (10 mL). The combined organic layers were washed twice with brine (15mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by C18 column (acetonitrile: water 05% to 80%) to give the title compound as a yellow solid (160mg, 93% yield).¹H NMR(400MHz,DMSO-d₆)δ9.45-9.44(m,0.6H),8.38(s,0.4H),8.00-7.95(m,2H),7.44-7.41(m,1H),7.35-7.31(m,1H),7.24-7.18(m,1H),5.97(s,0.5H),5.88(d,J＝3.2Hz,0.5H),4.22-4.18(m,1H),4.03-4.00(m,1H),3.74-3.70(m,1H),3.55-3.54(m,3H),3.29-3.23(m,2H),3.03-2.99(m,3H),2.56(s,3H),2.39(s,3H),1.37(s,3H),1.28(s,3H)。

Rac 375(160mg, 0.256mmol) was separated by chiral preparative SFC (column: Chiralpak IG 5 μm20 x 250 mm; mobile phase: CO₂50g/min MeOH (DEA) (75: 25: 0.3); the column temperature is 41.1 ℃; wavelength: 254 nm; back pressure: 100 bar) to yield the title compound 375C (50mg, 31% yield, 100% stereopure) and 375D (60mg, 38% yield, 100% stereopure) as yellow solids.

Compound 375C: chiral analysis (column: Chiralpak IG 5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH, DEA, 75:25:0.2, at 3.0 g/min; column temperature: 40 ℃; wavelength: 230nm, R_T＝6.14min)。¹H NMR(400MHz,DMSO-d₆)δ9.44(s,0.5H),8.38(s,0.5H),8.01-7.95(m,2H),7.45-7.40(m,1H),7.35-7.30(m,1H),7.24-7.19(m,1H),5.97(s,0.5H),5.88(s,0.5H),4.22-4.18(m,1H),4.04-4.00(m,1H),3.73-3.70(m,1H),3.55-3.54(m,3H),3.29-3.26(m,2H),3.03-2.99(m,3H),2.56(s,3H),2.39(s,3H),1.37(s,3H),1.28(s,3H)。

Compound 375D: chiral analysis (column: Chiralpak IG 5 μm4.6 x 250 mm; mobile phase: CO)₂MeOH, DEA, 75:25:0.2, at 3.0 g/min; column temperature: 40 ℃; wavelength: 230nm, R_T＝7.18min)。¹H NMR(400MHz,DMSO-d₆)δ9.45-9.44(m,0.6H),8.37(s,0.4H),8.01-7.95(m,2H),7.45-7.41(m,1H),7.35-7.30(m,1H),7.24-7.18(m,1H),5.97(s,0.5H),5.89-5.88(m,0.5H),4.23-4.17(m,1H),4.03-4.00(m,1H),3.73-3.70(m,1H),3.55-3.54(m,3H),3.29-3.26(m,2H),3.03-2.99(m,3H),2.56(s,3H),2.39(s,3H),1.37(s,3H),1.28(s,3H)。

Compound 376C: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (N- ((R) -2, 3-dihydroxypropyl) methylsulfonamido) bicyclo [1.1.1] pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (N- (((R) -2, 2-dimethyl-1, 3-dioxolan-4-yl) methyl) methylsulfonamido) bicyclo [1.1.1]To a solution of pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 375C (30mg, 0.048mmol) in acetonitrile (3mL) was added 1M aqueous hydrochloride solution (2 mL). After stirring at room temperature for 3 hours, the mixture was concentrated under reduced pressure to give a residue, which was diluted with water (10mL) and extracted twice with ethyl acetate (10 mL). The combined organic layers were washed twice with brine (10mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Gilson X-bright C18(5 μm 19X 150mm) mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 10% -70% (% B)) to give the title compound as a yellow solid (8mg, 29% yield). LC-MS (ESI): r_T＝3.876min，C₂₄H₂₆ClFN₄O₆S₂Calculated mass 584.1, M/z found value 585.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.44-9.40(m,0.5H),8.35(s,0.5H),8.01-7.99(m,1.5H),7.96-7.95(m,0.5H),7.45-7.41(m,1H),7.35-7.30(m,1H),7.25-7.18(m,1H),5.97(s,0.5H),5.88-5.87(m,0.5H),4.85-4.79(m,1H),4.60-4.54(m,1H),3.67-3.63(m,1H),3.55-3.54(m,3H),3.39-3.34(m,1H),3.30-3.21(m,2H),3.13-3.08(m,1H),3.02-2.98(m,3H),2.55-2.54(m,3H),2.38(s,3H)。

Compound 376D: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (N- ((R) -2, 3-dihydroxypropyl) methylsulfonamido) bicyclo [1.1.1] pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 376D was prepared from compound 375D in analogy to compound 376C, LC-ms (esi): r_T＝3.701min，C₂₄H₂₆ClFN₄O₆S₂Calculated mass 584.1, M/z found value 585.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.43(s,0.5H),8.35(s,0.5H),8.01-7.99(m,1.5H),7.96-7.95(m,0.5H),7.45-7.41(m,1H),7.35-7.30(m,1H),7.25-7.18(m,1H),5.97(s,0.5H),5.88(s,0.5H),4.85-4.79(m,1H),4.60-4.54(m,1H),3.65-3.64(m,1H),3.55-3.54(m,3H),3.38-3.35(m,1H),3.30-3.21(m,2H),3.13-3.08(m,1H),3.02-2.98(m,3H),2.54(s,3H),2.39-2.38(m,3H)。

Compound 379N: ethyl 4- (2-chloro-4-fluorophenyl) -6- ((trans) -2- (hydroxymethyl) -1- (methylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

A mixture of compound 378b (520mg, 0.655mmol) and tetrabutylammonium fluoride (601mg, 2.30mmol) was stirred at 50 ℃ under a nitrogen atmosphere overnight. The mixture was then cooled to room temperature and purified by a C18 column (acetonitrile: water 40% to 95%) to give the crude product, which was further purified by preparative HPLC (column: X-bridge C18(5 μm 21.2X 150mm) mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 35% to 80% (% B)) to give compound 379N as a pale yellow solid (170mg, 47% yield). LC-MS (ESI): r_T＝2.853min，C₂₃H₂₆ClFN₄O₅S₂Meter (2)Calculated mass 556.1, found M/z value 557.2[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝2.0Hz,0.8H),9.12(s,0.2H),7.99(s,1.7H),7.93(d,J＝3.2Hz,0.3H),7.42(dd,J＝8.8,2.4Hz,1H),7.37-7.32(m,1H),7.24-7.20(m,1H),6.03(s,0.2H),5.93(d,J＝2.8Hz,0.8H),4.95-4.91(m,1H),4.05-3.95(m,4H),3.77-3.68(m,2H),3.59-3.54(m,1H),3.10-3.07(m,1H),3.03(s,3H),2.10-2.02(m,1H),1.88-1.79(m,2H),1.70-1.63(m,0.3H),1.53-1.47(m,0.7H),1.12-1.05(m,3H)。

Racemic 379N (170mg, 0.306mmol) was separated by chiral preparative HPLC (column: Chiralpak IF 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.3 at 11 mL/min; temperature: 30 ℃ C; wavelength: 214nm) to give the title compound 379C (41mg, 24% yield, 100% stereopurity) and 379D (38mg, 22% yield, 97.2% stereopurity) as yellow solids.

Compound 379C: LC-MS (ESI): r_T＝2.559min，C₂₃H₂₆ClFN₄O₅S₂Calculated mass of 556.1, M/z found value 556.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IF 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of the chiral compound (column: Chiralpak IF 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 70:30: 0.2; temperature: 30 ℃; wavelength: 230_T＝10.071min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.2Hz,0.8H),9.14(s,0.2H),7.99(s,1.8H),7.93(d,J＝3.2Hz,0.2H),7.43(dd,J＝8.8,2.4Hz,1H),7.37-7.32(m,1H),7.25-7.20(m,1H),6.03(s,0.2H),5.92(d,J＝3.6Hz,0.8H),4.96-4.91(m,1H),4.07-3.95(m,4H),3.78-3.67(m,2H),3.59-3.53(m,1H),3.12-3.06(m,1H),3.04(s,0.5H),3.03(s,2.5H),2.20-2.15(m,0.2H),2.12-2.01(m,0.8H),1.87-1.75(m,2H),1.69-1.63(m,0.2H),1.53-1.47(m,0.8H),1.12-1.05(m,3H)。

Compound 379D: LC-MS (ESI): r_T＝2.290min，C₂₃H₂₆ClFN₄O₅S₂Calculated mass of 556.1, M/z found value 556.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IF 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of the chiral compound (column: Chiralpak IF 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 70:30: 0.2; temperature: 30 ℃; wavelength: 230_T＝13.403min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.2Hz,0.8H),9.14(s,0.2H),7.99(s,1.8H),7.93(d,J＝2.4Hz,0.2H),7.43(dd,J＝8.8,2.4Hz,1H),7.37-7.32(m,1H),7.25-7.20(m,1H),6.03(s,0.2H),5.93(d,J＝3.2Hz,0.8H),4.97-4.91(m,1H),4.05-3.95(m,4H),3.75-3.68(m,2H),3.60-3.53(m,1H),3.12-3.06(m,1H),3.03(s,3H),2.21-2.17(m,0.1H),2.14-2.01(m,0.9H),1.85-1.75(m,2H),1.68-1.65(m,0.2H),1.52-1.48(m,0.8H),1.12-1.05(m,3H)。

Compound 381: (trans) -methyl 4- (2-chloro-3-fluorophenyl) -6- (4-hydroxycyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a mixture of (trans) -methyl 6- (4- ((tert-butyldimethylsilyl) oxy) cyclohexyl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 380(200mg, 0.350mmol) in tetrahydrofuran (10mL) was added tetrabutylammonium fluoride (262mg, 1.05mmol) at 0 ℃. After stirring for 16 h at 23 ℃, the mixture was quenched with water (10mL) and extracted three times with toluene (30 mL). The combined organic layers were washed twice with water (20mL) and Na₂SO_4(s)Drying and concentration gave a residue which was purified by preparative TLC (petroleum ether: ethyl acetate ═ 2:3) to give compound 381 as a yellow solid (64mg, 44% yield). LC-MS (ESI): r_T＝3.418min，C₂₁H₂₁ClFN₃O₃Calculated mass of S449.1, found M/z 450.2[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝3.2Hz,0.6H),7.88(d,J＝3.2Hz,0.4H),7.74-7.73(m,1H),7.29-7.24(m,1H),7.21-7.11(m,2H),6.18(s,0.6H),6.10(s,0.4H),3.94-3.92(m,0.6H),3.69-3.63(m,1.4H),3.59(s,1.2H),3.58(s,1.8H),2.09-2.03(m,2.1H),1.99-1.82(m,2.1H),1.79-1.64(m,1.8H),1.47-1.29(m,2H)。

Rac 381(180mg, 0.400mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak OJ-H5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA: 90:10:0.3 at 18mL/min, temperature: 30 ℃, wavelength: 214nm) to give the title compounds 381A (23.7mg, 13% yield, 100% stereopurity) and 381B (19.9mg, 122% yield, 100% stereopurity) as yellow solids.

Compound 381A: LC-MS (ESI): r_T＝3.407min，C₂₁H₂₁ClFN₃O₃Calculated mass of S449.1, found M/z 450.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak OJ-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 85:15:0.2, at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝11.545min)。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝3.2Hz,0.6H),7.88(d,J＝3.2Hz,0.4H),7.74-7.73(m,1H),7.29-7.20(m,1H),7.19-7.11(m,2H),6.18(s,0.6H),6.10(s,0.4H),3.94-3.93(m,0.6H),3.69-3.65(m,1.4H),3.58(s,1.2H),3.56(s,1.8H),2.15-2.02(m,2H),1.98-1.87(m,2.2H),1.79-1.65(m,1.8H),1.46-1.29(m,2H)。

Compound 381B: LC-MS (ESI): r_T＝3.387min，C₂₁H₂₁ClFN₃O₃Calculated mass of S449.1, found M/z 450.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak OJ-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 85:15:0.2, at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝15.656min)。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝3.2Hz,0.6H),7.87(d,J＝2.8Hz,0.4H),7.74-7.73(m,1H),7.27-7.24(m,1H),7.20-7.13(m,2H),6.18(s,0.6H),6.10(s,0.4H),3.93-3.92(m,0.6H),3.69-3.64(m,1.4H),3.59(s,1.2H),3.58(s,1.8H),2.11-1.96(m,2.6H),1.88-1.64(m,3.4H),1.46-1.29(m,2H)。

Compound 388: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (N-methylmethanesulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 386: methyl 4- (2-chloro-4-fluorophenyl) -6- (4-oxocyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To methyl 4- (2-chloro-4-fluorophenyl) -6- (1, 4-dioxaspiro [4.5 ]]Dec-8-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-methylAcid ester 385(4.90g, according to¹H NMR purity 80%, 7.97mmol) in tetrahydrofuran (49mL) 2M hydrochloride in tetrahydrofuran (49mL, 98mmol) was added. After stirring at room temperature overnight, the mixture was concentrated to give a residue, which was dissolved in ethyl acetate (50mL), diluted with saturated aqueous sodium bicarbonate (50mL), and extracted three times with dichloromethane (50 mL). The combined organic layers were washed twice with brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: tetrahydrofuran ═ 10:1:0 to 10:1:1) to give the title compound (2.90g, 81% yield) as a yellow solid.¹H NMR(300MHz,CDCl₃)δ8.12(br s,0.2H),7.82-7.79(m,1H),7.50-7.49(m,0.8H),7.45(s,1H),7.31-7.28(m,1H),7.16-7.12(m,1H),6.98-6.88(m,1H),6.20(s,0.3H),6.07(d,J＝2.1Hz,0.7H),4.54-4.46(m,0.3H),4.31-4.23(m,0.7H),3.62(s,3H),2.57-2.49(m,4H),2.39-2.32(m,1H),2.25-2.14(m,2H),1.99-1.89(m,1H)。

Compound 387: (cis) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (methylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate and (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (methylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of 386(600mg, 1.34mmol) of methyl 4- (2-chloro-4-fluorophenyl) -6- (4-oxocyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate in dichloromethane (12mL) was added 2M methylamine (3.4mL, 6.80mmol), sodium triacetoxy hydroborate (2.84g, 13.4mmol) and acetic acid (402mg, 6.70mmol) in tetrahydrofuran at 0 ℃ under a nitrogen atmosphere. After stirring at room temperature overnight, the reaction mixture was slowly quenched with saturated aqueous sodium bicarbonate (30mL) and extracted three times with dichloromethane (30 mL). The combined organic layers were washed with brine (30mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (dichloromethane: methanol: ammonium hydroxide ═ 100:1:0.02 to 50:1:0.02) to give the title compound 387A (260mg, 42% yield) and 38 as a yellow solid7B (250mg, 40% yield).

Intermediate 387A:¹H NMR(400MHz,DMSO-d₆)δ8.00-7.93(m,2H),7.42-7.40(m,1H),7.34-7.31(m,1H),7.22-7.18(m,1H),6.01(s,0.7H),5.90(s,0.3H),3.89-3.83(m,0.7H),3.61-3.58(m,0.3H),3.50(s,3H),2.74-2.70(m,1H),2.33(s,3H),2.01-1.84(m,4H),1.59-1.42(m,4H)。

intermediate 387B:¹H NMR(400MHz,DMSO-d₆)δ8.85(br s,1H),7.99-7.93(m,2H),7.44-7.40(m,1H),7.38-7.30(m,1H),7.23-7.16(m,1H),6.00(s,0.4H),5.90(s,0.6H),3.82-3.75(m,0.6H),3.62-3.59(m,0.4H),3.51(s,3H),2.35-2.26(m,4H),2.02-1.96(m,2H),1.85-1.67(m,3H),1.58-1.55(m,1H),1.10-1.02(m,2H)。

compound 388: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (N-methylmethanesulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (methylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 387B (250mg, 0.540mmol) in dichloromethane (5mL) at 0 ℃ under a nitrogen atmosphere was added triethylamine (164mg, 1.62mmol) and methanesulfonyl chloride (68mg, 0.594 mmol). After stirring at room temperature overnight, the reaction mixture was slowly quenched with saturated aqueous sodium bicarbonate (20mL) and extracted three times with dichloromethane (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by C18 column (acetonitrile: water 40% to 95%) to give the title compound as a yellow solid (120mg, 41% yield). LC-MS (ESI): r_T＝3.751min，C₂₃H₂₆ClFN₄O₄S₂Calculated mass of 540.1, found value of M/z 540.7[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.45(d,J＝3.2Hz,0.6H),9.16(br s,0.4H),7.99-7.98(m,1.6H),7.93-7.92(m,0.4H),7.43-7.41(m,1H),7.36-7.29(m,1H),7.23-7.19(m,1H),6.00(s,0.4H),5.90(d,J＝3.2Hz,0.6H),3.85-3.82(m,1H),3.66-3.57(m,1H),3.53(s,1.7H),3.51(s,1.3H),2.92(s,3H),2.73(s,3H),2.07-1.97(m,0.5H),1.93-1.73(m,5H),1.66-1.59(m,2.5H)。

Rac 388(100mg, 0.185mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 20 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound 388A (32mg, 32% yield, 100% stereopurity) as a yellow solid and 388B (28mg, 28% yield, 100% stereopurity) as a yellow solid.

Compound 388A: LC-MS (ESI): r_T＝2.462min，C₂₃H₂₆ClFN₄O₄S₂Calculated mass of 540.1, M/z found value 541.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IA 5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30 ℃; wavelength: 230_T＝7.008min)。¹H NMR(400MHz,DMSO-d₆)δ9.43(d,J＝3.6Hz,0.6H),9.15(br s,0.4H),8.00-7.97(m,1.6H),7.93-7.92(m,0.4H),7.43-7.40(m,1H),7.36-7.29(m,1H),7.23-7.17(m,1H),6.00(s,0.4H),5.91(d,J＝3.6Hz,0.6H),3.89-3.78(m,1H),3.67-3.57(m,1H),3.53(s,1.7H),3.51(s,1.3H),2.92(d,J＝2.8Hz,3H),2.73(s,3H),2.14-2.05(m,0.5H),1.97-1.73(m,5H),1.66-1.59(m,2.5H)。

Compound 388B: LC-MS (ESI): r_T＝2.459min，C₂₃H₂₆ClFN₄O₄S₂Calculated mass of 540.1, M/z found value 541.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IA 5 μm4.6 x 0 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30 ℃; wavelength: 230_T＝8.755min)。¹H NMR(400MHz,DMSO-d₆)δ9.44(d,J＝3.6Hz,0.6H),9.16(br s,0.4H),8.00-7.98(m,1.6H),7.93-7.92(m,0.4H),7.44-7.40(m,1H),7.36-7.29(m,1H),7.23-7.17(m,1H),6.00(s,0.4H),5.90(d,J＝3.6Hz,0.6H),3.88-3.79(m,1H),3.66-3.56(m,1H),3.52(s,1.8H),3.51(s,1.2H),2.92(d,J＝2.4Hz,3H),2.73(s,3H),2.11-2.04(m,0.5H),1.97-1.73(m,5H),1.66-1.57(m,2.5H)。

Compound 390B: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (2-hydroxyethylsulfonamido) bicyclo [1.1.1] pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (2-methoxy-2-oxoethylsulfonamide) bicyclo [1.1.1] at 0 deg.C]To a solution of pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 389B (40mg, 0.070mmol) in tetrahydrofuran (1mL) was added lithium borohydride (12mg, 0.56 mmol). After stirring at a temperature of 0 ℃ to 10 ℃ for 4 hours, the mixture was concentrated under reduced pressure to give a residue, which was purified by C18 column (acetonitrile: water 50% -60%) to give the title compound as a yellow solid (18mg, 47% yield). LC-MS (ESI): r_T＝3.976min，C₂₂H₂₂ClFN₄O₅S₂Calculated mass of 540.1, M/z found value 541.1[ M + H [ ]]⁺.¹H NMR(400MHz,DMSO-d₆)9.44(s,0.5H),8.35(s,0.5H),8.01-7.97(m,1.5H),7.95(d,J＝2.8Hz,0.5H),7.45-7.40(m,1H),7.34-7.30(m,1H),7.24-7.18(m,1H),5.96(s,0.5H),5.86(s,0.5H),4.90(s,1H),3.77-3.74(m,2H),3.54(s,1.5H),3.53(s,1.5H),3.22-3.16(m,2H),2.43(s,3H),2.27(s,3H)。

Compound 393B: methyl 4- (2-chloro-4-fluorophenyl) -6- (3- (2, 3-dihydroxypropylsulfonamido) bicyclo [1.1.1] pent-1-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To methyl 6- (3- (1, 4-dioxaspiro [4.5 ]) at 0 deg.C]Dec-2-ylmethylsulfonamido) bicyclo [1.1.1]To a solution of pent-1-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 392B (30mg, 0.050mmol) in dichloromethane (2mL) was added trifluoroacetic acid (1mL) dropwise. After stirring at room temperature for 1 hour, the mixture was washed three times with saturated aqueous sodium bicarbonate solution (10mL), and then with water (10 mL). The separated organic phase was concentrated under reduced pressure to give a residue which was purified by C18 column (acetonitrile: water (0.1% ammonium bicarbonate) ═ 5% to 80%) to give the title compound as a yellow solid (10mg, 40% yield). LC-MS(ESI)：R_T＝3.624min，C₂₃H₂₄ClFN₄O₆S₂Calculated mass of 570.1, M/z found value 571.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.99(m,1H),7.92-7.87(m,1H),7.42(d,J＝2.4Hz,0.5H),7.40(d,J＝2.8Hz,0.5H),7.36-7.32(m,1H),7.22-7.17(m,1H),5.97-5.91(m,1H),3.98-3.94(m,1H),3.56(s,3H),3.48-3.44(m,1H),3.41-3.36(m,1H),3.31-3.30(m,0.5H),3.27-3.26(m,0.5H),3.09-3.03(m,1H),2.46-2.31(m,6H)。

Compound 401: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (S-methylsulfonylimino) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 400N: methyl 6- (1- (N- (tert-butyldimethylsilyl) -S-methylsulfonylimino) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a stirred solution of methanesulfonamide (2.00g, 21.0mmol) and tert-butylchlorodimethylsilane (4.80g, 31.6mmol) in chloroform (30mL) was added triethylamine (3.20g, 31.6mmol) at 0 ℃. After stirring at room temperature for 16 hours overnight, the mixture was concentrated under reduced pressure to give a residue, which was diluted with water (100mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were passed over Na₂SO₄₍s₎Dried and filtered. The filtrate was concentrated under reduced pressure to give N- (tert-butyldimethylsilyl) -methanesulfonamide as a white solid (3.20g, 73% yield).

To a stirred solution of triphenylphosphine dichloride (1.7g, 5.1mmol) in dry chloroform (10mL) under a nitrogen atmosphere was added triethylamine (697mg, 6.90mmol) at 0 ℃. After stirring at room temperature for ten minutes, the reaction mixture was cooled to 0 ℃ and a solution of N- (tert-butyldimethylsilyl) -methanesulfonamide (970mg, 5.50mmol) in dry chloroform (3mL) was added. After stirring for 20 min at 0 ℃, conditions (S) -methyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid esterificationA solution of compound 99(150mg, 0.350mmol, 100% stereopure) in chloroform (1 mL). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane ═ 10:1:1) to give the title compound (150mg, two steps 69% yield) as a yellow solid. LC-MS (ESI): r_T＝2.867min，C₂₇H₃₇ClFN₅O₃S₂Calculated mass of Si 625.2, found value of M/z 626.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.20(s,0.3H),7.83(d,J＝2.8Hz,1H),7.52(d,J＝2.8Hz,0.7H),7.45(d,J＝3.6Hz,0.3H),7.44(br s,0.7H),7.31-7.28(m,1H),7.16-7.12(m,1H),6.98-6.89(m,1H),6.20(d,J＝2.8Hz,0.3H),6.07(s,0.7H),4.13-3.93(m,2.3H),3.90-3.83(m,0.7H),3.61(s,1.8H),3.60(s,1.2H),2.77(s,1.8H),2.76(s,1.2H),2.71-2.61(m,2H),2.33-2.20(m,0.8H),2.15-1.70(m,3.2H),0.94(s,4H),3.93(s,5H),0.17-0.13(m,6H)。

Compound 401B: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (S-methylsulfonylimino) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (1- (N- (tert-butyldimethylsilyl) -S-methylsulfonylimino) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 400N (150mg, 0.240mmol) in methanol (2mL) at room temperature was added 2M aqueous hydrochloride solution (2 mL). After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in water (10mL), adjusted to pH 9-10 with 28% ammonia solution (1mL) and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: xbridge c18 HILIC (5 μm10 × 190mm) mobile phase a: water, mobile phase B: acetonitrile, UV: 214nm, flow rate: 50mL/min, gradient: 20% -95% (% B)) to give the title compound 401B as a yellow solid (101.0mg, 83% yield). LC-MS (ESI): r_T＝3.149min，C₂₁H₂₃ClFN₅O₃S₂Calculated mass of 511.1, M/z found value 511.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝3.2Hz,0.3H),7.89(d,J＝3.2Hz,0.7H),7.76-7.73(m,1H),7.41-7.37(m,1H),7.25-7.22(m,1H),7.08-7.04(m,1H),6.15(s,0.3H),6.07(s,0.7H),4.11-3.95(m,2.1H),3.89-3.83(m,0.9H),3.59(s,3H),2.88(s,3H),2.85-2.78(m,2H),2.24-2.14(m,0.7H),2.11-2.01(m,1H),1.98-1.91(m,1.5H),1.75-1.71(m,0.8H)。

Racemic 401B (60mg, 0.12mmol) was separated by chiral preparative SFC (column: Chiralpak IF 5 μm20 x 250 mm; mobile phase: CO₂MeOH 60:40 at 50 g/min; temperature: 30 ℃; wavelength: 230nm, back pressure: 100 bar) to yield the title compound 401X (7.7mg, 13% yield, 100% stereopurity) and 401Y (33.1mg, 55% yield, 100% stereopurity) as yellow solids.

Compound 401X: LC-MS (ESI): r_T＝3.621min，C₂₁H₂₃ClFN₅O₃S₂Calculated mass of 511.1, M/z found value 511.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IF 5 μm4.6 x 250 mm; mobile phase: CO)₂EtOH 60:40 at 2.999 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar, R_T＝4.52min)。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝2.8Hz,0.3H),7.89(d,J＝3.2Hz,0.7H),7.76-7.74(m,1H),7.41-7.37(m,1H),7.25-7.21(m,1H),7.08-7.03(m,1H),6.15(s,0.3H),6.08(s,0.7H),4.12-3.92(m,1.6H),3.90-3.83(m,1.4H),3.59(s,3H),2.88(s,3H),2.85-2.79(m,2H),2.27-2.20(m,0.8H),2.17-2.01(m,1.2H),1.94-1.92(m,1.3H),1.74-1.70(m,0.7H)。

Compound 401Y: LC-MS (ESI): r_T＝3.053min，C₂₁H₂₃ClFN₅O₃S₂Calculated mass of 511.1, M/z found value 511.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IF 5 μm4.6 x 250 mm; mobile phase: CO)₂EtOH 60:40 at 2.999 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar, R_T＝5.7min)。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝3.2Hz,0.3H),7.89(d,J＝3.2Hz,0.7H),7.76-7.74(m,1H),7.41-7.37(m,1H),7.25-7.21(m,1H),7.08-7.03(m,1H),6.15(s,0.3H),6.07(s,0.7H),4.09-3.95(m,2.3H),3.88-3.83(m,0.7H),3.59(s,3H),2.88(s,3H),2.86-2.78(m,2H),2.24-2.17(m,0.8H),2.13-2.04(m,1H),1.94-1.90(m,1.5H),1.75-1.72(m,0.7H)。

Compound 404N: ethyl 4- (2-chloro-4-fluorophenyl) -6- ((trans) -2- (fluoromethyl) -1- (methylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 402N: 1-tert-butyl 5-ethyl 6- (2-chloro-4-fluorophenyl) -4- ((trans) -2- (hydroxymethyl) -1- (methylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate

To a solution of compound 379N (1.44g, 2.59mmol) in tetrahydrofuran (50mL) was added 4-dimethylaminopyridine (379mg, 3.11mmol) and di-tert-butyl dicarbonate (671mg, 3.11mmol) at room temperature. After stirring under nitrogen at 60 ℃ overnight, it was cooled to room temperature and concentrated to give a residue which was purified by C18 column (acetonitrile: water 30% to 95%) to give the title compound as a yellow solid (900mg, 53% yield). LC-MS (ESI): r_T＝0.765min，C₂₈H₃₄ClFN₄O₇S₂Calculated mass of 656.2, M/z found value 656.8[ M + H ]]⁺。

Compound 403N: 1-tert-butyl 5-ethyl 6- (2-chloro-4-fluorophenyl) -4- ((trans) -2- (fluoromethyl) -1- (methylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate

To a solution of compound 402N (200mg, 0.305mmol) in dichloromethane (2mL) at-78 deg.C was added diethylaminosulfur trifluoride (147mg, 0.915 mmol). After stirring overnight at room temperature under a nitrogen atmosphere, the reaction mixture was diluted with water (2mL) and extracted three times with dichloromethane (10 mL). The combined organic layers were washed three times with cold brine (20mL) and Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by preparative HPLC (column: Waters X-bridge C18(5 μm 19X 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 40% -85% (% B)) to give the title compound as a yellow solid(64.0mg, 53% yield).¹HNMR(300MHz,CDCl₃)δ7.90(d,J＝1.5Hz,1H),7.50(d,J＝3.0Hz,1H),7.16-7.04(m,2H),6.85-6.78(m,1H),6.74(d,J＝3.6Hz,1H),5.16(br s,0.5H),5.02(br s,0.5H),4.28-4.14(m,3H),3.91-3.58(m,4H),3.03(s,3H),2.44-2.12(m,4H),1.26(s,12H)。

Compound 404N: ethyl 4- (2-chloro-4-fluorophenyl) -6- ((trans) -2- (fluoromethyl) -1- (methylsulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of compound 403N (64.0mg, 0.097mmol) in dichloromethane (1.5mL) at room temperature under a nitrogen atmosphere was added trifluoroacetic acid (1.5 mL). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give a residue which was further purified by preparative HPLC (column: Gilson X-bridge C18(5 μm 19X 150mm), mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 35% -85% (% B)) to give the title compound as a yellow solid (32.0mg, 59% yield). LC-MS (ESI): r_T＝3.980min，C₂₃H₂₅ClF₂N₄O₄S₂Calculated mass of 558.1, M/z found value 559.2[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.45(s,0.7H),9.30(s,0.3H),7.99-7.92(m,2H),7.44-7.41(m,1H),7.38-7.32(m,1H),7.25-7.21(m,1H),6.04(s,0.3H),5.95(d,J＝3.6Hz,0.7H),5.10(s,0.5H),4.98(s,0.5H),4.51(s,0.2H),4.21-4.18(m,0.8H),4.02-3.95(m,2H),3.77-3.66(m,0.4H),3.63-3.60(m,0.6H),3.55-3.53(m,0.8H),3.51-3.41(m,1.2H),3.39-3.36(m,1H),2.99(s,3H),2.28-1.98(m,4H),1.09-1.04(m,3H)。

Compound 416: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1-sulfamoylpiperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To methyl 6- (1- (N- (tert-butoxycarbonyl) sulfamoyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid was added under a nitrogen atmosphere at room temperatureTo a solution of ester compound 415(440mg, 0.69mmol) in methanol (10mL) was added 4N hydrochloride salt in 1, 4-dioxane (3.0mL, 12 mmol). After stirring at room temperature for 4 hours, the mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1 to 1:1) to give the title compound (225mg, 61% yield) as a yellow solid. LC-MS (ESI): r_T＝3.366min，C₂₀H₂₀ClF₂N₅O₄S₂Calculated mass of 531.1, M/z found value 532.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(s,0.8H),9.08(s,0.2H),8.01-7.99(m,1.8H),7.94(d,J＝3.2Hz,0.2H),7.48-7.42(m,1H),7.23-7.16(m,1H),6.77-6.74(m,2H),6.03(s,0.2H),5.93(s,0.8H),3.92-3.53(m,6H),2.67-2.54(m,2H),2.12-2.00(m,1H),1.93-1.88(m,1H),1.87-1.78(m,1H),1.66-1.63(m,1H)。

Rac 416(225mg, 0.422mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 12 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compounds 416A (6.4mg, 3% yield, 100% stereopurity) and 416B (5.3mg, 2% yield, 100% stereopurity) as yellow solids.

Compound 416A: LC-MS (ESI): r_T＝7.703min，C₂₀H₂₀ClF₂N₅O₄S₂Calculated mass of 531.1, M/z found value 532.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; chiral analysis of chiral molecules_T＝11.086min)。¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝3.2Hz,0.8H),9.09(s,0.2H),8.01-7.99(m,1.8H),7.94(d,J＝3.2Hz,0.2H),7.49-7.41(m,1H),7.23-7.15(m,1H),6.77-6.74(m,2H),6.03(s,0.2H),5.93(d,J＝3.2Hz,0.8H),3.92-3.58(m,3H),3.53(s,3H),2.67-2.54(m,2H),2.13-2.00(m,1H),1.95-1.87(m,1H),1.81-1.78(m,1H),1.67-1.63(m,1H)。

Compound 416B: LC-MS (ESI): r_T＝4.704min，C₂₀H₂₀ClF₂N₅O₄S₂Calculated mass of 531.1, M/z found value 532.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; chiral analysis of chiral molecules_T＝14.628min)。¹H NMR(400MHz,DMSO-d₆)δ9.62(s,0.8H),9.09(br s,0.2H),8.01(s,1.8H),7.94(br s,0.2H),7.48-7.41(m,1H),7.21(br s,1H),6.74(s,2H),6.02(br s,0.2H),5.93(s,0.8H),3.89-3.58(m,3H),3.53(s,3H),2.66-2.54(m,2H),2.09-2.00(m,1H),1.93-1.87(m,1H),1.81-1.78(m,1H),1.66-1.63(m,1H)。

Compound 431: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (N- (3-hydroxypropyl) methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 431-1: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- ((3-ethoxy-3-oxopropyl) amino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 6- (4-aminocyclohexyl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 125(1.67g, 97% pure, 2.87mmol) in ethanol (3mL) and tetrahydrofuran (3mL) was added ethyl acrylate (323mg, 97% pure, 3.13mmol) at 0 ℃ under a nitrogen atmosphere. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 8:1) to give the title compound 431-1(1.11g, 68% yield) as a yellow solid. LC-MS (ESI): r_T＝1.67min，C₂₆H₃₀ClFN₄O₄Calculated mass of S548.2, M/z found value 549.5[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.40(br s,0.3H),8.87(s,0.7H),8.03-7.96(m,1.7H),7.94(s,0.3H),7.46-7.43(m,1H),7.40-7.30(m,1H),7.25-7.17(m,1H),6.01(s,0.4H),5.94-5.90(m,0.6H),4.12-4.04(m,2H),3.85-3.75(m,0.5H),3.62-3.52(m,0.5H),3.51(s,3H),2.94-2.84(m,2H),2.65-2.57(m,1H),2.05-1.96(m,2H),1.89-1.56(m,5H),1.23-1.07(m,6H)。

Compound 431-2: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (N- (3-ethoxy-3-oxopropyl) methylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- ((3-ethoxy-3-oxopropyl) amino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 431-1(1.11g, 1.96mmol) in dichloromethane (30mL) was added triethylamine (614mg, 99% purity, 6.00mmol) and methanesulfonyl chloride (421mg, 98% purity, 3.60mmol) at room temperature under a nitrogen atmosphere. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the title compound 431-2(1.08g, purity 95%, 86% yield) as a yellow solid. LC-MS (ESI): r_T＝4.286min，C₂₇H₃₂ClFN₄O₆S₂Calculated mass of 626.1, M/z found value 627.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.43(d,J＝4.0Hz,0.6H),9.09(s,0.4H),8.00-7.98(m,1.5H),7.93(d,J＝3.6Hz,0.5H),7.44-7.40(m,1H),7.37-7.30(m,1H),7.24-7.18(m,1H),6.01(s,0.4H),5.91(d,J＝3.6Hz,0.6H),4.08(q,J＝7.2Hz,2H),3.87-3.75(m,1H),3.60-3.51(m,4H),3.41(t,J＝7.6Hz,2H),2.98(d,J＝3.6Hz,3H),2.61(t,J＝8.0Hz,2H),2.08-1.56(m,8H),1.21(t,J＝7.2Hz,3H)。

Compound 431: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (N- (3-hydroxypropyl) methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (N- (3-ethoxy-3-oxopropyl) methanesulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 431-2(520mg, 95% purity, 0.788mmol) in tetrahydrofuran (6mL) was added lithium borohydride (56mg, 97% purity, 2.59mmol) at 0 ℃ under a nitrogen atmosphere. After stirring at room temperature overnight, the mixture was cooled to 0 ℃, quenched with water (100mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with brine (50mL) and Na₂SO_4(s)Drying, filtration and concentration gave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:2) to give the title compound 431 as a yellow solid (300mg, purity 96%, 63% yield). LC-MS (ESI): r_T＝3.992min，C₂₅H₃₀ClFN₄O₅S₂Calculated mass 584.1, M/z found value 585.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.43(d,J＝3.2Hz,0.6H),9.10(s,0.4H),8.00-7.98(m,1.5H),7.93(d,J＝3.6Hz,0.5H),7.44-7.40(m,1H),7.36-7.30(m,1H),7.23-7.17(m,1H),6.00(s,0.4H),5.91(d,J＝3.6Hz,0.6H),4.49-4.47(m,1H),3.86-3.75(m,1H),3.60-3.55(m,2H),3.52(s,1.8H),3.51(s,1.2H),3.45-3.41(m,2H),3.20-3.16(m,2H),2.93(d,J＝2.8Hz,3H),1.95-1.60(m,10H)。

Rac 431(300mg, 96% purity, 0.492mmol) was separated by chiral preparative HPLC (column: Chiralpak IA 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 25 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compounds 431A (64.4mg, 98.6% purity, 22% yield, 100% stereopurity) and 431B (63.4mg, 99.8% purity, 22% yield, 98.8% stereopurity) as yellow solids.

Compound 431A: LC-MS (ESI): r_T＝3.689min，C₂₅H₃₀ClFN₄O₅S₂Calculated mass 584.1, M/z found value 584.7[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of the chiral structure of the chiral_T＝9.607min)。¹H NMR(400MHz,DMSO-d₆)δ9.44(d,J＝3.6Hz,0.6H),9.11(s,0.4H),8.00-7.98(m,1.5H),7.93(d,J＝3.6Hz,0.5H),7.44-7.40(m,1H),7.36-7.30(m,1H),7.24-7.18(m,1H),6.01(s,0.4H),5.91(d,J＝3.2Hz,0.6H),4.49(t,J＝4.8Hz,1H),3.86-3.75(m,1H),3.61-3.56(m,1H),3.53(s,1.8H),3.51(s,1.2H),3.44(q,J＝5.6Hz,2H),3.20-3.16(m,2H),2.94(d,J＝2.8Hz,3H),2.11-1.76(m,5H),1.73-1.61(m,5H)。

Compound 431B: LC-MS (ESI): r_T＝3.690min，C₂₅H₃₀ClFN₄O₅S₂Calculated mass 584.1, M/z found value 584.7[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of the chiral structure of the chiral_T＝11.156min)。¹H NMR(400MHz,DMSO-d₆)δ9.44(d,J＝3.6Hz,0.6H),9.11(s,0.4H),8.00-7.98(m,1.5H),7.93(d,J＝3.2Hz,0.5H),7.44-7.40(m,1H),7.36-7.30(m,1H),7.23-7.17(m,1H),6.00(s,0.4H),5.91(d,J＝3.6Hz,0.6H),4.48(t,J＝5.2Hz,1H),3.86-3.75(m,1H)3.60-3.55(m,1H),3.52(s,1.8H),3.51(s,1.2H),3.44(q,J＝5.6Hz,2H),3.18(t,J＝7.6Hz,2H),2.94(s,1.5H),2.93(s,1.5H),2.1

2-1.76(m,5H),1.73-1.61(m,5H)。

Compound 433: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (2-hydroxyethyl) acetamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 433-1: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4-oxocyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To 4- (2-chloro-3, 4-difluorophenyl) -6- (1, 4-dioxaspiro [4.5 ] at 0 deg.C]To a solution of dec-8-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 432(2.85g, 5.58mmol) in dichloromethane (25mL) was added trifluoroacetic acid (25 mL). After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give a residue, which was dissolved in dichloromethane (250mL) and washed twice with saturated aqueous sodium bicarbonate (200mL), washed with brine (200mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (1.72g, 66% yield).¹H NMR(400MHz,DMSO-d₆)δ9.63(s,0.7H),9.25(br s,0.3H),8.00-7.93(m,2H),7.45(q,J＝8.8Hz,1H),7.24-7.21(m,1H),6.04-5.95(m,1H),4.13-4.00(m,1H),3.56(s,3H),2.59-2.51(m,1H),2.36-2.29(m,3H),2.17-2.10(m,2H),2.02-1.94(m,2H)。

Compound 433-2: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- ((2-methoxy-2-oxoethyl) amino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4-oxocyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 433-1(1.98g, 4.24mmol) and methyl 2-aminoacetate hydrochloride (1.64g, 12.7mmol) in methanol (50mL) were added sodium acetate (1.60g, 19.1mmol) and sodium cyanoborohydride (1.31g, 20.4 mmol). After stirring overnight at room temperature, the mixture was quenched with water (100mL) and extracted three times with dichloromethane (100 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1 to 1:1) to give the title compounds 433-2A (1.30g, 54% yield) and 433-2B (500mg, 21% yield) as yellow solids.

Compound 433-2a (trans):¹H NMR(400MHz,CDCl₃)δ8.14-8.11(m,0.7H),7.81(s,1H),7.50-7.45(m,1.3H),7.08-6.96(m,2H),6.17(s,0.7H),6.03(s,0.3H),4.00-3.91(m,1H),3.76-3.73(m,4H),3.61-3.59(m,3H),3.52-3.46(m,2H),2.62-2.54(m,1H),2.35(br s,2H),1.99-1.90(m,2H),1.80-1.71(m,1H),1.44-1.34(m,2H)。

compound 433-2b (cis):¹H NMR(400MHz,CDCl₃)δ8.46-8.42(m,0.8H),7.83-7.82(m,1H),7.51-7.44(m,1.2H),7.10-6.96(m,2H),6.20-6.18(m,0.8H),6.05(br s,0.2H),4.04-3.96(m,1H),3.77(s,3H),3.59(s,3H),3.52-3.45(m,2H),2.95-2.89(m,1H),2.22-1.87(m,6H),1.77-1.70(m,2H)。

compound 433-3: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (2-methoxy-2-oxoethyl) acetamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- ((2-methoxy-2-oxoethyl) amino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 433-2A (475mg, 0.870mmol) in dichloromethane (10mL) was added acetic anhydride (903mg, 8.70mmol) at 0 ℃. After stirring at room temperature overnight, the mixture was concentrated under reduced pressureCondensation gave a residue which was dissolved in dichloromethane (200mL), washed twice with saturated aqueous sodium bicarbonate (10mL) and with brine (10mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1 to 1:1) to give the title compound (340mg, 55% yield) as a yellow solid.¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝3.6Hz,0.5H),9.28(s,0.2H),8.95(s,0.3H),8.00-7.99(m,1.5H),7.95(d,J＝3.2Hz,0.3H),7.93(d,J＝3.2Hz,0.2H),7.49-7.41(m,1H),7.20-7.12(m,1H),6.01(d,J＝6.0Hz,0.5H),5.91(t,J＝4.0Hz,0.5H),4.57-4.51(m,0.2H),4.37-4.31(m,0.2H),4.20(s,0.6H),3.96(s,1H),3.91-3.79(m,1H),3.71(s,1.5H),3.61(s,2H),3.53-3.51(m,3.5H),3.32(s,3H),2.13(s,2H),1.93-1.82(m,4H),1.63-1.55(m,2H)。

Compound 433: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (2-hydroxyethyl) acetamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (N- (2-methoxy-2-oxoethyl) acetamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 433-2A (270mg, 0.460mmol) in tetrahydrofuran (2mL) was added lithium borohydride (52mg, 2.32 mmol). After stirring overnight at room temperature, the mixture was quenched with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (5mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1 to 1:2) to give the title compound 433(200mg, 99.8% yield) as a yellow solid. LC-MS (ESI): r_T＝4.557min，C₂₅H₂₇ClF₂N₄O₄Calculated mass of S552.1, found value of M/z 553.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.55(t,J＝3.6Hz,0.5H),9.25(s,0.3H),8.99(s,0.2H),8.00-7.99(m,1.5H),7.95-7.93(m,0.5H),7.48-7.42(m,1H),7.21-7.12(m,1H),6.01(d,J＝4.8Hz,0.5H),5.92(t,J＝3.6Hz,0.5H),4.86-4.83(m,0.5H),4.66-4.63(m,0.5H),4.34-4.27(m,0.2H),4.17-4.11(m,0.3H),3.86-3.79(m,0.5H),3.62-3.47(m,5H),3.43-3.38(m,1H),3.30-3.28(m,1H),3.25-3.23(m,1H),2.09-2.05(m,3H),1.96-1.75(m,4H),1.70-1.57(m,4H)。

Rac 433(200mg, 0.362mmol) was separated by chiral preparative HPLC (column: Chiralpak AD-H5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 13 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 433A (54.5mg, 27% yield, 100% stereopurity) and 433B (37.5mg, 12% yield, 100% stereopurity) as yellow solids.

Compound 433A: LC-MS (ESI): r_T＝4.554min，C₂₅H₂₇ClF₂N₄O₄Calculated mass of S552.1, found value of M/z 553.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak AD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak AD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30_T＝4.737min)。¹H NMR(400MHz,DMSO-d₆)δ9.55(s,0.5H),9.24(s,0.3H),8.99(s,0.2H),8.00-7.99(m,1.5H),7.95-7.92(m,0.5H),7.49-7.42(m,1H),7.21-7.13(m,1H),6.01(d,J＝4.8Hz,0.4H),5.93-5.92(m,0.6H),4.88-4.85(m,0.5H),4.66(t,J＝5.6Hz,0.5H),4.33-4.27(m,0.2H),4.17-4.11(m,0.3H),3.87-3.76(m,0.5H),3.59-3.49(m,5H),3.41-3.38(m,1H),3.32-3.30(m,1H),3.25-3.24(m,1H),2.09-2.05(m,3H),1.95-1.75(m,4H),1.66-1.57(m,4H)。

Compound 433B: LC-MS (ESI): r_T＝4.554min，C₂₅H₂₇ClF₂N₄O₄Calculated mass of S552.1, found value of M/z 553.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak AD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis: chiral analysis (column: Chiralpak AD-H5 μm4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30_T＝11.148min)。¹H NMR(400MHz,DMSO-d₆)δ9.55(s,0.5H),9.25(s,0.3H),8.99(s,0.2H),8.00(s,1.5H),7.95-7.93(m,0.5H),7.49-7.42(m,1H),7.21-7.13(m,1H),6.02(d,J＝4.8Hz,0.5H),5.92(t,J＝3.2Hz,0.5H),4.88-4.85(m,0.5H),4.67-4.64(m,0.5H),4.31(br s,0.2H),4.14(br s,0.3H),3.89-3.76(m,0.5H),3.61-3.49(m,5H),3.43-3.38(m,1H),3.32-3.28(m,1H),3.25-3.22(m,1H),2.09-2.05(m,3H),1.96-1.75(m,4H),1.70-1.57(m,4H)。

Compound 434: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- ((2-hydroxyethyl) (2,2, 2-trifluoroethyl) amino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 434-1: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- ((2-methoxy-2-oxoethyl) (2,2, 2-trifluoroethyl) amino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- ((2-methoxy-2-oxoethyl) amino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 433-2A (340mg, 0.610mmol) in acetonitrile (2mL) was added sodium bicarbonate (310mg, 3.66mmol) and 2,2, 2-trifluoroethyl trifluoromethanesulfonate (438mg, 1.83 mmol). After stirring overnight at 85 ℃, the mixture was quenched with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (5mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1 to 1:1) to give the title compound 434-1(320mg, 52% yield) as a yellow solid.¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝3.6Hz,0.6H),9.01(s,0.4H),8.00-7.98(m,1.5H),7.94(d,J＝3.2Hz,0.5H),7.48-7.41(m,1H),7.20-7.12(m,1H),6.00(s,0.4H),5.90(d,J＝3.2Hz,0.6H),3.82-3.74(m,0.6H),3.69-3.61(m,3.4H),3.58(s,2H),3.52(s,1.8H),3.51(s,1.2H),3.48-3.43(m,2H),2.84-2.78(m,0.4H),2.71-2.65(m,0.6H),1.92-1.85(m,3H),1.81-1.72(m,2H),1.68-1.59(m,1H),1.33-1.23(m,2H)。

Compound 434: (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- ((2-hydroxyethyl) (2,2, 2-trifluoroethyl) amino) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- ((2-methoxy-2-oxoethyl) (2,2, 2-trifluoroethyl) ammoniaTo a solution of yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 434-1(247mg, 0.398mmol) in tetrahydrofuran (2mL) was added lithium borohydride (90mg, 4.13 mmol). After stirring overnight at room temperature, the mixture was quenched with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (5mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1 to 1:2) to give the title compound 434 as a yellow solid (70mg, 24% yield). LC-MS (ESI): r_T＝4.187min，C₂₅H₂₆ClF₅N₄O₃Calculated mass of S592.1, M/z found value 593.2[ M + H [ ]]⁺。¹HNMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.2Hz,0.5H),8.99(s,0.5H),8.00-7.97(m,1.5H),7.94(d,J＝2.8Hz,0.5H),7.49-7.41(m,1H),7.20-7.13(m,1H),6.01(s,0.4H),5.91(d,J＝3.6Hz,0.6H),4.43-4.39(m,1H),3.83-3.75(m,0.5H),3.52-3.51(m,3.5H),3.46-3.40(m,2H),3.30-3.26(m,2H),2.70(t,J＝6.8Hz,2H),2.59-2.56(m,1H),1.91-1.79(m,5H),1.75-1.64(m,1H),1.39-1.29(m,2H)。

Rac 434(70mg, 0.12mmol) was separated by chiral preparative SFC (column: Chiralpak IG 5 μm20 x 250 mm; mobile phase: CO₂MeOH 70:30 at 50 g/min; column temperature: 30 ℃; wavelength: 230nm, back pressure: 100 bar) to afford the title compound 434A (19.1mg, 27% yield, 100% stereopure) and 434B (19.8mg, 28% yield, 100% stereopure) as yellow solids.

Compound 434A: LC-MS (ESI): r_T＝4.165min，C₂₅H₂₆ClF₅N₄O₃Calculated mass of S592.1, M/z found value 593.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of chiral structure (column: Chiralpak IE 5 μm 4.6: 0.2; mobile phase: Hex: EtOH: DEA: 10: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝10.689min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.2Hz,0.5H),8.98(s,0.5H),8.00-7.97(m,1.5H),7.94(d,J＝3.6Hz,0.5H),7.49-7.41(m,1H),7.20-7.13(m,1H),6.01(s,0.5H),5.91(d,J＝3.2Hz,0.5H),4.43-4.39(m,1H),3.81-3.70(m,0.6H),3.53-3.52(m,3.4H),3.46-3.41(m,2H),3.28-3.26(m,2H),2.72-2.68(m,2H),2.60-2.56(m,1H),1.90-1.74(m,5H),1.70-1.64(m,1H),1.40-1.29(m,2H)。

Compound 434B: LC-MS (ESI): r_T＝4.169min，C₂₅H₂₆ClF₅N₄O₃Calculated mass of S592.1, M/z found value 593.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis of chiral structure (column: Chiralpak IE 5 μm 4.6: 0.2; mobile phase: Hex: EtOH: DEA: 10: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝12.458min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.6Hz,0.5H),8.98(s,0.5H),8.00-7.97(m,1.5H),7.94(d,J＝3.2Hz,0.5H),7.49-7.41(m,1H),7.20-7.13(m,1H),6.01(s,0.4H),5.91(d,J＝3.2Hz,0.6H),4.44-4.40(m,1H),3.81-3.76(m,0.6H),3.53-3.52(m,3.4H),3.46-3.42(m,2H),3.28-3.26(m,2H),2.71-2.68(m,2H),2.59-2.56(m,1H),1.88-1.73(m,5H),1.69-1.63(m,1H),1.40-1.29(m,2H)。

Compound 448: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (N- (cyanomethyl) methylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

Compound 448-1: (trans) -1-tert-butyl 5-methyl 6- (2-chloro-4-fluorophenyl) -4- (4- (methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate

A mixture of (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (methylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 126(1.44g, 2.73mmol), di-tert-butyl dicarbonate (631mg, 2.89mmol) and N, N-dimethylpyridin-4-amine (136mg, 1.11mmol) in tetrahydrofuran (10mL) was stirred at 60 ℃ overnight. After cooling to room temperature and quenching with water (100mL), the mixture was extracted three times with dichloromethane (100 mL). The combined organic layers were washed with saturated aqueous sodium sulfite (50mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1 to 1:1)To give the title compound 448-1 as a yellow solid (990mg, 58% yield). LC-MS (ESI): r_T＝1.82min，C₂₇H₃₂ClFN₄O₆S₂Calculated mass of 626.1, M/z found value 627.4[ M + H ]]⁺。

Compound 448-2: (trans) -1-tert-butyl 5-methyl 6- (2-chloro-4-fluorophenyl) -4- (4- (N- (cyanomethyl) methylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate

To a solution of (trans) -1-tert-butyl 5-methyl 6- (2-chloro-4-fluorophenyl) -4- (4- (methylsulfonylamino) cyclohexyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate 448-1(830mg, 1.32mmol) in tetrahydrofuran (6mL) at 0 deg.C was added 60% wt sodium hydride in mineral oil (160mg, 3.97 mmol). After stirring at room temperature for 1 hour, the mixture was cooled to 0 ℃ and 2-bromoacetonitrile (634mg, 5.28mmol) was added. After stirring at room temperature overnight, the mixture was diluted with water (100mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1 to 1:1) to give the title compound 448-2 as a yellow solid (550mg, 63% yield).¹H NMR(300MHz,DMSO-d₆)δ8.00(s,2H),7.48(dd,J＝8.4,2.4Hz,1H),7.17-7.11(m,1H),7.07-7.00(m,1H),6.55(s,1H),4.46(s,2H),3.79-3.71(m,1H),3.68(s,3H),3.49(br s,1H),3.12(s,3H),2.06-2.01(m,1H),1.91-1.62(m,6H),1.59(br s,1H),1.15(s,9H)。

Compound 448: (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (N- (cyanomethyl) methylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of (trans) -1-tert-butyl 5-methyl 6- (2-chloro-4-fluorophenyl) -4- (4- (N- (cyanomethyl) methylsulfonamido) cyclohexyl) -2- (thiazol-2-yl) pyrimidine-1, 5(6H) -dicarboxylate 448-2(500mg, 0.750mmol) in dichloromethane (2mL) was added trifluoroacetic acid (1mL) at 0 ℃. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure to give a residue, which was dissolved in dichloromethane (5mL) and saturated bicarbonate was addedWashed twice with aqueous sodium (3mL), washed with brine (3mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1 to 1:1) to give the title compound 448(280mg, 66% yield) as a yellow solid. LC-MS (ESI): r_T＝4.278min，C₂₄H₂₅ClFN₅O₄S₂Calculated mass 565.1, M/z found 566.0[ M + H ]]⁺。¹HNMR(400MHz,DMSO-d₆)δ9.43(d,J＝3.2Hz,0.6H),9.09(s,0.4H),8.00-7.93(m,2H),7.44-7.40(m,1H),7.37-7.30(m,1H),7.24-7.18(m,1H),6.01(s,0.4H),5.91(d,J＝3.2Hz,0.6H),4.45(s,2H),3.97-3.84(m,1H),3.74-3.68(m,0.5H),3.62-3.59(m,0.5H),3.54(s,1.5H),3.52(s,1.5H),3.11(s,1.5H),3.09(s,1.5H),1.99-1.66(m,8H)。

Rac 448(280mg, 0.495mmol) was separated by chiral preparative HPLC (column: Chiralpak IC 5 μm20 × 250 mm; mobile phase: Hex: EtOH ═ 70:30 at 25 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound 448A (52.6mg, 99.5% purity, 19% yield, 100% stereopurity) and 448B (46.1mg, 99.4% purity, 16% yield, 100% stereopurity) as yellow solids.

Compound 448A: LC-MS (ESI): r_T＝4.058min，C₂₄H₂₅ClFN₅O₄S₂Calculated mass 565.1, M/z found 566.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝12.949min)。¹H NMR(400MHz,DMSO-d₆)δ9.43(d,J＝3.2Hz,0.6H),9.08(s,0.4H),8.00-7.93(m,2H),7.43-7.41(m,1H),7.37-7.31(m,1H),7.24-7.17(m,1H),6.01(s,0.4H),5.91(d,J＝3.2Hz,0.6H),4.45(s,2H),3.97-3.84(m,1H),3.74-3.68(m,0.5H),3.61-3.59(m,0.5H),3.54(s,1.5H),3.52(s,1.5H),3.11(s,1.5H),3.09(s,1.5H),2.11-1.95(m,1H),1.92-1.69(m,7H)。

Compound 448B: LC-MS (ESI): r_T＝4.063min，C₂₄H₂₅ClFN₅O₄S₂The calculated mass of (a) of (b 565.1,m/z found 566.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC 5 μm4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝15.940min)。¹H NMR(400MHz,DMSO-d₆)δ9.43(s,0.6H),9.09(s,0.4H),7.99-7.93(m,2H),7.43-7.31(m,2H),7.23-7.20(m,1H),6.01(s,0.4H),5.92(s,0.6H),4.46(s,2H),3.96-3.85(m,1H),3.74-3.69(m,0.5H),3.62-3.59(m,0.5H),3.54(s,1.5H),3.53(s,1.5H),3.11(s,1.5H),3.10(s,1.5H),2.12-1.96(m,1H),1.92-1.69(m,7H)。

Compound 457: methyl 6- (1- ((3-amino-3-oxopropyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

A suspension of methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((3-methoxy-3-oxopropyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 104(130mg, 0.222mmol) in 3M ammonia in methanol (3mL, 9.00mmol) in a sealed tube was stirred at 45 ℃ overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Waters kinete EVO C18(5 μm 21.2 x 150mm) mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 20% -80% (% B)) to give the title compound 457(42.8mg, 99.2% purity, 34% yield) as a yellow solid. LC-MS (ESI): r_T＝3.767min，C₂₃H₂₅ClFN₅O₅S₂Calculated mass of 569.1, M/z found value 569.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.55(d,J＝3.6Hz,0.8H),9.18(s,0.2H),8.00-7.99(m,1.8H),7.94-7.93(m,0.2H),7.53(br s,1H),7.45-7.41(m,1H),7.38-7.31(m,1H),7.24-7.19(m,1H),7.04(br s,1H),6.02(s,0.2H),5.92(d,J＝3.2Hz,0.8H),4.00-3.92(m,0.2H),3.78-3.67(m,2.8H),3.53(s,3H),3.30-3.24(m,2H),2.93-2.84(m,2H),2.54-2.52(m,2H),2.12-1.75(m,3.2H),1.64-1.62(m,0.8H)。

Compound 462: 6- (4- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1H-pyrazol-1-yl) hexanoic acid

Compound 462-1: ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((1- (6-ethoxy-6-oxohexyl) -1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of ethyl 6- (1- ((1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 461(360mg, 80% purity, 0.482mmol) in N, N-dimethylformamide (10mL) were added ethyl 6-bromohexanoate (98mg, 99% purity, 0.435mmol), potassium carbonate (340mg, 99% purity, 2.44mmol), and sodium iodide (66mg, 99% purity, 0.436 mmol). After stirring overnight at 60 ℃, the mixture was diluted with water (30mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed three times with water (20mL), washed with brine (20mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: Waters Xbridge C18(5um 19 x 150mm), mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 65% -85% (% B)) to give the title compound 462-1 as a yellow solid (165mg, 98.7% purity, 46% yield). LC-MS (ESI): r_T＝3.076min，C₃₂H₃₇ClF₂N₆O₆S₂Calculated mass of 738.2, M/z found value 739.3[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.3H),7.86-7.81(m,1H),7.78-7.73(m,2H),7.56-7.51(m,0.7H),7.48-7.45(m,0.4H),7.36-7.32(m,0.6H),7.09-7.01(m,2H),6.18(s,0.4H),6.08-6.06(m,0.6H),4.21-4.09(m,4H),4.04-3.85(m,4.4H),3.79-3.69(m,0.6H),2.46-2.35(m,2H),2.34-2.29(m,2H),2.00-1.88(m,4H),1.73-1.66(m,2H),1.55-1.52(m,2H),1.42-1.33(m,2H),1.28-1.23(m,3H),1.12-1.04(m,3H)。

Compound 462: 6- (4- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1H-pyrazol-1-yl) hexanoic acid

To a solution of ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((1- (6-ethoxy-6-oxohexyl) -1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 462-1(159mg, 98.7% purity, 0.212mmol) in methanol (2mL), water (2mL) and tetrahydrofuran (6mL) was added lithium hydroxide monohydrate (22mg, 0.524mmol) at 0 ℃. After stirring at room temperature for 5 hours, the mixture was diluted with water (10mL), acidified to pH about 2 with 1M aqueous hydrochloride solution, and extracted three times with ethyl acetate (15 mL). The combined organic phases were washed with water (15mL), brine (15mL) and Na₂SO_4(s)Drying, filtration and concentration in vacuo gave a residue which was purified by C18 column (acetonitrile: water 10% to 95%) to give the title compound 462(90mg, purity 97%, 58% yield) as a yellow solid. LC-MS (ESI): r_T＝3.907min，C₃₀H₃₃ClF₂N₆O₆S₂Calculated mass of 710.2, M/z found value 710.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.41(s,1H),8.07-7.98(m,1.8H),7.94(s,0.2H),7.82(s,1H),7.45(dd,J＝9.2，16.8Hz,1H),7.24-7.15(m,1H),6.01(br s,0.2H),5.91(s,0.8H),4.18(t,J＝6.8Hz,2H),3.92(q,J＝6.8Hz,2H),3.75-3.64(m,2.2H),3.56-3.51(m,0.8H),2.33-2.12(m,4H),2.10-1.97(m,1H),1.92-1.89(m,4H),1.70-1.59(m,0.8H),1.55-1.43(m,2H),1.25-1.14(m,2.2H),1.05-0.95(m,3H)。

Compound 463: 5- (4- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1H-pyrazol-1-yl) pentanoic acid

Compound 463-1: ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((1- (5-methoxy-5-oxopentyl) -1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of ethyl 6- (1- ((1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 461(300mg, 75% purity, 0.377mmol) in N, N-dimethylformamide (5mL) was added methyl 5-bromovalerate (67mg, 0.344mmol), potassium carbonate (194mg, 1.41mmol), and sodium iodide (58mg, 0.387mmol) at room temperature. After stirring overnight at 60 ℃, the mixture was dissolved in ethyl acetate (40mL) and washed twice with water (100 mL). The combined aqueous layers were extracted twice with ethyl acetate (60 mL). The combined organic layers were washed twice with water (30mL) and brine (30mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Gilson Gemini C18(5 μm 19 x 150mm) mobile phase a: water (0.1% ammonium bicarbonate), B: acetonitrile, UV: 214nm, flow rate 15mL/min, gradient: 55% -70% (% B)) to give the title compound 463-1 as a yellow solid (150mg, 99% purity, 56% yield). LC-MS (ESI): r_T＝4.243min，C₃₀H₃₃ClF₂N₆O₆S₂Calculated mass of 710.2, M/z found value 710.8[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.64(d,J＝3.6Hz,0.8H),9.18(s,0.2H),8.43-8.42(m,1H),8.04-7.93(m,2H),7.84(d,J＝4.8Hz,1H),7.44(q,J＝8.8Hz,1H),7.22-7.18(m,1H),6.01(s,0.2H),5.91(d,J＝3.2Hz,0.8H),4.20(t,J＝6.8Hz,2H),3.95-3.89(m,2H),3.75-3.65(m,2.3H),3.56(s,3H),3.53-3.49(m,0.7H),2.35-2.30(m,2H),2.26-2.17(m,2H),2.09-2.03(m,1H),1.95-1.77(m,4H),1.66-1.63(m,1H),1.48-1.40(m,2H),1.03-0.96(m,3H)。

Compound 463: 5- (4- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1H-pyrazol-1-yl) pentanoic acid

To a solution of ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((1- (5-methoxy-5-oxopentyl) -1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 463-1(50mg, 99% purity, 0.070mmol) in tetrahydrofuran (1mL) and ethanol (1mL)To the solution was added a solution of lithium hydroxide hydrate (7mg, 0.163mmol) in water (0.5 mL). After stirring at room temperature for 5 hours, the mixture was concentrated to give a residue, which was diluted with water (10mL), acidified to pH 4-5 with 1M aqueous hydrochloride solution (1mL), and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed twice with water (10mL) and brine (10mL), over Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: Gilson Gemini C18(5 μm 19 x 150mm) mobile phase a: water (0.1% ammonium bicarbonate), B: acetonitrile, UV: 214nm, flow rate 15mL/min, gradient: 05% -80% (% B)) to give title compound 463(40mg, 99.5% purity, 82% yield) as a yellow solid. LC-MS (ESI): r_T＝3.667min，C₂₉H₃₁ClF₂N₆O₆S₂Calculated mass of 696.1, M/z found value 697.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.41(s,1H),8.03-7.94(m,2H),7.83(s,1H),7.43(q,J＝9.2Hz,1H),7.21-7.18(m,1H),6.01(s,0.2H),5.91(s,0.8H),4.20(t,J＝7.2Hz,2H),3.92(q,J＝7.2Hz,2H),3.75-3.65(m,2.2H),3.56-3.50(m,0.8H),2.26-2.17(m,4H),2.09-2.00(m,1H),1.92-1.77(m,4H),1.66-1.63(m,1H),1.45-1.38(m,2H),1.03-0.97(m,3H)。

Compound 465: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- ((1- (oxazol-2-ylmethyl) -1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (1- ((1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 324(90mg, 0.154mmol) in N, N-dimethylformamide (3mL) was added 2- (chloromethyl) oxazole (16mg, 0.136mmol), potassium carbonate (43mg, 0.312mmol), and sodium iodide (23mg, 0.153mmol) at 0 ℃. After stirring overnight at room temperature under a nitrogen atmosphere, the mixture was diluted with ethyl acetate (20mL) and washed with water (15 mL). The aqueous layer was washed with ethyl acetate (10 m)L) extraction was carried out three times. The combined organic layers were washed with brine (10mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 3:2) and then further purified by preparative HPLC (column: waters xbridge C18(5 μm 19 x 150mm) mobile phase a: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 20% -95% (% B)) to give the title compound 465 as a yellow solid (45mg, 98.6% purity, 43% yield). LC-MS (ESI): r_T＝3.869min，C₂₇H₂₄ClF₂N₇O₅S₂Calculated mass of 663.1, M/z found value 664.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.20(s,0.3H),7.95(d,J＝3.2Hz,1H),7.84-7.83(m,1H),7.80-7.79(s,1H),7.71(s,1H),7.54(d,J＝2.8Hz,0.6H),7.46(d,J＝2.8Hz,0.4H),7.43(s,0.7H),7.18(s,1H),7.08-7.01(m,2H),6.16(s,0.3H),6.05(d,J＝2.8Hz,0.7H),5.50(s,2H),4.02-3.91(m,2H),3.88-3.85(m,0.3H),3.76-3.70(m,0.7H),3.56(s,2H),3.55(s,1H),2.47-2.40(m,2H),2.32-2.14(m,1H),2.06-1.87(m,2.2H),1.73-1.70(m,0.8H)。

Compound 468: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((2- (2- (2-hydroxyethoxy) ethoxy) ethyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((2, 2-dimethyl-3, 3-diphenyl-4, 7, 10-trioxa-3-siladodec-12-yl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 467(150mg, 0.173mmol) in tetrahydrofuran (3mL) was added tetrabutylammonium fluoride in tetrahydrofuran (0.19mL, 0.190mmol) at room temperature. After stirring at room temperature overnight, the mixture was quenched with water (30mL) and then extracted twice with ethyl acetate (30mL), and the combined organic layers were washed with brine (20mL) and Na₂SO_4(s)Drying, filtering and concentrating to obtain a residue which is passed throughPurification by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:2 to 1:3) followed by further purification by C18 column (acetonitrile: water ═ 54% to 70%) gave the title compound 468(40mg, 37% yield) as a yellow solid. LC-MS (ESI): r_T＝3.170min，C₂₆H₃₂ClFN₄O₇S₂Calculated mass of 630.1, M/z found value 631.2[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.6Hz,0.8H),9.15(s,0.2H),8.00-7.98(m,1.8H),7.93(d,J＝3.2Hz,0.2H),7.43-7.35(m,2H),7.23-7.18(m,1H),6.02(s,0.2H),5.92(d,J＝3.6Hz,0.8H),4.56(t,J＝5.2Hz,1H),3.98-3.91(m,0.2H),3.78-3.65(m,4.8H),3.59-3.53(m,9H),3.47-3.45(m,2H),3.43-3.42(m,2H),2.92-2.84(m,2H),2.12-1.61(m,4H)。

Compound 471: 5- (4- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1H-pyrazol-1-yl) pentanoic acid

Compound 471-1: methyl 6- (1- ((1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (1- ((1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 466(100mg, 0.177mmol) and methyl 5-chloropentanoate (27mg, 0.177mmol) in N, N-dimethylformamide (5mL) was added potassium carbonate (122mg, 0.884mmol) and sodium iodide (27mg, 0.177mmol) at room temperature. After stirring overnight at 60 ℃, the mixture was diluted with water (20mL) and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound 471-1(115mg, 96% yield). LC-MS (ESI): r_T＝2.262min，C₂₉H₃₂ClFN₆O₆S₂Is calculated asAmount 678.2, M/z found value 679.0[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.87-7.72(m,4H),7.57-7.50(m,1H),7.50-7.40(m,1H),7.17-7.10(m,1H),6.99-6.88(m,1H),6.16(s,0.2H),6.05(s,0.8H),4.19(t,J＝7.2Hz,2H),4.00-3.82(m,3H),3.68(s,3H),3.55(s,3H),2.47-2.33(m,6H),1.99-1.94(m,3H),1.73-1.63(m,3H)。

Compound 471: 5- (4- ((4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) sulfonyl) -1H-pyrazol-1-yl) pentanoic acid

To a solution of methyl 6- (1- ((1H-pyrazol-4-yl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate compound 471-1(112mg, 0.165mmol) in methanol (0.45mL), water (0.45mL), and tetrahydrofuran (1.35mL) was added lithium hydroxide monohydrate (8.0mg, 0.190mmol) at 0 ℃. After stirring at room temperature for 3 hours, the mixture was diluted with water (10mL), acidified to pH about 2 with 1M aqueous hydrochloride solution, and extracted three times with ethyl acetate (15 mL). The combined organic phases were washed with water (15mL), brine (15mL) and Na₂SO_4(s)Dried and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by C18 column (acetonitrile: water 10% to 95%) to give the title compound 471(53mg, purity 97%, 48% yield) as a yellow solid. LC-MS (ESI): r_T＝3.530min，C₂₈H₃₀ClFN₆O₆S₂Calculated mass of 664.1, M/z found value 665.2[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ8.21(s,1H),7.97-7.87(m,1H),7.80(s,1H),7.78-7.71(m,1H),7.41-7.33(m,1H),7.26-7.19(m,1H),7.08-7.00(m,1H),6.11(s,0.2H),6.05(s,0.8H),4.25(t,J＝7.2Hz,2H),3.95-3.75(m,2.5H),3.70-3.66(m,0.5H),3.54(s,3H),2.46-2.34(m,2H),2.33-2.27(m,2H),2.24-2.12(m,1H),2.09-2.01(m,1H),1.97-1.88(m,3H),1.76-1.66(m,1H),1.63-1.53(m,2H)。

Compound 484: methyl 4- (2-chloro-4-fluorophenyl) -6- (1- ((2- (2-hydroxyethoxy) ethyl) sulfonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of methyl 6- (1- ((2- (2- ((tert-butyldiphenylsilyl) oxy) ethoxy) ethyl) sulfonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate 483(160mg, 95% purity, 0.184mmol) in tetrahydrofuran (2mL) at 0 ℃ was added dropwise 1M tetrabutylammonium fluoride in tetrahydrofuran (0.4mL, 0.400 mmol). After stirring at room temperature for 2 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride (5mL) and water (5mL), and then extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (dichloromethane: methanol 1:0 to 30:1) to give a crude product which was further purified by preparative HPLC (column: Water Xbridge C18(5 μm 19 x 150mm), mobile phase a: Water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 15mL/min, gradient: 30% -95% (% B)) to give the title compound 484(60.0mg, 98.5% purity, 55% yield) as a yellow solid. LC-MS (ESI): r_T＝3.803min，C₂₄H₂₈ClFN₄O₆S₂Calculated mass of 586.1, M/z found value 586.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.20(s,0.3H),7.83-7.81(m,1H),7.53-7.52(m,0.7H),7.45-7.44(m,1H),7.29-7.27(m,1H),7.15-7.11(m,1H),6.97-6.88(m,1H),6.18(s,0.3H),6.06(d,J＝2.8Hz,0.7H),4.21-4.13(m,0.3H),3.98-3.89(m,4.7H),3.83-3.77(m,2H),3.65-3.62(m,2H),3.59-3.58(m,3H),3.29-3.24(m,2H),3.09-2.92(m,2H),2.84-2.81(m,0.3H),2.47-2.44(m,0.7H),2.30-2.19(m,0.7H),2.12-2.00(m,1H),1.94-1.84(m,1.6H),1.73-1.69(m,0.7H)。

Example 1: HBV Assembly assay

The interference of the compounds of the invention on HBV capsid assembly can be measured using an in vitro assembly assay based on fluorescence quenching, developed according to the methods described by Zlotnick and coworkers (Nature Biotechnology [ natural Biotechnology ]2006,24: 358). In a typical assay, the mutated HBV C150 protein (amino acids 1-150, C49A, C61A, C107A, 150C) was cloned into a T7 RNA polymerase-based expression vector, expressed in e.coli, and purified as a homodimer. Purified HBV core protein was desalted and labeled with BODIPY-FL dye.

In a non-limiting example, the assembly assay is performed in a 96-well plate format. The assembly reaction was performed in 50mM hepes buffer at pH 7.5 and 150mM NaCl. The compounds were preincubated with HBV CA protein for 15 minutes, and then the assembly reaction was initiated by addition of NaCl. The reaction was allowed to continue at room temperature for 1 hour. Changes in fluorescence between DMSO-treated samples and compound-treated samples were recorded and analyzed for assembly adjustments.

Example 2: HBV inhibitory Activity and cytotoxicity assays

The inhibitory effect of the compounds of the invention on HBV replication and cytotoxicity assays were determined in cells infected or transfected with HBV or cells with stably integrated HBV (e.g.HepG2.2.15 cells) (Sells et al 1987). The method used here is as follows.

Hepg2.2.15 cells were seeded into 96-well plates in 2% FBS (fetal bovine serum) medium at a density of 40,000 cells/well and 5,000 cells/well for HBV inhibitory activity and cytotoxicity assays, respectively. After inoculation, the cell plates were incubated at 37 ℃ with 5% CO₂Incubate overnight. The next day, compound-containing medium was added to treat the cells for 6 days, and the medium was refreshed once in the middle of the treatment. Using eight dose points, each compound was diluted 3-fold, with the highest concentrations of compound being 10 μ M and 100 μ M for HBV inhibitory activity and cytotoxicity assays, respectively.

After 6 days of compound treatment, 20. mu.l of CCK-8 (cell counting kit-8 (Tianjin Biolite)) reagent was added to each well of the cytotoxicity assay plate, and the plate was incubated at 37 ℃ with 5% CO₂Incubate for 2.5 hours and measure the absorbance at 450nm wavelength while reading the absorbance at 630nm wavelength as a reference.

The change in HBVDAN in the cell culture medium induced by the compound was measured by the q-PCR (quantitative polymerase chain reaction) method. HBV DNA in the culture medium was extracted using QIAamp 96DNA blood kit according to the manual and then quantified by q-PCR using primers and probes in the following table:

EC50 and CC50 values were calculated by GraphPad Prism software and are averages of multiple measurements taken. Table 4 shows EC50 and CC50 values for those exemplary compounds with EC50 values below 1 μ M. EC50 values for other exemplary compounds were not measured or were above 1 μ M.

TABLE 4 Activity data

The disclosure of each and every patent, patent application, and publication cited herein is hereby incorporated by reference in its entirety.

Although the present invention has been disclosed with reference to specific embodiments, other embodiments and variations of the present invention may be devised by those skilled in the art without departing from the true spirit and scope of the invention. It is intended that the following claims be interpreted to embrace all such embodiments and all equivalent variations.