阅读说明：本技术 二氢嘧啶衍生物及其在治疗hbv感染或hbv诱发疾病中的用途 (Dihydropyrimidine derivatives and their use in the treatment of HBV infection or HBV-induced diseases ) 是由 邓刚 蒋益民 刘谦 梁超 万昭奎 张荣顺 程战领 徐彦平 于 2019-06-25 设计创作，主要内容包括：本申请描述了可用于治疗或预防HBV感染或HBV诱发疾病、更特别地是HBV慢性感染或由HBV慢性感染诱发的疾病的二氢嘧啶衍生物,及其制药或医学应用。(Dihydropyrimidine derivatives useful for the treatment or prevention of HBV infection or HBV-induced disease, more particularly HBV chronic infection or disease induced by HBV chronic infection, and their pharmaceutical or medical use are described.)

1. a compound having the formula (I)

Including deuterated isomers, stereoisomers, and tautomeric forms thereof,

wherein

Y₁Represents a bond or CR⁷R⁸；

Wherein

Y₂Represents a bond or CR⁷R⁸Wherein R is⁷And R⁸Independently selected from hydrogen and C1-C4 alkyl, and A represents CH or N; or

Y₂Is CR⁹And a is C, thereby forming a C ═ C bond, where R is⁹Is hydrogen or C1-C4 alkyl;

wherein Y is₃Represents CH;

or Y1 and Y2 represent a bond and there is a further-CH 2-directly linking a and Y3 to form a bridged 5-membered cyclic hydrocarbon;

Wherein Y is₄Is OH OR OR¹⁴Or R¹⁴Wherein R is¹⁴Is C₁-C₄An alkyl group;

wherein Q represents a bond or a 5-to 6-membered aromatic ring;

wherein the 5-to 6-membered aromatic ring optionally comprises 1-3 heteroatoms;

wherein the 5-to 6-membered aromatic ring is optionally substituted with one or more substituents each independently selected from the group consisting of:

C₁-C₄an alkyl group, a carboxyl group,

the halogen(s) are selected from the group consisting of,

OR¹³wherein R is¹³Is H or C1-C4 alkyl,

NR¹⁰R¹¹wherein R is¹⁰And R¹¹Independently selected from H and C1-C4 alkyl or R¹⁰And R¹¹Form a C4, C5 or C6 membered ring,

c substituted by one or more halogens₁-C₄An alkyl group, a carboxyl group,

is OR-ed¹²Substituted C₁-C₄Alkyl radical, wherein each R¹²Is H or C₁-C₄An alkyl group;

wherein if Q represents a bond, Y₄Selected from the group consisting of:

a phenyl group,

a pyrazolyl group which is a group of pyrazolyl groups,

an isoxazolyl group, a heterocyclic group,

a thiadiazolyl group,

phenyl substituted by C1-C4 alkyl,

pyrazolyl substituted by C1-C4 alkyl,

isoxazolyl substituted by C1-C4 alkyl, and

thiadiazolyl substituted with C1-C4 alkyl;

wherein L is₁Selected from the group consisting of:

a key(s) for the key(s),

C₁-C₄alkyl, and

c substituted with one or more substituents each independently selected from the group consisting of₁-C₄Alkyl, the group consisting of:

C₁-a C4 alkyl group,

the halogen(s) are selected from the group consisting of,

an oxo group is present in the amino group,

OR⁷wherein R is⁷Independently is hydrogen or C₁-C₄Alkyl, and

C1-C4 alkyl substituted with one or more halogens;

wherein L is₂Selected from the group consisting of:

a key(s) for the key(s),

C₁-C₄alkyl, and

a 3-7 membered saturated ring optionally containing one or more heteroatoms, said heteroatoms being nitrogen

Wherein said C₁-C₄Each of the alkyl and the 3-7 membered saturated ring is optionally substituted with one or more substituents each independently selected from the group consisting of:

C₁-C₄an alkyl group, a carboxyl group,

the halogen(s) are selected from the group consisting of,

OR¹⁵wherein R is¹⁵Independently is hydrogen or C₁-C₄Alkyl, and

c substituted by one or more halogens₁-C₄An alkyl group;

wherein p is an integer selected from 0 and 1, more particularly 1;

wherein R is₁Selected from the group consisting of: thiazolyl, pyridyl, thiazolyl substituted with one or more halo, and pyridyl substituted with one or more halo;

wherein R is³Is C₁-C₃An alkyl group; and is

Wherein R is⁴、R⁵And R⁶Each independently selected from the group consisting of: hydrogen, C₁-C₃Alkyl and halogen;

or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1, wherein Y⁴Is OH, -methoxy or ethoxy.

3. The compound of claim 1 or 2, wherein R³Is methyl or ethyl.

4. The compound of any one of claims 1-3, wherein R ⁴、R⁵And R⁶Each independently selected from CH₃F, Cl and Br, more particularly selected from F and Cl.

5. The compound of any one of claims 1-4, wherein Q is selected from the group consisting of: oxazolyl, isoxazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrazolyl, imidazo, thiazolyl, thiadiazolyl, and phenyl.

6. The compound of any one of claims 1-5, wherein Y is₁、Y₂And Y₃Is CH.

7. The compound of any one of claims 1-6, wherein L₂Is methylene, ethylene, isobutylene, or cyclobutene.

8. The compound of claim 1, selected from compounds satisfying the following formula:

9. a pharmaceutical composition comprising a compound of any one of claims 1-8 and further comprising at least one pharmaceutically acceptable carrier.

10. A compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 for use as a medicament.

11. A compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 for use in the prevention or treatment of HBV infection or HBV-induced disease in a mammal in need thereof.

12. A product comprising a first compound and a second compound as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of an HBV infection or an HBV-induced disease in a mammal in need thereof, wherein the first compound is different from the second compound, wherein the first compound is a compound according to any one of claims 1 to 8, and wherein the second compound is an HBV inhibitor selected from:

-a cytokine having HBV replication inhibitory activity,

an antibody having immune checkpoint modulating activity,

-a substituted pyrimidine having HBV capsid assembly inhibitory activity or having TLR agonist activity,

-antiretroviral nucleoside analogues, and

-combinations thereof.

13. The product of claim 12, wherein the second compound is an HBV inhibitor selected from:

-interferon, interferon-alpha, pegylated interferon-alpha,

an anti-PD 1 antibody,

-a substituted pyrimidine having HBV capsid assembly inhibitory activity or having TLR7 and/or TLR8 and/or TLR9 agonist activity,

lamivudine (or 3TC, CAS registry number 134678-17-4), adefovir dipivoxil, tenofovir disoproxil fumarate), and

-combinations thereof.

14. A method for producing a compound of formula I as defined in claim 1, wherein p is 1 and a is CH, the method comprising:

reacting an active acyl compound having the formula III-1

Reaction with R3-malonic ester to intermediates having the formula IV-1

Reacting a compound having formula IV-1 with a compound having the general formulae V and VI, i.e.,

conducting a multicomponent reaction in the presence of a base to provide an intermediate having formula VII

Subjecting an intermediate having formula VII to ester hydrolysis to provide a compound having formula I, wherein p is 1 and a is CH.

15. A method for producing a compound of formula I as defined in claim 1, wherein p is 1 and a is N, the method comprising:

reacting an active acyl compound having the formula III-2

And R³Reaction of malonic esters to intermediates having formula IV-2

Reacting a compound having formula IV-2 with a compound having general formulas V and VI, i.e.,

conducting a multicomponent reaction in the presence of a base to provide an intermediate having formula VIII,

subjecting a compound having formula VIII to a deprotection reaction to provide an intermediate having formula IX

Subjecting a compound having formula IX to a coupling reaction to provide an intermediate having formula XI

Subjecting an intermediate having the formula XI to ester hydrolysis to provide a compound having the compound of formula I, wherein p is 1 and a is N.

Background

Chronic Hepatitis B Virus (HBV) infection is a major global health problem affecting more than 5% of the world population (more than 3.5 million people worldwide, 125 million people in the united states).

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

Current treatments are incurable and limited to two classes of agents (interferon alpha and nucleoside analogs/viral polymerase inhibitors); resistance, poor efficacy and tolerability problems limit their impact. The low cure rate of HBV is due at least in part to the fact that complete inhibition of virus production is difficult with a single antiviral agent. However, continued suppression of HBV DNA slows the progression of liver disease and helps to prevent hepatocellular carcinoma. The current therapeutic goal of HBV infected patients is to reduce serum HBV DNA to low or undetectable levels and ultimately reduce or prevent the development of cirrhosis and hepatocellular carcinoma.

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.

Background references to dihydropyrimidine derivatives in the treatment of HBV infection include WO 2014/029193, CN 103664899, CN 103664925, and CN 103664897.

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.

Disclosure of Invention

In one aspect, compounds having formula (I) are provided

Including deuterated isomers, stereoisomers, and tautomeric forms thereof,

wherein

Y₁Represents a bond or CR⁷R⁸；

Wherein

Y₂Represents a bond or CR⁷R⁸Wherein R is⁷And R⁸Independently selected from hydrogen and C1-C4 alkyl, and A represents CH or N; or

Y₂Is CR⁹And a is C, thereby forming a C ═ C bond, where R is⁹Is hydrogen or C₁-C₄An alkyl group;

wherein Y is₃Represents CH;

or Y1 and Y2 represent a bond, and the presence of an additional-CH₂-directly linking a and Y3 to form a bridged 5-membered cyclic hydrocarbon;

wherein Y is₄Is OH OR OR¹⁴Or R¹⁴Wherein R is¹⁴Is C₁-C₄An alkyl group;

wherein Q represents a bond or a 5-to 6-membered aromatic ring;

wherein the 5-to 6-membered aromatic ring optionally comprises 1-3 heteroatoms;

wherein the 5-to 6-membered aromatic ring is optionally substituted with one or more substituents each independently selected from the group consisting of:

C₁-C₄an alkyl group, a carboxyl group,

the halogen(s) are selected from the group consisting of,

OR¹³wherein R is¹³Is H or C₁-C₄An alkyl group, a carboxyl group,

NR¹⁰R¹¹wherein R is¹⁰And R¹¹Independently selected from H and C₁-C₄Alkyl or R¹⁰And R¹¹Form a C4, C5 or C6 membered ring,

c substituted by one or more halogens₁-C₄An alkyl group, a carboxyl group,

is OR-ed¹²Substituted C₁-C₄Alkyl radical, wherein each R¹²Is H or C₁-C₄An alkyl group;

wherein if Q represents a bond, Y₄Selected from the group consisting of:

a phenyl group,

a pyrazolyl group which is a group of pyrazolyl groups,

an isoxazolyl group, a heterocyclic group,

a thiadiazolyl group,

quilt C ₁-C₄A phenyl group substituted with an alkyl group,

quilt C₁-C₄An alkyl-substituted pyrazolyl group which is substituted with an alkyl group,

quilt C₁-C₄An alkyl-substituted isoxazolyl, and

quilt C₁-C₄An alkyl-substituted thiadiazolyl group;

wherein L is₁Selected from the group consisting of:

a key(s) for the key(s),

C₁-C₄alkyl, and

c substituted with one or more substituents each independently selected from the group consisting of₁-C₄Alkyl, the group consisting of:

C₁-C₄an alkyl group, a carboxyl group,

the halogen(s) are selected from the group consisting of,

an oxo group is present in the amino group,

OR⁷wherein R is⁷Independently is hydrogen or C₁-C₄Alkyl, and

c substituted by one or more halogens₁-C₄An alkyl group;

wherein L is₂Selected from the group consisting of:

a key(s) for the key(s),

C₁-C₄alkyl, and

a 3-7 membered saturated ring optionally containing one or more heteroatoms, which is nitrogen

Wherein said C₁-C₄Each of the alkyl and the 3-7 membered saturated ring is optionally substituted with one or more substituents each independently selected from the group consisting of:

C₁-C₄an alkyl group, a carboxyl group,

the halogen(s) are selected from the group consisting of,

OR¹⁵wherein R is¹⁵Independently is hydrogen or C₁-C₄Alkyl, and

c substituted by one or more halogens₁-C₄An alkyl group;

wherein p is an integer selected from 0 and 1, more particularly 1;

wherein R is₁Selected from the group consisting of: thiazolyl, pyridyl, thiazolyl substituted with one or more halo, and pyridyl substituted with one or more halo;

wherein R is ³Is C₁-C₃An alkyl group; and is

Wherein R is⁴、R⁵And R⁶Each independently selected from the group consisting of: hydrogen, C₁-C₃Alkyl and halogen;

or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, provided herein is a pharmaceutical composition comprising at least one compound having 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 a still further aspect, provided herein is a product comprising a first compound and a second compound as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of HBV infection or HBV-induced disease in a mammal in need thereof, wherein the first compound is different from the second compound, wherein the first compound is a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9, and wherein the second compound is an HBV inhibitor selected from:

-a cytokine having HBV replication inhibitory activity,

an antibody having immune checkpoint modulating activity,

-a substituted pyrimidine having HBV capsid assembly inhibitory activity or having TLR agonist activity,

-antiretroviral nucleoside analogues, and

-combinations 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 having formula I or a pharmaceutically acceptable salt thereof.

In one embodiment, any of the methods provided herein can 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.

In still a further aspect, there is provided a method for producing a compound having formula I, wherein p is 1 and a is CH, comprising:

reacting an active acyl compound having the formula III-1

And R³Reaction of malonic esters to intermediates having formula IV-1

Reacting a compound having formula IV-1 with a compound having the general formulae V and VI, i.e.,

conducting a multicomponent reaction in the presence of a base to provide an intermediate having formula VII

Subjecting an intermediate having formula VII to ester hydrolysis to provide a compound having formula I.

Alternatively, another method is provided for producing a compound having formula I, wherein p is 1 and a is N, and wherein the produced compound is a compound satisfying formula II, the method comprising:

reacting an active acyl compound having the formula III-2

And R³Reaction of malonic esters to intermediates having formula IV-2

Reacting a compound having formula IV-2 with a compound having general formulas V and VI, i.e.,

conducting a multicomponent reaction in the presence of a base to provide an intermediate having formula VIII,

subjecting a compound having formula VIII to a deprotection reaction to provide an intermediate having formula IX

Subjecting a compound having formula IX to a coupling reaction to provide an intermediate having formula XI

Subjecting an intermediate having formula XI to ester hydrolysis to provide a compound having formula II (where formula II is equal to formula I).

Detailed Description

The present application provides compounds having formula (I),

Including deuterated isomers, stereoisomers, and tautomeric forms thereof,

wherein

Y₁Represents a bond or CR⁷R⁸；

Wherein

Y₂Represents a bond or CR⁷R⁸Wherein R is⁷And R⁸Independently selected from hydrogen and C1-C4 alkyl, and A represents CH or N; or

Y₂Is CR⁹And a is C, thereby forming a C ═ C bond, where R is⁹Is hydrogen or C1-C4 alkyl;

wherein Y is₃Represents CH;

or Y1 and Y2 represent a bond and there is a further-CH 2-directly linking a and Y3 to form a bridged 5-membered cyclic hydrocarbon;

wherein Y is₄Is OH OR OR¹⁴Or R¹⁴Wherein R is¹⁴Is C₁-C₄An alkyl group;

wherein Q represents a bond or a 5-to 6-membered aromatic ring;

wherein the 5-to 6-membered aromatic ring optionally comprises 1-3 heteroatoms;

wherein the 5-to 6-membered aromatic ring is optionally substituted with one or more substituents each independently selected from the group consisting of:

C₁-C₄an alkyl group, a carboxyl group,

the halogen(s) are selected from the group consisting of,

OR¹³wherein R is¹³Is H or C1-C4 alkyl,

NR¹⁰R¹¹wherein R is¹⁰And R¹¹Independently selected from H and C1-C4 alkyl or R¹⁰And R¹¹Form a C4, C5 or C6 membered ring,

c substituted by one or more halogens₁-C₄An alkyl group, a carboxyl group,

is OR-ed¹²Substituted C₁-C₄Alkyl radical, wherein each R¹²Is H or C₁-C₄An alkyl group;

wherein if Q represents a bond, Y₄Selected from the group consisting of:

a phenyl group,

a pyrazolyl group which is a group of pyrazolyl groups,

an isoxazolyl group, a heterocyclic group,

a thiadiazolyl group,

Phenyl substituted by C1-C4 alkyl,

pyrazolyl substituted by C1-C4 alkyl,

isoxazolyl substituted by C1-C4 alkyl, and

thiadiazolyl substituted with C1-C4 alkyl;

wherein L is₁Selected from the group consisting of:

a key(s) for the key(s),

C₁-C₄alkyl, and

c substituted with one or more substituents each independently selected from the group consisting of₁-C₄Alkyl, the group consisting of:

C₁-a C4 alkyl group,

the halogen(s) are selected from the group consisting of,

an oxo group is present in the amino group,

OR⁷wherein R is⁷Independently is hydrogen or C₁-C₄Alkyl, and

C1-C4 alkyl substituted with one or more halogens;

wherein L is₂Selected from the group consisting of:

a key(s) for the key(s),

C₁-C₄alkyl, and

a 3-7 membered saturated ring optionally containing one or more heteroatoms, said heteroatoms being nitrogen

Wherein said C₁-C₄Each of the alkyl and the 3-7 membered saturated ring is optionally substituted with one or more substituents each independently selected from the group consisting of:

C₁-C₄an alkyl group, a carboxyl group,

the halogen(s) are selected from the group consisting of,

OR¹⁵wherein R is¹⁵Independently is hydrogen or C₁-C₄Alkyl, and

c substituted by one or more halogens₁-C₄An alkyl group;

wherein p is an integer selected from 0 and 1, more particularly 1;

wherein R is₁Selected from the group consisting of: thiazolyl, pyridyl, thiazolyl substituted with one or more halo, and pyridyl substituted with one or more halo;

Wherein R is³Is C₁-C₃An alkyl group; and is

Wherein R is⁴、R⁵And R⁶Each independently selected from the group consisting of: hydrogen, C₁-C₃Alkyl and halogen;

or a pharmaceutically acceptable salt or solvate thereof.

Provided herein are compounds, e.g., compounds of formula (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 the application or administration of 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 the application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnostic or ex vivo applications). 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, but are not limited to, inorganic or organic acid salts of basic residues such as amines; an alkali metal or organic salt of an acidic residue such as a carboxylic acid; 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 free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts is found in Remington's Pharmaceutical Sciences [ Ramington's Pharmaceutical Sciences ], 17 th edition, Mack Publishing Company [ Mark Publishing Company ], Iston, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science [ Journal of Pharmaceutical Sciences ],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 serve 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 ] (Genaro, ed., Mark Publishing Co., Mack Publishing Co., 1985, Iston, Pa.), which are 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. Examples of alkyl groups include, but are not limited to, C ₁-C₁₀Alkyl radicals, e.g. C₁-C₆Alkyl radicals, e.g. C₁-C₄An alkyl group.

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, aziridines. 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 thiazolidinediones. 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). Examples of aryl 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 six to twelve 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 one to four further 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., R) ⁴Selected 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 ").

In one embodiment of the compound having formula (I), Y⁴Is OH, methoxy or ethoxy.

In one embodiment of the compound having formula (I), R³Is methyl or ethyl.

In one embodiment of the compound having formula (I), R⁴、R⁵And R⁶Each independently selected from CH₃F, Cl and Br, more particularly selected from F and Cl.

In one embodiment of the compound having formula (I), Q is selected from the group consisting of: oxazolyl, isoxazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrazolyl, imidazo, thiazolyl, thiadiazolyl, and phenyl.

In one embodiment of the compound having formula (I), Y₁、Y₂And Y₃Is CH.

In one embodiment of the compound having formula (I), L₂Is methylene, ethylene, isobutylene, or cyclobutene.

All combinations of the foregoing embodiments are explicitly included.

In embodiments, the compound having formula (I) is selected from compounds satisfying the following formula:

the disclosed compounds may have one or more stereocenters, and each stereocenter may independently exist in the R or S configuration. Although the compounds themselves have been isolated as single stereoisomers and are enantiomerically/diastereomerically pure, the stereoconfiguration at a designated center can be designated (×) when the absolute stereochemistry at the stereocenter is not yet determined. 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 can be used to examine the positive charge occupied by the substrate receptorA sub-emission tomography (PET) study. 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 procedures for preparing the compounds described herein are modified by the use of appropriate reagents and conditions in order to incorporate the various moieties shown in the formulae as 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. General synthetic schemes are given in the examples below.

Accordingly, there is provided a process for the preparation of a compound having formula (I), wherein the process comprises

Reacting an active acyl compound having the formula III-1

Reaction with R3-malonic ester to intermediates having the formula IV-1

Reacting a compound having formula IV-1 with a compound having the general formulae V and VI, i.e.,

conducting a multicomponent reaction in the presence of a base to provide an intermediate having formula VII

Subjecting an intermediate having formula VII to ester hydrolysis to provide a compound having formula I.

In another embodiment, there is provided a method for producing a compound having formula (I), wherein p is 1 and a is N, and wherein the produced compound is a compound satisfying formula II, the method comprising:

Reacting an active acyl compound having the formula III-2

And R³Reaction of malonic esters to intermediates having formula IV-2

Reacting a compound having formula IV-2 with a compound having general formulas V and VI, i.e.,

conducting a multicomponent reaction in the presence of a base to provide an intermediate having formula VIII,

subjecting a compound having formula VIII to a deprotection reaction to provide an intermediate having formula IX

Subjecting a compound having formula IX to a coupling reaction to provide an intermediate having formula XI

Subjecting an intermediate having formula XI to ester hydrolysis to provide a compound having formula II:

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 subject 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 having 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 having 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 alpha (IFN-alpha), interferon beta (IFN-beta), 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-gamma (IFN- γ); and type III, which includes interferon- λ (IFN- λ). The term "interferon" as used herein includes recombinant forms of interferon that have been developed and are commercially available. The term "interferon" as used herein also includes subtypes of interferon, such as chemically modified or mutated interferons. Chemically modified interferons may include pegylated interferons and glycosylated interferons. Examples of interferons also include, but are not limited to, interferon- α -2a, interferon- α -2b, interferon- α -n1, interferon- β -1a, interferon- β -1b, interferon- λ -1, interferon- λ -2, and interferon- λ -3. Examples of pegylated interferons include pegylated interferon-alpha-2 a and pegylated interferon alpha-2 b.

Thus, in one embodiment, the compound having formula I may be administered in combination with an interferon selected from the group consisting of: interferon alpha (IFN- α), interferon beta (IFN- β), interferon lambda (IFN- λ), and interferon gamma (IFN- γ). In a particular embodiment, the interferon is interferon- α -2a, interferon- α -2b or interferon- α -n 1. 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 one embodiment, the additional therapeutic agent is an immunomodulator that induces a natural, limited immune response, resulting in the induction of an immune response against an unrelated virus. In other words, immunomodulators can affect maturation of antigen presenting cells, proliferation of T cells, and cytokine release (e.g., IL-12, IL-18, IFN- α, IFN- β, IFN- γ, TNF- α, etc.),

in further embodiments, 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 and Scheiner,19981, clin. pharmacokinet. [ clinical pharmacokinetics ]]6:429-]114:313-]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 compounds 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 quantity of the disclosed compounds 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 1mg to about 2,500mg per month. 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

Example 1:

general scheme 1

General scheme 2

A general synthesis of the final compounds having general formula I is described in general scheme 1. Compounds having the general formula IV-1 can be synthesized using method A. As described in method a, for example, an acid having the general formula III-1 is activated to an acylimidazole and coupled under basic conditions with potassium methyl (or ethyl) malonate to generate an intermediate, which in turn undergoes decarboxylation to yield a ketoester having the general formula IV-1. The compounds having formula VII can be synthesized by a chemical method of multicomponent reaction (method B) of compounds having formulas IV-1, V and VI in a selected solvent (but not limited to ethanol) in the presence of a base (but not limited to sodium acetate NaOAc). The final product having the general formula I can be synthesized by ester hydrolysis reaction (method C).

A general synthesis of the final compounds having general formula II is described in general scheme 2. Compounds having the general formula IV-2 can be synthesized using method A. As described in method a, an acid having the general formula III-2 is converted to an activated ester by reaction with N, N-carbonyldiimidazole CDI, which is then coupled under basic conditions with potassium methyl (or ethyl) malonate to produce an intermediate, which in turn undergoes decarboxylation to produce a ketoester having the general formula IV-2. The compounds having formula VIII can be synthesized by a chemical method of multicomponent reaction (method B) of compounds having formulae IV-2, V and VI in a selected solvent (but not limited to ethanol) in the presence of a base (but not limited to sodium acetate NaOAc). Free amines having the general formula IX can be synthesized by deprotection reaction (method D). Can pass through S_NAr reaction (method E), and then synthesis of compounds having general formula II from general formula IX and general formula X by ester hydrolysis reaction (method C). Some of the final compounds having the general formula II were synthesized by forming a ketoester intermediate and then performing a multi-component reaction procedure.

Method A

To a solution of an acid of general formula III-1 or III-2 (1 equivalent) in acetonitrile was added N, N' -carbonyldiimidazole (1.1-2 equivalents) at room temperature. The mixture was stirred at room temperature for 2 hours under nitrogen atmosphere (mixture a). To potassium methyl malonate (2-2.1 equivalents, R) at room temperature ³Is methyl) or potassium ethyl malonate (2-2.1 equivalents, R)³Is ethyl) to a suspension in acetonitrile was added magnesium chloride (2.1-2.5 equivalents) and triethylamine (3-3.2 equivalents). After stirring under nitrogen for 2 hours, mixture a was added to the resulting mixture and stirring was continued at 80 ℃ to 100 ℃ for a period ranging from 3 hours to overnight. It was then cooled to room temperature and concentrated to give a residueThe residue is purified by silica gel column chromatography to provide a ketoester having the general formula IV-1 or IV-2.

Method B

To a solution of the ketoester of formula IV-1 or IV-2 (1 equivalent) in ethanol was added the aldehyde of formula V (1 equivalent), formamidine hydrochloride of formula VI (1 equivalent) and sodium acetate (1-1.2 equivalents). The mixture was warmed to 70-100 ℃ and stirred under nitrogen for 16 hours to overnight. After cooling to room temperature, it was concentrated to dryness. The residue was extracted from dichloromethane, washed with water, brine, and dried 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 having the formula VII, or formula VIII. Chiral chromatography is used, where applicable, to separate and purify stereoisomers of dihydropyrimidine products having the formula VII or formula VIII.

Method C

To a solution of an ester having formula VII (1 equivalent), or formula XI (1 equivalent), lithium hydroxide (2 equivalents) was added in a solvent of tetrahydrofuran methanol water 2:2:1 at 0 deg.C. After stirring at 0 ℃ for 2 hours, water was added to the mixture and concentrated under reduced pressure at room temperature to remove volatiles. The residue was acidified with 1M aqueous hydrochloric acid and purified by silica gel column chromatography to provide the final compound having general formula I, or II, respectively. Chiral chromatography is used, where applicable, to separate and purify the stereoisomers of the dihydropyrimidine products having the general formulae I and II.

Method D

Trifluoroacetic acid (80 equivalents) was added to a solution of formula VIII (1 equivalent) in dichloromethane at room temperature. After stirring at room temperature for 0.5 hour, the mixture was reducedConcentrated under reduced pressure to give a residue which was dissolved in ethyl acetate and washed three times with saturated aqueous sodium bicarbonate, three times with water and three times with brine, over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the final compound having formula IX.

Method E

To a solution of formula IX (1 equivalent) and formula X (1 equivalent) in a solvent (e.g. 1, 4-dioxane, DMF) is added a base (e.g. triethylamine, N-diisopropylethylamine, or potassium carbonate, 5 equivalents) at room temperature. After stirring at 100 ℃ for 5 hours under nitrogen and cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, over Na ₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by C18 column to give the product of formula XI. Chiral chromatography is used, where applicable, to separate and purify the stereoisomers of the dihydropyrimidine product of formula XI.

Part I: preparation of acids of the general formulae III-1 and III-2

Acid 1: 4- (4- (methoxycarbonyl) oxazol-2-yl) cyclohexane-1-carboxylic acid (A1)

Intermediate a 1-2:

4-Oxocyclohexanecarboxylic acid benzyl ester

To a solution of 4-oxocyclohexanecarboxylic acid A1-1(20.0g, 0.141mol), potassium carbonate (38.9g, 0.282mol) in N, N-dimethylformamide (100mL) was added (bromomethyl) benzene (28.8g, 0.169 mol). The mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water (450mL) and extracted three times with ethyl acetate (200 mL). The combined organic layers were washed with water (100mL), brine (100mL) and Na₂SO₄(solid) drying, filtration and concentration to give the crude product, which is purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1 to 5:1) toThe title compound was obtained as a yellow oil (30.0g, 92% yield).¹H NMR(300MHz,DMSO-d₆)δ7.37-7.26(m,5H),5.12-5.05(m,2H),2.91-2.79(m,1H),2.41-2.31(m,2H),2.23-2.08(m,4H),1.87-1.72(m,2H)。

Intermediate a 1-4:

benzyl 4- (methoxymethylene) cyclohexanecarboxylate

To a mixture of (methoxymethyl) triphenylphosphonium chloride A1-3(54.8g, 0.160mol) in tetrahydrofuran (350mL) at 0 deg.C was slowly added potassium tert-butoxide (17.9g, 0.160mol) to keep the internal temperature below 5 deg.C. After stirring at this temperature for 1 hour, a solution of benzyl 4-oxocyclohexanecarboxylate A1-2(23.7g, 0.100mol) in tetrahydrofuran (50mL) was added to the mixture. The mixture was slowly warmed to 25 ℃ and stirred at 25 ℃ for 16 minutes. The reaction mixture was diluted with water (500 mL). The organic phase was separated. 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 to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 200:1 to 50:1) to give the title compound as a colorless oil (19.1g, 72% yield).¹H NMR(300MHz,CDCl₃)δ7.38-7.29(m,5H),5.77(s,1H),5.11(s,2H),3.53(s,3H),2.76-2.71(m,1H),2.51-2.43(m,1H),2.13-2.08(m,1H),2.01-1.87(m,3H),1.79-1.71(m,1H),1.56-1.45(m,2H)。

Intermediate a 1-5:

benzyl 4-formylcyclohexanecarboxylate

To a mixture of benzyl 4- (methoxymethylene) cyclohexane-1-carboxylate A1-4(19.1g, 73.5mmol) in tetrahydrofuran (160mL) at 0 deg.C was added 6M aqueous hydrochloric acid (38.2mL, 229 mmol). After stirring at 25 ℃ for 2 h, the reaction mixture was quenched with brine (300 mL). The organic layer was precipitated. The aqueous layer was extracted three times with ethyl acetate (200 mL). The combined organic layers were washed with brine (200mL) and Na ₂SO₄(solid) dried and filtered. The filtrate was concentrated to give the title compound as a yellow oil (17.6g, 98% yield).¹H NMR(400MHz,CDCl₃)δ9.65(s,0.4H),9.63(s,0.6H),7.37-7.31(m,5H),5.12(s,1.2H),5.11(s,0.8H),2.51-2.48(m,0.3H),2.35-2.22(m,1.5H),2.15-2.04(m,2.7H),1.99-1.93(m,0.5H),1.79-1.75(m,1H),1.71-1.66(m,1H),1.56-1.47(m,1.5H),1.34-1.26(m,1.5H)。

Intermediate a 1-7:

methyl 2- (4- ((benzyloxy) carbonyl) cyclohexyl) -2, 5-dihydrooxazole-4-carboxylate

To a mixture of (R) -methyl 2-amino-3-hydroxypropionic acid hydrochloride A1-6(12.2g, 78.7mmol) in dichloromethane (350mL) was added 1, 4-diazabicyclo [2.2.2 [ ] -]Octane (24.1g, 215 mmol). After stirring at 25 ℃ for 20 minutes under a nitrogen atmosphere, a solution of benzyl 4-formylcyclohexanecarboxylate A1-5(17.6g, 71.5mmol) in dichloromethane (350mL) was added to the mixture. The mixture was stirred under nitrogen at 25 ℃ for 30 minutes. N-chlorosuccinimide (10.5g, 78.7mmol) was added to the mixture at 0 ℃ and the resulting mixture was stirred at 0 ℃ for 2 hours. The reaction mixture was quenched with saturated aqueous sodium metabisulfite (300 mL). The organic phase was separated. The aqueous layer was 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 to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1 to 5:1) to give the title compound (18.4g, 74% yield) as a colorless oil. ¹H NMR(400MHz,CDCl₃)δ7.38-7.30(m,5H),5.72-5.67(m,1H),5.14-5.11(m,2H),4.86-4.71(m,2H),3.92(s,3H),2.68-2.66(m,0.2H),2.35-2.31(m,0.8H),2.28-2.19(m,0.6H),2.16-2.06(m,1.6H),1.94-1.91(m,0.8H),1.84-1.69(m,2H),1.62-1.40(m,3H),1.26-1.17(m,1H)。

Intermediate A1-8:

methyl 2- (4- ((benzyloxy) carbonyl) cyclohexyl) oxazole-4-carboxylate

A mixture of methyl 2- (4- ((benzyloxy) carbonyl) cyclohexyl) -2, 5-dihydrooxazole-4-carboxylic acid ester A1-7(5.00g,14.5mmol), potassium carbonate (2.30g, 17.4mmol) in 1, 2-dichloroethane (150mL) was stirred at 25 ℃ under a nitrogen atmosphere for 30 minutes. Reacting N-bromosuccinimide(3.13g, 17.4mmol) was added to the mixture. After refluxing for 30 min, the reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium sulfite (50mL), saturated aqueous sodium bicarbonate (50mL) and separated. The aqueous layer was 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 ═ 10:1 to 3:2) to give the title compound as a white solid (3.30g, 66% yield). LC-MS (ESI): r_T＝1.823min,C₁₉H₂₁NO₅Calculated mass of 343.1, M/z found 344.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.15(s,1H),7.39-7.31(m,5H),5.13(s,2H),3.90(s,3H),3.03-2.97(m,0.2H),2.87-2.79(m,0.8H),2.64-2.58(m,0.2H),2.45-2.37(m,0.8H),2.23-2.14(m,4H),1.98-1.85(m,1H),1.75-1.69(m,1H),1.63-1.52(m,2H)。

Acid 1:

4- (4- (methoxycarbonyl) oxazol-2-yl) cyclohexanecarboxylic acid

To a mixture of methyl 2- (4- ((benzyloxy) carbonyl) cyclohexyl) oxazole-4-carboxylate a1-8(3.30g, 9.60mmol) in ethyl acetate (60mL) under a nitrogen atmosphere was added 10% wt. palladium on charcoal (660 mg). The mixture was put under a hydrogen atmosphere (H) ₂Balloon) was stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to give the title compound as a red solid (1.30g, 54% yield).¹H NMR(400MHz,CDCl₃)δ8.16(s,1H),3.91(s,3H),3.05-2.97(m,0.4H),2.88-2.79(m,0.6H),2.67-2.59(m,0.4H),2.43-2.33(m,0.6H),2.24-2.16(m,2H),2.10-2.02(m,2H),1.95-1.87(m,1H),1.76-1.50(m,3H)。

Acid 2: 3- (4- (methoxycarbonyl) oxazol-2-yl) bicyclo [1.1.1] pentane-1-carboxylic acid (A2)

Intermediate a 2-2:

1- (tert-butyl) 3-methylbicyclo [1.1.1] pentane-1, 3-dicarboxylate

To 3- (methoxycarbonyl) bicyclo [1.1.1] at room temperature]To a solution of pentane-1-carboxylic acid A2-1(1.94g, 11.2mmol) and di-tert-butyl dicarbonate (4.98g, 22.8mmol) in tert-butanol (32mL) was added N, N-dimethylpyridin-4-amine (1.53g, 12.5 mmol). After stirring at 50 ℃ for 20 h, the reaction mixture was concentrated under reduced pressure to remove volatiles and dissolved in ethyl acetate (100 mL). The resulting solution was washed with water (50mL), 0.2M aqueous hydrochloric acid (70mL), saturated aqueous sodium bicarbonate (60mL), water (50mL) and brine (50mL), and washed with Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.55g, obtained from¹Purity of H NMR 90%, 91% yield).¹H NMR(400MHz,CDCl₃)δ3.67(s,3H),2.45(s,6H),1.43(s,9H)。

Intermediate a 2-3:

3- (tert-Butoxycarbonyl) bicyclo [1.1.1] pentane-1-carboxylic acid

To 1-tert-butyl 3-methylbicyclo [1.1.1] at 0 deg.C ]To a solution of pentane-1, 3-dicarboxylate A2-2(2.55g, 90% purity, 10.1mmol) in tetrahydrofuran (30mL) and water (10mL) was added lithium hydroxide monohydrate (651mg, 15.5 mmol). After stirring at 0 ℃ for 2.5 h, the reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with water (10mL) and extracted with ethyl acetate (20 mL). The aqueous layer was then acidified to pH 3 to 4 with 0.2M aqueous hydrochloride solution and extracted three times with ethyl acetate (40 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 (2.10g, obtained from¹Purity of H NMR 90%, 88% yield).¹H NMR(300MHz,DMSO-d₆)δ12.53(br s,1H),2.13(s,6H),1.39(s,9H)。

Intermediate a 2-4:

tert-butyl 3- (hydroxymethyl) bicyclo [1.1.1] pentane-1-carboxylate

To 3- (tert-butoxycarbonyl) bicyclo [1.1.1] under nitrogen atmosphere at-70 deg.C]Pentane-1-carboxylic acid A2-3(2.10g, 90% purity, 8.91mmol) in tetrahydrofuran (33 m)l) to the solution was added 10M borane-dimethylsulfide complex (1.4mL, 14.0mmol) in tetrahydrofuran (7 mL). After allowing to warm to room temperature and stirring under nitrogen for 2 hours, the reaction mixture was quenched with water (15mL) and saturated aqueous sodium bicarbonate (15mL) at 0 ℃ and extracted three times with ethyl acetate (40 mL). The combined organic layers were washed with brine (40mL) and Na ₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.95g, obtained from¹Purity of H NMR 90%, 99% yield).¹H NMR(300MHz,CDCl₃)δ3.61(s,2H),1.93(s,6H),1.43(s,9H)。

Intermediate a 2-5:

tert-butyl 3-formylbicyclo [1.1.1] pentane-1-carboxylate

To a solution of dimethyl sulfoxide (1.68g, 21.5mmol) in dichloromethane (80ml) was slowly added oxalyl chloride (1.38g, 10.9mmol) at-78 ℃ under nitrogen. At the same temperature, the reaction mixture was allowed to warm to-60 ℃ and stirred for 15 minutes. Adding methyl 3- (hydroxymethyl) bicyclo [1.1.1] at-60 deg.C]After a solution of pentane-1-carboxylate A2-4(1.95g, 90% purity, 8.85mmol) in dichloromethane (15ml), the mixture was stirred at-60 ℃ for 30 minutes. After addition of triethylamine (4.52g, 44.3mmol) at-60 ℃ the reaction mixture was stirred for 30 min at-60 ℃. The reaction mixture was quenched with water (20ml) at-60 ℃ and warmed to room temperature. The organic layer was separated. The aqueous layer was extracted twice with dichloromethane (50 ml). The combined organic layers were washed with 0.3M aqueous hydrochloric acid (150mL), water (80mL), and brine (80mL) over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.84g, obtained from ¹Purity of H NMR 90%, 95% yield).¹H NMR(300MHz,DMSO-d₆)δ9.53(s,1H),2.17(s,6H),1.40(s,9H)。

Intermediate A2-6:

methyl-2- (3- (tert-butoxycarbonyl) bicyclo [1.1.1] pent-1-yl) -2, 3-dihydrooxazole-4-carboxylic acid ester

To D-serine methyl ester hydrochloride A1-6 (R) at room temperature1.47g, 9.45mmol) in dichloromethane (60mL) was added 1, 4-diazabicyclo [2.2.2]Octane (2.90g, 25.8 mmol). After stirring at room temperature for 30 minutes under a nitrogen atmosphere, the mixture was added to tert-butyl 3-formylbicyclo [1.1.1]Pentane-1-carboxylate a2-5(1.84g, 90% purity, 8.44mmol) in dichloromethane (40mL) and stirring at room temperature under nitrogen was continued for 30 minutes. 1-Chloropyrrolidine-2, 5-dione (1.27g, 9.32mmol) was then added at 0 ℃ and the mixture was stirred at 0 ℃ under nitrogen for 2 hours. It was then quenched with saturated aqueous sodium bisulfite (20mL) and water (20 mL). The aqueous layer was extracted three times with dichloromethane (50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50mL) and brine (50mL) over 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 and petroleum ether: ethyl acetate 100% to 3:1) to give the title compound (1.33g, obtained from ¹Purity of H NMR 90%, 48% yield). LC-MS (ESI): r_T＝1.55min,C₁₅H₂₁NO₅Calculated mass of 295.1, M/z found 296.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ5.83(dd,J＝6.4,4.8Hz,1H),4.79-4.68(m,2H),3.81(s,3H),1.87(s,6H),1.40(s,9H)。

Acid 2:

3- (4- (methoxycarbonyl) oxazol-2-yl) bicyclo [1.1.1] pentane-1-carboxylic acid

To methyl 2- (3- (tert-butoxycarbonyl) bicyclo [1.1.1 at room temperature]Pentan-1-yl) -2, 3-dihydrooxazole-4-carboxylic acid ester A2-6(1.33g, 90% purity, 4.05mmol) in 1, 2-dichloromethane (32mL) was addedMolecular sieves and potassium carbonate (672mg, 4.86 mmol). After stirring at room temperature for 30 minutes, 1-bromopyrrolidine-2, 5-dione (865mg, 4.86mmol) was added to the mixture, which was heated to reflux for 20 minutes and then cooled to 0 ℃. It was quenched by the addition of saturated aqueous sodium thiosulfate (6mL) and saturated aqueous sodium bicarbonate (10 mL). Filtering the mixture and filteringAnd (5) liquid separation. The aqueous layer was extracted three times with dichloromethane (30mL) and then acidified to pH 2 to 3 with 0.5M aqueous hydrochloric acid. It was extracted three times with ethyl acetate (30 mL). The combined ethyl acetate layers were washed with brine (30mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (550mg, obtained from¹Purity of H NMR 90%, 51% yield). LC-MS (ESI): r _T＝0.29min,C₁₁H₁₁NO₅Calculated mass of 237.1, M/z found 238.2[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.17(s,1H),3.91(s,3H),2.55(s,6H)。

Acid 3: 4- (4- (ethoxycarbonyl) oxazol-2-yl) cyclohex-3-enecarboxylic acid (A3)

Intermediate a 3-1:

tert-butyl 4-oxocyclohexanecarboxylic acid ester

To a solution of 4-oxocyclohexanecarboxylic acid A1-1(10.2g, 98% pure, 70.3mmol) in tert-butanol (100mL) were added N, N-dimethylpyridin-4-amine (12.7g, 95% pure, 98.5mmol) and di-tert-butyl dicarbonate (46.5g, 99% pure, 211 mmol). The reaction mixture was stirred at room temperature under nitrogen overnight. It was then concentrated in vacuo and the resulting residue was purified by silica gel column chromatography (petroleum: ethyl acetate ═ 10:1) to give the title compound as a colorless oil (13.3g, 99% purity, 94% yield).¹H NMR(300MHz,DMSO-d₆)δ2.74-2.64(m,1H),2.44-2.33(m,2H),2.26-2.18(m,2H),2.11-2.03(m,2H),1.83-1.70(m,2H),1.41(s,9H)。

Intermediate a 3-2:

tert-butyl 4- (((trifluoromethyl) sulfonyl) oxy) cyclohex-3-enecarboxylate

To tert-butyl 4-oxocyclohexanecarboxylate A3-1(2.00g, 95% purity, 9.58mmol) and 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (3.84g, 10.5mmol) at-78 deg.C in anhydrous tetra-NA solution in tetrahydrofuran (30mL) was added dropwise over 10 minutes to a solution of 1.0M potassium bis (trimethylsilyl) amide in tetrahydrofuran (12mL, 12.0 mmol). After the addition, the mixture was stirred at-78 ℃ for 30 minutes. The mixture was then stirred at room temperature for 1.5 hours. The mixture was diluted with water (50mL) and extracted three times with ethyl acetate (40 mL). The combined organic layers were washed with brine (100mL) and Na ₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel chromatography (petroleum ether: ethyl acetate 100:1 to 50:1) to give the title compound (2.4g, 95% purity from HNMR, 72% yield) as a colorless oil.¹H NMR(400MHz,DMSO-d₆)δ5.89(s,1H),2.58-2.52(m,1H),2.43-2.28(m,4H),2.01-1.94(m,1H),1.85-1.76(m,1H),1.40(s,9H)。

Intermediate a 3-3:

tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enecarboxylate

Tert-butyl 4- (((trifluoromethyl) sulfonyl) oxy) cyclohex-3-enecarboxylate A3-2(2.4g, 6.90mmol, 95% purity), bis (pinacolo) diboron (2.68g, 10.35mmol), [1,1' -bis (diphenylphosphino) ferrocene, was reacted at 70 ℃ under nitrogen]A suspension of palladium (II) dichloride (258mg, 0.345mmol) and potassium acetate (1.73g, 17.3mmol) in 1, 4-dioxane (25mL) was stirred overnight. The mixture was cooled and diluted with water (50 mL). The resulting solution was extracted three times with ethyl acetate (50 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 chromatography (petroleum ether: ethyl acetate 100:1 to 40:1) to give the title compound (1.05g, 95% purity from HNMR, 47% yield) as a white solid. LC-MS (ESI): r_T＝1.71min,C₁₇H₂₉BO₄Calculated mass of 308.2, M/z found 326.3[ M + NH ] ₄]⁺。¹H NMR(400MHz,CDCl₃)δ6.54(s,1H),2.45-2.37(m,1H),2.29-2.24(m,3H),2.14-2.06(m,1H),2.00-1.94(m,1H),1.58-1.50(m,1H),1.44(s,9H),1.26(s,12H)。

Intermediate a 3-4:

ethyl 2- (4- (tert-butoxycarbonyl) cyclohex-1-en-1-yl) oxazole-4-carboxylate

A suspension of tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enecarboxylate A3-3(950mg, 95% purity, 2.93mmol), ethyl 2-chlorooxazole-4-carboxylate (629mg, 3.51mmol), tetrakis (triphenylphosphine) palladium (172mg, 0.15mmol) and potassium carbonate (1.24g, 8.78mmol) in N, N-dimethylformamide (30mL) was stirred overnight at 100 ℃ under a nitrogen atmosphere. After cooling, the mixture was diluted with water (100mL) and extracted twice with ethyl acetate (100 mL). The combined organic layers were washed with water (100mL), and then brine (100mL), over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound (630mg, purity 95 from HNMR, 64% yield) as a white solid. LC-MS (ESI): r_T＝1.73min,C₁₇H₂₃NO₅Calculated mass of 321.2, M/z found 322.3[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.12(s,1H),6.85(s,1H),3.39(q,J＝7.2Hz,2H),2.76-2.72(m,1H),2.54-2.48(m,4H),2.15-2.09(m,1H),1.81-1.72(m,1H),1.46(s,9H),1.38(t,J＝7.2Hz,3H)。

Acid 3:

4- (4- (ethoxycarbonyl) oxazol-2-yl) cyclohex-3-enecarboxylic acid

To a solution of ethyl 2- (4- (tert-butoxycarbonyl) cyclohex-1-en-1-yl) oxazole-4-carboxylate a3-4(630mg, 95% purity, 1.86mmol) in dichloromethane (2.5mL) was added trifluoroacetic acid (2.5 mL). After stirring at room temperature for 1 hour, the mixture was concentrated to give the title compound (540mg, purity 90% from HNMR, 98% yield) as a pale yellow solid. LC-MS (ESI): r _T＝1.08min,C₁₃H₁₅NO₅Calculated mass of 265.1, M/z found 266.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.77(s,1H),6.78(s,1H),4.28(q,J＝7.2Hz,2H),2.60-2.53(m,2H),2.47-2.33(m,3H),2.08-2.03(m,1H),1.72-1.62(m,1H),1.28(t,J＝7.2Hz,3H)。

Acid 4: 4- (4- (methoxycarbonyl) -5-methyloxazol-2-yl) cyclohexanecarboxylic acid (A4)

Intermediate a 4-2:

4- ((benzyloxy) carbonyl) cyclohexanecarboxylic acid

To a solution of cyclohexane-1, 4-dicarboxylic acid A4-1(10.5g, 60.0mmol) in N, N-dimethylformamide (50mL) was added potassium carbonate (7.96g, 57.0mmol) under a nitrogen atmosphere. The mixture was stirred at 60 ℃ for 1 h, then (bromomethyl) benzene (9.85g, 57.0mmol) was added. The mixture was stirred at 80 ℃ overnight. After cooling to room temperature, the mixture was acidified to pH 6 with 1M aqueous hydrochloric acid and extracted twice with ethyl acetate (100 mL). The separated organic layer was washed twice with water (200mL) over anhydrous Na₂SO₄(solid) dried, filtered and concentrated to give the title compound as a white solid (3.4g, 23% yield).¹H NMR(300MHz,DMSO-d₆)δ12.03(br s,1H),7.38-7.29(m,5H),5.06(s,2H),2.34-2.26(m,1H),2.18-2.11(m,1H),1.96-1.87(m,4H),1.42-1.24(m,4H)。

Intermediate a 4-4:

benzyl 4- (((2R,3R) -3-hydroxy-1-methoxy-1-oxobutan-2-yl) carbamoyl) cyclohexanecarboxylate

To a solution of 4- ((benzyloxy) carbonyl) cyclohexanecarboxylic acid A4-2(4.00g, 14.4mmol), (2R,3R) -methyl 2-amino-3-hydroxybutyric acid hydrochloride A4-3(4.00g, 23.2mmol) and 1-hydroxybenzotriazole (2.40g, 17.4mmol) in N, N-dimethylformamide (50mL) was added triethylamine (4.50g, 43.4 mmol). The resulting solution was cooled to 0 ℃ and then N was added ¹- ((ethylimino) methylene) -N³,N³Dimethylpropane-1, 3-diamine hydrochloride (3.40g, 17.4 mmol). After stirring at room temperature overnight, the reaction mixture was poured into water (200mL) and extracted twice with ethyl acetate (400 mL). The combined organic layers were washed with water (200mL), brine (200mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give the title compound as a colorless oil (4.00g, 70% yield). LC-MS (ESI): r_T＝1.42min,C₂₀H₂₇NO₆Calculated mass 377.2, M/z found 378.4[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ7.37-7.35(m,5H),6.34(d,J＝8.7Hz,1H),5.13-5.08(m,2H),4.61-4.56(m,1H),4.38-4.32(m,1H),3.76-3.73(m,3H),2.37-1.98(m,7H),1.53-1.42(m,4H),1.21-1.16(m,3H)。

Intermediate a 4-5:

methyl 2- (4- ((benzyloxy) carbonyl) cyclohexyl) -5-methyl-4, 5-dihydrooxazole-4-carboxylate

To a solution of benzyl 4- (((2R,3R) -3-hydroxy-1-methoxy-1-oxobutan-2-yl) carbamoyl) cyclohexanecarboxylate A4-4(4.00g, 10.6mmol) in acetonitrile (40mL) and dichloromethane (15mL) was added triphenylphosphine (3.60g, 13.8mmol) and N, N-diisopropylethylamine (1.90g, 14.8 mmol). After carbon tetrachloride (2.10g, 13.8mmol) was slowly added dropwise, the reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 ℃ and diluted in ethyl acetate (100mL) and saturated aqueous sodium bicarbonate (100 mL). After stirring for 10 min, the organic layer was separated and washed with brine (100mL), Na ₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel chromatography (petroleum ether: ethyl acetate 10:1 to 4:1) to give the title compound as a colorless oil (3.80g, 39% yield). LC-MS (ESI): r_T＝1.63min,C₂₀H₂₅NO₅Calculated mass of 359.2, M/z found 360.3[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ7.38-7.29(m,5H),5.12-5.10(m,2H),4.87-4.71(m,2H),3.75-3.71(m,3H),2.57-2.51(m,0.5H),2.40-2.29(m,1.5H),2.13-1.92(m,4H),1.76-1.66(m,1H),1.52-1.46(m,3H),1.27-1.23(m,3H)。

Intermediate A4-6:

methyl 2- (4- ((benzyloxy) carbonyl) cyclohexyl) -5-methyloxazole-4-carboxylate

To a solution of methyl 2- (4- ((benzyloxy) carbonyl) cyclohexyl) -5-methyl-4, 5-dihydrooxazole-4-carboxylate A4-5(1.00g, 2.80mmol) in dichloromethane (10mL) was added dropwise anhydrous 1, 8-diazabicyclo [5.4.0]Undec-7-ene (471mg, 3.10mmol), followed by trichlorobromomethane (608mg, 3.10mmol) dropwise. After stirring overnight at room temperatureThe mixture was poured into saturated aqueous ammonium chloride (20mL) and extracted twice with dichloromethane (20 mL). The combined organic layers were passed over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel chromatography (petroleum ether: ethyl acetate 8:1 to 5:1) to give the title compound as a white solid (450mg, 45% yield). LC-MS (ESI): r_T＝1.70min,C₂₀H₂₃NO₅Calculated mass 357.2, M/z found 358.3[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ7.39-7.31(m,5H),5.12(s,2H),3.89(s,3H),2.95-2.90(m,0.3H),2.78-2.72(m,0.7H),2.65-2.62(m,0.3H),2.59(s,3H),2.42-2.36(m,0.7H),2.20-1.98(m,4H),1.90-1.83(m,0.5H),1.76-1.70(m,0.5H),1.60-1.55(m,3H)。

Acid 4:

4- (4- (methoxycarbonyl) -5-methyloxazol-2-yl) cyclohexanecarboxylic acid

To a solution of methyl 2- (4- ((benzyloxy) carbonyl) cyclohexyl) -5-methyloxazole-4-carboxylate a4-6(1.42g, 90% purity, 3.58mmol) in ethyl acetate (35mL) was added 10% wt. palladium on charcoal (420 mg). The mixture was stirred under hydrogen atmosphere (balloon) at 30 ℃ overnight. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound as a white solid (1.00g, 90% purity, 94% yield). LC-MS (ESI): r_T＝0.30min,C₁₃H₁₇NO₅Calculated mass of 267.1, M/z found 268.2[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ3.89(s,3H),2.81-2.73(m,1H),2.59(s,3H),2.42-2.35(m,1H),2.23-2.14(m,4H),1.70-1.48(m,4H)。

Acid 5: 4- ((4- (methoxycarbonyl) oxazol-2-yl) methyl) cyclohexanecarboxylic acid (A5)

Intermediate a 5-2:

((4- (methoxycarbonyl) oxazol-2-yl) methyl) triphenylphosphonium chloride

To methyl 2- (chloromethyl) oxazole-4-carboxylate A5-1 (5) at room temperature00g, 28.2mmol) in dry toluene (30mL) triphenylphosphine (7.50g, 28.2mmol) was added. After stirring overnight at 85 ℃ under nitrogen, the reaction mixture was cooled to room temperature and filtered to give the title compound (5.60g, from¹Purity of H NMR 99%, 45% yield).¹H NMR(300MHz,CDCl₃)δ8.06-8.05(m,1H),7.94-7.87(m,6H),7.80-7.75(m,3H),7.69-7.62(m,6H),6.26(d,J＝15.3Hz,2H),3.81(s,3H)。

Intermediate a 5-3:

methyl 2- ((4- ((benzyloxy) carbonyl) cyclohexylidene) methyl) oxazole-4-carboxylate

To a solution of ((4- (methoxycarbonyl) oxazol-2-yl) methyl) triphenylphosphonium chloride a5-2(6.50g, 99% purity, 14.7mmol) in anhydrous dichloromethane (45mL) at-78 ℃ was added potassium 2-methylpropan-2-ol (1.70g, 6.03 mmol). After stirring at-78 ℃ under nitrogen for 1 hour, a solution of benzyl 4-oxocyclohexanecarboxylate A1-2(1.06g, 4.50mmol) in dichloromethane (5mL) was added slowly. After stirring at room temperature under nitrogen for 16 hours, the mixture was diluted with dichloromethane (60 mL). The resulting solution was washed with water (100mL), and then brine (100mL), over Na ₂SO₄(solid) 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 3:1) to give the title compound as a yellow oil (1.00g, 98% purity, 31% yield). LC-MS (ESI): r_T＝1.71min,C₂₀H₂₁NO₅Calculated Mass 355.1, found M/z 356.2[ M + H ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ8.79-8.75(m,1H),7.45-7.31(m,5H),6.17(s,1H),5.32(s,1H),5.11(s,1H),3.81(s,1.5H),3.61(s,1.5H),3.56-3.49(m,1H),2.73-2.64(m,1H),2.46-2.42(m,1H),2.35-2.26(m,2H),2.09-1.99(m,2H),1.62-1.46(m,2H)。

Acid 5:

4- ((4- (methoxycarbonyl) oxazol-2-yl) methyl) cyclohexanecarboxylic acid

To methyl 2- ((4- ((benzyloxy) carbonyl) cyclohexylidene) methyl) oxazole-4-carboxylate A5-3(1.60g, 98% purity, 4.41mmol)To a solution in methanol (25mL) was added 10% wt. palladium on charcoal (353 mg). The mixture was stirred under a balloon of hydrogen at 25 ℃ overnight. The mixture was then filtered off and the filtrate was concentrated to give the title compound as a pale yellow solid (1.30g, 90% purity, 99% yield). LC-MS (ESI): r_T＝1.14min,C₁₃H₁₇NO₅Calculated Mass of 267.1, found value of M/z 266.1[ M-H]^-。¹H NMR(400MHz,DMSO-d₆)δ11.86(br s,1H),8.75(s,1H),3.79(s,3H),2.72-2.67(m,2H),2.48-2.43(m,0.6H),2.15-2.07(m,0.4H),1.93-1.81(m,2.5H),1.71-1.68(m,1H),1.54-1.45(m,2.5H),1.30-1.17(m,2H),1.11-0.98(m,1H)。

Acid 6: 4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexane-1-carboxylic acid (A6)

Intermediate a 6-1:

benzyl 4-carbamoyl cyclohexanecarboxylate

To a solution of 4- ((benzyloxy) carbonyl) cyclohexanecarboxylic acid A4-2(9.20g, 35.1mmol) in ethyl acetate (100mL) was added N, N' -carbonyldiimidazole (7.39g, 52.6mmol) at room temperature. After stirring at room temperature for 1 hour, an ammonia solution (20mL) was added. The mixture was stirred at room temperature for 20 minutes. The mixture was then diluted with water, acidified with 1M aqueous hydrochloric acid (55mL), and extracted twice with ethyl acetate (100 mL). The separated organic layer was washed with aqueous bicarbonate solution (100mL) over anhydrous Na ₂SO₄(solid) dried, filtered and concentrated to give the title compound as a yellow solid (10.0g, 99% yield). LC-MS (ESI): r_T＝0.61min,C₁₅H₁₉NO₃Calculated mass of 261.1, M/z Mass found 262.3[ M + H [ ].]⁺。

Intermediate a 6-3:

benzyl 4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexanecarboxylate

To benzyl 4-carbamoyl cyclohexanecarboxylate A6-1(6.00g, 16.1mmol) in toluene (50.00 g)mL) and 1, 4-dioxane (50mL) was added ethyl 4-chloro-3-oxobutyrate a6-2(5.40g, 32.2 mmol). The reaction mixture was heated to 120 ℃ and stirred at 120 ℃ under nitrogen overnight. After cooling to room temperature, the mixture was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1 to 7:1) to give the title compound (5.30g, 80% yield) as a pale yellow oil. LC-MS (ESI): r_T＝1.87min,C₂₁H₂₅NO₅371.2, M/z found 372.0[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.54-7.53(m,1H),7.39-7.31(m,5H),5.12(s,2H),4.25-4.13(m,2H),3.58(s,0.6H),3.57(s,1.4H),2.98-2.92(m,0.3H),2.78-2.72(m,0.7H),2.61-2.56(m,0.3H),2.43-2.35(m,0.7H),2.20-1.95(m,4H),1.88-1.73(m,1H),1.60-1.42(m,3H),1.32-1.24(m,3H)。

Acid 6:

4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexanecarboxylic acid

To a solution of benzyl 4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexanecarboxylate a6-3(3.00g, 1.25mmol, 90% purity) in ethyl acetate (50mL) was added 10% wt. palladium on charcoal (1.00 g). The mixture was stirred at room temperature under a hydrogen atmosphere overnight. The 10% palladium on charcoal was filtered off and the filtrate was concentrated to give the title compound as a white solid (2.10g, 98% yield). ¹H NMR(400MHz,DMSO-d₆)δ12.09(br s,1H),7.83-7.82(m,1H),4.09(q,J＝7.2Hz,2H),3.56(d,J＝1.2Hz,0.6H),3.54(d,J＝0.8Hz,1.4H),2.97-2.91(m,0.3H),2.78-2.70(m,0.7H),2.27-2.17(m,1H),2.05-2.02(m,1H),1.97-1.94(m,1H),1.85-1.71(m,2H),1.68-1.60(m,1H),1.49-1.41(m,3H),1.20-1.17(m,3H)。

Acid 7: 4- (4- (2-ethoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexanecarboxylic acid (A7)

Intermediate a 7-2:

benzyl 4- (4- (2-ethoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexanecarboxylate

To a solution of ethyl 4-bromo-3-oxopentanoate a7-1(2.000g, 80% purity, 6.123mmol) in 1, 4-dioxane (60mL) and toluene (60mL) was added benzyl 4-carbamoylcyclohexanecarboxylate a6-1(1.710g, 80% purity, 6.133mmol) at room temperature under a nitrogen atmosphere. After refluxing at 120 ℃ overnight, the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to provide a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1 to 5:1) to provide the product (360mg, from ca) as a colorless oil¹Purity of H NMR 80%, 12% yield). LC-MS (ESI): r_T＝1.925min,C₂₂H₂₇NO₅Calculated mass of 385.2, found value of M/z 386.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.37-7.32(m,5H),5.12(s,2H),4.16(q,J＝7.2Hz,2H),3.44(s,2H),2.90-2.88(m,0.2H),2.71-2.67(m,0.7H),2.60-2.57(m,0.3H),2.40-2.35(m,0.8H),2.23(s,2.3H),2.18(s,0.7H),2.16-2.12(m,3H),2.02-1.97(m,1H),1.86-1.81(m,0.7H),1.72-1.69(m,0.3H),1.58-1.53(m,3H),1.26(t,J＝7.2Hz,3H)。

Acid 7:

4- (4- (2-ethoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexanecarboxylic acid

To a solution of benzyl 4- (4- (2-ethoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexanecarboxylate a7-2(460mg, 85% purity, 1.01mmol) in ethyl acetate (10mL) was added 10% wt. palladium on charcoal (55 mg). The mixture was stirred at room temperature under a hydrogen atmosphere overnight. The catalyst was then filtered off and the filtrate was concentrated to give the title compound (310mg, from ¹Purity of H NMR 80%, 83% yield).¹H NMR(400MHz,CDCl₃)δ9.56(br s,1H),4.19-4.12(m,2H),3.47(s,2H),2.90-2.86(m,0.2H),2.75-2.69(m,0.7H),2.61-2.59(m,0.3H),2.38-2.33(m,0.8H),2.24(s,2.3H),2.19(s,0.7H),2.16-2.12(m,3H),2.02-1.96(m,1H),1.88-1.84(m,0.5H),1.72-1.67(m,0.5H),1.60-1.53(m,3H),1.26(t,J＝7.2Hz,3H)。

Acid 8: 1- (4- (tert-Butoxycarbonyl) phenyl) piperidine-4-carboxylic acid (A8)

Intermediate A8-3:

ethyl 1- (4- (tert-butoxycarbonyl) phenyl) piperidine-4-carboxylate

To a mixture of tert-butyl 4-fluorobenzoate A8-1(589mg, 3.00mmol) and ethylpiperidine-4-carboxylate A8-2(472mg, 3.00mmol) in dimethylsulfoxide (3mL) was added potassium carbonate (1.24g, 9.00mmol) at room temperature. After stirring at 120 ℃ for 16 h, the mixture was poured into water (20mL) and extracted three times with ethyl acetate (30 mL). The combined organic layers were washed with water (30mL) and Na₂SO₄The (solid) was dried and concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:1 to 10:1) to provide the title compound as a white solid (480mg, 48% yield).¹H NMR(400MHz,CDCl₃)δ7.86(d,J＝8.8Hz,2H),6.85(d,J＝8.8Hz,2H),4.15(q,J＝7.2Hz,2H),3.82-3.77(m,2H),2.96-2.89(m,2H),2.54-2.46(m,1H),2.04-1.99(m,2H),1.88-1.78(m,2H),1.57(s,9H),1.27(t,J＝7.2Hz,3H)。

Acid 8:

1- (4- (tert-Butoxycarbonyl) phenyl) piperidine-4-carboxylic acid

To a solution of ethyl 1- (4- (tert-butoxycarbonyl) phenyl) piperidine-4-carboxylate A8-3(480mg, 1.40mmol) in methanol (6mL) and water (1.5mL) under a nitrogen atmosphere was added lithium hydroxide monohydrate (176mg, 4.20 mmol). After stirring at room temperature for 16 h, the solvent was removed and the residue was diluted with water (10mL), acidified to pH 4 with 1M aqueous hydrochloride solution and extracted three times with ethyl acetate (30 mL). The combined organic layers were passed over Na ₂SO₄(solid) dried and concentrated to provide the title compound as a white solid (400mg, 94% yield).¹H NMR(400MHz,CDCl₃)δ7.90(d,J＝8.8Hz,2H),6.90(d,J＝8.8Hz,2H),3.86-3.82(m,2H),3.02-2.96(m,2H),2.64-2.57(m,1H),2.11-2.07(m,2H),1.95-1.85(m,2H),1.61(s,9H)。

Acid 9: 4- (4- (3-methoxy-3-oxopropyl) oxazol-2-yl) cyclohexane-1-carboxylic acid (A9)

Intermediate a 9-2:

methyl 5-bromo-4-oxopentanoate

To a solution of 4-pentanoic acid A9-1(10.0g, 84.4mmol) in methanol (86mL) at 0 deg.C was added bromine (13.6g, 84.4 mmol). After stirring at room temperature under nitrogen for 1 hour, the reaction mixture was diluted with water (20mL) and extracted twice with dichloromethane (100 mL). The separated organic layer was washed with saturated aqueous sodium bicarbonate (20mL) and dried over anhydrous Na₂SO₄The (solid) was dried, filtered and concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound as a yellow oil (4.70g, 27% yield).¹H NMR(300MHz,DMSO-d₆)δ4.36-4.33(m,2H),3.57-3.52(m,3H),2.85-2.79(m,2H),2.51-2.45(m,2H)。

Intermediate a 9-3:

benzyl 4- (4- (3-methoxy-3-oxopropyl) oxazol-2-yl) cyclohexanecarboxylate

To a solution of benzyl 4-carbamoylcyclohexanecarboxylate A6-1(500mg, 1.91mmol) in N, N-dimethylformamide (5mL) was added methyl 5-bromo-4-oxopentanoate A9-2(599mg, 2.87 mmol). After stirring overnight at 120 ℃, the mixture was diluted with water (20mL) and extracted twice with dichloromethane (20 mL). The separated organic layer was washed with saturated aqueous sodium bicarbonate (20mL) and dried over anhydrous Na ₂SO₄The (solid) was dried, filtered and 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 as a yellow oil (1.20g, 32% yield).¹H NMR(300MHz,DMSO-d₆)δ7.64(s,1H),7.35-7.29(m,5H),5.06(s,2H),3.55(s,3H),2.73-2.66(m,1H),2.67-2.62(m,2H),2.57-2.52(m,2H),2.42-2.33(m,1H),2.01-1.95(m,4H),1.52-1.36(m,4H)。

Acid 9:

4- (4- (3-methoxy-3-oxopropyl) oxazol-2-yl) cyclohexanecarboxylic acid

To a solution of benzyl 4- (4- (3-methoxy-3-oxopropyl) oxazol-2-yl) cyclohexanecarboxylate a9-3(1.43g, 3.89mmol) in tetrahydrofuran (150mL) was added 10% wt. palladium on charcoal (2.00 g). The reaction mixture was stirred under an atmosphere of hydrogen (50psi) at room temperature overnight. The complete reaction mixture was filtered and the filtrate was concentrated to give the crude product as a white solid (980mg, 91% yield).¹H NMR(300MHz,DMSO-d₆)δ12.06(br s,1H),7.64(d,J＝3.0Hz,1H),3.57-3.55(m,3H),2.70-2.67(m,1H),2.65-2.62(m,2H),2.48-2.37(m,2H),2.24-2.12(m,1H),2.01-1.91(m,4H),1.50-1.33(m,4H)。

Acid 10: 4- (4- (3-ethoxy-2, 2-dimethyl-3-oxopropyl) oxazol-2-yl) cyclohexane-1-carboxylic acid (A10)

Intermediate a 10-2:

ethyl 4-chloro-2, 2-dimethylpent-4-enoate

To a solution of ethyl isobutyrate A10-1(10.0g, 86.1mmol) in tetrahydrofuran (40mL) was added 2M lithium diisopropylamide in tetrahydrofuran (52mL, 104mmol) at-78 ℃ under a nitrogen atmosphere. After stirring at-78 ℃ for 1 hour, 2, 3-dichloroprop-1-ene (9.60g, 86.5mmol) was added at-78 ℃. The mixture was then slowly warmed to room temperature and stirred overnight. It was then quenched with saturated aqueous ammonium chloride (50mL) and extracted twice with ethyl acetate (50 mL). The combined organic layers were washed with brine (30mL) and Na ₂SO₄(solid) dried, filtered and concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give the desired compound (13.0g, from¹Purity of H NMR 90%, 71% yield).¹H NMR(300MHz,CDCl₃)δ5.22(s,1H),5.11(s,1H),4.11(q,J＝6.9Hz,2H),2.63(s,2H),1.27-1.22(m,9H)。

Intermediate a 10-3:

ethyl 5-bromo-2, 2-dimethyl-4-oxopentanoate

To a solution of ethyl 4-chloro-2, 2-dimethylpent-4-enoate A10-2(11.0g, 90% purity, 51.9mmol) in water (50mL) under nitrogen was added N-bromosuccinimide (11.0g, 61.8 mmol). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (10mL) and extracted twice with ethyl acetate (40 mL). The combined organic layers were washed with brine (20mL) 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 ═ 10:1) to give the desired compound (11.0g, obtained from¹Purity of H NMR 90%, 76% yield).¹H NMR(300MHz,CDCl₃)δ4.07(q,J＝7.2Hz,2H),3.85(s,2H),2.89(s,2H),1.22-1.45(m,9H)。

Intermediate a 10-4:

benzyl 4- (4- (3-ethoxy-2, 2-dimethyl-3-oxopropyl) oxazol-2-yl) cyclohexanecarboxylate

To a solution of benzyl 4-carbamoyl cyclohexanecarboxylate a6-1(7.00g, 90% purity, 24.1mmol) in toluene (20mL) and 1, 4-dioxane (20mL) was added ethyl 5-bromo-2, 2-dimethyl-4-oxopentanoate a10-3(10.0g, 90% purity, 35.8mmol) under a nitrogen atmosphere. After stirring overnight at 120 ℃, the reaction mixture was cooled to room temperature, diluted with water (20mL), and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na ₂SO₄(solid) dried, filtered and concentrated to give a residue which was purified by C18 column (acetonitrile: water 67% to 72%) to give the title compound (2.40g, from b > k ═ C) as a colourless oil¹Purity of H NMR 90%, 23% yield). LC-MS (ESI): r_T＝1.65min,C₂₄H₃₁NO₅Calculated mass of 413.2, M/z found 414.0[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ7.42-7.31(m,5H),7.27-7.25(m,1H),5.12(s,2H),4.12(q,J＝7.2Hz,2H),2.79-2.66(m,2H),2.48-1.63(m,10H),1.30-1.21(m,9H)。

Acid 10:

4- (4- (3-ethoxy-2, 2-dimethyl-3-oxopropyl) oxazol-2-yl) cyclohexanecarboxylic acid

To a solution of benzyl 4- (4- (3-ethoxy-2, 2-dimethyl-3-oxopropyl) oxazol-2-yl) cyclohexanecarboxylate a10-4(1.40g, 90% pure, 3.05mmol) in ethyl acetate (10mL) was added 10% wt. palladium on charcoal (500mg, 4.70mmol) at room temperature. After stirring overnight at room temperature under a balloon hydrogen atmosphere, the reaction mixture was filtered and concentrated to give the title compound (900mg, from¹Purity of H NMR 90%, 82% yield).¹H NMR(300MHz,CDCl₃)δ7.25(s,1H),4.12(q,J＝7.2Hz,2H),2.76(s,2H),2.65-1.95(m,6H),1.89-1.40(m,4H),1.28-1.15(m,9H)。

Acid 11: mixture of 4- (5- (ethoxycarbonyl) oxazol-2-yl) cyclohexanecarboxylic acid and 4- (5- (ethoxycarbonyl) oxazol-2-yl) cyclohex-3-enecarboxylic acid (A11)

Intermediate a 11-1:

benzyl 4- (((trifluoromethyl) sulfonyl) oxy) cyclohex-3-enecarboxylate

To a solution of benzyl 4-oxocyclohexanecarboxylate A1-2(15.0g, 98% purity, 63.3mmol) and 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (27.2g, 76.1mmol) in tetrahydrofuran (350mL) at-60 ℃ under a nitrogen atmosphere was added 1M potassium bis (trimethylsilyl) amide in tetrahydrofuran (85mL, 85.0 mmol). After stirring at-60 ℃ for 4 hours, the mixture was diluted with water (200mL) and extracted twice with ethyl acetate (200 mL). The combined organic layers were washed with brine (150mL) and Na ₂SO₄(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 5:1) to give the desired compound (12.5g, obtained from¹Purity by H NMR 95%, 51% yield).¹H NMR(400MHz,CDCl₃)δ7.39-7.33(m,5H),7.77-7.75(m,1H),5.14(s,2H),2.69-2.62(m,1H),2.49-2.46(m,2H),2.43-2.39(m,2H),2.19-2.13(m,1H),2.00-1.89(m,1H)。

Intermediate a 11-2:

benzyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enecarboxylate

To a solution of benzyl 4- (((trifluoromethyl) sulfonyl) oxy) cyclohex-3-enecarboxylate a11-1(8.00g, 95% purity, 20.9mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2 '-bis (1,3, 2-dioxaborolan) (15.9g, 62.6mmol) and potassium acetate (6.14g, 62.6mmol) in 1, 4-dioxane (150mL) was added 1,1' -bis (diphenylphosphino) ferrocene-dichloropalladium (II) (0.76g, 1.04mmol) at room temperature under a nitrogen atmosphere. After stirring overnight at 80 ℃ under a nitrogen atmosphere, the mixture was diluted with water (70mL) and brine (70 mL). The organic layer was separated and the aqueous phase was 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 a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1 to 5:1), and then further purified by C18 column (acetonitrile: water: 85% to 90%) to give the desired compound as a yellow oil (4.60g, 95% purity, 61% yield). LC-MS (ESI): r _T＝0.26min,C₂₀H₂₇BO₄Calculated mass of 342.2, M/z found 343.3[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.39-7.32(m,5H),6.54(s,1H),5.13(s,2H),2.63-2.55(m,1H),2.38-2.35(m,2H),2.30-2.25(m,1H),2.17-2.01(m,2H),1.68-1.58(m,1H),1.26(s,12H)。

Intermediate a 11-4:

ethyl 2- (4- ((benzyloxy) carbonyl) cyclohex-1-en-1-yl) oxazole-5-carboxylate

To a solution of ethyl 2-chlorooxazole-5-carboxylate a11-3(3.00g, 98% purity, 16.7mmol) in 1, 4-dioxane (100mL) was added benzyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enecarboxylate a11-2(7.85g, 95% purity, 21.8mmol), 1' -bis (diphenylphosphine) ferrocene dichloropalladium (II) (1.30g, 98% purity, 1.74mmol) and potassium carbonate (4.80g,98% purity, 34.0 mmol). After stirring at 100 ℃ under nitrogen for 6 hours, the mixture was allowed to cool to room temperature and slowly diluted with water (100mL) and 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 (petroleum ether: ethyl acetate ═ 3:1 to 1:1) to give the title compound (5.50g, obtained from¹Purity by H NMR 95%, 88% yield). LC-MS (ESI): r_T＝1.899min,C₂₀H₂₁NO₅Calculated Mass 355.1, found M/z 356.1[ M + H ]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.97(s,1H),7.39-7.31(m,5H),6.89-6.88(m,1H),5.15(s,1H),5.14(s,1H),4.32(q,J＝7.2Hz,2H),2.79-2.72(m,1H),2.58-2.53(m,2H),2.49-2.37(m,2H),2.13-2.06(m,1H),1.77-1.67(m,1H),1.30(t,J＝7.2Hz,3H)。

Acid 11:

mixtures of 4- (5- (ethoxycarbonyl) oxazol-2-yl) cyclohexanecarboxylic acid and 4- (5- (ethoxycarbonyl) oxazol-2-yl) cyclohex-3-enecarboxylic acid

To a solution of ethyl 2- (4- ((benzyloxy) carbonyl) cyclohex-1-en-1-yl) oxazole-5-carboxylate a11-4(4.60g, 95% purity, 12.3mmol) in methanol (150mL) was added 10% wt. palladium on charcoal (1.00g) at room temperature under a nitrogen atmosphere. After replacing the inert nitrogen atmosphere with hydrogen, the mixture was stirred at 25 ℃ for 1.5 hours under a hydrogen atmosphere of a balloon. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title product as a yellow oil (3.60g, 90% purity, 99% yield). LC-MS (ESI): r_T0.224min and 0.293min, C₁₃H₁₇NO₅And C₁₃H₁₅NO₅Calculated masses of 267.1 and 265.1, respectively, found at M/z of 268.1[ M + H]⁺And 266.0[ M + H ]]⁺。

Acid 12: 4- (4- (1-ethoxy-2-methyl-1-oxoprop-2-yl) oxazol-2-yl) cyclohexanecarboxylic acid (A12)

Intermediate a 12-1:

benzyl 4- (4- (1-ethoxy-2-methyl-1-oxoprop-2-yl) oxazol-2-yl) cyclohexanecarboxylate

To a solution of benzyl 4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexanecarboxylate A6-3(1.90g, 90% pure, 4.60mmol) in anhydrous tetrahydrofuran (20mL) was added dropwise 1.0M lithium hexamethyldisilazide in tetrahydrofuran (18.4mL, 18.4mmol) at-70 ℃. After stirring for 1 hour at-70 ℃, iodomethane (2.61g, 18.4mmol) was added dropwise at-70 ℃ and the resulting reaction mixture was allowed to warm to room temperature and stirring was continued overnight. It was then acidified to pH 7-8 with saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed twice with water (30mL), twice with brine (30mL), and over Na ₂SO₄(solid) dried, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (1.90g, 80% purity from HNMR, 83% yield). LC-MS (ESI): r_T＝2.029min,C₂₃H₂₉NO₅Calculated Mass of 399.2, M/z found 400.2[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ7.36-7.33(m,6H),5.12(s,2H),4.17-4.11(m,2H),2.98-2.94(m,0.3H),2.80-2.74(m,0.7H),2.60-2.57(m,0.2H),2.43-2.35(m,0.8H),2.17-1.96(m,4H),1.83-1.72(m,1H),1.60-1.54(m,3H),1.51(s,6H),1.24-1.19(m,3H)。

Acid 12:

4- (4- (1-ethoxy-2-methyl-1-oxoprop-2-yl) oxazol-2-yl) cyclohexanecarboxylic acid

To a solution of benzyl 4- (4- (1-ethoxy-2-methyl-1-oxoprop-2-yl) oxazol-2-yl) cyclohexanecarboxylate a12-1(1.90g, 80% purity, 3.81mmol) in ethyl acetate (20mL) under nitrogen atmosphere was added 10% wt. palladium on charcoal (1 g). After stirring at room temperature for 2.5 h under a hydrogen balloon, the mixture was filtered and concentrated to give the title compound (1.50g, crude) as a white solid. LC-MS (ESI): r_T＝1.22min,C₁₆H₂₃NO₅Calculated mass of 309.2, M/z found 308.0[ M-H [)]^-。

Acid 13: 4- (1- (2-ethoxy-2-oxoethyl) -1H-pyrazol-4-yl) cyclohexanecarboxylic acid (A13)

Intermediate a 13-1:

benzyl 4- (1H-pyrazol-4-yl) cyclohex-3-enecarboxylate

To a suspension of benzyl 4- (((trifluoromethyl) sulfonyl) oxy) cyclohex-3-enecarboxylate a11-1(10.0g, 27.5mmol) and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (5.90g, 30.4mmol) and cesium carbonate (17.9g, 54.9mmol) in a mixed solvent of 1, 4-dioxane (100mL) and water (33mL) was added [1,1' -bis (diphenylphosphino) ferrocene at room temperature ]Palladium (II) dichloride (1.20g, 1.60 mmol). After stirring at 95 ℃ under nitrogen atmosphere for 5 hours and cooling to room temperature, the mixture was concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 5:1 to 1:1) and C18 column (acetonitrile: water: 05% to 95%) to afford the desired product as a brown solid (3.70g, 48% yield). LC-MS (ESI): r_T＝1.78min，C₁₇H₁₈N₂O₂Calculated mass of 282.1, M/z found 283.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.90(s,0.5H),7.62(s,0.5H),7.58(s,2H),7.37-7.36(m,5H),6.37(s,0.2H),6.01(s,0.8H),5.15(s,2H),2.68-2.66(m,1H),2.45-2.40(m,4H),2.19-2.15(m,1H),1.88-1.84(m,1H)。

Intermediate a 13-2:

benzyl 4- (1- (2-ethoxy-2-oxoethyl) -1H-pyrazol-4-yl) cyclohex-3-enecarboxylate

To a mixture of benzyl 4- (1H-pyrazol-4-yl) cyclohex-3-enecarboxylate A13-1(1.40g, 4.96mmol) and potassium carbonate (1.40g, 10.0mmol) in N, N-dimethylformamide (20mL) at 0 deg.C was added ethyl 2-bromoacetate (1.08g, 6.45mmol) in N, N-dimethylformamide (15 mL). The mixture was then stirred at 45 ℃ overnight. After cooling to room temperature, the mixture was poured into water (100mL) and extracted with ethyl acetate (30mL)Taken four times. The combined organic layers were concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate: 10:1 to 3:1) followed by C18 column (acetonitrile: water: 5% to 95%) to give the desired product as a light green oil (1.10g, 61% yield). LC-MS (ESI): r _T＝1.882min,C₂₁H₂₄N₂O₄Calculated Mass of 368.2, found M/z 369.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.60(s,1H),7.39(s,1H),7.38-7.32(m,5H),5.99-5.98(m,1H),5.15(s,2H),4.86(s,2H),4.26-4.21(m,2H),2.69-2.62(m,1H),2.44-2.35(m,4H),2.17-2.13(m,1H),1.90-1.79(m,1H),1.32-1.24(m,3H)。

Acid 13:

4- (1- (2-ethoxy-2-oxoethyl) -1H-pyrazol-4-yl) cyclohexanecarboxylic acid

To a solution of benzyl 4- (1- (2-ethoxy-2-oxoethyl) -1H-pyrazol-4-yl) cyclohex-3-enecarboxylate a13-2(1.10g, 2.99mmol) in methanol (20mL) was added 10% wt. palladium on charcoal (600mg) at room temperature under nitrogen atmosphere. The mixture was then stirred at room temperature under a hydrogen atmosphere overnight. The other batch (280mg) was pooled for work-up. The mixture was then filtered and the filtrate was concentrated to give the desired product as a black oil (1.2g, crude).¹H NMR(400MHz,CDCl₃)δ7.41(s,1H),7.25(s,1H),4.86(s,2H),4.25-4.22(m,2H),2.73-2.59(m,2H),2.16-2.00(m,2H),1.90-1.77(m,2H),1.72-1.60(m,4H),1.31-1.24(m,3H)。

Acid 14: 4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohexane-1-carboxylic acid (A14)

Intermediate a 14-1:

benzyl 4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohex-3-enecarboxylate

To a solution of benzyl 4- (1H-pyrazol-4-yl) cyclohex-3-enecarboxylate A13-1(1.40g, 95% purity, 4.71mmol) in N, N-dimethylformamide (15mL) was added carbonic acid at room temperaturePotassium (1.95g, 14.1mmol) and methyl acrylate (486mg, 5.65 mmol). After stirring overnight at 60 ℃ under nitrogen, it was cooled and poured into water (50mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed with brine (30mL) and Na ₂SO₄(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 give the title compound as a white oil (1.40g, 65% yield).¹H NMR(400MHz,CDCl₃)δ7.54(s,1H),7.39-7.30(m,6H),6.23-6.22(m,0.2H),5.95(br s,0.8H),5.15(s,2H),4.39-4.36(m,2H),3.68(s,3H),2.91-2.87(m,2H),2.68-2.61(m,1H),2.43-2.30(m,4H),2.18-2.12(m,1H),1.89-1.79(m,1H)。

Acid 14:

4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohexane-1-carboxylic acid

To a solution of benzyl 4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohex-3-enecarboxylate a14-1(1.60g, 80% pure, 3.47mmol) in ethanol (40mL) was added 10% wt. palladium on charcoal (500mg) at room temperature. After stirring overnight at room temperature under a balloon hydrogen atmosphere, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (1.40g, obtained from¹Purity of H NMR 65%, 93% yield).¹H NMR(400MHz,CDCl₃)δ7.61(d,J＝2.0Hz,0.1H),7.52(d,J＝1.2Hz,0.2H),7.45(d,J＝2.0Hz,0.3H),7.36(s,0.7H),7.22(s,0.7H),5.65(br s,1H),4.45(t,J＝6.4Hz,0.5H),4.37(t,J＝6.4Hz,1.5H),3.68(d,J＝2.0Hz,3H),2.93-2.87(m,2H),2.64(br s,1H),2.47-2.30(m,0.4H),2.12-2.03(m,2.6H),1.86-1.79(m,1.3H),1.71-1.52(m,2.7H),1.36-1.26(m,2H)。

Acid 15: 4- (1- (4-methoxy-2-methyl-4-oxobutan-2-yl) -1H-pyrazol-4-yl) cyclohexanecarboxylic acid (A15)

Intermediate a 15-2:

benzyl 4- (1- (4-methoxy-2-methyl-4-oxobut-2-yl) -1H-pyrazol-4-yl) cyclohex-3-enecarboxylate

To a solution of benzyl 4- (1H-pyrazol-4-yl) cyclohex-3-enecarboxylate A13-1(3.00g, 80% purity, 8.50mmol) and methyl 3-methyl-2-butenoate A15-1(1.95g, 17.9mmol) in N, N-dimethylformamide (30mL) was added potassium carbonate (3.53g, 25.5mmol) at room temperature. After stirring at 90 ℃ for 48 h, the reaction mixture was cooled to room temperature and diluted with water (200 mL). It was extracted three times with ethyl acetate (100 mL). The combined organic layers were washed with brine (100mL) and Na ₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a residue which was purified by C18 column (acetonitrile: water 60% to 90%) to give the title compound as a yellow oil (2.40g, 97.8% purity, 70% yield).¹H NMR(400MHz,CDCl₃)δ7.57(s,1H),7.46(s,1H),7.40-7.30(m,5H),5.97-5.95(m,1H),5.15(s,2H),3.58(s,3H),2.90(s,2H),2.69-2.61(m,1H),2.44-2.30(m,4H),2.18-2.12(m,1H),1.89-1.79(m,1H),1.70(s,6H)。

Acid 15:

4- (1- (4-methoxy-2-methyl-4-oxobutan-2-yl) -1H-pyrazol-4-yl) cyclohexanecarboxylic acid

To a mixture of benzyl 4- (1- (4-methoxy-2-methyl-4-oxobut-2-yl) -1H-pyrazol-4-yl) cyclohex-3-enecarboxylate a15-2(2.40g, 97.8% purity, 5.92mmol) in methanol (50mL) was added 10% wt. palladium activated charcoal (500mg) under nitrogen. After stirring at 15 ℃ under an atmosphere of hydrogen (balloon) for 16 h, the mixture was filtered and the filtrate was concentrated to give the title compound (1.90g, from¹Purity of H NMR 90%, 94% yield).¹H NMR(400MHz,DMSO-d₆)δ12.07(s,1H),7.56(s,0.4H),7.54(s,0.6H),7.28(s,0.4H),7.26(s,0.6H),3.47(s,1.2H),3.46(s,1.8H),2.84(s,2H),2.60-2.53(m,0.6H),2.42-2.34(m,0.4H),2.22-2.15(m,0.4H),1.95-1.85(m,2.6H),1.78-1.69(m,1.6H),1.63-1.51(m,9H),1.42-1.23(m,1.4H)。

Acid 16: 4- (1- (4-methoxy-4-oxobut-2-yl) -1H-pyrazol-4-yl) cyclohexane-1-carboxylic acid (A16)

Intermediate a 16-1:

benzyl 4- (1- (4-methoxy-4-oxobut-2-yl) -1H-pyrazol-4-yl) cyclohex-3-enecarboxylate

To a solution of benzyl 4- (1H-pyrazol-4-yl) cyclohex-3-enecarboxylate A13-1(6.40g, 50% purity, 11.3mmol) in N, N-dimethylformamide (30mL) was added (E) -methylbut-2-enoate (4.10g, 40.9mmol) and potassium carbonate (5.80g, 42.0mmol) at room temperature. After stirring overnight at 60 ℃ under nitrogen atmosphere, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue which was diluted with water (100mL) and extracted three times with ethyl acetate (80 mL). The combined organic layers were washed twice with water (80mL), twice with brine (80mL), over Na ₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by C18 column (acetonitrile: water ═ 65% to 70%) to give the title compound (5.00g, obtained from¹Purity by H NMR 70%, 81% yield).¹H NMR(400MHz,CDCl₃)δ7.55(s,1H),7.37-7.30(m,6H),5.95(d,J＝1.6Hz,1H),5.15(s,2H),4.77-4.70(m,1H),3.64(s,3H),3.02-3.00(m,1H),2.76-2.72(m,1H),2.69-2.60(m,1H),2.44-2.33(m,4H),2.18-2.14(m,1H),1.89-1.80(m,1H),1.58-1.53(m,3H)。

Acid 16:

4- (1- (4-methoxy-4-oxobutan-2-yl) -1H-pyrazol-4-yl) cyclohexane-1-carboxylic acid

To a solution of benzyl 4- (1- (4-methoxy-4-oxobut-2-yl) -1H-pyrazol-4-yl) cyclohex-3-enecarboxylate a16-1(5.00g, 70% purity, 9.15mmol) in methanol (100mL) was added 10% wt. palladium on charcoal (500 mg). After stirring at room temperature under a hydrogen atmosphere of balloon for 16 hours, the mixture was filtered and the filtrate was concentrated to give the title compound (4.30g, obtained from¹Purity by H NMR 62%, 99% yield).¹H NMR(400MHz,CDCl₃)δ7.37(s,1H),7.22(s,1H),6.21(t,J＝2.4H,1H),4.78-4.69(m,2H),3.64(s,3H),3.02-2.97(m,1H),2.76-2.72(m,1H),2.65-2.61(m,1.0H),2.11-2.03(m,2.4H),1.85-1.81(m,1.6H),1.71-1.67(m,3.2H),1.55-1.53(m,3H),1.42-1.25(m,0.8H)。

Acid 17: 4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohexane-1-carboxylic acid (A17)

Intermediate a 17-1:

benzyl 4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohex-3-enecarboxylate

To a solution of benzyl 4- (1H-pyrazol-4-yl) cyclohex-3-enecarboxylate A13-1(2.2g, 7.8mmol) in N, N-dimethylformamide (400mL) was added methyl acrylate (1.34g, 15.6mmol) and potassium carbonate (2.15g, 15.6mmol) at room temperature. After stirring overnight at 50 ℃ under nitrogen, the mixture was cooled to room temperature, poured into water (80mL), and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed three times with water (50mL), washed with brine (50mL), and Na ₂SO₄(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 ═ 4:1 to 2:1) to give the title compound as a colorless oil (1.8g, 63% yield). LC-MS (ESI): r_TCalculated mass C of 2.467min₂₁H₂₄N₂O₄368.2, found M/z 369.1[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ7.54(s,1H),7.44-7.36(m,6H),5.96-5.94(m,1H),5.15(s,2H),4.37(t,J＝6.8Hz,2H),3.68(s,3H),2.90-2.87(m,2H),2.68-2.61(m,1H),2.44-2.41(m,2H),2.36-2.32(m,2H),2.18-2.11(m,1H),1.89-1.79(m,1H)。

Acid 17:

4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohexane-1-carboxylic acid

To a solution of benzyl 4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohex-3-enecarboxylate A17-1(1.80g, 4.89mmol) in methanol (20mL) was added 10% wt palladium on charcoal (200 mg).The reaction was stirred at room temperature under a hydrogen atmosphere overnight. The complete reaction was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (1.0g, 75% yield).¹H NMR(400MHz,DMSO-d₆)δ12.04(br s,1H),7.47(s,1H),7.26(s,1H),4.27(t,J＝6.8Hz,2H),3.58(s,3H),2.83(t,J＝6.8Hz,2H),2.55-2.51(m,1H),2.50-2.49(m,1H),1.94-1.86(m,3H),1.73-1.70(m,2H),1.60-1.48(m,3H)。

Acid 18: (cis) -4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexanecarboxylic acid (A18)

Intermediate a 18-2:

benzyl 4- (3-methyl-1H-pyrazol-4-yl) cyclohex-3-enecarboxylate

To a solution of benzyl 4- (((trifluoromethyl) sulfonyl) oxy) cyclohex-3-enecarboxylate a11-1(1.0g, 90% purity, 2.47mmol) and 3-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole a18-1(857mg, 4.12mmol) in 1, 4-dioxane (20mL) and water (4mL) was added potassium carbonate (1.12g, 8.10mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] at room temperature under a nitrogen atmosphere ]Palladium (II) dichloride (198mg, 0.27 mmol). After stirring at 95 ℃ overnight, the mixture was concentrated under reduced pressure to give the crude product, which 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 and purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1 to 1:1) to give the title compound as a colorless oil (670mg, purity 73%, 67% yield). LC-MS (ESI): r_T＝2.350min,C₁₈H₂₀N₂O₂Calculated mass of 296.2, found M/z 297.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.44(s,1H),7.37-7.31(m,5H),5.78(s,1H),5.16(s,2H),2.71-2.64(m,1H),2.48-2.43(m,2H),2.42-2.37(m,2H),2.35(s,3H),2.20-2.10(m,1H),1.91-1.78(m,1H)。

Intermediate a 18-3:

mixtures of benzyl 4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohex-3-enecarboxylate and benzyl 4- (1- (3-methoxy-3-oxopropyl) -5-methyl-1H-pyrazol-4-yl) cyclohex-3-enecarboxylate

To a solution of benzyl 4- (3-methyl-1H-pyrazol-4-yl) cyclohex-3-enecarboxylate A18-2(500mg, 73% purity, 1.23mmol) in N, N-dimethylformamide (10mL) was added potassium carbonate (466mg, 3.37mmol) and methyl acrylate (291mg, 3.38mmol) at room temperature under a nitrogen atmosphere. After stirring overnight at 50 ℃, the mixture was diluted with water (15mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed three times with brine (10mL) and Na ₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1 to 1:1) to give a crude product, which was then further purified by C18 column (acetonitrile: water 5% to 80%) to give the title compound as a pale yellow oil (300mg, 95% purity, 61% yield). LC-MS (ESI): r_T＝2.509min,C₂₂H₂₆N₂O₄Calculated mass of 382.2, M/z found 383.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.39-7.31(m,5H),7.27(s,1H),5.83-5.77(m,0.7H),5.67-5.62(m,0.3H),5.16(s,2H),4.30(t,J＝6.4Hz,2H),3.68(s,3H),2.89(t,J＝7.2Hz,0.5H),2.86(t,J＝6.4Hz,1.5H),2.71-2.62(m,1H),2.46-2.42(m,2H),2.40-2.33(m,2H),2.31(s,1H),2.30(s,2H),2.17-2.12(m,1H),1.92-1.79(m,1H)。

Intermediate a 18-4:

mixture of 4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexanecarboxylic acid and 4- (1- (3-methoxy-3-oxopropyl) -5-methyl-1H-pyrazol-4-yl) cyclohexanecarboxylic acid

To benzyl 4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohex-3-enemethylTo a solution of a mixture of the acid ester and benzyl 4- (1- (3-methoxy-3-oxopropyl) -5-methyl-1H-pyrazol-4-yl) cyclohex-3-enecarboxylate A18-3(300mg, 95% purity, 0.745mmol) in methanol (5mL) was added 10% wt. palladium on charcoal (30 mg). The reaction was stirred at room temperature under a balloon of hydrogen atmosphere overnight. The complete reaction was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (220mg, 90% purity, 90% yield). ¹H NMR(400MHz,DMSO-d₆)δ12.15(br s,1H),7.33(s,0.8H),7.13(s,0.2H),4.17(t,J＝6.8Hz,2H),3.58(s,1.6H),3.57(s,1.4H),2.83-2.78(m,2H),2.56-2.53(m,1H),2.44-2.35(m,0.7H),2.33-2.23(m,0.3H),2.17(s,1H),2.06(s,2H),2.04-1.91(m,2H),1.67-1.51(m,3.4H),1.47-1.22(m,2.6H)。

Intermediate a 18-5:

mixture of benzyl 4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexanecarboxylate (mixture of 2 stereoisomers) and benzyl 4- (1- (3-methoxy-3-oxopropyl) -5-methyl-1H-pyrazol-4-yl) cyclohexanecarboxylate (mixture of 2 stereoisomers)

To a solution of a mixture of 4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexanecarboxylic acid and 4- (1- (3-methoxy-3-oxopropyl) -5-methyl-1H-pyrazol-4-yl) cyclohexanecarboxylic acid a18-4(220mg, 90% purity, 0.673mmol) in N, N-dimethylformamide (5mL) was added potassium carbonate (207mg, 1.49mmol) and (bromomethyl) benzene (193mg, 1.13mmol) at room temperature under a nitrogen atmosphere. After stirring at room temperature overnight, the mixture was diluted with water (15mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were washed three times with brine (10mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1 to 1:1) to give the title compound (240mg, obtained from¹Purity by H NMR 95%, 88% yield). LC-MS (ESI): r_T＝2.556min,C₂₂H₂₈N₂O₄Calculated mass of 384.2, M/z found 385.1[ M + H ] ]⁺。¹H NMR(400MHz,CDCl₃)δ7.39-7.30(m,5H),7.21(s,0.3H),7.09(s,0.2H),7.05(s,0.5H),5.17(s,0.5H),5.16(s,1H),5.13(s,0.5H),4.30-4.25(m,2H),3.67(s,3H),2.91-2.83(m,2H),2.73-2.68(m,0.8H),2.49-2.31(m,1.2H),2.23-2.15(m,4H),2.12-1.87(m,1H),1.76-1.39(m,6H)。

Intermediates a18-5A, A18-5B and a 18-5C: (cis) -benzyl 4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexanecarboxylate (single stereoisomer), (trans) -benzyl 4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexanecarboxylate (single stereoisomer) and (cis) -benzyl 4- (1- (3-methoxy-3-oxopropyl) -5-methyl-1H-pyrazol-4-yl) cyclohexanecarboxylate and (trans) -benzyl 4- (1- (3-methoxy-3-oxopropyl) -5-methyl- 1H-pyrazol-4-yl) cyclohexanecarboxylic acid ester (mixture of 2 stereoisomers)

A mixture of benzyl 4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexanecarboxylate and benzyl 4- (1- (3-methoxy-3-oxopropyl) -5-methyl-1H-pyrazol-4-yl) cyclohexanecarboxylate A18-5(7.90g, 95% purity, 19.5mmol) was passed over a chiral preparative SFC (separation conditions: column: Chiralpak IE 5 μm 20 × 250 nm; mobile phase: CO₂MeOH 60:40 at 45 g/min; temperature: 30 ℃; wavelength: 214nm) to provide the title compound a18-5A (4.35g, 88% purity, 51% yield) as a pale yellow oil, a18-5B (1.04g, 87% purity, 12% yield) as a pale yellow oil, and a18-5C (1.70g, 84% purity, 19% yield) as a pale yellow oil.

A18-5A：LC-MS(ESI)：R_T＝2.544min，C₂₂H₂₈N₂O₄Calculated mass of 384.2, M/z found 385.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH 60:40 at 3 g/min; temperature: 30 ℃; wavelength: 230nm, back pressure: 100 bar, R_T＝3.03min)。¹H NMR(400MHz,CDCl₃)δ7.40-7.36(m,5H),7.05(s,1H),5.16(s,2H),4.27(t,J＝6.8Hz,2H),3.67(s,3H),2.84(t,J＝6.8Hz,2H),2.72-2.68(m,1H),2.48-2.41(m,1H),2.19-2.15(m,5H),1.76-1.71(m,2H),1.68-1.60(m,2H),1.52-1.42(m,2H)。

A18-5B:LC-MS(ESI)：R_T＝2.689min，C₂₂H₂₈N₂O₄Calculated mass of 384.2, M/z found 385.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH 60:40 at 3 g/min; temperature: 30 ℃; wavelength: 230nm, back pressure: 100 bar, R_T＝3.71min)。¹H NMR(400MHz,CDCl₃)δ7.39-7.30(m,5H),7.09(s,1H),5.13(s,2H),4.29(t,J＝6.4Hz,2H),3.67(s,3H),2.85(t,J＝6.4Hz,2H),2.41-2.32(m,2H),2.19(s,3H),2.11-2.06(m,2H),1.98-1.94(m,2H),1.63-1.53(m,2H),1.33-1.23(m,2H)。

A18-5C:LC-MS(ESI)：R_T＝2.588min，C₂₂H₂₈N₂O₄Calculated mass of 384.2, M/z found 385.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH 60:40 at 3 g/min; temperature: 30 ℃; wavelength: 230nm, back pressure: 100 bar, R_T＝4.45min)。¹H NMR(400MHz,CDCl₃)δ7.37-7.31(m,5H),7.21(s,1H),5.17(s,1.6H),5.13(s,0.4H),4.29-4.25(m,2H),3.67(s,3H),2.91-2.87(m,2H),2.75-2.67(m,0.8H),2.43-2.31(m,1.2H),2.25-2.17(m,4.5H),2.15-2.08(m,0.5H),1.91-1.87(m,0.5H),1.72-1.52(m,5H),1.43-1.37(m,0.5H)。

Acid 18:

(cis) -4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexanecarboxylic acid

To a solution of (cis) -benzyl 4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexanecarboxylate A18-5A (4.35g, 88% purity, 9.96mmol) in methanol (20mL) was added 10% wt. palladium on charcoal (440 mg). After stirring under hydrogen atmosphere (balloon) at room temperature overnight, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (3.22g, 80% purity, 88% yield). LC-MS (ESI): r _T＝1.718min,C₁₅H₂₂N₂O₄Calculated mass of 294.2, M/z found 295.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.11(s,1H),7.33(s,1H),4.17(t,J＝6.8Hz,2H),3.58(s,3H),2.80(t,J＝6.8Hz,2H),2.59-2.57(m,1H),2.43-2.37(m,1H),2.06(s,3H),2.02-1.98(m,2H),1.67-1.63(m,2H),1.59-1.51(m,2H),1.40-1.34(m,2H)。

Acid 19: 4- (1- (3- (tert-butoxycarbonyl) cyclobutyl) -1H-pyrazol-4-yl) cyclohexane-1-carboxylic acid (A19)

Intermediate a 19-2:

tert-butyl 3-oxocyclobutanecarboxylic acid ester

To a solution of 3-oxocyclobutanecarboxylic acid A19-1(20.0g, 98% pure, 0.172mol) in 2-methylpropan-2-ol (200mL) was slowly added N, N-dimethylpyridin-4-amine (8.48g, 99% pure, 68.7mmol) and di-tert-butyl dicarbonate (75.5g, 99.3% pure, 0.344mol) at room temperature. After stirring at room temperature for 12 hours under a nitrogen atmosphere, the reaction mixture was slowly quenched with 1M aqueous hydrochloride solution (200mL) and extracted three times with dichloromethane (200 mL). The combined organic layers were washed with brine (200mL) and Na₂SO₄(solid) dried, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:1 to 30:1) to give the title compound (17.9g, obtained from¹Purity by H NMR 95%, 58% yield).¹H NMR(400MHz,CDCl₃)δ3.39-3.32(m,2H),3.27-3.20(m,2H),3.13-3.07(m,1H),1.47(s,9H)。

Intermediate a 19-3:

tert-butyl 3-hydroxycyclobutanecarboxylate

To a solution of tert-butyl 3-oxocyclobutanecarboxylate A19-2(17.9g, 95% purity, 0.100mol) in methanol (180mL) at 0 deg.C was added sodium tetrahydroborate (3.86g, 98.5% purity, 0.101 mol). After stirring at room temperature for 1 hour under a nitrogen atmosphere, the reaction mixture was slowly quenched with saturated aqueous sodium bicarbonate solution (200mL) and extracted three times with dichloromethane (200 mL). The combined organic layers were washed with brine (200mL) and Na ₂SO₄(solid) drying, passingFiltered and concentrated under reduced pressure to give the title compound as a colorless oil (17.9g, obtained from¹Purity by H NMR 95%, 99% yield).¹H NMR(400MHz,CDCl₃)δ4.15(br s,1H),2.59-2.46(m,3H),2.24-2.17(m,1H),2.12-2.04(m,2H),1.44(s,9H)。

Intermediate a 19-4:

tert-butyl 3- ((methylsulfonyl) oxy) cyclobutanecarboxylic acid ester

To a solution of tert-butyl 3-hydroxycyclobutanecarboxylate A19-3(5.00g, 95% purity, 27.6mmol) in dichloromethane (50mL) was added triethylamine (5.61g, 99% purity, 54.9mmol) and methanesulfonyl chloride (4.79g, 99% purity, 41.4mmol) at room temperature. After stirring at room temperature for 1 hour under a nitrogen atmosphere, the reaction mixture was slowly quenched with saturated aqueous sodium bicarbonate (50mL) and extracted three times with dichloromethane (50 mL). The combined organic layers were washed with brine (50mL) and Na₂SO₄(solid) dried, filtered and concentrated under reduced pressure to afford the title compound as a yellow solid (7.10g, 85% purity, 87% yield).¹H NMR(300MHz,CDCl₃)δ4.95-4.85(m,1H),3.00(s,3H),2.71-2.61(m,3H),2.55-2.46(m,2H),1.45(s,9H)。

Intermediate a 19-5:

benzyl 4- (1- (3- (tert-butoxycarbonyl) cyclobutyl) -1H-pyrazol-4-yl) cyclohex-3-enecarboxylate

To a solution of benzyl 4- (1H-pyrazol-4-yl) cyclohex-3-enecarboxylate a13-1(3.00g, 90% purity, 9.56mmol) in N, N-dimethylformamide (30mL) was added tert-butyl 3- ((methylsulfonyl) oxy) cyclobutanecarboxylate a19-4(4.22g, 85% purity, 14.3mmol) and cesium carbonate (9.44g, 99% purity, 28.7mmol) at room temperature. After stirring at 120 ℃ for 12 h under nitrogen atmosphere, the reaction mixture was slowly quenched with water (50mL) and extracted three times with ethyl acetate (50 mL). The combined organic layers were washed with brine (50mL) and Na ₂SO₄(solid) dried, filtered and 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 (980mg, 95%Purity, 22% yield). LC-MS (ESI): r_T＝2.100min,C₂₆H₃₂N₂O₄Calculated mass of 436.2, M/z found 437.2[ M + H ]]⁺。

Acid 19:

4- (1- (3- (tert-butoxycarbonyl) cyclobutyl) -1H-pyrazol-4-yl) cyclohexane-1-carboxylic acid

To a solution of benzyl 4- (1- (3- (tert-butoxycarbonyl) cyclobutyl) -1H-pyrazol-4-yl) cyclohex-3-enecarboxylate a19-5(980mg, 95% purity, 2.13mmol) in methanol (20mL) at room temperature under nitrogen was added 10% wt. palladium on charcoal (100 mg). After replacing the internal nitrogen atmosphere with hydrogen, the mixture was stirred at 50 ℃ overnight under a hydrogen atmosphere (50 psi). After cooling to room temperature and releasing the internal pressure to normal pressure, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title compound as a gray solid (490mg, 95% purity, 63% yield).¹H NMR(400MHz,CDCl₃)δ7.38-7.17(m,2H),6.43(br s,1H),4.94-4.86(m,0.5H),4.66-4.57(m,0.5H),3.07-3.01(m,0.5H),2.84-2.76(m,1.5H),2.68-2.63(m,4H),2.53-2.50(m,0.8H),2.43-2.37(m,0.2H),2.00-1.98(m,2.5H),1.79-1.74(m,1.5H),1.66-1.58(m,3H),1.48(s,4H),1.45(s,5H),1.32-1.21(m,1H)。

Acid 20: 4- (3- (methoxycarbonyl) -1-methyl-1H-pyrazol-5-yl) cyclohexanecarboxylic acid (A20)

Intermediate a 20-2:

mixtures of methyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylate and methyl 1-methyl-3-nitro-1H-pyrazole-5-carboxylate

To a solution of methyl 5-nitro-1H-pyrazole-3-carboxylate A20-1(8.4g, 97% purity, 47.6mmol) in N, N-dimethylformamide (100mL) was added potassium carbonate (13.139g, 95.068mmol), followed by dropwise addition of methyl iodide (7.451g, 52.495mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour. The solvent was concentrated under reduced pressure to give the title compound as a yellow solid (8.0g, 88% purity, 80% yield).LC-MS(ESI)：R_T1.11min and 1.30 min.

Intermediates a20-3A and a 20-3B:

methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate and methyl 3-amino-1-methyl-1H-pyrazole-5-carboxylate

To a solution of A20-2(8.0g, 88% purity, 38.0mmol) in ethanol (100mL) was added 10% wt. palladium on charcoal (1.0g) at room temperature. The reaction mixture was stirred under an atmosphere of hydrogen (30psi) at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1 to dichloromethane: methanol ═ 20:1) to give the title compound a20-3A (970mg, from¹Purity of HNMR 95%, 16% yield) and A20-3B (5.26g, from¹Purity of HNMR 98%, 89% yield).

A20-3A:LC-MS(ESI)：R_T＝0.32min,C₆H₉N₃O₂Calculated mass of 155.1, M/z found 156.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)6.08(s,1H),3.89(s,3H),3.75(s,3H),3.68(br s,2H)。

A20-3B:LC-MS(ESI)：R_T＝0.38min,C₆H₉N₃O₂Calculated mass of 155.1, M/z found 156.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)6.11(s,1H),3.98(s,3H),3.83(s,3H),3.65(br s,2H)。

Intermediate a 20-4:

methyl 5-iodo-1-methyl-1H-pyrazole-3-carboxylate

To a solution of methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate A20-3A (970mg, 95% purity, 5.94mmol) and potassium iodide (2.2g, 13.3mmol) in acetic acid (10mL) and water (3mL) was added sodium nitrite (534mg, 97% purity, 7.51mmol) in water (7 mL). After addition, the reaction mixture was stirred at 0 ℃ for 3 hours, then basified to pH 7-8 with saturated aqueous sodium bicarbonate (200 mL). The mixture was extracted twice with ethyl acetate (100 mL). The combined organic layers were washed twice 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 ═ 5:1) to give the title compound a20-4(700mg, 95% purity, 40% yield) as a white solid. LC-MS (ESI): r_T＝1.26min,C₆H₇IN₂O₂Calculated mass of 266.0, M/z found 266.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)6.97(s,1H),4.00(s,3H),3.91(s,3H)。

Intermediate A20-6:

methyl 5- (4- ((benzyloxy) carbonyl) cyclohex-1-en-1-yl) -1-methyl-1H-pyrazole-3-carboxylate

A mixture of methyl 5-iodo-1-methyl-1H-pyrazole-3-carboxylate a20-4(550mg, 95% purity, 1.96mmol), benzyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enecarboxylate a20-5(1.7g, 91% purity, 4.5mmol), tetrakis (triphenylphosphine) palladium (0) (232mg, 0.201mmol) and potassium carbonate (560mg, 4.05mmol) in dioxane (10mL) and water (0.5mL) was stirred under nitrogen at 90 ℃ overnight. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the title compound a20-6(390mg, 96% purity, 54% yield) as a yellow oil. LC-MS (ESI): r _T＝1.63min,C₂₀H₂₂N₂O₄Calculated mass of 354.2, M/z found 355.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)7.38-7.33(m,5H),6.64(s,1H),5.93-5.90(m,1H),5.16(s,2H),3.91(s,3H),3.87(s,3H),2.74-2.70(m,1H),2.53-2.50(m,2H),2.35-2.32(m,2H),2.17-2.14(m,1H),1.92-1.90(m,1H)。

Acid 20:

4- (3- (methoxycarbonyl) -1-methyl-1H-pyrazol-5-yl) cyclohexanecarboxylic acid

To a solution of methyl 5- (4- ((benzyloxy) carbonyl) cyclohex-1-en-1-yl) -1-methyl-1H-pyrazole-3-carboxylate a20-6(810mg, 97% purity, 2.22mmol) in methanol (5mL) was added palladium on charcoal (80mg, 10% wt) at room temperature. The reaction mixture was stirred under an atmosphere of hydrogen (50psi) at 50 ℃ overnight. Cooling the reaction mixtureBrought to room temperature and filtered. The filtrate was concentrated to give the title compound a20(550mg, obtained from¹Purity of HNMR 90%, 84% yield).¹H NMR(300MHz,CDCl₃)6.61(s,0.8H),6.59(s,0.2H),3.91-3.89(m,6H),2.79-2.77(m,1H),2.66-2.42(m,2H),2.30-2.18(m,2H),2.05-2.03(m,1H),1.87-1.80(m,2H),1.74-1.66(m,2H)。

Acid 21: 4- (5- (methoxycarbonyl) -1-methyl-1H-pyrazol-3-yl) cyclohexanecarboxylic acid (A21)

Intermediate a 21-1:

N-methoxy-N-methyl-4-oxocyclohexanecarboxamide

To a solution of 4-oxocyclohexanecarboxylic acid A1-1(20.0g, 141mmol) in dichloromethane (400mL) was added N, O-dimethylhydroxylamine hydrochloride (20.5g, 211mmol) and N, N' -carbonyldiimidazole (27.3g, 169mmol) at room temperature. After stirring at room temperature for 1 hour, the mixture was diluted with water (300mL) and extracted twice with dichloromethane (400 mL). The combined organic layers were concentrated under reduced pressure to give the title compound as a yellow oil (13.3g, 51% yield). LC-MS (ESI): r _T＝0.63min,C₉H₁₅NO₃Calculated mass of 185.1, M/z Mass found 186.0[ M + H [ ]]⁺。¹H NMR(300MHz,CD₃OD)δ3.75(s,3H),3.14(s,3H),2.54-2.43(m,3H),2.30-2.22(m,2H),2.05-1.99(m,2H),1.80-1.65(m,2H)

Intermediate a 21-2:

N-methoxy-N-methyl-1, 4-dioxaspiro [4.5] decane-8-carboxamide

To a solution of N-methoxy-N-methyl-4-oxocyclohexanecarboxamide A21-1(13.3g, 71.8mmol) and ethane-1, 2-diol (15.5g, 250mmol) in toluene (150mL) was added 4-methylbenzenesulfonic acid (3.69g, 21.4 mmol). At room temperatureAfter stirring overnight, the mixture was concentrated to give a residue, which was dissolved in dichloromethane (100 mL). The resulting solution was washed with water (100mL) and then concentrated under reduced pressure to give the title compound as a yellow oil (9.00g, 55% yield).¹H NMR(300MHz,DMSO-d₆)δ3.92-3.86(m,4H),3.66-3.63(m,3H),3.13-3.12(m,3H),2.68-2.62(m,1H),1.86-1.74(m,6H),1.58-1.47(m,2H)

Intermediate a 21-3:

1- (1, 4-dioxaspiro [4.5] decan-8-yl) ethanones

To N-methoxy-N-methyl-1, 4-dioxaspiro [4.5] at 0 deg.C]To a solution of decane-8-carboxamide A21-2(9.00g, 39.2mmol) in anhydrous tetrahydrofuran (60mL) was added dropwise 2M methylmagnesium bromide in tetrahydrofuran (79mL, 158 mmol). After stirring at 0 ℃ for 1 hour, the mixture was quenched with saturated aqueous ammonium chloride (79mL) and then extracted three times with ethyl acetate (100 mL). The separated combined organic layers were washed with brine (100mL) and Na₂SO₄The (solid) was dried and 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 as a yellow oil (4.00g, 55% yield). LC-MS (ESI): r _T＝0.88min,C₁₀H₁₆O₃Calculated mass of 184.1, M/z measured value of 185.1[ M + H ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ3.83-3.76(m,4H),2.40-2.29(m,1H),2.09-2.02(m,3H),1.78-1.72(m,2H),1.70-1.58(m,2H),1.46-1.40(m,4H)。

Intermediate a 21-4:

ethyl 2-hydroxy-4-oxo-4- (1, 4-dioxaspiro [4.5] decan-8-yl) but-2-enoic acid ester

To 1- (1, 4-dioxaspiro [4.5] spiro at room temperature]To a solution of decan-8-yl) ethanone A21-3(3.30g, 17.9mmol) in toluene (40mL) was added 60% wt. sodium hydride in mineral oil (716mg, 17.9 mmol). After stirring at room temperature for 1 hour, diethyl oxalate (3.93g, 26.9mmol) was added. After stirring at room temperature overnight, the mixture was acidified to pH 3 to 4 with 10% wt. aqueous citric acid and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with water (20mL), brine(10mL) washed with anhydrous Na₂SO₄The (solid) was dried, filtered and concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 15:1) to give the title compound as a yellow oil (3.30g, 65% yield). LC-MS (ESI): r_T＝1.45min,C₁₄H₂₀O₆Calculated mass of 284.1, M/z found 285.2[ M + H [ ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ7.24-7.13(m,1H),6.39(s,1H),4.28-4.19(m,2H),3.84-3.80(m,4H),2.4-2.47(m,1H),1.81-1.49(m,8H),1.27-1.16(m,3H)。

Intermediates a21-5A and a 21-5B:

ethyl 1-methyl-3- (1, 4-dioxaspiro [4.5] decan-8-yl) -1H-pyrazole-5-carboxylate and Ethyl 1-methyl-5- (1, 4-dioxaspiro [4.5] decan-8-yl) -1H-pyrazole-3-carboxylate

To a solution of triethylamine (2.35g, 23.2mmol) in ethanol (300mL) was added hydrazine methyl sulfate (1.67g, 11.6mmol) at room temperature. After stirring at room temperature for 1 hour, ethyl 2-hydroxy-4-oxo-4- (1, 4-dioxaspiro [4.5] spiro was added ]Decan-8-yl) but-2-enoate A21-4(3.30g, 11.6 mmol). After stirring at room temperature overnight, the mixture was concentrated to give a residue, which was dissolved in ethyl acetate (150 mL). The resulting solution was washed with water (100mL), brine (100mL), and Na₂SO₄The (solid) was 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 2:1) to give the title compound a21-5A (1.50g, 44% yield) and a21-5B (520mg, 15% yield) as yellow oils.

A21-5A:¹H NMR(300MHz,CDCl₃)δ6.67(s,1H),4.32(q,J＝5.4Hz,2H),4.11(s,3H),3.96(s,4H),2.74-2.66(m,1H),1.99-1.95(m,2H),1.85-1.81(m,2H),1.78-1.63(m,4H),1.37(t,J＝5.4Hz,3H)。

A21-5B:¹H NMR(300MHz,DMSO-d₆)δ6.49(s,1H),4.23(q,J＝5.4Hz,2H),3.88(s,4H),3.85(s,3H),2.84-2.77(m,1H),1.88-1.84(m,2H),1.76-1.73(m,2H),1.67-1.50(m,4H),1.27(t,J＝5.4Hz,3H)。

Intermediate A21-6:

ethyl 1-methyl-3- (4-oxocyclohexyl) -1H-pyrazole-5-carboxylate

To ethyl 1-methyl-3- (1, 4-dioxaspiro [4.5 ] spiro at room temperature]To a solution of decan-8-yl) -1H-pyrazole-5-carboxylic acid ester A21-5A (830mg, 2.82mmol) in dichloromethane (20mL) was added trifluoroacetic acid (5 mL). After stirring at room temperature overnight, the reaction mixture was concentrated to give a residue, which was dissolved in ethyl acetate (40 mL). The resulting solution was washed with saturated aqueous sodium bicarbonate (50mL), brine (15mL), and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (700mg, 99% yield). LC-MS (ESI): r _T＝1.38min,C₁₃H₁₈N₂O₃Calculated mass of 250.1, M/z Mass found 251.2[ M + H [ ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ6.68-6.64(m,1H),4.35-4.28(m,2H),4.14-4.06(m,3H),3.18-3.06(m,1H),2.48-2.41(m,2H),2.27-2.26(m,2H),2.02-1.86(m,2H),1.68-1.53(m,2H),1.38-1.32(m,3H)。

Intermediate A21-8:

methyl 3- (4- (methoxymethylene) cyclohexyl) -1-methyl-1H-pyrazole-5-carboxylate

To a solution of ethyl 1-methyl-3- (4-oxocyclohexyl) -1H-pyrazole-5-carboxylate A21-6(736mg, 2.94mmol) and dimethyl (1-diazo-2-oxopropyl) phosphate A21-7(840mg, 4.37mmol) in dry methanol (15mL) at 0 ℃ under nitrogen was added potassium carbonate (845mg, 6.11 mmol). After stirring at 0 ℃ for 30 minutes and then at room temperature for 2 hours, the reaction mixture was diluted with water (20mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed with water (30mL), twice with brine (30mL), over 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 ═ 15:1) to give the title compound (380mg, 49% yield) as a yellow oil. LC-MS (ESI): r_T＝1.78min,C₁₄H₂₀N₂O₃Calculated mass 264.2, m/z mass measurementValue 265.2[ M + H]⁺。¹H NMR(300MHz,DMSO-d₆)δ6.64(s,1H),5.84(s,1H),3.98-3.97(m,3H),3.77-3.76(m,3H),3.45-3.44(m,3H),2.70-2.60(m,1H),1.92-1.60(m,4H),1.32-1.05(m,4H)。

Intermediate a 21-9:

methyl 3- (4-formylcyclohexyl) -1-methyl-1H-pyrazole-5-carboxylate

To a solution of methyl 3- (4- (methoxymethylene) cyclohexyl) -1-methyl-1H-pyrazole-5-carboxylate a21-8(380mg, 1.44mmol) in acetonitrile (18mL) at 0 ℃ was added 1M aqueous hydrochloric acid (4mL, 4.0 mmol). After stirring at room temperature for 3 hours, the reaction mixture was basified to pH 7 to 8 with saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed twice with brine (20mL) and Na ₂SO₄(solid) dried, filtered and concentrated under reduced pressure to give the crude title compound as a brown oil (300mg, 83% yield). LC-MS (ESI): r_T＝1.43min,C₁₃H₁₈N₂O₃Calculated mass of 250.1, M/z Mass found 251.2[ M + H [ ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ9.63-9.59(m,1H),6.71-6.65(m,1H),4.05-4.00(m,3H),3.84-3.80(m,3H),2.70-2.62(m,1H)2.34-2.26(m,1H),2.01-1.97(m,2H),1.79-1.59(m,2H),1.49-1.41(m,2H),1.36-1.22(m,2H)。

Acid 21:

4- (5- (methoxycarbonyl) -1-methyl-1H-pyrazol-3-yl) cyclohexanecarboxylic acid

To a solution of methyl 3- (4-formylcyclohexyl) -1-methyl-1H-pyrazole-5-carboxylate a21-9(320mg, 1.28mmol) in acetone (15mL) and water (3mL) was added potassium permanganate (504mg, 3.19mmol) at 0 ℃. After stirring at 0 ℃ for 1h, sodium bisulfite (660mg, 6.34mmol) was added. The mixture was then diluted with acetone (10mL) and water (5 mL). The resulting suspension was stirred at room temperature for 15 minutes and filtered through a pad of celite. The filtrate was concentrated at room temperature under reduced pressure to remove acetone. The resulting aqueous solution was acidified with citric acid (solid) to pH 3 to 4 and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried, filtered and concentrated under reduced pressure to give the title compound as a white solid (250mg, 73% yield).¹H NMR(300MHz,DMSO-d₆)δ11.98(s,1H),6.67-6.64(m,1H),4.00-3.99(m,3H),3.79-3.78(m,3H),2.72-2.63(m,1H),2.27-2.11(m,0.5H),1.96-1.91(m,0.5H),1.89-1.78(m,2H),1.71-1.57(m,4H),1.43-1.32(m,2H)。

Acid 22: 4- (1- (3- (tert-butoxy) -2, 2-dimethyl-3-oxopropyl) -1H-pyrazol-4-yl) cyclohexane-1-carboxylic acid (A22)

Intermediate a 22-2:

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 t-butyl methyl malonate A22-1(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 a 22-3:

tert-butyl 3-hydroxy-2, 2-dimethylpropionate

To a solution of 1-tert-butyl 3-methyl 2, 2-dimethylmalonate A22-2(5.00g, 24.7mmol) in tetrahydrofuran (30mL) at-78 deg.C under a nitrogen atmosphere was added dropwise 1.5M diisobutylaluminum hydride (41.3mL, 61.9mmol) in toluene. 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 Na ₂SO₄(solid) 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 a 22-4:

tert-butyl 2, 2-dimethyl-3- (tosyloxy) propionate

To a solution of tert-butyl 3-hydroxy-2, 2-dimethylpropionate A22-3(2.00g, 11.5mmol) in pyridine (8mL) and dichloromethane (20mL) was added tosyl chloride (5.49g, 28.7mmol) at 0 deg.C. 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 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 (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 a 22-5:

benzyl 4- (1- (3- (tert-butoxy) -2, 2-dimethyl-3-oxopropyl) -1H-pyrazol-4-yl) cyclohex-3-enecarboxylate

To a suspension of benzyl 4- (1H-pyrazol-4-yl) cyclohex-3-enecarboxylate a13-1(1.18g, 95% purity, 3.97mmol) and cesium carbonate (2.60g, 7.98mmol) in N, N-dimethylformamide (30mL) was added tert-butyl 2, 2-dimethyl-3- (tosyloxy) propionate a22-4(1.10g, 95% purity, 3.18mmol) at room temperature. After stirring overnight at 100 ℃, the reaction mixture was quenched with water (60mL) and extracted three times with ethyl acetate (60 mL). The combined organic layers were washed with water (60mL), brine (60mL) and Na ₂SO₄(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 3:1) to give a crude productThis was further purified by a C18 column (acetonitrile: water ═ 70% to 100%) to give the title compound (700mg, obtained from¹Purity by H NMR 95%, 38% yield). LC-MS (ESI): r_T＝1.92min,C₂₆H₃₄N₂O₄Calculated mass of 438.3, M/z found 439.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.50(s,1H),7.39-7.30(m,6H),5.94(t,J＝4.0Hz,1H),5.14(s,2H),4.20(s,2H),2.68-2.61(m,1H),2.46-2.38(m,2H),2.37-2.27(m,2H),2.17-2.11(m,1H),1.88-1.78(m,1H),1.45(s,9H),1.15(s,6H)。

Acid 22:

4- (1- (3- (tert-butoxy) -2, 2-dimethyl-3-oxopropyl) -1H-pyrazol-4-yl) cyclohexane-1-carboxylic acid

To a solution of benzyl 4- (1- (3- (tert-butoxy) -2, 2-dimethyl-3-oxopropyl) -1H-pyrazol-4-yl) cyclohex-3-enecarboxylate A22-5(700mg, 95% purity, 1.52mmol) in methanol (30mL) was added 10% wt. palladium on charcoal (400mg) at room temperature. The reaction was stirred under a hydrogen atmosphere (50Psi) at 50 ℃ for 5 hours. The catalyst was filtered off and the filtrate was concentrated to give the title compound (570mg, from¹Purity of H NMR 90%, 97% yield). LC-MS (ESI): r_T1.46 and 1.59min, C₁₉H₃₀N₂O₄Calculated mass of 350.2, M/z found 351.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.31(d,J＝2.8Hz,1H),7.17(s,1H),4.19(s,2H),2.66-2.56(m,1.5H),2.48-2.42(m,0.3H),2.34-2.28(m,0.2H),2.12-1.98(m,2.5H),1.84-1.74(m,1.5H),1.69-1.53(m,3.2H),1.44-1.43(m,9H),1.35-1.25(m,0.8H),1.13-1.12(m,6H)。

Acid 23: 2- (3-ethoxy-2, 2-dimethyl-3-oxopropyl) -4,5,6, 7-tetrahydro-2H-indazole-5-carboxylic acid (A23)

Intermediate a 23-1:

benzyl 4-hydroxycyclohexanecarboxylate

To a solution of benzyl 4-oxocyclohexanecarboxylate A1-2(17.3g, 93% purity, 70.8mmol) in methanol (150mL) at 0 deg.C under nitrogen was added sodium borohydride (5.40g, 143 mmol). After stirring at 0 ℃ for 1.0 h, the mixture was quenched with water (100mL) and acidified to pH about 1 with 2M aqueous hydrochloric acid, then extracted twice with ethyl acetate (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 a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1 to 4:1) to give the desired compound (13.5g, obtained from¹Purity of H NMR 90%, 76% yield). LC-MS (ESI): r_TCalculated mass C of 1.53min₁₄H₁₈O₃234.1, found M/z 235.0[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ7.39-7.30(m,5H),5.13(s,0.7H),5.11(s,1.3H),3.92-3.88(m,0.3H),3.65-3.57(m,0.7H),2.47-2.42(m,0.3H),2.35-2.27(m,0.7H),2.05-2.01(m,3H),1.74-1.61(m,2H),1.58-1.47(m,2H),1.34-1.24(m,1H)。

Intermediate a 23-2:

ethyl 1- (4- ((benzyloxy) carbonyl) cyclohexyl) -1H-pyrazole-4-carboxylate

To a solution of benzyl 4-hydroxycyclohexanecarboxylate A23-1(5.00g, 90% purity, 19.8mmol), ethyl 1H-pyrazole-4-carboxylate (2.78g, 19.8mmol) and triphenylphosphine (10.4g, 39.7mmol) in tetrahydrofuran (70mL) was added dropwise diisopropylazo-1, 2-dicarboxylate (8.03g, 39.7mmol) at 0 ℃ under a nitrogen atmosphere. After stirring at 0 ℃ to room temperature for 16 hours under a nitrogen atmosphere, the mixture was quenched with water (80mL) and extracted twice with ethyl acetate (100 mL). The combined organic layers were washed with brine (80mL) and Na ₂SO₄(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 5:1) and further purified by C18 column (acetonitrile: water: 65% to 72%) to give the title compound (2.20g, obtained from acetonitrile: water) as a white solid¹Purity of H NMR 90%, 28% yield). LC-MS (ESI): r_T＝1.74min,C₂₀H₂₄N₂O₄Calculated mass of 356.2, M/z found 357.1[ M + H [ ].]⁺。¹H NMR(400MHz,CDCl₃)δ7.91(s,0.2H),7.90(s,0.2H),7.89(s,0.8H),7.87(s,0.8H),7.40-7.32(m,5H),5.17(s,1.6H),5.14(s,0.4H),4.32-4.26(m,2H),4.22-4.16(m,1H),2.75-2.70(m,0.8H),2.46-2.39(m,0.2H),2.28-2.18(m,2.5H),2.09-1.84(m,3H),1.84-1.64(m,2.5H),1.37-1.32(m,3H)。

Acid 23:

2- (3-ethoxy-2, 2-dimethyl-3-oxopropyl) -4,5,6, 7-tetrahydro-2H-indazole-5-carboxylic acid

To a solution of ethyl 1- (4- ((benzyloxy) carbonyl) cyclohexyl) -1H-pyrazole-4-carboxylate a23-2(2.15g, 90% purity, 5.43mmol) in ethyl acetate (26mL) was added 10% wt. palladium on charcoal (400 mg). The mixture was stirred under hydrogen atmosphere (balloon) at 30 ℃ overnight. The catalyst was filtered off and the filtrate was concentrated to give the title compound as a white solid (1.58g, 90% purity, 98% yield). LC-MS (ESI): r_T＝1.12min,C₁₃H₁₈N₂O₄266.1 calculated mass of (M/z) found 267.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.96(s,0.8H),7.93(s,0.2H),7.92(s,1H),4.29(q,J＝7.2Hz,2H),4.24-4.15(m,1H),2.78-2.66(m,1H),2.31-2.22(m,2.6H),2.12-1.99(m,3.4H),1.87-1.69(m,2H),1.34(t,J＝7.2Hz,3H)。

Acid 24: 4- (5- (ethoxycarbonyl) -1H-pyrazol-1-yl) cyclohexanecarboxylic acid (A24)

Intermediate a 24-2:

ethyl 1- (4- ((benzyloxy) carbonyl) cyclohexyl) -1H-pyrazole-5-carboxylate

To a solution of benzyl 4-hydroxycyclohexanecarboxylate A23-1(5.7g, 90% purity, 21.9mmol), ethyl 1H-pyrazole-3-carboxylate A24-1(4.70g, 33.5mmol) and triphenylphosphine (11.7g, 44.6mmol) in tetrahydrofuran (100mL) was added dropwise diisopropyl azodicarboxylate (9.04g, 44.7mmol) at 0 ℃. In the roomAfter stirring at room temperature for 16 hours, the mixture was concentrated and dichloromethane (100mL) was added. It was washed twice with water (50mL), then with brine (50mL), over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to leave a yellow oil, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 50:1 to 30:1) and further purified by C18 column (acetonitrile: water ═ 20% to 80%) to give the title compound (3.66g, 96% purity, 45% yield) as a colorless oil. LC-MS (ESI): r_T1.62 and 1.63min, C₂₀H₂₄N₂O₄Calculated mass of 356.2, M/z found 357.3[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.49(d,J＝2.0Hz,1H),7.37-7.30(m,5H),6.83(d,J＝2.0Hz,1H),5.18(s,2H),5.17-5.11(m,1H),4.33(q,J＝7.2Hz,2H),2.78-2.69(m,1H),2.45-2.32(m,2H),2.17-2.06(m,2H),1.98-1.88(m,2H),1.80-1.68(m,2H),1.38(t,J＝7.2Hz,3H)。

Acid 24:

4- (5- (ethoxycarbonyl) -1H-pyrazol-1-yl) cyclohexanecarboxylic acid

To a solution of ethyl 1- (4- ((benzyloxy) carbonyl) cyclohexyl) -1H-pyrazole-5-carboxylate a24-2(2.0g, 96% purity, 5.33mmol) in methanol (50mL) was added 10% wt. palladium on charcoal (284mg, 0.267mmol) at room temperature under a nitrogen atmosphere. After stirring at room temperature for 16 hours under a hydrogen atmosphere, the mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure to give the title compound (1.45g, obtained from ¹Purity by H NMR 95%, 97% yield).¹H NMR(400MHz,CDCl₃)δ7.52(d,J＝1.6Hz,1H),6.83(d,J＝1.6Hz,1H),5.24-5.14(m,1H),4.34(q,J＝7.2Hz,2H),2.79-2.72(m,1H),2.44-2.35(m,2H),2.23-1.12(m,2H),1.99-1.90(m,2H),1.79-1.66(m,2H),1.39(t,J＝7.2Hz,3H)。

Acid 25: 4- (5- (ethoxycarbonyl) pyrimidin-2-yl) cyclohexanecarboxylic acid (A25)

Intermediate a 25-2:

ethyl 2- (4- ((benzyloxy) carbonyl) cyclohex-1-en-1-yl) pyrimidine-5-carboxylate

To a solution of benzyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enecarboxylate A11-2(2.00g, 5.84mmol) and ethyl 2-chloropyrimidine-5-carboxylate A25-1(0.90g, 4.82mmol) in tetrahydrofuran (20mL) and water (5mL) was added potassium carbonate (1.60g, 11.6mmol) under a nitrogen atmosphere. The resulting mixture was purged three times with nitrogen, and then [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium (II) dichloride (200mg, 0.29 mmol). It was then purged again three times with nitrogen and stirred overnight at 70 ℃. After cooling and quenching with water (20mL), the mixture 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 a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 8:1) to give the title compound (230mg, 13% yield) as a yellow solid. LC-MS (ESI): r_T＝1.80min,C₂₁H₂₂N₂O₄Calculated mass of 366.2, M/z found 367.1[ M + H ] ]⁺。¹H NMR(400MHz,CDCl₃)δ9.18(s,2H),7.47(s,1H),7.38-7.33(m,5H),5.17(s,2H),4.42(q,J＝7.2Hz,2H),2.90-2.84(m,1H),2.76-2.69(m,1H),2.64-2.62(m,2H),2.58-2.49(m,1H),2.29-2.24(m,1H),1.92-1.82(m,1H),1.41(t,J＝7.2Hz,3H)。

Acid 25:

4- (5- (ethoxycarbonyl) pyrimidin-2-yl) cyclohexanecarboxylic acid

To a solution of ethyl 2- (4- ((benzyloxy) carbonyl) cyclohex-1-en-1-yl) pyrimidine-5-carboxylate a25-2(600mg, 1.64mmol) in ethyl acetate (25mL) was added 10% wt. palladium on charcoal (300 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 (400mg, 87% yield). LC-MS (ESI): r_T＝0.494min,C₁₄H₁₈N₂O₄Calculated mass of 278.1, M/z found 279.1[ M + H ]]⁺。

Acid 26: 4- (4- (ethoxycarbonyl) thiazol-2-yl) cyclohexanecarboxylic acid (A26)

Intermediate a 26-2:

1-tert-butyl 4-methylcyclohexane-1, 4-dicarboxylate

To a solution of 4- (methoxycarbonyl) cyclohexanecarboxylic acid A26-1(14.4g, 75.8mmol) in tert-butanol (200mL) were added di-tert-butyl dicarbonate (43.9g, 197mmol) and 4-dimethylaminopyridine (3.78g, 30.3 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 (200 mL). The resulting solution was washed with 1M aqueous hydrochloric acid (100mL), saturated sodium bicarbonate (100mL), brine (100mL), and then washed with Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 100:1 to 20:1) to give the title compound as a colorless oil (11.8g, 58% yield, 90% purity). ¹H NMR(300MHz,DMSO-d₆)δ3.60(s,1.8H),3.59(s,1.2H),2.48-2.45(m,0.4H),2.40-2.09(m,1.6H),1.92-1.82(m,2H),1.76-1.53(m,4H),1.39(s,9H),1.34-1.24(m,2H)。

Intermediate a 26-3:

4- (tert-Butoxycarbonyl) cyclohexanecarboxylic acid

To a solution of 1-tert-butyl 4-methylcyclohexane-1, 4-dicarboxylate A26-2(11.8g, 90% purity, 43.8mmol) in tetrahydrofuran (39mL) and methanol (13mL) was added a solution of lithium hydroxide monohydrate (1.87g, 95% purity, 42.3mmol) in water (13 mL). After stirring at 0 ℃ for 6 h, the mixture was poured into water (150mL) and washed with ethyl acetate (100 mL). The aqueous layer was acidified to pH 2 with 1M aqueous hydrochloric acid. The solid formed was collected by filtration and dried under reduced pressure to give the title compound as a white solid (7.8g, 77% yield).¹H NMR(300MHz,DMSO-d₆)δ12.07(br s,1H),2.40-2.31(m,1H),2.17-2.08(m,1H),1.93-1.83(m,2H),1.75-1.51(m,4H),1.39(s,9H),1.33-1.26(m,2H)。

Intermediate a 26-4:

tert-butyl 4-carbamoyl cyclohexanecarboxylic acid ester

To a solution of 4- (tert-butoxycarbonyl) cyclohexanecarboxylic acid A26-3(7.80g, 34.2mmol) in ethyl acetate (150mL) was added N, N-carbonyldiimidazole (7.20g, 44.5mmol) at room temperature. After stirring at room temperature for 0.5 h, 25% wt. aqueous ammonium hydroxide (48.0g, 34.2mmol) was added. Stirring was continued for another 0.5 hours at room temperature. The separated organic layer was then adjusted to pH 2-3 with 0.2M aqueous hydrochloric acid, washed with water (100mL), brine (100mL), and washed with Na₂SO₄(solid) was dried, filtered and concentrated to give a crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1 to 6:1, then 100% ethyl acetate) to give the title compound as a white solid (6.4g, 82% yield). ¹H NMR(300MHz,DMSO-d₆)δ7.13(s,1H),6.63(s,1H),2.38-2.35(m,0.5H),2.14-1.94(m,1.5H),1.85-1.71(m,3H),1.55-1.41(m,3H),1.37-1.34(m,9H),1.26-1.18(m,2H)。

Intermediate a 26-5:

tert-butyl 4-aminomethylthiacylcyclohexanecarboxylate

To a solution of tert-butyl 4-carbamoyl cyclohexanecarboxylate A26-4(6.40g, 28.2mmol) in tetrahydrofuran (100mL) was added 2, 4-bis- (4-methoxy-phenyl) - [1,3,2,4 ] was added]Dithiadiphosphetanyl 2, 4-disulfide (5.70g, 14.1 mmol). The reaction mixture was stirred at 70 ℃ for 2 hours. The reaction mixture was then allowed to cool to room temperature and concentrated under reduced pressure to give a residue, which was diluted with ethyl acetate (50 mL). The solution was washed with saturated aqueous sodium bicarbonate to pH 7-8, then water (50mL), brine (50mL), Na₂SO₄The (solid) was dried, filtered and concentrated to give the crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1 to 2:1) to give the title compound as a white solid (4.30g, 62% yield).¹H NMR(300MHz,DMSO-d₆)δ9.26(s,1H),9.00(s,1H),2.42-2.35(m,1H),2.09-2.02(m,1H),1.87-1.83(m,2H),1.70-1.66(m,2H),1.55-1.42(m,2H),1.35-1.18(m,11H)。

Intermediate A26-6:

ethyl 2- (4- (tert-butoxycarbonyl) cyclohexyl) thiazole-4-carboxylate

To a solution of tert-butyl 4-aminomethylthiacylcyclohexanecarboxylate A26-5(3.20g, 13.2mmol) in 2-methylpropan-2-ol (50mL) was added ethyl 3-bromo-2-oxopropionate (3.2g, 16.4 mmol). After stirring at room temperature for 1 hour, it was warmed to 50 ℃ and stirred at 50 ℃ for 2 hours. After cooling to room temperature, the mixture was concentrated to give a residue which was diluted with ethyl acetate (25 mL). The solution was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate. The separated organic layer was washed with water (10mL), brine (10mL) and Na ₂SO₄The (solid) was dried, filtered and concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1 to 6:1) to give the title compound (2.6g, 58% yield) as a yellow solid.¹H NMR(400MHz,DMSO-d₆)δ8.41(s,0.5H),8.40(s,0.5H),4.29(q,J＝7.2Hz,2H),3.18-3.11(m,0.5H),3.04-2.97(m,0.5H),2.56-2.54(m,0.5H),2.29-2.22(m,0.5H),2.12-2.10(m,1H),1.98-1.88(m,3H),1.80-1.72(m,1H),1.67-1.61(m,1H),1.57-1.44(m,2H),1.40(s,9H),1.29(t,J＝7.2Hz,3H)。

Acid 26:

4- (4- (ethoxycarbonyl) thiazol-2-yl) cyclohexanecarboxylic acid

To a solution of ethyl 2- (4- (tert-butoxycarbonyl) cyclohexyl) thiazole-4-carboxylate A26-6(2.60g, 7.67mmol) in dichloromethane (20mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was then removed to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1 to 2:1, then 100% ethyl acetate) to give the title compound as a yellow solid (2.1g, 96% yield).¹H NMR(300MHz,DMSO-d₆)δ8.39-8.36(m,1H),4.30-4.21(m,2H),3.15-3.08(m,0.6H),3.02-2.94(m,0.4H),2.57-2.52(m,0.6H),2.28-2.21(m,0.4H),2.11-2.06(m,1H),1.99-1.86(m,3H),1.78-1.56(m,2.5H),1.52-1.41(m,1.5H),1.29-1.23(m,3H)。

Acid 27: 4- (3- (methoxycarbonyl) isoxazol-5-yl) cyclohexanecarboxylic acid (A27)

A27-1：

Cyclohexane-1, 4-diyl dimethanol

To a solution of cyclohexane-1, 4-dicarboxylic acid A4-1(50.0g, 0.276mol) in tetrahydrofuran (500mL) at 0 deg.C was added 10M borane-methyl sulfide complex (80mL, 0.800 mol). After stirring at room temperature for 24 hours, the reaction mixture was slowly quenched with methanol (100mL) and water (200mL), then extracted three times with ethyl acetate (200 mL). The combined organic layers were washed with brine (200mL) and Na ₂SO₄(solid) was dried, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the title compound (42.0g, obtained from¹Purity of H NMR 90%, 90% yield).¹H NMR(400MHz,DMSO-d₆)δ4.28(br s,2H),3.26-3.14(m,4H),1.71-1.69(m,3H),1.35-1.19(m,4H),0.84-0.77(m,3H)。

Intermediate a 27-2:

(4- (hydroxymethyl) cyclohexyl) acetic acid methyl ester

To a solution of cyclohexane-1, 4-dimethanol A27-1(80.0g, 90% purity, 0.499mol) in tetrahydrofuran (500mL) at 0 deg.C was added 60% wt. sodium hydride (30.6g, 1.25mol) and acetyl chloride (41.3g, 95% purity, 0.499mol) in mineral oil. After stirring at room temperature for 12 hours. The reaction mixture was concentrated to dryness under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the title compound (21.0g, obtained from¹Purity by H NMR 95%, 21% yield).¹H NMR(400MHz,DMSO-d₆)δ4.36(m,1H),3.82(d,J＝6.4Hz,1.6H),3.30-3.27(m,0.4H),3.21-3.18(m,1.6H),1.99(s,3H),1.75-1.70(m,3H),1.53-1.23(m,4H),0.94-0.87(m,3H)。

Intermediate a 27-3:

(4-Formylcyclohexyl) acetic acid methyl ester

To a solution of dimethyl sulfoxide (40.0g, 99% pure, 0.507mol) in methylene chloride (200mL) at-78 deg.C was added a solution of oxalyl chloride (43.8g, 98% pure, 0.338mol) in methylene chloride (50 mL). After stirring at-78 ℃ for 1 hour, a solution of (4- (hydroxymethyl) cyclohexyl) methyl A27-2(22.1g, 95% pure, 0.113mol) was added at-78 ℃. After stirring at-78 ℃ for 3 hours, the reaction was quenched by the addition of triethylamine (57.6g, 99% pure, 0.564mol) dropwise at-78 ℃. The reaction mixture was allowed to warm to room temperature and extracted three times with dichloromethane (200 mL). The combined organic layers were passed over anhydrous Na ₂SO₄(solid) dried, filtered and concentrated to give the title compound as a yellow oil (16.0g, from¹Purity by H NMR 95%, 73% yield).¹H NMR(400MHz,DMSO-d₆)δ9.57(s,0.5H),5.76(s,0.5H),3.85-3.79(m,2H),2.25-2.19(m,0.5H),2.01(s,3H),1.94-1.92(m,1H),1.79-1.70(m,2.5H),1.58-1.43(m,2H),1.22-1.11(m,1.5H),1.05-0.90(m,2.5H)。

Intermediate a 27-4:

(4-ethynylcyclohexyl) methanol

To a solution of methyl (4-formylcyclohexyl) acetate A27-3(13.1g, 95% pure, 67.7mmol) in methanol (100mL) was added dimethyl (1-diazo-2-oxopropyl) phosphate (20.5g, 95% pure, 101mmol) and potassium carbonate (28.1g, 203mmol) at room temperature. After stirring overnight at room temperature under nitrogen atmosphere, the mixture was allowed to cool to room temperature 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 (4.00g, obtained from¹Purity by H NMR 95%, 41% yield).¹H NMR(400MHz,DMSO-d₆)δ3.45(d,J＝6.4Hz,2H),2.22-2.16(m,1H),2.06-2.02(m,3H),1.84-1.80(m,2H),1.53-1.38(m,5H)。

Intermediate a 27-5:

methyl 5- (4- (hydroxymethyl) cyclohexyl) isoxazole-3-carboxylic acid ester

To (4-ethynylcyclohexyl) methanol A27-4(1.16g, 95% purity, 7.97mmol) in methanol (10mL)To the solution were added methyl 2-nitroacetate (2.11g, 90% purity, 15.9mmol) and triethylenediamine (110mg, 98% purity, 0.961 mmol). After stirring overnight at 80 ℃ under nitrogen atmosphere, the mixture was allowed to cool to room temperature 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 give the title compound (1.30g, obtained from ¹Purity by H NMR 95%, 65% yield). LC-MS (ESI): r_T＝1.484min,C₁₂H₁₇NO₄Calculated mass of 239.1, M/z found 240.1[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ6.67(s,1H),3.88(s,3H),3.24(d,J＝6.0Hz,2H),2.85-2.78(m,1H),2.06-2.01(m,2H),1.84-1.80(m,2H),1.46-1.36(m,3H),1.08-0.98(m,2H)。

Acid 27:

4- (3- (methoxycarbonyl) isoxazol-5-yl) cyclohexanecarboxylic acid

To a solution of periodic acid (1.73g, 99% pure, 7.52mmol) in acetonitrile (20mL) was added chromium (VI) oxide (100mg, 99% pure, 0.990mmol) at room temperature under nitrogen over 2 hours. Thereafter, methyl 5- (4- (hydroxymethyl) cyclohexyl) isoxazole-3-carboxylate a27-5(928mg, 95% purity, 3.69mmol) was added at 0 ℃ and stirring was continued for 2 hours at 0 ℃ under nitrogen atmosphere. The reaction mixture was then diluted with water (10mL) and extracted three times with ethyl acetate (10 mL). The combined organic layers were passed over anhydrous Na₂SO₄(solid) dried, filtered and concentrated to give the title compound as a white solid (800mg, 90% purity, 77% yield). LC-MS (ESI): r_T＝1.005min,C₁₂H₁₅NO₅Calculated mass of 253.1, found value of M/z 254.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.13(br s,1H),6.69(s,1H),3.88(s,3H),2.91-2.84(m,1H),2.28-2.21(m,1H),2.07-1.97(m,4H),1.51-1.40(m,4H)。

Acid 28: 4- (4- (ethoxycarbonyl) thiazol-2-yl) cyclohexanecarboxylic acid (A28)

Intermediate a 28-1:

benzyl 4- ((hydroxyimino) methyl) cyclohexanecarboxylate

To a solution of benzyl 4-formylcyclohexanecarboxylate A1-5(17.6g, 71.5mmol) in ethanol (348mL) was added a solution of sodium acetate (11.7g, 143mmol) and hydroxylamine hydrochloride (7.45g, 107mmol) in water (26 mL). After stirring at 90 ℃ for 1 hour, the mixture was cooled to room temperature and filtered off and then the filtrate was concentrated to give a residue which was diluted with ethyl acetate (300 mL). The organic phase was washed three times with water (60mL) and Na ₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (17.5g, 96% yield). LC-MS (ESI): r_TCalculated mass C of 2.069min₁₅H₁₉NO₃261.1, found M/z 262.1[ M + H [)]⁺。¹H NMR(300MHz,DMSO-d₆)δ10.97-10.71(m,0.3H),10.42-10.39(m,0.7H),7.34-7.27(m,5H),7.21-7.18(m,1H),5.09-5.05(m,2H),2.34-2.23(m,1H),2.16-2.02(m,1H),1.93-1.87(m,2H),1.79-1.74(m,2H),1.61-1.53(m,1H),1.49-1.21(m,3H)。

Intermediate a 28-2:

ethyl 3- (4- ((benzyloxy) carbonyl) cyclohexyl) isoxazole-5-carboxylate

To a solution of 1-chloropyrrolidine-2, 5-dione (8.95g, 67.0mmol) and pyridine (530mg, 6.70mmol) in dichloromethane (150mL) at about 5 deg.C was added benzyl 4- ((hydroxyimino) methyl) cyclohexanecarboxylate A28-1(17.5g,67.0 mmol). After stirring at room temperature for 10 minutes, a solution of ethyl propiolate (8.22g, 83.0mmol) and triethylamine (6.77g, 67.0mmol) in dichloromethane (30mL) was added to the mixture. The mixture was stirred under nitrogen at 18 ℃ for 2 hours. The mixture was washed three times with water (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 ═ 3:1) to give the title compound (11.0g, 46% yield) as a yellow solid. LC-MS (ESI): r_T＝2.552min,C₂₀H₂₃NO₅Calculated mass of 357.2, found value of M/z 358.1[ M + H ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ7.38-7.28(m,5H),7.23-7.13(m,1H),5.08(s,2H),4.35-4.19(m,2H),3.10-2.64(m,1H),2.42-2.32(m,1H),2.03-1.95(m,2H),1.91-1.81(m,1H),1.77-1.59(m,2H),1.53-1.44(m,3H),1.32-1.23(m,3H)。

Acid 28:

4- (5- (ethoxycarbonyl) isoxazol-3-yl) cyclohexanecarboxylic acid

To a solution of ethyl 3- (4- ((benzyloxy) carbonyl) cyclohexyl) isoxazole-5-carboxylate a28-2(7.00g, 19.0mmol) in ethanol (200mL) was added 10% wt. palladium on charcoal (500mg) at room temperature under a nitrogen atmosphere. After replacing the internal nitrogen atmosphere with hydrogen, the mixture was stirred at 25 ℃ for 15 minutes under a hydrogen atmosphere. The catalyst was filtered off and 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 (2.30g, 44% yield) as a white solid. LC-MS (ESI): r_T＝0.720min,C₁₃H₁₇NO₅Calculated mass of 267.1, M/z found 268.1[ M + H [)]⁺。¹H NMR(300MHz,DMSO-d₆)δ12.06(s,1H),7.24(s,1H),4.31(q,J＝7.2Hz,2H),2.77-2.67(m,1H),2.25-2.16(m,1H),1.96-1.92(m,4H),1.53-1.34(m,4H),1.30-1.25(m,3H)。

Acid 29: 5-methyl isoxazole-4-carbonyl chloride (A29)

Acid 30: 4- (4- (methoxycarbonyl) phenyl) cyclohexanecarboxylic acid (A30)

Intermediate a 30-1:

4-benzyl-4 ' -methyl-2, 3,4, 5-tetrahydro- [1,1' -biphenyl ] -4,4' -dicarboxylate

To a solution of methyl 4-bromobenzoate (760mg, 3.55mmol), potassium carbonate (1.37g, 9.93mmol) and tetrakis (triphenylphosphine) palladium (462mg, 0.40mmol) in dioxane (75mL) and water (15mL) was added benzyl 4- (4,4,5, 5-tetramethyl-1, 3-tetramethyl at room temperature2-Dioxolanyl-2-yl) cyclohex-3-enecarboxylate A11-2(1.49g, 3.94 mmol). After stirring at 90 ℃ for 12 hours under nitrogen atmosphere, the reaction mixture was cooled to room temperature, filtered and 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 (1.15g, 83% yield) as a white solid. ¹H NMR(300MHz,DMSO-d₆)δ7.95-7.86(m,2H),7.59-7.49(m,2H),7.40-7.33(m,5H),6.34(s,1H),5.14(s,2H),3.85-3.83(m,3H),2.75-2.66(m,1H),2.48-2.38(m,4H),2.14-2.08(m,1H),1.82-1.63(m,1H)。

Acid 30:

4- (4- (methoxycarbonyl) phenyl) cyclohexanecarboxylic acid

To 4-benzyl-4 '-methyl-2, 3,4, 5-tetrahydro- [1,1' -biphenyl ] at room temperature]To a solution of-4, 4' -dicarboxylate A30-1(1.10g, 3.97mmol) in methanol (50mL) was added 10% wt. palladium on charcoal (110 mg). After stirring overnight at room temperature under a hydrogen atmosphere, the reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a white solid (800mg, 97% yield). LC-MS (ESI): r_T＝0.27min,C₁₅H₁₈O₄Calculated Mass 262.1, M/z found 261.2[ M-H [ ]]^-。¹H NMR(300MHz,DMSO-d₆)δ7.90-7.87(m,2H),7.39-7.32(m,2H),3.83(s,3H),2.63(s,1.6H),2.30-2.22(m,0.4H),2.12-1.98(m,2H),1.85-1.44(m,6H)。

Acid 31: 4- (1- (3- (tert-butoxy) -2, 2-dimethyl-3-oxopropyl) -1H-pyrazol-4-yl) cyclohexane-1-carboxylic acid (A31)

Intermediate a 31-2:

ethyl 2-amino-2- (hydroxyimino) acetic acid ester

Water (150mL) was added dropwise to a stirred mixture of ethyl cyanoformate A31-1(25.5g, 250mmol), hydroxylamine hydrochloride (26.1g, 375mmol) and sodium carbonate (20.5g, 193mmol) in ethanol (250 mL). After stirring the mixture at room temperature for 2 hours, the solvent was removed andthe aqueous layer was extracted three times with dichloromethane (900 mL). The combined organic layers were passed over Na₂SO₄(solid) dried, filtered and concentrated to provide the title compound as a white solid (21.0g, 88% yield).¹H NMR(300MHz,CDCl₃)δ9.52(br s,1H),5.15(s,2H),4.35-4.27(m,2H),1.36-1.31(m,3H)。

Intermediate a 31-3:

Tert-butyl 4- ((2-ethoxy-1- (hydroxyimino) -2-oxoethyl) carbamoyl) cyclohexanecarboxylate

To a solution of 4- (tert-butoxycarbonyl) cyclohexanecarboxylic acid A26-3(1.60g, 90% purity, 6.31mmol) in 1, 4-dioxane (30mL) was added 1H-benzo [ d ] at room temperature][1,2,3]Triazol-1-ol (947mg, 90% purity, 6.31mmol) and N₁- ((ethylimino) methylene) -N₂,N₂Dimethylethane-1, 2-diamine hydrochloride (2.50g, 90% purity, 12.7 mmol). After stirring at room temperature for 1 hour, ethyl 2-amino-2- (hydroxyimino) acetate A31-2(926mg, 90% purity, 6.31mmol) was added. After stirring at 80 ℃ overnight, it was cooled to room temperature and concentrated to give a residue, which was diluted with water (50mL) and extracted five times with ethyl acetate (100 mL). The combined organic layers were washed with water (50mL), brine (50mL) and Na₂SO₄(solid) was dried, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (100% dichloromethane, then dichloromethane: ethyl acetate ═ 6:1) to give the title compound (1.90g, from which was obtained as a yellow solid)¹Purity by H NMR 95%, 84% yield). LC-MS (ESI): r_T＝1.58min,C₁₆H₂₆N₂O₆Calculated mass of 342.2, M/z found 343.3[ M + H ] ]⁺。¹H NMR(300MHz,DMSO-d₆)δ6.89(s,2H),4.27-4.15(m,2H),2.40-2.31(m,1H),2.15-2.10(m,1H),1.93-1.81(m,4H),1.38-1.29(m,12H),1.25-1.17(m,4H)

Intermediate a 31-4:

ethyl 5- (4- (tert-butoxycarbonyl) cyclohexyl) -1,2, 4-oxadiazole-3-carboxylate

Reacting (tert-butyl-4- ((2-ethoxy-1- (hydroxyimino) -2-Oxoethyl) carbamoyl) cyclohexanecarboxylic acid ester A31-3(1.90g, 95% purity, 5.27mmol) in pyridine (20mL) was stirred at 120 ℃ overnight. It was then cooled to room temperature, the solvent was removed to give a residue, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1 to 4:1) to give the title compound (1.50g, obtained from¹Purity by H NMR 95%, 83% yield). LC-MS (ESI): r_T＝1.73min,C₁₆H₂₄N₂O₅Calculated mass of 324.2, M/z found 325.3[ M + H ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ4.51-4.44(m,2H),3.24-3.13(m,1H),2.38-2.30(m,1H),2.23-2.18(m,2H),2.07-2.01(m,2H),1.72-1.45(m,13H),1.43-1.37(m,3H)

Acid 31:

4- (3- (ethoxycarbonyl) -1,2, 4-oxadiazol-5-yl) cyclohexanecarboxylic acid

To a solution of ethyl 5- (4- (tert-butoxycarbonyl) cyclohexyl) -1,2, 4-oxadiazole-3-carboxylate A31-4(1.50g, 95% purity, 4.39mmol) in dichloromethane (10mL) was added trifluoroacetic acid (5mL) at room temperature. After stirring at room temperature overnight, the mixture was concentrated to give a residue, which was purified by silica gel column chromatography (dichloromethane: ethyl acetate ═ 1:1) to give the title compound (1.20g, obtained from ¹Purity of H NMR 90%, 92% yield).¹H NMR(300MHz,DMSO-d₆)δ12.09(s,1H),4.39-4.30(m,2H),3.10-3.00(m,1H),2.28-2.18(m,1H),2.09-2.05(m,2H),1.96-1.93(m,2H),1.59-1.39(m,4H),1.30-1.23(m,3H)。

Acid 32: 1- (tert-Butoxycarbonyl) piperidine-4-carboxylic acid (A32)

Acid 33: (cis) -1- (tert-butoxycarbonyl) -2-methylpiperidine-4-carboxylic acid (A33)

Intermediate a 33-2:

methyl 2-isonicotinic acid methyl ester

To a 500mL flaskTo this was added 2-methyl-isonicotinic acid A33-1(10g, 72.9mmol), methanol (200mL) and concentrated sulfuric acid (10 mL). After stirring at 85 ℃ for 6 hours, the reaction mixture was cooled to room temperature. The solvent was evaporated under reduced pressure to give a residue, which was diluted with dichloromethane (100mL) and washed twice with saturated sodium bicarbonate solution (100mL), over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a colorless liquid (10g, 90% yield). LC-MS (ESI): r_T＝1.37min,C₈H₉NO₂Calculated mass of 151.1, M/z found 151.9[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.63-8.61(m,1H),7.66(s,1H),7.60-7.57(m,1H),3.85(s,3H),2.53(s,3H)。

Intermediate a 33-3:

(cis) -1-tert-butyl 4-methyl 2-methylpiperidine-1, 4-dicarboxylate

To a solution of methyl 2-isonicotinate A33-2(6g, 39.7mmol) in acetic acid (60mL) was added platinum (IV) oxide (600mg, 2.6 mmol). The mixture was stirred at 40 ℃ under a hydrogen atmosphere of 3MPa for 3 days. The mixture was filtered and the filtrate was concentrated under reduced pressure to give crude intermediate (11g, 70.0 mmol). To a mixture of the crude intermediate in water (100mL) were added di-tert-butyl dicarbonate (18.3g, 84.0mmol) and potassium carbonate (14.5g, 105.0 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then extracted twice with ethyl acetate (70 mL). The combined organic layers were passed over Na ₂SO₄(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 9:1) to give the title compound as a colorless oil (9.2g, 90% yield). LC-MS (ESI): r_T＝1.839min,C₁₃H₂₃NO₄Calculated mass of 257.2, found M/z 258.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ4.20-4.15(m,1H),3.90-3.81(m,1H),3.71(s,3H),3.13-3.05(m,1H),2.62-2.56(m,1H),2.00-1.87(m,3H),1.79-1.72(m,1H),1.47(s,9H),1.08(d,J＝6.8Hz,3H)。

Acid 33:

(cis) -1- (tert-butoxycarbonyl) -2-methylpiperidine-4-carboxylic acid

To a solution of 1-tert-butyl 4-methyl 2-methylpiperidine-1, 4-dicarboxylate A33-3(2.5g, 9.72mmol) in tetrahydrofuran/water (13mL/6.5mL) at 0 deg.C was added a solution of lithium hydroxide monohydrate (2.16g, 51.4mmol) in water (6 mL). The reaction mixture was stirred at 30 ℃ for 4 hours. The tetrahydrofuran was removed under reduced pressure. The residue was then diluted with water (30mL) and washed with ethyl acetate (20 mL). The aqueous layer was acidified to pH 4 to 5 with 1M aqueous hydrochloric acid and extracted with ethyl acetate (30 mL). Subjecting the organic layer to Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a white solid (2.5g, 90% purity, 95% yield). LC-MS (ESI): r_T＝0.39min,C₁₂H₂₁NO₄Calculated mass 243.1, M/z found 242.0[ M-H [)]^-。¹H NMR(400MHz,DMSO-d₆)δ12.31(s,1H),4.06-3.99(m,1H),3.67-3.61(m,1H),3.06-2.98(m,1H),2.53-2.47(m,1H),1.88-1.76(m,3H),1.62-1.53(m,1H),1.39(s,9H),1.05(d,J＝6.8Hz,3H)。

Acid 34: 1- (tert-Butoxycarbonyl) pyrrolidine-3-carboxylic acid (A34)

Acid 35: tert-butyl 3- (3-ethoxy-3-oxopropanoyl) azetidine-1-carboxylate (A35)

Acid 36: 4- (5- (1- (methoxycarbonyl) cyclopropyl) pyrimidin-2-yl) cyclohexane-1-carboxylic acid (A36)

Intermediate a 36-2:

methyl 1- (2-chloropyrimidin-5-yl) cyclopropanecarboxylate

To a solution of methyl 2- (2-chloropyrimidin-5-yl) acetate A36-1(700mg, 3.75mmol) in N, N-dimethylformamide (21mL) at 0 deg.C was added 60% sodium hydride in mineral oil (330mg, 8.25 mmol). The resulting mixture was stirred at 0 ℃ under nitrogen for 30 minutes and then 1, 2-dibromoethane (700mg, 3.73mmol) was added. After stirring at room temperature for 1 hour, the reaction was mixedThe material was quenched with ice water (30mL) at 0 ℃ and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed twice with water (50mL) and twice with brine (50mL), over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1 to 9:1) to give the title compound (456mg, 57% yield) as a white solid. LC-MS (ESI): r_T＝1.36min，C₉H₉ClN₂O₂Calculated mass of 212.0, M/z found 213.0[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.59(s,2H),3.67(s,3H),1.75(dd,J＝7.2Hz,4.4Hz,2H),1.23(dd,J＝7.2Hz,4.4Hz,2H)。

Intermediate a 36-3:

tert-butyl 4- (5- (1- (methoxycarbonyl) cyclopropyl) pyrimidin-2-yl) cyclohex-3-enecarboxylate

To a solution of tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enecarboxylate A3-3(600mg, 1.95mmol) in 1, 4-dioxane (38mL) and water (3.8mL) was added methyl 1- (2-chloropyrimidin-5-yl) cyclopropanecarboxylate a36-2(454mg, 2.14mmol), potassium carbonate (538mg, 3.89mmol) and [1,1' -bis (diphenylphosphino) ferrocene at room temperature]Palladium (II) dichloride (142mg, 0.194 mmol). After stirring at 100 ℃ under nitrogen for 6 hours, the reaction mixture was cooled to room temperature, slowly diluted with water (100mL), and then 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 and purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1 to 4:1) to give the title compound as a white solid (600mg, 86% yield). LC-MS (ESI): r_T＝1.80min,C₁₉H₂₆N₂O₄Calculated mass of 358.2, M/z found 359.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.62(s,2H),7.29-7.27(m,1H),3.65(s,3H),2.87-2.81(m,1H),2.57-2.47(m,4H),2.21-2.15(m,1H),1.83-1.73(m,1H),1.70(dd,J＝7.2Hz,4.0Hz,2H),1.47(s,9H),1.20(dd,J＝7.2Hz,4.0Hz,2H)。

Intermediate a 36-4:

tert-butyl 4- (5- (1- (methoxycarbonyl) cyclopropyl) pyrimidin-2-yl) cyclohexanecarboxylate

To a mixture of tert-butyl 4- (5- (1- (methoxycarbonyl) cyclopropyl) pyrimidin-2-yl) cyclohex-3-enecarboxylate A36-3(600mg, 1.67mmol) and triethylamine (846mg, 8.38mmol) in ethyl acetate (20mL) under a nitrogen atmosphere was added 10% wt. palladium on charcoal (200 mg). After stirring at room temperature for 16 hours under a hydrogen atmosphere (balloon pressure), the mixture was filtered. The filtrate was concentrated to give the title compound as a brown oil (500mg, 83% yield). LC-MS (ESI): r _T＝1.76min,C₂₀H₂₈N₂O₄Calculated mass of 360.2, M/z found 361.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.61(s,2H),3.65(s,3H),3.00-2.93(m,0.8H),2.90-2.83(m,0.2H),2.55-2.50(m,0.8H),2.30-2.22(m,0.2H),2.14-1.96(m,4.4H),1.92-1.85(m,1.6H),1.71-1.67(m,2.6H),1.63-1.53(m,1.6H),1.45(s,9H),1.20(dd,J＝7.2Hz,4.0Hz,2H)。

Acid 36:

4- (5- (1- (methoxycarbonyl) cyclopropyl) pyrimidin-2-yl) cyclohexane-1-carboxylic acid

To a solution of tert-butyl 4- (5- (1- (methoxycarbonyl) cyclopropyl) pyrimidin-2-yl) cyclohexanecarboxylate A36-4(500mg, 1.39mmol) in dichloromethane (10mL) at 0 deg.C was added trifluoroacetic acid (5 mL). After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to give the title compound as a brown oil (400mg, 95% yield). LC-MS (ESI): r_T＝1.12min,1.27min,C₁₆H₂₀N₂O₄Calculated mass of 304.1, M/z found 305.1[ M + H ]]⁺。

Acid 37: 4- (4- (ethoxycarbonyl) -5-methylpyrimidin-2-yl) cyclohexane-1-carboxylic acid (A37)

Intermediate a 37-2:

ethyl 2- (4- (tert-butoxycarbonyl) cyclohex-1-en-1-yl) -5-methylpyrimidin-4-carboxylate

To a solution of ethyl 2-chloro-5-methylpyrimidine-4-carboxylate (3g, 97% purity, 14.5mmol), A37-1, and tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enecarboxylate A3-3(5.947g, 93% purity, 17.9mmol) in tetrahydrofuran (100mL) under a nitrogen atmosphere was added a solution of potassium carbonate (4.151g, 30.1mmol) in water (20mL), followed by [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (1.094g, 1.50 mmol). After stirring at 70 ℃ for 12 h, the reaction mixture was cooled to room temperature and poured into water (60 mL). The aqueous layer was extracted twice with ethyl acetate (60 mL). The combined organic layers were passed over Na ₂SO₄(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 (4.9g, purity 95.7%, 93% yield) as a colorless oil. LC-MS (ESI): r_T＝2.009min,C₁₉H₂₆N₂O₄Calculated mass of 346.2, M/z found 347.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.80(s,1H),7.19-7.18(m,1H),4.38(q,J＝7.2Hz,2H),2.70-2.66(m,1H),2.56-2.52(m,1H),2.46-2.37(m,3H),2.35(s,3H),2.07-2.03(m,1H),1.70-1.61(m,1H),1.42(s,9H),1.33(t,J＝7.2Hz,3H)。

Intermediate a 37-3:

ethyl 2- (4- (tert-butoxycarbonyl) cyclohexyl) -5-methylpyrimidine-4-carboxylate

To a solution of ethyl 2- (4- (tert-butoxycarbonyl) cyclohex-1-en-1-yl) -5-methylpyrimidine-4-carboxylate A37-2(2g, 95.7% purity, 5.53mmol) in ethyl acetate (20mL) under nitrogen was added 10% wt. palladium on charcoal (600 mg). After stirring at room temperature for 12 hours under a hydrogen atmosphere, the mixture was filtered. The filtrate was concentrated to give the title compound (2g, from¹Purity of H NMR 90%, 94% yield).¹H NMR(400MHz,DMSO-d₆)δ8.80(s,1H),4.39-4.34(m,2H),2.95-2.87(m,0.7H),2.82-2.75(m,0.3H),2.34(s,3H),1.98-1.85(m,4H),1.77-1.73(m,2H),1.63-1.56(m,3H),1.41(s,9H),1.32(t,J＝7.2Hz,3H)。

Acid 37:

4- (4-ethoxycarbonyl) -5-methylpyrimidin-2-yl) cyclohexanecarboxylic acid

To a solution of ethyl 2- (4- (tert-butoxycarbonyl) cyclohexyl) -5-methylpyrimidine-4-carboxylate A37-3(2g, 90% purity, 5.17mmol) in dichloromethane (5mL) at 0 deg.C was added trifluoroacetic acid (5 mL). After stirring at room temperature overnight, the reaction mixture was concentrated and purified by C18 column (acetonitrile: water-20% to 80%) to give the title compound as a colorless oil (1.2g, 97.7% purity, 78% yield). LC-MS (ESI): r _T＝1.111min,C₁₅H₂₀N₂O₄Calculated Mass of 292.1M/z found 291.1[ M-H ]]^-。

Acid 38: 4- (4- (2-methoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexanecarboxylic acid (A38)

Intermediate a 38-3:

2- (4- ((benzyloxy) carbonyl) cyclohexanecarboxamide) -4-methoxy-4-oxobutanoic acid

To a solution of 2-amino-4-methoxy-4-oxobutanoic acid hydrochloride A38-2(600mg, 98% purity, 3.20mmol) in acetone (25mL) and saturated aqueous sodium bicarbonate solution (25mL) at room temperature was added dropwise a solution of benzyl 4- (chlorocarbonyl) cyclohexanecarboxylate A38-1(1g, 95% purity, 3.38mmol) in tetrahydrofuran (5mL) over 30 minutes. After stirring at room temperature for 2 hours, the mixture was concentrated at room temperature under reduced pressure to give a residue, which was diluted with water (100mL) and acidified with 1M aqueous hydrochloride solution to pH 3 to 4. The resulting mixture was extracted twice with ethyl acetate (100 mL). The combined organic layers were washed twice with water (50mL) and brine (50mL), over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by C18 column (acetonitrile: water 50% to 70%) to give the title compound (500mg, obtained from¹Purity of H NMR 90%, 36% yield). LC-MS (ESI): r_T＝1.48min,C₂₀H₂₅NO₇391.2, found value of M/z 391.9[ M + H [) ]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.73(br s,1H),8.08-8.04(m,1H),7.40-7.30(m,5H),5.11(s,1.2H),5.08(m,0.8H),4.56-4.50(m,1H),3.58(s,1.2H),3.57(s,1.8H),2.79-2.73(m,1H),2.65-2.59(m,1H),2.36-2.24(m,1H),2.16-2.07(m,0.5H),1.95-1.90(m,2H),1.77-1.72(m,1H),1.64-1.53(m,3.5H),1.41-1.24(m,2H)。

Intermediate a 38-4:

benzyl 4- ((1-methoxy-1, 4-dioxopent-3-yl) carbamoyl) cyclohexanecarboxylate

To a solution of 2- (4- ((benzyloxy) carbonyl) cyclohexanecarboxamide) -4-methoxy-4-oxobutanoic acid A38-3(2.4g, 95% purity, 5.8mmol) in toluene (20mL) was added pyridine (11mL) and acetic anhydride (9mL) at room temperature. After stirring at 90 ℃ for 2 hours, the mixture was cooled to room temperature and concentrated under reduced pressure to give a residue, which was dissolved in water (20mL) and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed twice with water (10mL) and brine (10mL), over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by C18 column (acetonitrile: water 50% to 70%) to give the title compound (1.0g, obtained from¹Purity by H NMR 95%, 42% yield). LC-MS (ESI): r_T＝1.52min,C₂₁H₂₇NO₆Calculated mass of 389.2, found value of M/z 390.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.40-7.30(m,6H),5.11(s,1.2H),5.08(s,0.8H),4.50-4.45(m,1H),3.58(s,1H),3.57(s,2H),2.79-2.74(m,1H),2.68-2.62(m,1H),2.34-2.27(m,1H),2.06(s,1H),2.05(s,2H),1.96-1.91(m,2H),1.78-1.75(m,1H),1.62-1.53(m,4H),1.43-1.32(m,2H)。

Intermediate a 38-5:

benzyl 4- (4- (2-methoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexanecarboxylate

To a solution of benzyl 4- ((1-methoxy-1, 4-dioxopent-3-yl) carbamoyl) cyclohexanecarboxylate A38-4(860mg, 95% pure, 2.10mmol) in N, N-dimethylformamide (8mL) at 0 deg.C was added phosphoryl trichloride (985mg, 6.3 mmol). After stirring for 30 minutes at 90 ℃, the mixture was cooled to At room temperature, dissolved in water (50mL) and extracted twice with ethyl acetate (100 mL). The combined organic layers were washed twice with water (50mL) and brine (50mL), over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by C18 column (acetonitrile: water 50% to 70%) to give the title compound (530mg, obtained from¹Purity by H NMR 95%, 65% yield). LC-MS (ESI): r_T＝1.72min,C₂₁H₂₅NO₅Calculated mass 371.2, M/z found 372.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.39-7.29(m,5H),5.10(s,2H),3.60(s,3H),3.49(s,1.2H),3.48(s,0.8H),2.92-2.86(m,0.6H),2.72-2.61(m,1H),2.43-2.38(m,0.4H),2.21(s,3H),2.03-1.95(m,1.6H),1.84-1.75(m,3.4H),1.70-1.62(m,1.4H),1.52-1.41(m,1.6H)。

Acid 38:

4- (4- (2-methoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexanecarboxylic acid

To a solution of benzyl 4- (4- (2-methoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexanecarboxylate a38-5(400mg, 95% purity, 1.02mmol) in ethyl acetate (20mL) and water (1mL) was added 10% palladium on charcoal (40mg, wt.%) at room temperature. After stirring overnight under a hydrogen atmosphere (balloon) at room temperature, the mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (300mg, obtained from¹Purity by H NMR 95%, 99% yield).¹H NMR(400MHz,DMSO-d₆)δ12.09(br s,1H),3.60(s,3H),3.48(s,1.2H),3.47(s,0.8H),2.89-2.85(m,0.6H),2.70-2.62(m,0.4H),2.45-2.42(m,0.6H),2.25-2.14(m,3.4H),2.05-2.00(m,0.6H),1.96-1.94(m,0.8H),1.83-1.69(m,3.6H),1.65-1.59(m,1.3H),1.49-1.34(m,1.7H)。

Acid 39: 4- (5- (2-methoxy-2-oxoethyl) pyrimidin-2-yl) cyclohexane-1-carboxylic acid (A39)

Intermediate a 39-1:

tert-butyl 4- (5- (2-methoxy-2-oxoethyl) pyrimidin-2-yl) cyclohex-3-enecarboxylate

Methyl 2- (2-Chloropyrimidin-5-yl) acetate A36-1(1.8g, 9.65mmol), tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enecarboxylate A3-3(2.79g, 9.05mmol), potassium carbonate (2.47g, 17.9mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] at 95 ℃ under a nitrogen atmosphere]A mixture of dichloropalladium (II) (0.76g, 1.04mmol) in dioxane (25mL) and water (2.5mL) was stirred for 6 hours. After cooling to room temperature, the mixture was filtered, concentrated under reduced pressure and purified by silica gel chromatography (petroleum ether: ethyl acetate 10:1) to give the title compound (1.88g, from¹Purity by H NMR 95%, 59% yield). LC-MS (ESI): r_T＝1.70min,C₁₈H₂₄N₂O₄Calculated mass of 332.2, M/z found 333.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.66(s,2H),7.20(s,1H),3.77(s,2H),3.65(s,3H),2.71-2.67(m,1H),2.54-2.53(m,1H),2.47-2.32(m,3H),2.07-2.04(m,1H),1.69-1.63(m,1H),1.42(s,9H)。

Intermediate a 39-2:

tert-butyl 4- (5- (2-methoxy-2-oxoethyl) pyrimidin-2-yl) cyclohexanecarboxylic acid ester

To a solution of tert-butyl 4- (5- (2-methoxy-2-oxoethyl) pyrimidin-2-yl) cyclohex-3-enecarboxylate A39-1(1.42g, 95% pure, 4.06mmol) in ethyl acetate (10mL) and triethylamine (2.1g, 20.8mmol) was added 10% wt. palladium on charcoal (0.42g) at room temperature. After stirring overnight at room temperature under a hydrogen atmosphere, the mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.4g, obtained from ¹Purity of H NMR 90%, 93% yield). LC-MS (ESI): r_T＝1.67min,C₁₈H₂₆N₂O₄Calculated mass of 334.2, found value of M/z 335.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.64(s,2H),3.75(s,2H),3.65(s,3H),2.93-2.86(m,0.8H),2.78-2.74(m,0.2H),2.56-2.53(m,0.7H),2.23-2.18(m,0.3H),2.01-1.93(m,0.4H),1.90-1.87(m,3.6H),1.79-1.75(m,2H),1.64-1.56(m,2H),1.40(s,9H)。

Acid 39:

4- (5- (2-methoxy-2-oxoethyl) pyrimidin-2-yl) cyclohexanecarboxylic acid

To a solution of tert-butyl 4- (5- (2-methoxy-2-oxoethyl) pyrimidin-2-yl) cyclohexanecarboxylate A39-2(1.4g, 90% pure, 3.77mmol) in dichloromethane (10mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give the compound (1.2g, obtained from¹Purity of H NMR 90%, 100% yield). LC-MS (ESI): r_T＝1.10min,C₁₄H₁₈N₂O₄Calculated mass of 278.1, M/z found 279.2[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.63(s,2H),3.75(s,2H),3.65(s,3H),2.93-2.86(m,1H),2.31-2.15(m,1H),1.99-1.93(m,2H),1.89-1.83(m,1H),1.78-1.72(m,2H),1.63-1.56(m,2H),1.50-1.39(m,1H)。

Acid 40: 1- (5- (4- (ethoxycarbonyl) piperidin-1-yl) pyrimidin-2-yl) piperidine-4-carboxylic acid (A40)

Intermediate a 40-2:

tert-butyl 1- (5-bromopyrimidin-2-yl) piperidine-4-carboxylate

To a solution of 1- (5-bromopyrimidin-2-yl) piperidine-4-carboxylic acid A40-1(14.8g, 90% pure, 46.6mmol) in t-butanol (150mL) was added di-tert-butyl dicarbonate (16.0g, 73.3mmol) and 4-dimethylaminopyridine (12.0g, 98.2mmol) at room temperature. After stirring at room temperature overnight, the reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to provide the title compound (13.0g, from ¹Purity of H NMR 90%, 73% yield).¹H NMR(400MHz,CDCl₃)δ8.27(s,2H),4.57-4.52(m,2H),3.08-3.01(m,2H),2.51-2.43(m,1H),1.95-1.91(m,2H),1.70-1.60(m,2H),1.45(s,9H)。

Intermediate a 40-3:

tert-butyl 1- (5- (4- (ethoxycarbonyl) piperidin-1-yl) pyrimidin-2-yl) piperidine-4-carboxylate

To a solution of tert-butyl 1- (5-bromopyrimidin-2-yl) piperidine-4-carboxylate a40-2(1.2g, 90% purity, 3.16mmol), ethylpiperidine-4-carboxylate a40-3(600mg, 3.82mmol) and cesium carbonate (3.10g, 9.51mmol) in 1, 4-dioxane (60mL) was added dicyclohexyl (2',4',6 '-triisopropyl- [1,1' -biphenyl ] at room temperature under a nitrogen atmosphere]-2-yl) phosphine (300mg, 0.629mmol) and tris (dibenzylideneacetone) dipalladium (0) (290mg, 0.317 mmol). After stirring under nitrogen at 100 ℃ overnight, the reaction mixture was cooled to room temperature, concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 12:1 to 3:1) to give the title compound (980mg, from¹Purity of H NMR 90%, 67% yield). LC-MS (ESI): r_T＝1.990min,C₂₂H₃₄N₄O₄Calculated mass of 418.3, found M/z 419.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.10(s,2H),4.54-4.49(m,2H),4.16(q,J＝7.2Hz,2H),3.35-3.30(m,2H),3.02-2.95(m,2H),2.73-2.67(m,2H),2.47-2.35(m,2H),2.05-2.01(m,2H),1.94-1.87(m,4H),1.71-1.62(m,2H),1.44(s,9H),1.27(t,J＝7.2Hz,3H)。

Acid 40:

1- (5- (4- (ethoxycarbonyl) piperidin-1-yl) pyrimidin-2-yl) piperidine-4-carboxylic acid

To a solution of tert-butyl 1- (5- (4- (ethoxycarbonyl) piperidin-1-yl) pyrimidin-2-yl) piperidine-4-carboxylate a40-4(980mg, 90% pure, 2.11mmol) in dichloromethane (6mL) was added trifluoroacetic acid (3mL) at 0 ℃. After stirring at room temperature for 3 hours, the mixture was poured into water (15mL) and extracted twice with ethyl acetate (15 mL). The combined organic layers were washed with brine (20mL) and Na ₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (840mg, obtained from¹Purity of H NMR 90%, 98% yield). LC-MS (ESI): r_T＝1.269min,C₁₈H₂₆N₄O₄Calculated mass of 362.2, M/z found 363.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.23(s,2H),4.56-4.51(m,2H),4.17(q,J＝7.2Hz,2H),3.41-3.36(m,2H),3.17-3.10(m,2H),2.84-2.78(m,2H),2.65-2.60(m,1H),2.47-2.41(m,1H),2.12-1.92(m,6H),1.80-1.70(m,2H),1.28(t,J＝7.2Hz,3H)。

Acid 41: 1- (5- (3- (tert-butoxy) -3-oxopropyl) pyridin-2-yl) piperidine-4-carboxylic acid (A41)

Intermediate a 41-3:

ethyl 1- (5-bromopyridin-2-yl) piperidine-4-carboxylate

To a solution of ethylpiperidine-4-carboxylate A41-2(5.9g, 37.5mmol) in N, N-dimethylformamide (80mL) was added cesium carbonate (19.0g, 58.3mmol) and 5-bromo-2-fluoropyridine A41-1(5.0g, 28.4mmol) at room temperature under a nitrogen atmosphere. After stirring at 100 ℃ for 6 hours, the mixture was cooled to room temperature and filtered. The filtrate was poured into water (100mL) and extracted three times with ethyl acetate (150 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 50:1 to 20:1) to give the title compound (7.1g, obtained from¹Purity by H NMR 95%, 76% yield). LC-MS (ESI): r_T＝1.66min,C₁₃H₁₇BrN₂O₂Calculated mass of 312.0, M/z found 313.0[ M + H ] ]⁺。¹H NMR(400MHz,CDCl₃)δ8.17(d,J＝2.4Hz,1H),7.51(dd,J＝9.2Hz,2.8Hz,1H),6.56(d,J＝9.2Hz,1H),4.15(q,J＝7.2Hz,4H),3.00-2.93(m,2H),2.56-2.49(m,1H),2.01-1.95(m,2H),1.80-1.70(m,2H),1.26(t,J＝7.2Hz,3H)。

Intermediate a 41-5:

(E) -Ethyl 1- (5- (3- (tert-butoxy) -3-oxopropyl-1-en-1-yl) pyridin-2-yl) piperidine-4-carboxylic acid ester

To ethyl 1- (5-bromopyridin-2-yl) piperidine-4-carboxylate A41-3(3g, 9.1mmol) and tert-butyl acrylate A41-4(2.40g, 18.7mmol) in N, N-dimethylformamide at room temperature under a nitrogen atmosphereTo a solution (90mL) was added tri (o-tolyl) phosphine (1.40g, 4.60mmol), triethylamine (5.70g, 56.3mmol) and diacetoxypalladium (0.30g, 1.34 mmol). After stirring overnight at 100 ℃ under nitrogen, the mixture was cooled to room temperature, poured into water (100mL), and extracted three times with ethyl acetate (150 mL). The combined organic layers were washed with water (250mL) and brine (250mL) and washed with Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1 to 8:1) to give the title compound (3.6g, obtained from¹Purity of H NMR 90%, 99% yield). LC-MS (ESI): r_T＝1.78min,C₂₀H₂₈N₂O₄Calculated mass of 360.2, M/z found 361.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.24(d,J＝2.4Hz,1H),7.63(dd,J＝9.2Hz,2.4Hz,1H),7.48(d,J＝15.6Hz,1H),6.64(d,J＝8.8Hz,1H),6.17(d,J＝16.0Hz,1H),4.29(dt,J＝13.6Hz,3.6Hz,2H),4.15(q,J＝7.2Hz,2H),3.09-3.02(m,2H),2.60-2.53(m,1H),2.02-1.98(m,2H),1.80-1.71(m,2H),1.53(s,9H),1.26(t,J＝7.2Hz,3H)。

Intermediate A41-6:

ethyl 1- (5- (3- (tert-butoxy) -3-oxopropyl) pyridin-2-yl) piperidine-4-carboxylate

To a solution of ethyl 1- (5- (3- (tert-butoxy) -3-oxopropyl-1-en-1-yl) pyridin-2-yl) piperidine-4-carboxylate a41-5(1.50g, 90% purity, 3.75mmol) in ethanol (40mL) was added 10% palladium on charcoal (450mg, wt.). After stirring overnight at 30 ℃ under a hydrogen atmosphere, the mixture was filtered and the filtrate was concentrated to give the title compound (1.37g, from ¹Purity of H NMR 90%, 91% yield). LC-MS (ESI): r_T＝1.68min,C₂₀H₃₀N₂O₄Calculated mass of 362.2, M/z found 363.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.03(d,J＝2.4Hz,1H),7.33(dd,J＝8.8Hz,2.4Hz,1H),6.61(d,J＝8.8Hz,1H),4.19-4.12(m,4H),2.95-2.89(m,2H),2.77(t,J＝8.0Hz,2H),2.53-2.45(m,3H),2.02-1.96(m,2H),1.81-1.72(m,2H),1.42(s,9H),1.26(t,J＝7.2Hz,3H)。

Acid 41:

1- (5- (3- (tert-butoxy) -3-oxopropyl) pyridin-2-yl) piperidine-4-carboxylic acid

To a solution of ethyl 1- (5- (3- (tert-butoxy) -3-oxopropyl) pyridin-2-yl) piperidine-4-carboxylate A41-6(1.37g, 90% pure, 3.40mmol) in methanol (32mL) and water (8mL) was added lithium hydroxide monohydrate (430mg, 10.2mmol) at room temperature under a nitrogen atmosphere. After stirring at room temperature for 8 hours, the mixture was poured into ethyl acetate (80 mL). The mixture was acidified with 1M aqueous hydrochloric acid to pH 5 to 6, then washed twice with water (40mL) and brine (50mL), over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.1g, obtained from¹Purity by H NMR 95%, 92% yield). LC-MS (ESI): r_T＝0.94min,C₁₈H₂₆N₂O₄Calculated mass of 334.2, M/z found 335.0[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.04(d,J＝2.0Hz,1H),7.36(dd,J＝8.8Hz,2.4Hz,1H),6.64(d,J＝8.8Hz,1H),4.17-4.12(m,2H),3.00-2.94(m,2H),2.78(t,J＝8.0Hz,2H),2.61-2.53(m,1H),2.47(t,J＝8.0Hz,2H),2.05-2.02(m,2H),1.85-1.75(m,2H),1.42(s,9H)。

Part II: preparation of Keto esters having the general formulae IV-1 and IV-2

An intermediate KT 1: (exemplified by method A)

Methyl 2- (4- (3-methoxy-3-oxopropanoyl) cyclohexyl) oxazole-4-carboxylate

To a solution of 4- (4- (methoxycarbonyl) oxazol-2-yl) cyclohexanecarboxylic acid a1(1.30g, 5.14mmol) in acetonitrile (18mL) was added N, N' -carbonyldiimidazole (998mg, 6.17mmol) at room temperature. The solution was stirred at room temperature under nitrogen for 2 hours (mixture a). To a suspension of potassium 3-methoxy-3-oxopropionate (1.67g, 10.7mmol) and magnesium chloride (1.21g, 12.8mmol) in acetonitrile (25mL) was added triethylamine (1.65g, 16.3 mmol). After stirring at room temperature under nitrogen for 1 hour, the suspension was added to mixture a and stirring was continued at 80 ℃ under nitrogen for 3 hours, then it was cooled and concentrated under reduced pressure to give a residue, The residue was taken up in water (100mL) and ethyl acetate (100 mL). The mixture was acidified with 0.5M aqueous hydrochloric acid to give a clear solution and then the organic phase was separated. The aqueous layer was 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 (1.55g, 98.1% yield). LC-MS (ESI): r_T＝1.399min,C₁₅H₁₉NO₆Calculated mass of 309.1, M/z found 310.1[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ8.16(s,1H),3.91(s,1.2H),3.90(s,1.8H),3.75(s,1.2H),3.73(s,1.8H),3.53(s,1.08H),3.51(s,0.72H),3.10-3.05(m,0.4H),2.87-2.77(m,0.6H),2.69-2.63(m,0.4H),2.56-2.50(m,0.6H),2.28-2.23(m,1H),2.-2.03(m,2H),1.89-1.83(m,1H),1.79-1.61(m,3H),1.54-1.44(m,1H)。

Spectroscopic analysis of ketoesters

An intermediate KT 2:

methyl 2- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) oxazole-4-carboxylate

The title compound was synthesized as a colorless oil from a1 by a similar procedure using method a. LC-MS (ESI): r_T＝1.454min,C₁₆H₂₁NO₆Calculated mass 323.1, M/z found 324.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.16(s,1H),4.23-4.16(m,2H),3.91(s,1.5H),3.90(s,1.5H),3.51-3.45(m,2H),3.09-3.05(m,0.4H),2.86-2.78(m,0.6H),2.69-2.63(m,0.4H),2.58-2.50(m,0.6H),2.23-2.02(m,3H),1.88-1.77(m,2H),1.68-1.54(m,2H),1.47-1.39(m,1H),1.30-1.26(m,3H)。

An intermediate KT 3:

methyl 2- (3- (3-methoxy-3-oxopropanoyl) bicyclo [1.1.1] pent-1-yl) oxazole-4-carboxylate

The title compound was synthesized from a2 as a gray solid by a similar procedure using method a. LC-MS (ESI): r_T＝1.815min,C₁₄H₁₅NO₆Calculated mass of 293.1, found M/z 293.9[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ11.75(s,0.4H),8.17(s,1H),5.02(s,0.4H),3.91(s,3H),3.74(s,3H),3.52(s,1.2H),2.52(s,3.8H),2.44(m,2.2H)。

An intermediate KT 4:

ethyl 2- (4- (3-ethoxy-3-oxopropanoyl) cyclohex-1-en-1-yl) oxazole-4-carboxylate

The title compound was synthesized from a3 as a gray solid by a similar procedure using method a.

LC-MS(ESI)：R_T＝1.53min,C₁₇H₂₁NO₆Calculated mass of 335.1, found value of M/z 336.3[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.13(s,1H),6.86(s,1H),4.39(q,J＝7.2Hz,2H),4.21(q,J＝7.2Hz,2H),3.61(s,0.5H),3.56(s,1.5H),2.87-2.77(m,2H),2.55-2.42(m,3H),2.20-2.16(m,1H),1.76-1.68(m,1H),1.38(t,J＝7.2Hz,3H),1.29(t,J＝7.2Hz,3H)。

An intermediate KT 5:

methyl 2- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) -5-methyloxazole-4-carboxylate

The title compound was synthesized as a white solid from a4 by a similar procedure using method a.

LC-MS(ESI)：R_T＝1.57min,C₁₇H₂₃NO₆Calculated mass of 337.2, M/z found 338.3[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ12.21(s,0.1H),5.02(s,0.1H),4.22(s,2H),3.92(d,J＝1.6Hz,3H),3.53(s,1.8H),3.02(s,0.4H),2.78-2.56(m,4.6H),2.26-2.09(m,4H),1.79-1.49(m,4H),1.34-1.28(m,3H)。

An intermediate KT 6:

methyl 2- ((4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) methyl) oxazole-4-carboxylate

The title compound was synthesized from a5 as a yellow oil by a procedure analogous to method a, which was used without further purification. LC-MS (ESI): r_T＝1.65min,C₁₇H₂₃NO₆Calculated mass of 337.2, M/z found 338.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.73(s,1H),4.09-4.04(m,2H),3.79(s,3H),3.64-3.63(m,2H),2.73-2.69(m,2H),2.65-2.60(m,0.6H),2.44-2.37(m,0.4H),1.99-1.68(m,4H),1.59-1.48(m,2.7H),1.26-1.22(m,1.3H),1.19-1.16(m,3H),1.09-1.02(m,1H)。

An intermediate KT 7:

methyl 3- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -3-oxopropanoate

The title compound was synthesized as a yellow oil from a6 by a similar procedure using method a.¹H NMR(400MHz,CDCl₃)δ7.54(s,1H),4.22-4.16(m,2H),3.74-3.73(m,3H),3.60-3.56(m,2H),3.53-3.48(m,2H),3.03-3.00(m,0.3H),2.78-2.71(m,0.7H),2.62-2.61(m,0.3H),2.56-2.47(m,0.7H),2.24-2.12(m,2H),2.11-2.01(m,1.5H),1.84-1.76(m,1.5H),1.65-1.43(m,3H),1.30-1.24(m,3H)。

An intermediate KT 8:

methyl 3- (4- (4- (2-ethoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexyl) -3-oxopropanoate

The title compound was synthesized as a yellow oil from a7 by a similar procedure using method a. LC-MS (ESI): r_T＝1.55min,C₁₈H₂₅NO₆Calculated mass of 351.2, found M/z 352.0[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ4.16(q,J＝6.8Hz,2H),3.75-3.73(m,3H),3.53(s,1.5H),3.51(s,0.5H),3.45(s,2H),2.96-2.93(m,0.2H),2.71-2.65(m,1H),2.54-2.48(m,0.8H),2.24(s,2H),2.19(s,1H),2.07-2.04(m,2H),1.86-1.74(m,2H),1.62-1.44(m,4H),1.26(t,J＝7.2Hz,3H)。

An intermediate KT 9:

ethyl 3- (4- (4- (2-methoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -3-oxopropanoate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow oil from a6 by a similar procedure using method a.

LC-MS(ESI)：R_T＝1.49min,C₁₈H₂₅NO₆Calculated mass of 351.2, M/z found 352.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ12.2(s,0.1H),7.54(s,1H),4.99(s,0.1H),4.23-4.16(m,4H),3.61-3.58(m,1.8H),3.51-3.48(m,2H),3.04-2.99(m,0.3H),2.78-2.71(m,0.7H),2.65-2.60(m,0.3H),2.57-2.48(m,0.7H),2.24-1.98(m,4H),1.84-1.74(m,1H),1.65-1.47(m,3H),1.30-1.26(m,6H)。

An intermediate KT 10:

ethyl 3- (4- (4- (3-methoxy-3-oxopropyl) oxazol-2-yl) cyclohexyl) -3-oxopropanoate

The title compound was synthesized as a yellow oil from a9 by a similar procedure using method a.¹H NMR(300MHz,DMSO-d₆)δ7.65(s,1H),4.06(q,J＝7.2Hz,2H),3.63(s,2H),3.56(s,3H),2.71-2.67(m,1H),2.65-2.63(m,2H),2.58-2.56(m,2H),2.05-2.01(m,2H),1.95-1.90(m,2H),1.70-1.55(m,1H),1.48-1.24(m,4H),1.15(t,J＝7.2Hz,3H)。

An intermediate KT 11:

ethyl 3- (2- (4- (3-methoxy-3-oxopropanoyl) cyclohexyl) oxazol-4-yl) -2, 2-dimethylpropionate

The title compound was synthesized as a yellow oil from a10 by a similar procedure using method a.¹H NMR(300MHz,CDCl₃)δ7.24(s,1H),4.11(q,J＝6.9Hz,2H),3.73-3.72(m,3H),3.52-3.50(m,2H),2.73(s,2H),2.71-2.64(m,1H),2.58-2.43(m,1H),2.24-2.19(m,1H),2.11-1.99(m,2H),1.84-1.38(m,5H),1.26-1.20(m,9H)。

An intermediate KT 12:

ethyl 2- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) oxazole-5-carboxylate (mixture of 2 stereoisomers)

An intermediate KT 12-1:

mixtures of ethyl 2- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) oxazole-5-carboxylate and ethyl 2- (4- (3-ethoxy-3-oxopropanoyl) cyclohex-1-en-1-yl) oxazole-5-carboxylate

The title compound was synthesized as a yellow oil by a similar procedure using method a. LC-MS (ESI): r_T＝1.635min,C₁₇H₂₃NO₆And C₁₇H₂₁NO₆Calculated masses of 337.2 and 335.1, M/z found 338.1[ M + H ] respectively]⁺And 336.1[ M + H]⁺。

An intermediate KT 12:

ethyl 2- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) oxazole-5-carboxylate (mixture of 2 stereoisomers)

To a mixture of ethyl 2- (4- (3-ethoxy-3-oxopropanoyl) cyclohex-1-en-1-yl) oxazole-5-carboxylate and ethyl 2- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) oxazole-5-carboxylate KT12-1(3.48g, 90% purity, about 9.34mmol)) in methanol (100mL) was added 10% wt. palladium on charcoal (1.00g) at room temperature under nitrogen atmosphere. After replacing the inert nitrogen atmosphere with hydrogen, the mixture was stirred at 25 ℃ for 1.5 hours under a hydrogen atmosphere of a balloon. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (3.05g, from¹Purity of H NMR 90%, 87% yield). LC-MS (ESI): r_T＝1.498min,C₁₇H₂₃NO₆Calculated mass of 337.2, M/z found 338.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.89(s,0.5H),7.88(s,0.5H),4.31(q,J＝7.2Hz,2H),4.12-4.05(m,2H),3.68(s,1H),3.65(s,1H),3.17-3.14(m,0.6H),2.94-2.85(m,0.4H),2.72-2.63(m,0.5H),2.13-2.09(m,0.5H),1.99-1.97(m,2H),1.85-1.74(m,2H),1.64-1.57(m,2H),1.47-1.36(m,2H),1.29(t,J＝7.2Hz,3H),1.21-1.16(m,3H)。

An intermediate KT 13:

ethyl 3- (4- (4- (1-ethoxy-2-methyl-1-oxoprop-2-yl) oxazol-2-yl) cyclohexyl) -3-oxopropionate

The title compound was synthesized as a colorless oil from a12 by a similar procedure using method a. LC-MS (ESI): r_T＝2.138min,C₂₀H₂₉NO₆Calculated mass of 379.2, M/z found 380.1[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ7.37(s,1H),4.23-4.12(m,4H),3.50-3.48(m,2H),3.04-3.00(m,0.2H),2.81-2.72(m,0.8H),2.62-2.51(m,1H),2.20-2.00(m,3.5H),1.86-1.55(m,4.5H),1.51(s,6H),1.30-1.21(m,6H)。

An intermediate KT 14:

ethyl 3- (4- (1- (2-ethoxy-2-oxoethyl) -1H-pyrazol-4-yl) cyclohexyl) -3-oxopropanoate

Synthesis of a pink oil from A13 by a similar procedure using method A The title compound. LC-MS (ESI): r_T＝1.918min,C₁₈H₂₆N₂O₅Calculated mass of 350.2, M/z found 351.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ12.24(s,0.1H),12.17(s,0.1H),7.41(s,1H),7.25(s,1H),4.87(s,0.6H),4.85(s,1.4H),4.25-4.18(m,4H),3.51(s,0.5H),3.49(s,1.3H),2.75-2.65(m,1H),2.53-2.46(m,0.3H),2.11-1.67(m,6.7H),1.57-1.35(m,2H),1.30-1.26(m,6H)。

An intermediate KT 15:

methyl 3- (4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohexyl) -3-oxopropanoate

The title compound was synthesized from a14 by using a procedure analogous to method a, which was used without further purification. LC-MS (ESI): r_T＝1.46min，C₁₇H₂₄N₂O₅Calculated mass of 336.2, found M/z 337.0[ M + H ]]⁺。

An intermediate KT 16:

methyl 3- (4- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) -1H-pyrazol-1-yl) -3-methylbutyrate

The title compound was synthesized as a yellow oil from a15 by a similar procedure using method a. LC-MS (ESI): r_T＝1.867min,C₂₀H₃₀N₂O₅Calculated Mass of 378.2, M/z found 379.2[ M + H [, M + z]⁺。¹HNMR(400MHz,CDCl₃)δ7.37(s,0.4H),7.35(s,0.6H),7.29(s,0.4H),7.28(s,0.6H),4.23-4.15(m,2H),3.57(s,1.2H),3.56(s,1.8H),3.51(s,0.8H),3.50(s,1.2H),2.88(s,0.8H),2.87(s,1.2H),2.72-2.64(m,1.4H),2.53-2.43(m,0.6H),2.12-1.92(m,3H),1.83-1.73(m,3H),1.71-1.67(m,6H),1.53-1.30(m,1.5H),1.27-1.24(m,3.5H)。

An intermediate KT 17:

methyl 3- (4- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) -1H-pyrazol-1-yl) butanoate

The title compound was synthesized from a16 as a brown oil by a similar procedure using method a, which was used without further purification.¹H NMR(400MHz,CDCl₃)δ7.36-7.33(m,1H),7.21-7.20(m,1H),4.77-4.68(m,1H),4.19(q,J＝7.2Hz,2H),3.64(s,3H),3.51-3.49(m,2H),3.06-2.95(m,1.4H),2.78-2.68(m,2.5H),2.09-1.91(m,2H),1.82-1.66(m,4H),1.58-1.53(m,4H),1.49-1.33(m,1H),1.30-1.26(m,3H)。

An intermediate KT 18:

ethyl 3- (4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohexyl) -3-oxopropanoate

The title compound was synthesized as a colorless oil from a17 by a similar procedure using method a. LC-MS (ESI): r _T＝2.134min,C₁₈H₂₆N₂O₅Calculated mass of 350.2, M/z found 351.2[ M + H [ ]]⁺。

An intermediate KT 19:

ethyl 3- (4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexyl) -3-oxopropanoate

The title compound was synthesized from a18 as a pale yellow oil by a similar procedure using method a. LC-MS (ESI): r_T＝2.592min,C₁₉H₂₈N₂O₅Calculated Mass 364.2, M/z found 365.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ12.34(s,0.1H),7.12(s,1H),5.07(s,0.1H),4.28(t,J＝6.8Hz,2H),4.23-4.18(m,2H),3.68(s,3H),3.52(s,1.8H),2.84(t,J＝6.8Hz,2H),2.77-2.71(m,0.7H),2.55-2.46(m,1H),2.40-2.30(m,0.3H),2.19(s,1H),2.18(s,2H),2.09-1.97(m,2.5H),1.77-1.64(m,3.5H),1.56-1.44(m,2H),1.29(t,J＝7.2Hz,3H)。

An intermediate KT 20:

tert-butyl 3- (4- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) -1H-pyrazol-1-yl) cyclobutanecarboxylate

The title compound was synthesized as a colorless oil from a19 by a similar procedure using method a.¹H NMR(400MHz,CDCl₃)δ7.40-7.29(m,2H),5.00-4.90(m,0.5H),4.70-4.62(m,0.5H),4.21-4.16(m,2H),3.61(s,0.3H),3.51-3.49(m,1.5H),3.36(s,0.2H),3.08-3.01(m,0.4H),2.87-2.78(m,1.6H),2.72-2.64(m,4H),2.17(s,1H),2.09-1.93(m,2H),1.84-1.76(m,1.5H),1.73-1.67(m,2.5H),1.49(s,4H),1.46(s,5H),1.33-1.25(m,5H)。

An intermediate KT 21:

methyl 5- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) -1-methyl-1H-pyrazole-3-carboxylate

The title compound was synthesized as a colorless oil from a20 by a similar procedure using method a. LC-MS (ESI): r_T1.38min and 1.43min, C₁₇H₂₄N₂O₅Calculated mass of 336.2, M/z found 337.2[ M + H [ ]]⁺。

An intermediate KT 22:

methyl 3- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) -1-methyl-1H-pyrazole-5-carboxylate

The title compound was synthesized as a yellow oil from a21 by a similar procedure using method a. LC-MS (ESI): r_T＝1.52min,C₁₇H₂₄N₂O₅Calculated mass of 336.2, M/z Mass found 337.3[ M + H [ ] ]⁺。¹H NMR(300MHz,DMSO-d₆)δ6.68-6.66(m,1H),4.12-4.04(m,2H),4.02-3.99(m,3H),3.80-3.79(m,3H),3.66-3.61(m,2H),2.80-2.64(m,1H),2.01-1.98(m,1H),1.95-1.91(m,2H),1.82-1.61(m,4H),1.42-1.33(m,2H),1.18-1.12(m,3H)。

An intermediate KT 23:

tert-butyl 3- (4- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) -1H-pyrazol-1-yl) -2, 2-dimethylpropionate

The title compound was synthesized as a colorless oil from a22 by a similar procedure using method a. LC-MS (ESI): r_T＝1.80min,C₂₃H₃₆N₂O₅Calculated mass of 420.3, M/z found 421.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ12.22-12.16(m,0.1H),7.32-7.27(m,1H),7.22-7.15(m,1H),4.98-4.97(m,0.1H),4.29-4.10(m,4H),3.60(s,0.1H),3.50(s,0.4H),3.47(s,1H),3.36(s,0.3H),2.88-2.44(m,1.5H),2.14-1.59(m,8.5H),1.45-1.44(m,9H),1.30-1.23(m,3H),1.14-1.13(m,6H)。

An intermediate KT 24:

ethyl 1- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) -1H-pyrazole-4-carboxylate

The title compound was synthesized as a white solid from a23 by a similar procedure using method a.

LC-MS(ESI)：R_T＝1.55min,C₁₇H₂₄N₂O₅Calculated mass of 336.2, found M/z 337.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ12.35(s,0.1H),7.93(s,0.8H),7.92(s,0.2H),7.91(s,0.2H),7.90(s,0.8H),6.36(s,0.1H),4.29(q,J＝7.2Hz,2H),4.24-4.20(m,3H),3.53(s,1.5H),3.52(s,0.3H),2.82-2.77(m,0.7H),2.63-2.55(m,0.3H),2.30-2.03(m,5H),1.84-1.73(m,2H),1.63-1.56(m,1H),1.36-1.29(m,6H)。

An intermediate KT 25:

ethyl 1- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) -1H-pyrazole-5-carboxylate

The title compound was synthesized as a colorless oil from a24 by a similar procedure using method a. LC-MS (ESI): r_T＝1.88min,C₁₇H₂₄N₂O₅Calculated mass of 336.2, M/z found 337.4[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ12.41(s,0.1H),7.54-7.45(m,1H),6.87-6.80(m,1H),5.27-5.09(m,1.1H),4.38-4.29(m,2H),4.24-4.17(m,2H),3.61-3.48(m,1.8H),2.81-2.72(m,0.7H),2.64-2.53(m,0.3H),2.37-2.18(m,1.8H),2.14-1.99(m,2.4H),1.94-1.86(m,1.8H),1.84-1.71(m,2H),1.38(t,J＝7.2Hz,3H),1.29(t,J＝7.2Hz,3H)。

An intermediate KT 26:

ethyl 2- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) pyrimidine-5-carboxylate

The title compound was synthesized as a yellow solid from a25 by a similar procedure using method a.

LC-MS(ESI)：R_T1.671min and 1.987min, C₁₈H₂₄N₂O₅Calculated mass of 348.2, found M/z 349.1[ M + H [)]⁺。

An intermediate KT 27:

(trans) -ethyl 2- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) thiazole-4-carboxylate

The title compound was synthesized as a yellow oil from a26 by a similar procedure using method a.

¹H NMR(400MHz,DMSO-d₆)δ12.15(s,0.1H),8.40(s,1H),5.10(m,0.1H),4.29(q,J＝7.2Hz,2H),4.12(q,J＝7.2Hz,2H),3.68(s,1.8H),3.01(tt,J＝12.0,3.6Hz,1H),2.57(tt,J＝12.0,3.6Hz,1H),2.16-2.13(m,2H),2.02-1.99(m,2H),1.58-1.48(m,2H),1.45-1.35(m,2H),1.30(t,J＝7.2Hz,3H),1.19(t,J＝7.2Hz,3H)。

An intermediate KT 28:

methyl 5- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) isoxazole-3-carboxylate

The title compound was synthesized as a yellow oil from a27 by a similar procedure using method a.

LC-MS(ESI)：R_T＝1.721min,C₁₆H₂₁NO₆Calculated mass 323.1, M/z found 324.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ6.70(s,0.7H),6.68(s,0.3H),4.12-4.07(m,2H),3.88(s,3H),3.68(s,2H),2.90-2.84(m,1H),2.57-2.51(m,1H),2.10-2.07(m,2H),2.00-1.96(m,2H),1.51-1.36(m,4H),1.19(t,J＝7.0Hz,3H)。

An intermediate KT 29:

ethyl 3- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) isoxazole-5-carboxylate

The title compound was synthesized as a yellow oil from a28 by a similar procedure using method a.

LC-MS(ESI)：R_T＝2.114min,C₁₇H₂₃NO₆Calculated mass of 337.2, M/z found 338.1[ M + H]⁺。¹H NMR(300MHz,DMSO-d₆)δ7.25(s,1H),4.32(q,J＝7.2Hz,2H),4.06(q,J＝7.2Hz,2H),3.65(s,2H),2.77-2.66(m,1H),2.55-2.48(m,1H),2.03-1.89(m,4H),1.53-1.31(m,4H),1.28(t,J＝7.2Hz,3H),1.16(t,J＝7.2Hz,3H)。

An intermediate KT 30:

tert-butyl 4- (4- (3-ethoxy-3-oxopropanoyl) piperidin-1-yl) benzoate

The title compound was synthesized as a yellow solid from A8 by a similar procedure using method a.

¹H NMR(400MHz,CDCl₃)δ12.18(br s,0.1H),7.86(d,J＝8.8Hz,2H),6.84(d,J＝8.8Hz,2H),5.00(s,0.1H),4.23-4.18(m,2H),3.92-3.84(m,2H),3.52(s,1.8H),2.93-2.82(m,2H),2.72-2.64(m,1H),2.00-1.93(m,2H),1.81-1.71(m,2H),1.57(s,9H),1.31-1.24(m,3H)。

An intermediate KT 31:

methyl 4- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) benzoate

The title compound was synthesized as a colorless oil from a30 by a similar procedure using method a.¹H NMR(300MHz,DMSO-d₆)δ7.91-7.88(m,2H),7.41-7.32(m,2H),4.15-4.07(m,2H),3.84(s,3H),3.70(s,2H),2.86-2.58(m,2H),2.13-1.98(m,2H),1.89-1.37(m,6H),1.25-1.18(m,3H)。

An intermediate KT 32:

(trans) -ethyl 5- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) -1,2, 4-oxadiazole-3-carboxylic acid ester

The title compound was synthesized as a yellow solid from a31 by a similar procedure using method a.

¹H NMR(400MHz,DMSO-d₆)δ4.40(q,J＝7.2Hz,2H),4.10(q,J＝7.2Hz,2H),3.68(s,2H),3.11(tt,J＝11.6,4.0Hz,1H),2.56(tt,J＝12.0,3.6Hz,1H),2.19-2.15(m,2H),2.02-1.98(m,2H),1.57(qd,J＝12.4,3.6Hz,2H),1.40(qd,J＝12.0,3.2Hz,2H),1.32(t,J＝7.2Hz,3H),1.19(t,J＝7.2Hz,3H)。

An intermediate KT 33:

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

The title compound was synthesized from a32 by a similar procedure using method a.

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)。

An intermediate KT 34:

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

The title compound was synthesized from a32 by a similar procedure using method a.

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)。

An intermediate KT 35:

tert-butyl 4- (3-ethoxy-3-oxopropanoyl) -2-methylpiperidine-1-carboxylate

The title compound was synthesized as a colorless oil from a33 by a similar procedure using method a. LC-MS (ESI): r_T＝2.043min,C₁₆H₂₇NO₅Calculated mass of 313.2, M/z found 314.1[ M + H ]]⁺。¹HNMR(400MHz,CDCl₃)δ12.24(s,0.1H),12.17(s,0.1H),5.02(s,0.1H),4.97(s,0.1H),4.20(q,J＝7.2Hz,2H),4.10-4.05(m,1H),3.87-3.81(m,1H),3.52(s,1H),3.49(s,0.6H)3.08-3.00(m,0.8H),2.86-2.70(m,1.2H),2.05-1.98(m,0.7H),1.89-1.85(m,2H),1.72-1.67(m,1.3H),1.46(s,9H),1.30-1.26(m,3H),1.14-1.11(m,3H)。

An intermediate KT 36:

tert-butyl 3- (3-ethoxy-3-oxopropanoyl) pyrrolidine-1-carboxylate

The title compound was synthesized from a34 by a similar procedure using method a.

LC-MS(ESI)：R_T＝1.939min,C₁₄H₂₃NO₅Calculated Mass of 285.2, found 230.1[ M-Boc + H ] M/z]⁺。¹H NMR(400MHz,CDCl₃)δ12.12(br s,0.2H),6.17(br s,0.2H),4.17(q,J＝7.2Hz,2H),3.64-3.58(m,1.4H),3.49(s,1.6H),3.39-3.27(m,3.6H),2.09-2.05(m,2H),1.42(s,9H),1.25(t,J＝7.2Hz,3H)。

An intermediate KT 37:

tert-butyl 3- (3-ethoxy-3-oxopropanoyl) azetidine-1-carboxylate

The title compound was synthesized as a red oil from a35 by a similar procedure using method a.¹H NMR(300MHz,CDCl₃)δ12.17(br s,0.2H),5.06(s,0.2H),4.18(q,J＝7.2Hz,2H),4.10-4.00(m,4H),3.64-3.55(m,0.8H),3.45(s,1.6H),3.26-3.20(m,0.2H),1.41(s,9H),1.27(t,J＝7.2Hz,3H)。

An intermediate KT 38:

tert-butyl 3- (3-methoxy-3-oxopropanoyl) azetidine-1-carboxylate

An intermediate KT 38-3:

tert-butyl 3- (2, 2-dimethyl-4, 6-dioxo-1, 3-dioxane-5-carbonyl) azetidine-1-carboxylate

To a solution of 1- (tert-butoxycarbonyl) azetidine-3-carboxylic acid KT38-1(4.00g, 19.9mmol), 2-dimethyl-1, 3-dioxane-4, 6-dione KT38-2(3.15g, 21.9mmol), and 4-dimethylaminopyridine (3.64g, 29.8mmol) in dichloromethane (80mL) was added N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (4.58g, 23.9 mmol). The reaction mixture was stirred at room temperature under nitrogen overnight. The mixture was then diluted with dichloromethane (100mL) and washed three times with 5% aqueous potassium hydrogen sulfate (200 mL). The combined organic layers were passed over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give the title compound as a yellow oil (6.3g, 97% yield).¹H NMR(300MHz,CDCl₃)δ4.60-4.50(m,1H),4.27(t,J＝8.7Hz,2H),4.16-4.11(m,3H),1.75(s,6H),1.45(s,9H)。

An intermediate KT 38:

tert-butyl 3- (3-methoxy-3-oxopropanoyl) azetidine-1-carboxylate

A solution of tert-butyl 3- (2, 2-dimethyl-4, 6-dioxo-1, 3-dioxane-5-carbonyl) azetidine-1-carboxylate KT38-3(6.30g, 19.3mmol) in methanol (80mL) was heated to 80 ℃. After stirring at 80 ℃ overnight, the mixture was allowed to cool to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1 to 2:1) to give the title compound as a yellow oil (3.3g, 67% yield). L is C-MS(ESI)：R_T＝1.44min,C₁₂H₁₉NO₅Calculated mass of 257.1, found M/z 258.2[ M + H ]]⁺。¹H NMR(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)。

An intermediate KT 39:

methyl 1- (2- (4- (3-methoxy-3-oxopropanoyl) cyclohexyl) pyrimidin-5-yl) cyclopropane-1-carboxylate

The title compound was synthesized as a red oil from a36 by a similar procedure using method a.¹H NMR(300MHz,CDCl₃)δ12.17(br s,0.2H),5.06(s,0.2H),4.18(q,J＝7.2Hz,2H),4.10-4.00(m,4H),3.64-3.55(m,0.8H),3.45(s,1.6H),3.26-3.20(m,0.2H),1.41(s,9H),1.27(t,J＝7.2Hz,3H)。

An intermediate KT 40:

ethyl 2- (4- (3-methoxy-3-oxopropanoyl) cyclohexyl) -5-methylpyrimidine-4-carboxylate

The title compound was synthesized as a brown oil from a37 by a similar procedure using method a. LC-MS (ESI): r_T＝1.599min,C₁₈H₂₄N₂O₅Calculated mass of 348.2, found M/z 349.1[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)8.80(s,1H),4.37(q,J＝7.2Hz,2H),3.72(s,0.5H),3.69(s,1.5H),3.63(s,0.8H),3.62(s,2.2H),2.99-2.94(m,0.7H),2.82-2.73(m,1H),2.58-2.55(m,0.3H),2.34(s,3H),2.01-1.99(m,0.8H),1.91-1.85(m,3H),1.76-1.54(m,4.2H),1.32(t,J＝7.2H,3H)。

An intermediate KT 41:

methyl 3- (4- (4- (2-methoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexyl) -3-oxopropanoate

The title compound was synthesized as a colorless oil from a38 by a similar procedure using method a.¹H NMR(400MHz,DMSO-d₆)δ3.69-3.65(m,2H),3.63-3.60(m,6H),3.49(s,1.2H),3.48(s,0.8H),2.94-2.89(m,0.5H),2.69-2.62(m,1H),2.56-2.52(m,0.3H),2.49-2.47(m,0.2H),2.21(s,3H),2.05-1.84(m,3H),1.74-1.65(m,3H),1.46-1.31(m,2H)。

An intermediate KT 42:

methyl 3- (4- (5- (2-methoxy-2-oxoethyl) pyrimidin-2-yl) cyclohexyl) -3-oxopropanoate

The title compound was synthesized as a colorless oil from a39 by a similar procedure using method a.¹H NMR(400MHz,CDCl₃)δ8.61-8.59(m,2H),3.75-3.73(m,6H),3.60-3.29(m,2H),3.54-3.53(m,2H),3.06-3.02(m,0.5H),2.89-2.87(m,0.5H),2.73-2.70(m,0.5H),2.59-2.53(m,0.5H),2.18-2.07(m,3H),2.03-1.97(m,1H),1.91-1.85(m,1H),1.78-1.73(m,2H),1.58-1.53(m,1H)。

An intermediate KT 43:

ethyl 1- (2- (4- (3-methoxy-3-oxopropanoyl) piperidin-1-yl) pyrimidin-5-yl) piperidine-4-carboxylate

The title compound was synthesized as a yellow solid from a40 by a similar procedure using method a. LC-MS (ESI): r _T＝1.671min，C₂₁H₃₀N₄O₅Calculated mass of 418.2, found M/z 419.2[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.10(s,2H),4.74-4.63(m,2H),4.16(q,J＝7.2Hz,2H),3.75(s,3H),3.54(s,2H),3.35-3.31(m,2H),2.98-2.87(m,2H),2.75-2.67(m,3H),2.43-2.34(m,1H),2.05-2.01(m,2H),1.95-1.82(m,4H),1.69-1.55(m,2H),1.27(t,J＝7.2Hz,3H)。

An intermediate KT 44:

methyl 3- (1- (5- (3- (tert-butoxy) -3-oxopropyl) pyridin-2-yl) piperidin-4-yl) -3-oxopropanoate

The title compound was synthesized as a brown oil from a41 by a similar procedure using method a. LC-MS (ESI): r_T＝1.56min,C₂₁H₃₀N₂O₅Calculated mass of 390.2, found M/z 391.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ12.09(s,0.2H),8.02(d,J＝2.4Hz,1H),7.34(dd,J＝8.8Hz,2.4Hz,1H),6.61(d,J＝8.8Hz,1H),5.01(s,0.2H),4.32-4.23(m,2H),3.75-3.73(m,3H),3.54(s,1.6H),2.92-2.82(m,2H),2.77(t,J＝8.0Hz,2H),2.73-2.65(m,1H),2.47(t,J＝7.2Hz,2H),1.97-1.91(m,2H),1.71-1.67(m,2H),1.42(s,9H)。

Part III: preparation of aryl aldehydes (P1) having the general formula V

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

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

Aldehyde 3, AL 3: 4-fluoro-2-methylbenzaldehyde

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

Aldehyde 5, AL 5: 3-fluoro-2-methyl-benzaldehyde

Aldehyde 6, AL 6: 2-bromo-3, 4-difluorobenzaldehyde

Aldehyde 7, AL 7: 4-fluoro-2-methyl-benzaldehyde

Aldehyde 8, AL 8: 2-bromo-3-fluoro-benzaldehyde

Aldehyde 9, AL 9: 2-chloro-3, 4-difluorobenzamide

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

Aldehyde 11, AL 11: 4-bromo-2-chlorobenzaldehyde

Aldehyde 6, AL 6: 2-bromo-3, 4-difluorobenzaldehyde

Intermediate AL 6-3:

2-bromo-3, 4-difluoro-N-methoxy-N-methyl-benzamide

To a solution of 2-bromo-3, 4-difluorobenzoic acid AL6-1(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 minutes and N, O-dimethylhydroxylamine hydrochloride AL6-2(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 over Na ₂SO₄The (solid) was dried, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1 to 5:1) to give the title compound (1.9g, 66% yield) as a yellow solid.¹H NMR(300MHz,CDCl₃)δ7.26-7.17(m,1H),7.14-7.09(m,1H),3.93-3.16(m,6H)。

Aldehyde 6:

2-bromo-3, 4-difluoro-benzaldehyde

To a solution of 2-bromo-3, 4-difluoro-N-methoxy-N-methyl-benzamide AL6-3(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 for 1 hour at-78 ℃, 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) over 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 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)。

Aldehyde 9, AL 9: 2-chloro-3, 4-difluorobenzamide

Intermediate AL 9-1: 2-chloro-3, 4-difluorobenzoic acid

Will N¹,N¹,N²,N²A solution of-tetramethylethane-1, 2-diamine (3.7g, 69.6mmol) in tetrahydrofuran (45Ml) was cooled to-70 ℃ under nitrogen, then 1.3M sec-butyllithium (60Ml, 75.9mmol) in hexane 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. Stirring was continued for 2 hours at-70 ℃. 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 by using concentrated aqueous hydrochloric acid and extracted twice with diethyl ether (125 Ml). The combined organic extracts were concentrated in vacuo to give a yellow solid which was recrystallized from ethyl acetate (30Ml) to afford 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 AL 9-2: 2-chloro-3, 4-difluoro-N-methoxy-N-methyl-benzamide

To a solution of 2-chloro-3, 4-difluorobenzoic acid intermediate AL9-1(1.0g, 5.2mmol) in N, N-dimethylformamide (10Ml) under a nitrogen atmosphere at room temperature was added 1-hydroxybenzotriazole (1.1g, 7.8mmol), N-diisopropylethylamine (4.6Ml, 26mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (1.5g, 7.8 mmol). 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 9: 2-chloro-3, 4-difluorobenzaldehyde

To a solution of 2-chloro-3, 4-difluoro-N-methoxy-N-methyl-benzamide intermediate AL9-2(500mg, 2.13mmol) in tetrahydrofuran (8Ml) was added dropwise 1M diisobutylaluminum hydride (2.8Ml, 2.8mmol) in toluene at-78 ℃ under a nitrogen atmosphere. 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 Na ₂SO₄The (solid) was dried, filtered and evaporated under reduced pressure to leave a yellow residue which was 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)。

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

Intermediate AL 10-1: 3, 4-difluoro-N-methoxy-N, 2-dimethylbenzamide

To a solution of 3, 4-difluoro-2-methylbenzoic acid (3.0g, 17.4mmol) in N, N-dimethylformamide (30Ml) was added 1-hydroxybenzotriazole (3.5g, 26.2mmol), N-diisopropylethylamine (15.4Ml, 87.0mmol) and N, N-diisopropylethylamine (N, N-dimethylformamide) at room temperature under a nitrogen atmosphere¹- ((ethylimino) methylene) -N³,N³Dimethylpropane-1, 3-diamine hydrochloride (5.0g, 26.2 mmol). After stirring at room temperature for 10 minutes, N, O-dimethylhydroxylamine hydrochloride (1.7g, 17.4mmol) was added to the resulting mixture and stirring was continued at room temperature overnight. After quenching with water (50Ml), the mixture was extracted three times with ethyl acetate (50 Ml). The combined organic layers were washed with water (50Ml), brine (50Ml), and Na₂SO₄The (solid) was dried and concentrated to leave a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 8:1 to 5:1) to give the title compound as a yellow oil (3.1g, 84% yield). ¹H NMR(300MHz,CDCl₃)δ7.07-6.96(m,2H),3.47(s,3H),3.30(s,3H),2.26(s,3H)。

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

To a solution of 3, 4-difluoro-N-methoxy-N, 2-dimethylbenzamide AL10-1(3.1g, 14.4mmol) in tetrahydrofuran (40Ml) was added dropwise 1.5M diisobutylaluminum hydride (12.5Ml, 18.7mmol) in toluene at-78 ℃ under nitrogen. After the addition, the mixture was stirred at-78 ℃ for 1.5 hours. It was then quenched with water (15Ml) and extracted three times with ethyl acetate (50 Ml). The combined organic layers were washed three times with water (50Ml), washed with brine (50Ml), over Na₂SO₄The (solid) was dried and evaporated under reduced pressure to leave a yellow 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 (1.87g, 85% yield).¹H NMR(400MHz,CDCl₃)δ10.15(s,1H),7.61-7.57(m,1H),7.18-7.12(m,1H),2.61(s,3H)。

Part IV: preparation of formamidine (P2) having the general formula VI

Formamidine 1: thiazole-2-carboxamidine hydrochloride (Ca1)

Formamidine 2: 3, 5-Difluoropyrimidine hydrochloride (Ca2)

To a stirred suspension of ammonium chloride (1.89g, 35.7mmol) in toluene (100Ml) was added dropwise 2M trimethylaluminum (21Ml, 42.8mmol) in toluene at 0 ℃ under a nitrogen atmosphere. 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 (1) 193.0, found 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)。

Part V: assembly of dihydropyrimidines of the formulae VII and VIII

Compound VII-1-X: (exemplified by method B)

(trans) -methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (single stereoisomer) intermediates VII-1-P and VII-1-Q:

(cis) -methyl 2- (-4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (a mixture of 2 stereoisomers) and (trans) -methyl 2- (-4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (a mixture of 2 stereoisomers).

To a solution of methyl 2- (4- (3-ethoxy-3-oxopropanoyl) cyclohexyl) oxazole-4-carboxylate KT1(1.55g, 5.02mmol), 2-chloro-3, 4-difluorobenzaldehyde AL9(893mg, 5.02mmol) and thiazole-2-carboxamidine hydrochloride Ca1(823mg, 5.02mmol) in methanol (40Ml) was added sodium acetate (412mg, 5.02 mmol). The mixture was heated to 70 ℃ for 16 hours. The mixture was allowed to cool 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 2:1) and further purified by a C18 column (acetonitrile: water ═ 30% to 75%) to give the title compound VII-1-P (320mg, 12% yield) as a yellow solid and VII-1-Q (700mg, 26% yield) as a yellow solid. VII-1-P: LC-MS (ESI): r _T＝1.63min，C₂₆H₂₃ClF₂N₄O₅The calculated mass of S is 576.1, found M/z 576.9[ M + H [)]⁺。¹HNMR(400MHz,DMSO-d₆)δ9.55(d,J＝4.0Hz,1H),8.87-8.86(m,0.8H),8.71(s,0.2H),7.98-7.92(m,2H),7.48-7.41(m,1H),7.18-7.14(m,1H),6.02(s,0.3H),5.89(d,J＝3.6Hz,0.7H),3.90-3.86(m,0.3H),3.83(s,2.1H),3.82(s,0.9H),3.73-3.68(m,0.7H),3.53(s,2.1H),3.52(s,0.9H),3.31(s,0.3H),3.28(br s,0.7H),2.42-2.31(m,2H),1.96-1.44(m,6H)。

VII-1-Q：LC-MS(ESI)：R_T＝1.967min，C₂₆H₂₃ClF₂N₄O₅The calculated mass of S is 576.1, found M/z 577.0[ M + H ]]⁺。¹HNMR(400MHz,DMSO-d₆)δ9.58(d,J＝3.6Hz,0.6H),9.07(s,0.4H),8.78(d,J＝4.0Hz,1H),8.01(s,1.5H),7.95(d,J＝3.2Hz,0.5H),7.50-7.41(m,1H),7.23-7.15(m,1H),6.03(s,0.4H),5.93(d,J＝4.0Hz,0.6H),3.96-3.87(m,0.4H),3.80(s,3H),3.70-3.61(m,0.6H),3.54(s,1.8H),3.53(s,1.2H),3.10-3.01(m,0.4H),2.93-2.86(m,0.6H),2.26-2.14(m,2H),2.10-2.01(m,0.4H),1.95-1.50(m,5.6H)。

The stereoisomeric mixture of (trans) -methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate VII-1-Q (700mg, 1.15mmol, 90% purity) was purified by passage through chiral preparative SFC (column:chiralpak IC5 μm20 × 250 mm; mobile phase: CO 2₂MeOH 70:30 at 50 g/min; temperature: 40 ℃; wavelength: 254 nm; back pressure: 100 bar) to give VII-1-X as a yellow solid (280mg, 41% yield, 98.0% purity, 100% stereopurity) and VII-1-Y as a yellow solid (300mg, 44% yield, 98.2% purity, 98.0% stereopurity).

VII-1-X:LC-MS(ESI)：R_T＝2.028min，C₂₆H₂₃ClF₂N₄O₅The calculated mass of S is 576.1, found M/z 577.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 3 g/min; temperature: 40 ℃; wavelength: 254nm, back pressure: 100 bar, R_T＝6.41min)。¹H NMR(400MHz,CDCl₃)δ8.18(s,1H),8.17(s,0.5H),7.83(t,J＝2.8Hz,1H),7.51(d,J＝2.8Hz,0.4H),7.46(d,J＝3.2Hz,0.6H),7.39(d,J＝1.6Hz,0.5H),7.10-7.01(m,2H),6.19(s,0.6H),6.06(d,J＝2.4Hz,0.4H),4.09-4.02(m,0.6H),3.92(s,3H),3.86-3.78(m,0.4H),3.63(s,1.2H),3.60(s,1.8H),3.01-2.93(m,1H),2.36-2.11(m,2.5H),2.05-2.01(m,1.5H),1.92-1.78(m,3H),1.72-1.62(m,1H)。

VII-1-Y:LC-MS(ESI)：R_T＝2.026min，C₂₆H₂₃ClF₂N₄O₅The calculated mass of S is 576.1, found M/z 577.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 3 g/min; temperature: 40 ℃; wavelength: 254nm, back pressure: 100 bar, R _T＝7.98min)。¹H NMR(400MHz,CDCl₃)δ8.18(s,1H),8.17(s,0.5),7.83(d,J＝2.8Hz,1H),7.51(d,J＝3.2Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.39(d,J＝1.2Hz,0.5H),7.10-6.99(m,2H),6.19(s,0.6H),6.06(d,J＝2.4Hz,0.4H),4.10-4.03(m,0.6H),3.92(s,3H),3.86-3.77(m,0.4H),3.63(s,1.2H),3.60(s,1.8H),3.01-2.95(m,1H),2.36-2.10(m,2.6H),2.05-2.01(m,1.4H),1.92-1.71(m,3H),1.68-1.61(m,1H)。

The assembly of dihydropyrimidines of the general formula VII/VIII by a combination of an acid of the general formula III-1 or III-2, an arylaldehyde (P1) and a formamidine (P2) by two sequential reaction steps is shown belowTABLE 1The method comprises the following steps:

table 1:

spectroscopic analysis of assembled dihydropyrimidines of the general formula VII/VIII

Compound VII-2-Y:

(trans) -methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (single stereoisomer) intermediates VII-2-P and VII-2-Q:

(cis) -methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (mixture of 2 stereoisomers) and (trans) -methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

Compound VII-2-P: LC-MS (ESI): r_T＝3.919min，C₂₇H₂₅ClF₂N₄O₅The calculated mass of S is 590.1, found M/z 591.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.26(s,1H),8.17(s,1H),7.80-7.78(m,1H),7.45(d,J＝3.2Hz,0.3H),7.42(d,J＝2.8Hz,0.7H),7.09-6.96(m,2H),6.20(s,0.7H),6.06(d,J＝2.8Hz,0.3H),4.11-3.99(m,3H),3.94(s,2.1H),3.92(s,0.9H),3.38-3.33(m,0.7H),3.31-3.26(m,0.3H),2.57-2.43(m,2H),2.1-1.65(m,6H),1.14(t,J＝7.2Hz,3H)。

Compounds VII-2-Q: LC-MS (ESI): r_T＝4.351min，C₂₇H₂₅ClF₂N₄O₅The calculated mass of S is 590.1, found M/z 591.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,1H),8.14(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),7.33(s,0.5H),7.12-6.99(m,2H),6.21(s,0.6H),6.08(d,J＝2.8Hz,0.4H),4.10-4.00(m,2.6H),3.92(s,3H),3.85-3.78(m,0.4H),3.02-2.93(m,1H),2.38-2.21(m,2.8H),2.15-2.01(m,1.2H),1.91-1.65(m,4H),1.17-1.12(m,3H)。

The stereoisomeric mixture of (trans) -methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate VII-2-Q (160mg, 0.270mmol, 98.6% purity) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μm 20 250 mm; mobile phase: Hex: EtOH: DEA 50:50:0.2 at 25 mL/min; temperature: 30 ℃ c; wavelength: 230nm) to give compounds VII-2-X (70mg, 43% yield, 100% stereopurity) and VII-2-Y (65mg, 40% yield), 99.6% stereopure).

Compound VII-2-X: LC-MS (ESI): r_T＝2.878min，C₂₇H₂₅ClF₂N₄O₅The calculated mass of S is 590.1, found M/z 591.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2 at 1 mL/min; wavelength: 230nm, R_T＝5.865min)。¹H NMR(400MHz,CDCl₃)δ8.18(s,1H),8.14(s,0.6H),7.83(d,J＝3.6Hz,1H),7.51(d,J＝3.2Hz,0.4H),7.46(d,J＝3.2Hz,0.6H),7.33(s,0.4H),7.12-6.99(m,2H),6.21(s,0.6H),6.08(d,J＝2.8Hz,0.4H),4.12-3.98(m,2.8H),3.92(s,3H),3.86-3.77(m,0.2H),3.03-2.92(m,1H),2.36-2.17(m,2.6H),2.10-2.01(m,1.2H),1.93-1.65(m,4.2H),1.17-1.12(m,3H)。

Compound VII-2-Y: LC-MS (ESI): r_T＝2.849min，C₂₇H₂₅ClF₂N₄O₅The calculated mass of S is 590.1, found M/z 591.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2 at 1 mL/min; wavelength: 230nm, R_T＝6.610min)。¹H NMR(400MHz,CDCl₃)δ8.18(s,1H),8.15(s,0.5H),7.83-7.82(m,1H),7.51(d,J＝3.2Hz,0.4H),7.46(d,J＝2.8Hz,0.6H),7.33(s,0.5H),7.12-6.99(m,2H),6.21(s,0.6H),6.08(d,J＝2.4Hz,0.4H),4.10-4.00(m,2.8H),3.92(s,3H),3.85-3.78(m,0.2H),3.01-2.92(m,1H),2.38-2.17(m,2.8H),2.10-1.98(m,1.2H),1.92-1.65(m,4H),1.17-1.12(m,3H)。

Compound VII-3-H:

(trans) -methyl 2- (4- (6- (3-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (single stereoisomer) intermediate VII-3-1:

methyl 2- (4- (3- (3-fluoro-2-methylphenyl) -2- (methoxycarbonyl) acryloyl) cyclohexyl) oxazole-4-carboxylate

To a solution of methyl 2- (4- (3-methoxy-3-oxopropanoyl) cyclohexyl) oxazole-4-carboxylate KT1(700mg, 1.86mmol) and 3-fluoro-2-methylbenzaldehyde AL5(307mg, 2.22mmol) in propan-2-ol (30mL) was added one drop of piperidine and one drop of acetic acid at room temperature. After stirring at 70 ℃ under nitrogen overnight, the reaction mixture was cooled and concentrated under reduced pressure to give a residue which was purified by C18 column (acetonitrile: water 62% to 69%) to give the title compound as a yellow solid (510mg, 64% yield). LC-MS (ESI): r _T＝1.72min,C₂₃H₂₄FNO₆Calculated Mass of 429.1, M/z found 429.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18-8.11(m,1H),7.97-7.94(m,0.7H),7.79-7.75(m,0.3H),7.15-6.94(m,3H),3.91(s,2H),3.89(s,1H),3.85(s,1.3H),3.83(s,0.7H),3.70(s,0.7H),3.68(s,0.3H),3.13-3.05(m,0.3H),2.97-2.78(m,0.7H),2.73-2.66(m,0.3H),2.30-1.63(m,9.7H),1.46-1.24(m,2H)。

Intermediates VII-3-Q and VII-3-P:

(trans) -methyl 2- (4- (6- (3-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (mixture of 2 stereoisomers) and (cis) -methyl 2- (4- (6- (3-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (mixture of 2 stereoisomers)

To a solution of methyl 2- (4- (3- (3-fluoro-2-methylphenyl) -2- (methoxycarbonyl) acryloyl) cyclohexyl) oxazole-4-carboxylate VII-3-1(500mg, 1.08mmol) and thiazole-2-carboxamidine hydrochloride Ca1(212mg, 1.30mmol) in N, N-dimethylformamide (26mL) was added sodium bicarbonate (273mg, 3.25mmol) at room temperature. After stirring overnight at 90 ℃ under a nitrogen atmosphere, the reaction mixture was cooled and diluted with water (100mL) and extracted twice with ethyl acetate (100 mL). The combined organic layers were washed with water (30mL), brine (50mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 4:1 to 3:1 to 2:1) to give compound VII-3-P (53mg, 8% yield) and VII-3-Q (82mg, 14% yield) as yellow solids.

VII-3-P：LC-MS(ESI)：R_T＝1.78min,C₂₇H₂₇FN₄O₅Calculated mass of S538.2, found M/z 539.0[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.27(s,1H),8.13(s,0.8H),7.76(d,J＝3.2Hz,1H),7.52(s,0.2H),7.40(d,J＝2.8Hz,1H),7.08-7.00(m,2H),6.91-6.85(m,1H),5.98(s,1H),4.10-4.04(m,0.8H),3.94(s,3H),3.76-3.73(m,0.2H),3.59(s,3H),3.38-3,31(m,1H),2.58-2.49(m,5H),2.05-1.77(m,6H)。

VII-3-Q：LC-MS(ESI)：R_T＝1.76min,C₂₇H₂₇FN₄O₅Calculated mass of S538.2, found M/z 539.0[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(d,J＝3.2Hz,1H),8.11(s,0.7H),7.80(d,J＝2.8Hz,1H),7.52(s,0.3H),7.50(d,J＝3.2Hz,0.2H),7.43(d,J＝3.6Hz,0.8H),7.15-7.00(m,2H),6.95-6.88(m,1H),6.01(s,0.8H),5.91(d,J＝2.0Hz,0.2H),4.09-4.05(m,0.8H),3.93(s,2.4H),3.92(s,0.6H),3.75-3.70(m,0.2H),3.60(s,2.4H),3.59(s,0.6H),3.02-2.94(m,1H),2.55(d,J＝2.0Hz,2.4H),2.40-2.21(m,3.6H),2.10-1.62(m,5H)。

A stereoisomeric mixture of trans-methyl 2- (4- (6- (3-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate VII-3-Q (98mg, 0.164mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE 5 μm 20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to provide compounds VII-3-G (41mg, 42% yield, 100% stereopurity) and VII-3-H (38mg, 39% yield) as yellow solids, 97.7% stereopure).

VII-3-G：LC-MS(ESI)：R_T＝1.72min,C₂₇H₂₇FN₄O₅Calculated mass of S538.2, found M/z 539.2[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝18.513min)。¹H NMR(400MHz,CDCl₃)δ8.18(d,J＝3.2Hz,1H),8.11(s,0.8H),7.80(d,J＝3.2Hz,1H),7.50(d,J＝3.2Hz,0.2H),7.43(d,J＝3.6Hz,1H),7.17-7.00(m,2H),6.95-6.88(m,1H),6.01(s,0.8H),5.91(d,J＝2.0Hz,0.2H),4.13-4.04(m,0.8H),3.93(s,2.4H),3.92(s,0.6H),3.75-3.69(m,0.2H),3.60(s,2.4H),3.59(s,0.6H),3.03-2.94(m,1H),2.55(d,J＝2.0Hz,2.4H),2.40-2.22(m,3.6H),2.10-1.62(m,5H)。

VII-3-H：LC-MS(ESI)：R_T＝1.72min,C₂₇H₂₇FN₄O₅Calculated mass of S538.2, found M/z 539.2[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝20.813min)。¹H NMR(400MHz,CDCl₃)δ8.18(d,J＝3.2Hz,1H),8.11(s,0.8H),7.80(d,J＝2.8Hz,1H),7.50(d,J＝2.8Hz,0.2H),7.43(d,J＝2.8Hz,1H),7.17-7.00(m,2H),6.95-6.88(m,1H),6.01(s,0.8H),5.91(d,J＝2.0Hz,0.2H),4.13-4.04(m,0.8H),3.93(s,3H),3.74-3.69(m,0.2H),3.60(s,3H),3.02-2.94(m,1H),2.55(d,J＝2.0Hz,2.4H),2.41-2.22(m,3.6H),2.10-1.62(m,5H)。

Compound VII-4-N:

(trans) -methyl 2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester (single stereoisomer)

Intermediate VII-4-R:

methyl 2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester (mixture of 4 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.¹HNMR(400MHz,CDCl₃)δ8.26(s,0.5H),8.18(s,0.5H),7.86(t,J＝2.8Hz,1H),7.54(d,J＝2.8Hz,1H),7.33-7.28(m,1H),7.16-7.11(m,1H),6.96-6.89(m,1H),6.20(s,0.5H),6.17(s,0.5H),3.93(s,1.5H),3.92(s,1.5H),3.62(s,1.5H),3.61(s,1.5H),3.39-3.30(m,1H),2.38-2.19(m,2H),2.00-1.64(m,6H),1.36-1.14(m,1H)。

Intermediates VII-4-M, VII-4-N and VII-4-P:

(trans) -methyl 2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (single stereoisomer), (trans) -methyl 2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (single stereoisomer)

And (cis) -methyl 2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester (mixture of 2 stereoisomers)

A stereoisomeric mixture of methyl 2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester VII-4-R (710mg, 1.27mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μ M20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 13 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound VII-4-M (100mg, 14% yield, 100% stereopurity), VII-4-N (100mg, 14% yield, 100% stereopurity) and VII-4-P (190mg, 27% yield).

VII-4-M：LC-MS(ESI)：R_T＝1.72min，C₂₆H₂₄ClFN₄O₅Calculated mass of S558.1, M/z found 559.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: hex EtOH DEA 60:40:0.2 at 1 mL/min; wavelength: 230nm, R_T＝10.485min)。¹H NMR(400MHz,DMSO-d₆)δ9.48-9.44(m,0.6H),9.02(s,0.4H),8.79(s,0.4H),8.78(s,0.6H),8.01-7.99(m,1.5H),7.95-7.94(m,0.4H),7.46-7.40(m,1H),7.39-732(m,1H),7.26-7.18(m,1H),6.02(s,0.4H),5.92(d,J＝3.6Hz,0.6H),3.94-3.85(m,0.4H),3.80(s,3H),3.70-3.61(m,0.7H),3.53(d,J＝5.2Hz,3H),3.10-3.01(m,0.4H),2.95-2.85(m,0.6H),2.24-2.16(m,2H),2.07-1.76(m,3.4H),1.73-1.51(m,2.6H)。

VII-4-N：LC-MS(ESI)：R_T＝1.73min，C₂₆H₂₄ClFN₄O₅Calculated mass of S558.1, M/z found 559.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak OJ-H5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1 mL/min; wavelength: 230nm, R_T＝13.163min)。¹H NMR(400MHz,DMSO-d₆)δ9.47-9.46(m,0.6H),9.01(s,0.4H),8.79(s,0.4H),8.78(s,0.6H),8.00-7.99(m,1.6H),7.95-7.94(m,0.4H),7.45-7.41(m,1H),7.38-7.33(m,1H),7.25-7.19(m,1H),6.02(s,0.4H),5.92(d,J＝3.2Hz,0.6H),3.96-3.86(m,0.4H),3.80(s,3H),3.71-3.61(m,0.6H),3.53(d,J＝5.6Hz,3H),3.11-3.00(m,0.4H),2.95-2.85(m,0.6H),2.25-2.12(m,2H),2.09-1.77(m,3.4H),1.73-1.50(m,2.6H)。

VII-4-P：LC-MS(ESI)：R_T＝1.74min，C₂₆H₂₄ClFN₄O₅Calculated mass of S558.1, M/z found 559.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak OJ-H5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1 mL/min; wavelength: 230nm, R_T7.430min and 7.778 min).¹H NMR(400MHz,DMSO-d₆)δ9.43(s,0.7H),9.42(s,0.3H),8.86-8.85(m,1H),7.97-7.92(m,2H),7.42-7.39(m,1H),7.32-7.29(m,1H),7.20-7.19(m,1H),6.01(s,0.3H),5.88(d,J＝3.6Hz,0.7H),3.83(s,3H),3.75-3.66(m,1H),3.53(s,2.1H),3.52(s,0.9H),3.29-3.25(m,1H),2.44-2.29(m,2H),2.00-1.78(m,4H),1.72-1.58(m,1.3H),1.52-1.38(m,0.7H)。

Compounds VII-5-Q:

(trans) -methyl 2- (4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester (single stereoisomer)

Intermediates VII-5-M and VII-5-N:

(cis) -methyl-2- (4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester (mixture of 2 stereoisomers) and (trans) -methyl-2- (4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

VII-5-M:¹H NMR(400MHz,CDCl₃)δ8.29-8.24(m,1H),8.20-8.13(m,0.7H),7.83-7.74(m,1H),7.48-7.44(m,0.4H),7.43-7.41(m,0.6H),7.38-7.35(m,0.3H),7.19-7.08(m,2H),7.07-6.99(m,1H),6.25(s,0.6H),6.09(d,J＝2.8Hz,0.4H),4.15-4.02(m,1H),3.94(s,1.9H),3.92(s,1.1H),3.61(s,1.1H),3.59(s,1.9H),3.89-3.33(m,0.6H),3.31-3.26(m,0.4H),2.58-2.43(m,2H),2.00-1.90(m,3H),1.89-1.83(m,2H),1.77-1.65(m,1H)。

VII-5-N:¹H NMR(400MHz,CDCl₃)δ8.20-8.14(m,1.5H),7.81(d,J＝2.8Hz,1H),7.49(d,J＝3.2Hz,0.5H),7.45-7.42(m,1H),7.22-7.10(m,2H),7.08-6.99(m,1H),6.24(s,0.5H),6.10(d,J＝2.8Hz,0.5H),4.09-4.02(m,0.5H),3.91(s,3H),3.86-3.78(m,0.5H),3.60(s,1.4H),3.58(s,1.6H),3.04-2.94(m,1H),2.37-2.26(m,2H),2.23-2.20(m,1H),2.12-2.03(m,2H),1.98-1.85(m,2H),1.72-1.58(m,1H)。

A stereoisomeric mixture of (trans) -methyl 2- (4- (6- (2-chloro-3-fluorophenyl) -5 (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate VII-5-N (300mg, 90% purity, 0.483mmol) was separated by chiral HPLC (separation conditions: column: Chiralpak IA 5 μm 20: 250mm, mobile phase: Hex: EtOH: DEA 60:40:0.3, at 20 ml/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound VII-5-P (119mg, purity from NMR 95%, 42% yield, 99.8% stereopurity) and VII-5-Q (129 mg), purity from NMR 95%, 45% yield, 96.9% stereopure).

VII-5-P:¹H NMR(400MHz,CDCl₃) δ 8.18(s,1H),8.14(s,0.5H),7.86-7.80(m,1H),7.50(d, J ═ 3.2Hz,0.5H),7.45(d, J ═ 2.8Hz,0.5H),7.43(m,0.5H),7.22-7.20(m,0.6H),7.16-7.11(m,1.4H),7.10-7.00(m,1H),6.26(s,0.5H),6.12(d, J ═ 2.4Hz,0.5H),4.12-4.03(m,0.5H),3.92(s,3H),3.87-3.79(m,0.5H),3.62(s,1.5H),3.60(s,1.5H), 3.92 (m, 2.2H), 3.26-2.26 (m,1H), 7.2.2H, 1.7.7.2H, 7.26 (m,1H), 7.2.5H). Chiral analysis (column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1 ml/min; column temperature: 30 ℃; wavelength: 230nm, back pressure: 100 bar; R _T＝6.960min)。

VII-5-Q:¹H NMR(400MHz,CDCl₃) δ 8.19-8.18(m,1.5H),7.84-7.82(m,1H),7.50(d, J ═ 3.2Hz,0.5H),7.46(d, J ═ 3.2Hz,1H),7.22-7.15(m,2H),7.10-7.02(m,1H),6.26(s,0.5H),6.12(s,0.5H),4.10-4.04(m,0.5H),3.92(s,3H),3.86-3.81(m,0.5H),3.62(s,1.4H),3.60(s,1.6H),3.01-2.95(m,1H),2.35-2.28(m,1.6H),2.24-2.18(m,1.1H), 2.01-2.77 (m,1.6H), 7.7.7-7.7H). Chiral analysis (column: Chiralpak IA5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1 ml/min; column temperature: 30 ℃; wavelength: 230nm, back pressure: 100 bar; R_T＝9.952min)。

Compounds VII-6-Q:

(trans) -methyl 2- (4- (6- (4-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (single stereoisomer) intermediate: VII-6-M and VII-6-N

(cis) -methyl 2- (4- (6- (4-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester (mixture of 2 stereoisomers) and (trans) -methyl 2- (4- (6- (4-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

VII-6-M:¹H NMR(400MHz,CDCl₃)δ8.27(s,1H),8.12(s,0.8H),7.76(d,J＝3.2Hz,1H),7.43(d,J＝3.2Hz,0.2H),7.39(d,J＝3.2Hz,0.8H),7.32-7.28(m,0.2H),7.18-7.10(m,0.8H),7.00-6.96(m,0.2H),6.92-6.82(m,1.2H),6.79-6.72(m,0.8H),5.94(s,0.8H),5.85-5.81(m,0.2H),4.14-4.03(m,0.8H),3.94(s,2.3H),3.93(s,0.7H),3.81-3.73(m,0.2H),3.60(s,2.3H),3.59(s,0.7H),3.40-3.33(m,0.8H),3.31-3.26(m,0.2H),2.62(s,2.5H),2.58-2.49(m,2H),2.47(s,0.5H),2.08-1.91(m,3H),1.90-1.79(m,2H),1.75-1.68(m,1H)。

VII-6-N：¹H NMR(400MHz,CDCl₃)δ8.21-8.17(m,1H),8.12(s,0.7H),7.82-7.79(m,1H),7.50(d,J＝3.2Hz,0.3H),7.43(d,J＝3.2Hz,0.7H),7.35-7.29(m,0.3H),7.20-7.15(m,0.7H),7.09-7.05(m,0.3H),6.92-6.83(m,1.3H),6.82-6.75(m,0.7H),5.96(s,0.7H),5.88-5.85(m,0.3H),4.12-4.02(m,0.7H),3.93(s,2.2H),3.92(s,0.8H),3.73-3.70(m,0.3H),3.61(s,2.2H),3.60(s,0.8H),3.02-2.97(m,1H),2.64(s,2.2H),2.49(s,0.8H),2.41-2.30(m,1.8H),2.25-2.22(m,1.4H),2.12-2.01(m,1.2H),1.97-1.84(m,2H),1.71-1.57(m,1.6H)。

A stereoisomeric mixture of (trans) -methyl 2- (4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate VII-6-N (365mg, 80% purity, 0.542mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA 5 μm 20: 250mm, mobile phase: Hex: EtOH: DEA 60:40:0.3, at 22 mL/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound VII-6-P as a yellow solid (105mg, obtained from¹H NMR purity 95%, 34% yield, 100% stereopure) and VII-6-Q (110mg, from¹Purity by H NMR 95%, 36% yield, 94.5% stereopure).

VII-6-P:¹H NMR(400MHz,CDCl₃)δ8.23-8.16(m,1H),8.11(s,0.7H),7.80(d,J＝3.2Hz,1H),7.50(d,J＝3.2Hz,0.3H),7.42(d,J＝2.8Hz,0.7H),7.35-7.30(m,0.3H),7.21-7.14(m,0.7H),7.02(s,0.3H),6.92-6.87(m,1.2H),6.84-6.75(m,0.8H),5.96(s,0.7H),5.89-5.83(m,0.3H),4.12-4.02(m,0.7H),3.93(s,3H),3.74-3.67(m,0.3H),3.60(s,3H),3.03-2.92(m,1H),2.64(s,2.2H),2.49(s,0.8H),2.39-2.33(m,1.7H),2.27-2.17(m,1.3H),2.12-1.99(m,1.4H),1.97-1.83(m,2H),1.82-1.65(m, 1.6H). Chiral analysis: (column: Chiralpak IA 5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA: 60:40:0.2 at 1 mL/min; column temperature: 30 ℃; wavelength: 230 nm; R; (R); column temperature: 30 ℃; R;)_T＝6.321min)。

VII-6-Q:¹H NMR(400MHz,CDCl₃) δ 8.20 to 8.16(m,1H),8.10(s,0.7H),7.80(d, J ═ 2.8Hz,1H),7.50(d, J ═ 3.2Hz,0.3H),7.42(d, J ═ 3.2Hz,0.7H),7.34 to 7.29(m,0.3H),7.18 to 7.15(m,0.7H),7.01(s,0.3H),6.91 to 6.87(m,1.2H),6.83 to 6.75(m,0.8H),5.95(s,0.7H),5.88 to 5.85(m,0.3H),4.12 to 4.02(m,0.7H),3.92(s,3H),3.72 to 3.66(m,0.3H),3.60 (m, 3.3H), 3.3.3H (m, 1.3.3H), 1.3.3 to 2H), 1.3H, 1.3.3H, 1.3H, 3 m, 3H, 1.3H, 3H, 1.3H, 3H, 1.3H, 1.6H). Chiral analysis: (column: Chiralpak IA 5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA: 60:40:0.2 at 1 mL/min; column temperature: 30 ℃; wavelength: 230 nm; R; (R); column temperature: 30 ℃; R;) _T＝8.167min)。

Compound VII-7-N:

(trans) -methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -5- (methoxycarbonyl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester (single stereoisomer)

Intermediate VII-7-S:

(trans) -methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -5- (methoxycarbonyl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝2.052min，C₂₈H₂₃ClF₄N₄O₅Is 606.0, M/z found 607.1[ M + H [)]⁺。¹H NMR(300MHz,CDCl₃)δ8.70(s,1H),8.34-8.20(m,2H),7.09-6.97(m,2H),6.30(d,J＝6.0Hz,0.8H),6.05-6.02(m,0.2H),4.17-4.08(m,1H),3.95(s,2.4H),3.93(s,0.6H),3.61(s,3H),3.41-3.34(m,1H),2.54-2.46(m,1H),2.38-2.11(m,1H),2.05-1.91(m,3H),1.86-1.82(m,2H),1.71-1.58(m,1H)。

Reacting (trans) -methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-di-phenyl)A stereoisomeric mixture of fluoropyridin-2-yl) - (methoxycarbonyl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate VII-7-S (340mg, 90% purity, 0.504mmol) was purified by chiral preparative HPLC (separation conditions: column: chiralpak IC 5 μm 20 × 250 mm; mobile phase: hex 50:50 EtOH at 11 mL/min; temperature: 30 ℃; wavelength: 214nm) to provide the desired compound VII-7-M (36mg, obtained from¹Purity by H NMR 90%, 11% yield, 100% stereopure) and VII-7-N (101mg, obtained from ¹Purity by H NMR 90%, 30% yield, 98.5% stereopure).

VII-7-M: chiral analysis: (column: Chiralpak IC 5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1 mL/min; temperature: 40 ℃ C.; wavelength: 230nm, back pressure: 100 bar; R: 100 bar; R: C.; and_T＝7.887min)。¹H NMR(400MHz,DMSO-d₆)δ9.32(s,0.7H),9.21(s,0.3H),8.79(s,0.7H),8.77(s,0.3H),8.58(d,J＝7.2Hz,1H),8.10-8.04(m,1H),7.54-7.44(m,1H),7.25-7.16(m,1H),6.04(s,0.7H),5.94(d,J＝2.4Hz,0.3H),4.00-3.92(m,0.6H),3.80(s,3H),3.70-3.64(m,0.4H),3.53(s,2H),3.51(s,1H),2.95-2.84(m,1H),2.29-2.16(m,2H),1.98-1.77(m,4H),1.68-1.54(m,2H)。

VII-7-N; chiral analysis: (column: Chiralpak IC 5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH 50:50 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, back pressure: 100 bar, RT 12.115 min).¹H NMR(400MHz,DMSO-d₆)δ9.31(s,0.7H),9.21(s,0.3H),8.79(s,0.7H),8.77(s,0.3H),8.59-8.57(m,1H),8.10-8.05(m,1H),7.53-7.44(m,1H),7.25-7.17(m,1H),6.05(s,0.7H),5.94(d,J＝3.2Hz,0.3H),3.99-3.93(m,0.7H),3.80(s,3H),3.71-3.63(m,0.3H),3.54(s,2H),3.51(s,1H),2.95-2.85(m,1H),2.23-2.13(m,2H),1.97-1.80(m,4H),1.70-1.53(m,2H)。

Compound VII-8-N:

methyl 2- (3- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) bicyclo [1.1.1] pent-1-yl) oxazole-4-carboxylate (single stereoisomer) intermediate VII-8-R:

methyl 2- (3- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) bicyclo [1.1.1] pent-1-yl) oxazole-4-carboxylic acid ester (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B. LC-MS (ESI): r_T＝1.77min,C₂₅H₁₉ClF₂N₄O₅Calculated mass of S560.1, found M/z 561.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝3.2Hz,0.6H),8.83(s,0.4H),8.80(s,0.6H),8.49(s,0.4H),8.03-8.01(m,1.6H),7.97-7.96(m,0.4H),7.51-7.44(m,1H),7.23-7.17(m,1H),6.00(s,0.4H),5.91(d,J＝3.2Hz,0.6H),3.80(s,3H),3.58-3.57(m,3H),2.68(s,2.3H),2.52(s,3.7H)。

A stereoisomeric mixture of methyl 2- (3- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) bicyclo [1.1.1] pent-1-yl) oxazole-4-carboxylic acid ester VII-8-R (150mg, 95% purity, 0.254mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE 5 μ M20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 12 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound VII-8-M (60mg, 95% purity, 40% yield, 100% stereopurity) and VII-8-N (60 mg) as a yellow solid, 95% purity, 40% yield, 100% stereopurity).

VII-8-M：LC-MS(ESI)：R_T＝1.80min,C₂₅H₁₉ClF₂N₄O₅Calculated mass of S560.1, found M/z 561.0[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm 4.6 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＝11.217min)。¹H NMR(400MHz,CDCl₃)δ8.19(d,J＝2.0Hz,1H),7.93(s,0.7H),7.84-7.82(m,1H),7.51(d,J＝3.2Hz,0.3H),7.46(d,J＝3.2Hz,0.7H),7.42(s,0.3H),7.10-7.01(m,2H),6.17(s,0.7H),6.05(d,J＝1.6Hz,0.3H),3.93(s,3H),3.66(s,1H),3.62(s,2H),2.76(s,4H),2.70(s,2H)。

VII-8-N：LC-MS(ESI)：R_T＝1.80min,C₂₅H₁₉ClF₂N₄O₅Calculated mass of S560.1, m/z found value561.0[M+H]⁺. Chiral HPLC (column: Chiralpak IE 5 μm 4.6 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＝15.313min)。¹H NMR(400MHz,CDCl₃)δ8.19(d,J＝2.0Hz,1H),7.93(s,0.7H),7.84-7.82(m,1H),7.51(d,J＝3.2Hz,0.3H),7.46(d,J＝3.2Hz,0.7H),7.42(s,0.3H),7.10-7.01(m,2H),6.17(s,0.7H),6.05(d,J＝2.4Hz,0.3H),3.93(s,3H),3.66(s,1H),3.62(s,2H),2.76(s,4H),2.70(s,2H)。

Compound VII-9-F:

(trans) -methyl 2- (4- (6- (2-chloro-3-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester (single stereoisomer)

Intermediates VII-9-M and VII-9-N:

(cis) -methyl 2- (4- (6- (2-chloro-3-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (mixture of 2 stereoisomers) and (trans) -methyl 2- (4- (6- (2-chloro-3-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

VII-9-M：LC-MS(ESI)：R_T＝4.322min,C₂₇H₂₆ClFN₄O₅Calculated mass of S572.1, found M/z 572.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.29(s,0.6H),8.26(s,0.4H),8.14(s,0.6H),7.81-7.76(m,1H),7.44(d,J＝3.2Hz,0.4H),7.41(d,J＝3.2Hz,0.6H),7.31-7.29(m,0.4H),7.21-7.09(m,2H),7.09-6.98(m,1H),6.27(s,0.6H),6.14-6.09(d,J＝8.0Hz,0.4H),4.14-3.97(m,3H),3.94(s,2H),3.92(s,1H),3.38-3.33(m,0.6H),3.31-3.26(m,0.4H),2.58-2.43(m,2H),2.15-2.03(m,0.5H),1.99-1.89(m,2.5H),1.89-1.77(m,2H),1.77-1.63(m,1H),1.16-1.08(m,3H)。

VII-9-N：LC-MS(ESI)：R_T＝4.420min，C₂₇H₂₆ClFN₄O₅Calculated mass of S572.1, found M/z 573.1[ M + H ] ]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.50(d,J＝3.6Hz,0.6H),8.98(s,0.4H),8.79(s,0.4H),8.78(s,0.6H),8.01-7.94(m,2H),7.42-7.28(m,2H),7.24-7.17(m,1H),6.09(s,0.4H),5.98(d,J＝3.6Hz,0.6H),4.01-3.94(m,2H),3.93-3.88(m,0.3H),3.80(s,3H),3.71-3.60(m,0.7H),3.10-3.03(m,0.4H),2.94-2.85(m,0.6H),2.26-2.11(m,2H),2.01-1.86(m,2.3H),1.86-1.67(m,1.7H),1.66-1.48(m,2H),1.11-1.00(m,3H)。

A stereoisomeric mixture of VII-9-N (740mg, 99.7% purity, 1.29mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μm 20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.3, at 10 ml/min; temperature: 30 ℃; wavelength: 214nm) to give the title compound VII-9-E as a yellow solid (210mg, 98.8% purity, 28% yield, 100% ee) and VII-9-F as a yellow solid (229mg, 98.1% purity, 31% yield, 99.7% ee).

VII-9-E:LC-MS(ESI)：R_T＝4.253min，C₂₇H₂₆ClFN₄O₅Calculated mass of S572.1, found M/z 573.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,1H),8.13(s,0.5H),7.83(s,0.5H),7.82(s,0.5H),7.50(d,J＝3.2Hz,0.5H),7.45(d,J＝3.2Hz,0.5H),7.36(s,0.5H),7.24-7.12(m,2H),7.11-6.99(m,1H),6.28(s,0.5H),6.14(d,J＝2.4Hz,0.5H),4.10-3.98(m,2.5H),3.92(s,3H),3.88-3.79(m,0.5H),3.03-2.93(m,1H),2.38-2.16(m,2.8H),2.12-2.00(m,1.5H),1.94-1.65(m,3.7H),1.16-1.09(m,3H)。

VII-9-F:LC-MS(ESI)：R_T＝2.265min，C₂₇H₂₆ClFN₄O₅Calculated mass of S572.1, found M/z 573.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,1H),8.13(s,0.5H),7.84-7.81(m,1H),7.50(d,J＝3.2Hz,0.5H),7.45(d,J＝2.8Hz,0.5H),7.37(d,J＝2.4Hz,0.5H),7.24-7.13(m,2H),7.10-7.00(m,1H),6.28(s,0.5H),6.14(d,J＝2.8Hz,0.5H),4.09-4.01(m,2.5H),3.92(s,3H),3.87-3.79(m,0.5H),3.03-2.93(m,1H),2.38-2.16(m,2.8H),2.12-2.02(m,1.4H),1.96-1.74(m,3.1H),1.74-1.64(m,0.7H),1.17-1.09(m,3H)。

Compound VII-10-P:

(trans) -methyl 2- (4- (6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester (single stereoisomer)

Intermediate: VII-10-X and VII-10-Y

(cis) -methyl 2- (4- (6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (mixture of 2 stereoisomers) and (trans) -methyl 2- (4- (6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

VII-10-X:LC-MS(ESI)：R_T＝3.644min，C₂₇H₂₆ClFN₄O₅Calculated mass of S572.1, found M/z 572.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ8.55(d,J＝3.2Hz,1H),7.86-7.84(m,1H),7.71-6.68(m,1H),7.40-7.34(m,1H),7.25-7.20(m,1H),7.06-7.00(m,1H),6.13(s,0.5H),6.05(s,0.5H),4.07-4.01(m,2.5H),3.91-3.81(m,3.5H),3.37-3.31(m,0.5H),3.30-3.24(m,0.5H),2.55-2.42(m,2H),2.10-1.79(m,4H),1.77-1.72(m,1.5H),1.57-1.53(m,0.5H),1.14(t,J＝7.2Hz,3H)。

VII-10-Y:LC-MS(ESI)：R_T＝2.496min，C₂₇H₂₆ClFN₄O₅Calculated mass of S572.1, found M/z 572.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ8.48(s,1H),8.29-8.26(m,2H),7.57-7.53(m,1H),7.4-27.40(m,1H),7.24-7.19(m,1H),6.32(s,1H),4.17-4.10(m,2H),3.99-3.92(m,1H),3.88(s,3H),3.05-2.97(m,1H),2.32-2.29(m,2H),2.06-1.83(m,4H),1.76-1.68(m,2H),1.18(t,J＝7.2Hz,3H)。

The stereoisomeric mixture of (trans) -methyl 2- (4- (6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate VII-10-Y (200mg, 90% purity, 0.314mmol) was separated by chiral preparative HPLC (column: Chiralpak S-OJ 5 μm 21 250 mm; mobile phase: Hex: EtOH: DEA 70:30:0.05, at 20 mL/min; temperature: 35 ℃ c; wavelength: 254nm) to give the title compound VII-10-P as a yellow solid (80mg, 99% purity, 44% yield, 98.6% stereopurity) and VII-10-Q as a yellow solid (75mg, 99.2% purity, 41% yield, 99.9% stereopurity).

VII-10-P：LC-MS(ESI)：R_T＝4.289min，C₂₇H₂₆ClFN₄O₅Calculated mass of S572.1, found M/z 572.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak S-OJ 5 μm 4.6 x 150 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.05 at 1 mL/min; wavelength: 254nm, R_T＝5.657min)。¹H NMR(400MHz,CD₃OD)δ8.37(s,0.5H),8.36(s,0.5H),7.84-7.83(m,0.5H),7.80-7.79(m,0.5H),7.66-7.65(m,1H),7.34-7.29(m,1H),7.16-7.11(m,1H),6.99-6.92(m,1H),6.06(s,0.5H),5.99(s,0.5H),3.98-3.92(m,2.5H),3.79(s,3H),3.74-3.67(m,0.5H),2.98-2.80(m,1H),2.24-2.03(m,2H),1.93-1.60(m,6H),1.07-1.02(m,3H)。

VII-10-Q：LC-MS(ESI)：R_T＝4.289min，C₂₇H₂₆ClFN₄O₅Calculated mass of S572.1, found M/z 572.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak S-OJ 5 μm 4.6 x 150 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.05 at 1 mL/min; wavelength: 254nm, R _T＝7.812min)。¹H NMR(400MHz,CD₃OD)δ8.50(s,0.5H),8.49(s,0.5H),7.97-7.96(m,0.5H),7.92-7.92(m,0.5H),7.78-7.77(m,0.5H),7.46-7.42(m,1H),7.28-7.23(m,1H),7.11-7.04(m,1H),6.18(s,0.5H),6.11(s,0.5H),4.10-4.05(m,2.5H),3.91(s,3H),3.86-3.80(m,0.5H),3.14-2.93(m,1H),2.37-2.21(m,2H),2.14-1.73(m,6H),1.17(t,J＝7.2Hz,3H)。

Compounds VII-11-Q:

(trans) -methyl 2- (4- (5- (ethoxycarbonyl) -6- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (single stereoisomer) intermediates VII-11-M and VII-11-N:

(cis) -methyl 2- (4- (5- (ethoxycarbonyl) -6- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (mixture of 2 stereoisomers) and (trans) -methyl 2- (4- (5- (ethoxycarbonyl) -6- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

VII-11-M:¹H NMR(400MHz,CDCl₃)δ8.27(s,1H),8.12(s,1H),7.76(d,J＝3.2Hz,1H),7.46-7.43(m,0.2H),7.42-7.37(m,0.8H),7.14-6.99(m,2H),6.97-6.84(m,1H),6.01(s,0.8H),5.90(s,0.2H),4.16-3.98(m,3H),3.94(s,3H),3.40-3.33(m,0.8H),3.31-3.25(m,0.2H),2.57-2.45(m,4.5H),2.41-2.36(m,0.5H),1.98-1.91(m,1H),1.86-1.80(m,2H),1.75-1.67(m,3H),1.13(t,J＝7.2Hz,3H)。

VII-11-N:¹H NMR(300MHz,CDCl₃)δ8.24(s,1H),8.19-8.11(m,1H),7.89-7.83(m,1H),7.57-7.45(m,1H),7.19-7.05(m,2H),7.01-6.91(m,1H),6.07(s,0.8H),5.99(s,0.2H),4.13-4.04(m,3H),3.98(s,3H),3.02-2.99(m,1H),2.64-2.55(m,2H),2.52-2.22(m,4H),2.03-1.83(m,3H),1.81-1.58(m,2H),1.81(t,J＝7.2Hz,3H)。

A stereoisomeric mixture of (trans) -methyl 2- (4- (5- (ethoxycarbonyl) -6- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester VII-11-N (376mg, 90% purity, 0.612mmol) was passed through chiral preparative SFC (column: Chiralpak IC 5 μm20 mm; mobile phase: CO₂EtOH, DEA 70:30:0.3 at 50 g/min; column temperature: 40 ℃; wavelength: 214 nm; back pressure: 100 bar) was added to the reaction solution to give compound VII-11-P (165mg, obtained from ¹H NMR 95% pure, 46% yield, 100% stereopure) and VII-11-Q (150mg, obtained from¹Purity by H NMR 95%, yield 42%, 100% stereopure).

VII-11-P chiral assay (column: Chiralpak IC 5 μm 4.6 x 250 mm; mobile phase: CO₂EtOH, DEA 70:30:0.2 at 3 g/min; column temperature: 40 ℃; wavelength: 280nm, back pressure: 100 bar; r_T＝4.38min)。¹H NMR(300MHz,CDCl₃)δ8.19(s,1H),8.10(s,0.7H),7.83-7.78(m,1H),7.52-7.40(m,1H),7.16-7.00(m,2.3H),6.96-6.87(m,1H),6.02(s,0.8H),5.97-5.91(m,0.2H),4.09-4.02(m,2.8H),3.92(s,3H),3.77-3.69(m,0.2H),2.94-2.91(m,1H),2.54(s,2.5H),2.45-2.41(m,0.5H),2.37-2.18(m,3H),2.13-2.08(m,0.5H),1.94-1.79(m,2.5H),1.76-1.54(m,2H),1.13(t,J＝7.2Hz,3H)。

VII-11-Q chiral assay (column: Chiralpak IC 5 μm 4.6 x 250 mm; mobile phase: CO)₂EtOH, DEA 70:30:0.2 at 3 g/min; column temperature: 40 ℃; wavelength: 280nm, back pressure: 100 bar; r_T＝5.03min)。¹H NMR(300MHz,CDCl₃)δ8.19(s,1H),8.10(s,0.7H),7.83-7.78(m,1H),7.53-7.49(m,0.2H),7.49-7.41(m,0.8H),7.18-7.15(m,0.3H),7.13-7.01(m,2H),6.99-6.86(m,1H),6.03(s,0.8H),5.96-5.91(m,0.2H),4.11-4.03(m,2.7H),3.93(s,3H),3.78-3.67(m,0.3H),2.97-2.94(m,1H),2.55(s,2.5H),2.42-2.41(m,0.5H),2.37-2.18(m,3H),2.13-2.05(m,1.3H),1.95-1.78(m,2.7H),1.71-1.60(m,1H),1.14(t,J＝7.2Hz,3H)。

Compound VII-12-P:

(trans) -methyl 2- (4- (5- (ethoxycarbonyl) -6- (4-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate (single stereoisomer) intermediates VII-12-X and VII-12-Y:

(cis) -methyl 2- (4- (5- (ethoxycarbonyl) -6- (4-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester (mixture of 2 stereoisomers)

And (trans) -methyl 2- (4- (5- (ethoxycarbonyl) -6- (4-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid ester (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

VII-12-X:LC-MS(ESI)：R_T＝3.737min，C₂₈H₂₉FN₄O₅Calculated mass of S552.2, M/z found 553.0[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.27(s,1H),8.10(s,0.7H),7.76(d,J＝3.2Hz,1H),7.45(d,J＝3.2Hz,0.3H),7.39(d,J＝3.2Hz,0.8H),7.30-7.26(m,0.2H),7.17-7.14(m,0.8H),6.92-6.74(m,2.2H),5.95(s,0.8H),5.84(d,J＝2.0Hz,0.2H),4.11-3.99(m,3H),3.94(s,2H),3.93(s,1H),3.36(s,0.8H),3.28(s,0.2H),2.62(s,2.3H),2.55-2.47(m,2.7H),2.04-1.69(m,6H),1.15-1.10(m,3H)。

VII-12-Y:LC-MS(ESI)：R_T＝4.521min，C₂₈H₂₉FN₄O₅Calculated mass of S552.2, found M/z 553.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.19(s,0.7H),8.18(s,0.3H),8.08(s,0.7H),7.81-7.80(m,1H),7.50(d,J＝3.2Hz,0.3H),7.42(d,J＝2.8Hz,0.7H),7.33-7.29(m,0.3H),7.20-7.17(m,0.7H),6.97-6.90(m,0.3H),6.84-6.77(m,2H),5.97(s,0.7H),5.87(d,J＝2.0Hz,0.3H),4.11-4.01(m,3H),3.92(d,J＝2.0Hz,3H),3.02-2.94(m,1H),2.64(s,2H),2.49(s,1H),2.38-2.22(m,2.7H),2.10-1.62(m,5.3H),1.13(d,J＝7.2Hz,3H)。

A stereoisomeric mixture of (trans) -methyl 2- (4- (5- (ethoxycarbonyl) -6- (4-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate VII-12-Y (120mg, 95% purity, 0.206mmol) was separated by chiral preparative HPLC (column: Chiralpak IC 5 μm 20 250 mm; mobile phase: Hex: EtOH: DEA 80:20:0.3 at 25 mL/min; temperature: 30 ℃ c; wavelength: 214nm) to give the title compound VII-12-P (65mg, 95.5% purity, 54% yield, 100% stereopurity) and VII-12-Q (50mg, 97.8% purity, 43% yield, 95.3% stereopurity).

VII-12-P：LC-MS(ESI)：R_T＝2.037min，C₂₈H₂₉FN₄O₅Calculated mass of S552.2, found M/z 553.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2 at 1 mL/min; wavelength: 230nm, R_T＝12.418min)。¹H NMR(400MHz,CDCl₃)δ8.18(d,J＝2.8Hz,1H),8.08(s,0.7H),7.81-7.80(m,1H),7.50(d,J＝2.8Hz,0.3H),7.42(d,J＝3.6Hz,0.7H),7.34-7.30(m,0.3H),7.20-7.17(m,0.8H),6.98-6.97(m,0.2H),6.89-6.75(m,2H),5.97(s,0.7H),5.87(d,J＝2.0Hz,0.3H),4.12-4.00(m,3H),3.93(s,2H),3.92(s,1H),3.03-2.93(m,1H),2.63(s,2H),2.49(s,1H),2.37-2.21(m,3H),2.04-1.67(m,5H),1.13(t,J＝7.2Hz,3H)。

VII-12-Q：LC-MS(ESI)：R_T＝2.037min，C₂₈H₂₉FN₄O₅Calculated mass of S552.2, found M/z 553.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2 at 1 mL/min; wavelength: 230nm, R_T＝13.758min)。¹H NMR(400MHz,CDCl₃)δ8.18(d,J＝3.2Hz,1H),8.08(s,0.7H),7.81-7.80(m,1H),7.50(d,J＝3.2Hz,0.3H),7.42(d,J＝3.2Hz,0.7H),7.34-7.30(m,0.3H),7.20-7.17(m,0.8H),6.97-6.95(m,0.2H),6.90-6.77(m,2H),5.97(s,0.7H),5.87(d,J＝2.0Hz,0.3H),4.11-4.00(m,3H),3.93(s,2H),3.92(s,1H),3.01-2.93(m,1H),2.63(s,2.2H),2.49(s,0.8H),2.37-2.22(m,3H),2.10-1.65(m,5H),1.13(d,J＝7.2Hz,3H)。

Compound VII-13-P and compound VII-13-Q:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohex-1-en-1-yl) oxazole-4-carboxylic acid ester (single stereoisomer) and 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohex-1-en-1-yl) oxazole-4-carboxylic acid ester (single stereoisomer).

Intermediate VII-13-R:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohex-1-en-1-yl) oxazole-4-carboxylic acid ester (mixture of 4 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

Intermediate VII-13-R: LC-MS (ESI): r_T＝4.032min，C₂₈H₂₅ClF₂N₄O₅The calculated mass of S was 602.1, found value of M/z 602.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.64-9.61(m,0.8H),9.15(s,0.1H),9.08(s,0.1H),8.81-8.78(m,1H),8.00-7.94(m,2H),7.51-7.45(m,1H),7.28-7.20(m,1H),6.94-6.90(m,1H),6.07(s,0.1H),6.05(s,0.1H),5.97-5.95(m,0.8H),4.29(q,J＝7.2Hz,2H),4.14(br s,0.2H),4.00-3.89(m,2.8H),2.75-2.58(m,2H),2.49-2.26(m,2H),2.08-1.83(m,2H),1.30(t,J＝7.2Hz,3H),1.08-1.01(m,3H)。

A stereoisomeric mixture of ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohex-1-en-1-yl) oxazole-4-carboxylate VII-13-R (420mg, 99.7% purity, 0.69mmol) was passed through chiral preparative HPLC (first separation conditions: column: Chiralpak ID 5 μm20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 15 mL/min; wavelength: 214 nm; second separation conditions: column: Chiralpak IF 5 μm20 × 250 mm; mobile phase: CO₂MeOH 60:40 at 45 g/min; the column temperature is 40 ℃; wavelength: 254 nm; back pressure: 100 bar; third separation conditions: column: chiralpak ID 5 μm20 × 250 mm; mobile phase: hex EtOH DEA 70:30:0.3 at 15 mL/min; wavelength: 214nm) to give the title compounds VII-13-M (60mg, 96.5% purity, 34% yield, 98.2% de), VII-13-N (80mg, 95.2% purity, 45% yield, 98.4% de), VII-13-P (60mg, 99.1% purity, 38% yield, 100% de) and VII-13-Q (70mg, 99.7% purity, 44% yield, 99.5% de).

VII-13-M:LC-MS(ESI)：R_T＝4.227min,C₂₈H₂₅ClF₂N₄O₅Calculated mass of S602.1, M/z found 603.1[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IF 5 μm 4.6 x 250 mm; mobile phase: CO2: MeOH 60:40 at 3 g/min; temperature: 40 ℃; wavelength: 254nm, R_T＝3.85min)。¹H NMR(400MHz,DMSO-d₆)δ9.63(d,J＝3.2Hz,0.7H),9.17(s,0.3H),8.81-8.79(m,1H),8.01-7.93(m,2H),7.51-7.45(m,1H),7.26-7.20(m,1H),6.93-6.90(m,1H),6.07(s,0.3H),5.97(d,J＝3.6Hz,0.7H),4.29(q,J＝7.2Hz,2H),4.13(br s,0.3H),4.00-3.88(m,2.7H),2.78-2.59(m,2H),2.46-2.36(m,2H),2.10-1.82(m,2H),1.29(t,J＝7.2Hz,3H),1.08-1.01(m,3H)。

VII-13-N:LC-MS(ESI)：R_T＝4.113min,C₂₈H₂₅ClF₂N₄O₅Calculated mass of S602.1, M/z found 602.9[ M + H]⁺. Chiral HPLC (column: Chiralpak IF 5 μm 4.6 x 250 mm; mobile phase: CO2: MeOH 60:40 at 3 g/min; temperature: 40 ℃; wavelength: 254nm, R_T＝5.43min)。¹H NMR(400MHz,DMSO-d₆)δ9.65(d,J＝3.2Hz,0.7H),9.09(s,0.3H),8.81-8.79(m,1H),8.02-7.94(m,2H),7.53-7.47(m,1H),7.28-7.25(m,1H),6.91-6.88(m,1H),6.05(s,0.2H),5.96(d,J＝3.2Hz,0.8H),4.29(q,J＝7.2Hz,2H),4.13(br s,0.3H),4.00-3.89(m,2.7H),2.76-2.58(m,2H),2.44-2.26(m,2H),2.20-1.99(m,2H),1.30(t,J＝7.2Hz,3H),1.08-1.01(m,3H)。

VII-13-P:LC-MS(ESI)：R_T＝3.346min,C₂₈H₂₅ClF₂N₄O₅Calculated mass of S602.1, M/z found 603.1[ M + H [)]⁺. Chiral HPLC (column: Chiralpak ID 5 μm 4.6 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＝8.847min)。¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝3.2Hz,0.6H),9.16(s,0.4H),8.81-8.78(m,1H),8.01-7.93(m,2H),7.51-7.45(m,1H),7.26-7.20(m,1H),6.93-6.89(m,1H),6.07(s,0.3H),5.97(d,J＝2.8Hz,0.7H),4.29(q,J＝7.2Hz,2H),4.16-4.09(m,0.3H),4.00-3.87(m,2.7H),2.79-2.58(m,2H),2.46-2.33(m,2H),2.08-1.82(m,2H),1.29(t,J＝7.2Hz,3H),1.08-1.01(m,3H)。

VII-13-Q:LC-MS(ESI)：R_T＝3.604min,C₂₈H₂₅ClF₂N₄O₅Calculated mass of S602.1, M/z found 603.1[ M + H [)]⁺. Chiral HPLC (column: Chiralpak ID 5 μm 4.6 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＝13.800min)。¹H NMR(400MHz,DMSO-d₆)δ9.64(d,J＝3.2Hz,0.7H),9.08(s,0.3H),8.81-8.78(m,1H),8.01-7.93(m,2H),7.53-7.45(m,1H),7.28-7.25(m,1H),6.91-6.88(m,1H),6.05(s,0.2H),5.96(d,J＝3.6Hz,0.8H),4.29(q,J＝7.2Hz,2H),4.16-4.10(m,0.3H),4.00-3.89(m,2.7H),2.75-2.57(m,2H),2.44-2.26(m,2H),2.19-1.99(m,2H),1.30(t,J＝7.2Hz,3H),1.08-1.01(m,3H)。

Compound VII-14-N:

(trans) -methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -5-methyloxazole-4-carboxylate (single stereoisomer)

Intermediate VII-14-8:

(trans) -methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -5-methyloxazole-4-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B. LC-MS (ESI): r_T＝1.723min,C₂₈H₂₇ClF₂N₄O₅Calculated mass of S604.1, M/z found 605.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.14(s,0.6H),7.83(d,J＝2.8Hz,1H),7.51(d,J＝3.2Hz,0.4H),7.46(d,J＝3.2Hz,0.6H),7.32(s,0.4H),7.12-7.01(m,2H),6.21(s,0.6H),6.08(d,J＝2.8Hz,0.4H),4.10-4.02(m,2.6H),3.91(s,3H),3.81(br s,0.4H),2.93-2.87(m,1H),2.61(s,3H),2.29-1.63(m,8H),1.17-1.12(m,3H)。

The stereoisomeric mixture of (trans) -methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -5-methyloxazole-4-carboxylic acid ester VII-14-8(630mg, 99% pure, 1.03mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA 5 μ M30: 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.3 at 22 mL/min; wavelength: 214nm) to give the title compound VII-14-M (200mg, 98.7% pure, 32% yield, 100% stereopure) and the other isomer (190mg, 88% stereopure), which was further purified by chiral preparative HPLC (column: chiralpak IA 5 μm 30 × 250 mm; mobile phase: hex EtOH DEA 80:20:0.3 at 22 mL/min; wavelength: 214nm) to give the title compound VII-14-N as a yellow solid (60mg, 99.9% purity, 9.6% yield, 99.6% stereopurity).

VII-14-M:LC-MS(ESI)：R_T＝3.051min,C₂₈H₂₇ClF₂N₄O₅Calculated mass of S604.1, M/z found 604.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 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＝9.303min)。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.6Hz,0.6H),9.00(s,0.4H),8.01-8.00(m,1.6H),7.95(d,J＝3.2Hz,0.4H),7.51-7.43(m,1H),7.22-7.17(m,1H),6.04(s,0.4H),5.93(d,J＝3.6Hz,0.6H),4.02-3.87(m,2.4H),3.79(s,3H),3.68-3.62(m,0.6H),3.01-2.94(m,0.4H),2.84-2.78(m,0.6H),2.56-2.55(m,3H),2.19-1.54(m,8H),1.11-1.04(m,3H)。

VII-14-N:LC-MS(ESI)：R_T＝4.134min,C₂₈H₂₇ClF₂N₄O₅Calculated mass of S604.1, M/z found 605.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 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＝11.057min)。¹H NMR(400MHz,DMSO-d₆)δ9.55(d,J＝3.2Hz,0.6H),9.00(s,0.4H),8.01-8.00(m,1.6H),7.95(d,J＝3.2Hz,0.4H),7.51-7.43(m,1H),7.23-7.17(m,1H),6.04(s,0.4H),5.93(d,J＝3.6Hz,0.6H),4.02-3.86(m,2.4H),3.79(s,3H),3.67-3.61(m,0.6H),3.01-2.95(m,0.4H),2.84-2.77(m,0.6H),2.56-2.55(m,3H),2.16-1.51(m,8H),1.10-1.04(m,3H)。

Compound VII-15-M:

(trans) -methyl-2- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) methyl) oxazole-4-carboxylic acid ester (single stereoisomer)

Intermediate VII-15-R:

methyl 2- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) methyl) oxazole-4-carboxylic acid ester (mixture of 4 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

LC-MS(ESI)：R_T＝1.94min,C₂₈H₂₇ClF₂N₄O₅Calculated mass of S604.1, M/z found 604.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.57-9.48(m,0.7H),8.96(s,0.3H),8.80-8.78(m,1H),8.03-7.93(m,2H),7.50-7.42(m,1H),7.23-7.15(m,1H),6.03-6.02(m,0.4H),5.92-5.91(m,0.6H),3.99-3.92(m,2H),3.88-3.80(m,3.5H),3.74-3.66(m,0.2H),3.62-3.54(m,0.3H),3.21-3.19(m,0.3H),3.00-0.97(m,0.4H),2.75-2.74(m,1.3H),2.30-2.25(m,0.3H),2.09-1.38(m,7.7H),1.17-1.11(m,1H),1.09-1.02(m,3H)。

Intermediates VII-15-X and VII-15-Y:

(trans) -methyl 2- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) methyl) oxazole-4-carboxylate (a mixture of 2 stereoisomers) and (cis) -methyl 2- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) methyl) oxazole-4-carboxylate (a mixture of 2 stereoisomers).

A mixture of methyl 2- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) methyl) oxazole-4-carboxylate VII-15-R (480mg, 95% purity, 0.75mmol) was separated by chiral preparative HPLC (column: Chiralpak IC 5 μm 20: 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.3, at 15 mL/min; temperature: 30 ℃; wavelength: 254nm) to give the title compounds VII-15-X (140mg, 98% purity, 29% yield) and VII-15-Y (260mg, 98% purity) as yellow solids, 54% yield).

Intermediate VII-15-X: chiral analysis (Chiralpak IC 5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1 mL/min; temperature: 30 ℃ C.; wavelength: 254nm, R: M;)_T11.072min and 11.491 min).¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝3.6Hz,0.5H),8.96(br s,0.5H),8.79-8.78(m,1H),8.00-7.94(m,2H),7.49-7.42(m,1H),7.21-7.14(m,1H),6.02(s,0.5H),5.91(d,J＝3.6Hz,0.5H),3.99-3.92(m,2H),3.86-3.80(m,3.5H),3.62-3.55(m,0.5H),2.79-2.70(m,2H),2.02-1.57(m,7H),1.18-1.02(m,5H)。

Intermediate VII-15-Y: chiral analysis (Chiralpak IC 5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2 at 1 mL/min; temperature: 30 ℃ C.; wavelength: 254nm, R: M;)_T＝14.629min)。¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝3.2Hz,0.5H),9.48(s,0.5H),8.80-8.79(m,1H),8.03-7.93(m,2H),7.51-7.44(m,1H),7.24-7.15(m,1H),6.03(s,0.5H),5.93-5.92(d,J＝3.6Hz,0.5H),3.99-3.92(m,2H),3.99-3.80(m,3.5H),3.73-3.64(m,0.5H),3.21-3.19(m,1H),3.04-3.93(m,1H),2.33-2.27(m,1H),2.09-1.86(m,2H),1.63-1.38(m,6H),1.09-1.03(m,3H)。

A stereoisomeric mixture of (trans) -methyl-4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) methyl) oxazole-4-carboxylic acid ester VII-15-X (240mg, 98% purity, 0.377mmol) was purified by chiral preparative SFC (column: chiralpak IA 5 μm 20 × 250 mm; mobile phase: CO 2 ₂IPA 75:25 at 50 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar) to give compound VII-15-M (110mg, 95% pure, 46% yield, 100% stereopure) and VII-15-N (80mg, 95% pure, 33% yield, 99% stereopure) as yellow solids.

VII-15-M: chiral analysis (Chiralpak IA 5 μm 4.6X 250 mm; mobile phase: CO)₂IPA 75:25 at 3 g/min; column temperature: 40 ℃; wavelength: 220nm, back pressure: 100 bar, R_T＝4.98min)。

VII-15-N: chiral analysis (Chiralpak IA 5 μm 4.6X 250 mm; mobile phase: CO)₂IPA 75:25 at 3 g/min; column temperature: 40 ℃; wavelength: 220nm, back pressure: 100 bar, R_T＝5.87min)。

Compound VII-16-N:

(trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediates VII-16-X and VII-16-Y:

(trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers) and (cis) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers).

The title compound was synthesized by a similar procedure using method B.

Intermediate VII-16-X:¹H NMR(400MHz,DMSO-d₆)δ9.59(d,J＝3.6Hz,0.7H),9.07(s,0.3H),8.01-8.00(m,1.5H),7.96-7.95(m,0.5H),7.86-7.85(m,1H),7.50-7.43(m,1H),7.22-7.15(m,1H),6.02(s,0.4H),5.93(d,J＝3.6Hz,0.6H),4.13-4.08(m,2H),3.94-3.89(m,0.5H),3.69-3.62(m,2.5H),3.54(s,1.8H),3.53(m,1.2H),3.00-2.94(m,0.4H),2.83-2.76(m,0.6H),2.18-2.10(m,2H),2.06-1.66(m,4H),1.62-1.48(m,2H),1.22-1.18(m,3H)。

intermediate VII-16-Y:¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝3.6Hz,0.7H),8.49(s,0.3H),7.98-7.91(m,3H),7.48-7.40(m,1H),7.18-7.14(m,1H),6.02(s,0.3H),5.89(d,J＝3.6Hz,0.7H),4.12-4.06(m,2H),3.93-3.88(m,0.3H),3.71-3.66(m,1.4H),3.62(s,1.3H),3.53(s,1.8H),3.52(s,1.2H),3.29-2.27(m,0.3H),3.18-3.16(m,0.7H),2.34-2.24(m,2H),1.97-1.58(m,5.3H),1.44-1.41(m,0.7H),1.19-1.15(m,3H)。

the stereoisomeric mixture of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-16-X (300mg, 95% purity, 0.471mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μ M20: 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.3 at 10mL/min, temperature: 30 ℃, wavelength: 230nm) to afford VII-16-M (110mg, from) as a yellow solid¹H NMR purity 95%, 37% yield, 100% stereopure) and VII-16-N (110mg, from¹Purity by H NMR 95%, 37% yield, 99.8% stereopure).

VII-16-M chiral analysis (column: Chiralpak IE 5 μ M4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2, at 1.0mL/min, temperature: 30 ℃; wavelength: 230nm, R_T＝6.781min)。¹H NMR(400MHz,DMSO-d₆)δ9.58-9.57(m,0.6H),9.05(s,0.4H),8.01(s,1.5H),7.96-7.95(m,0.5H),7.86-7.84(m,1H),7.50-7.43(m,1H),7.21-7.14(m,1H),6.02(s,0.4H),5.93-5.92(m,0.6H),4.10(q,J＝7.2Hz,2H),3.94-3.88(m,0.5H),3.68-3.61(m,0.5H),3.57(s,2H),3.54(s,1.8H),3.53(s,1.2H),3.00-2.94(m,0.4H),2.84-2.76(m,0.6H),2.18-2.10(m,2H),2.04-1.66(m,4H),1.61-1.51(m,2H),1.20(t,J＝7.2Hz,3H)。

VII-16-N chiral analysis (column: Chiralpak IE 5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2 at 1.0mL/min, temperature: 30 ℃; wavelength: 230nm, R_T＝12.009min)。¹H NMR(400MHz,DMSO-d₆)δ9.58-9.57(m,0.6H),9.05(s,0.4H),8.01(s,1.5H),7.96-7.95(m,0.5H),7.85-7.84(m,1H),7.50-7.43(m,1H),7.22-7.16(m,1H),6.02(s,0.4H),5.93-5.92(m,0.6H),4.10(q,J＝7.2Hz,2H),3.95-3.88(m,0.5H),3.67-3.61(m,0.5H),3.57(s,2H),3.54(s,1.8H),3.53(s,1.2H),,3.00-2.94(m,0.4H),2.83-2.76(m,0.6H),2.18-2.11(m,2H),2.04-1.67(m,4H),1.61-1.51(m,2H),1.20(t,J＝7.2Hz,3H)。

Compound VII-17-M:

(trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer) intermediates VII-17-X and VII-17-Y

(trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (a mixture of 2 stereoisomers) and (cis) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (a mixture of 2 stereoisomers).

The title compound was synthesized by a similar procedure using method B.

VII-17-X:¹H NMR(400MHz,CDCl₃)δ8.16(s,0.4H),7.83-7.82(m,1H),7.56-7.54(m,1H),7.50(d,J＝3.2Hz,0.4H),7.46-7.45(d,J＝2.8Hz,0.6H),7.40(br s,0.6H),7.32-7.28(m,1H),7.14-7.12(m,1H),6.96-6.89(m,1H),6.19(s,0.6H),6.06-6.05(m,0.4H),4.23-4.18(m,2H),4.08-4.01(m,0.6H),3.84-3.78(m,0.4),3.62-3.60(m,4H),2.93-2.86(m,1H),2.33-2.14(m,3H),2.10-2.07(m,1H),1.88-1.64(m,4H),1.31-1.24(m,3H)。

VII-17-Y ¹H NMR(400MHz,CDCl₃)δ8.27(s,0.7H),7.83-7.82(d,J＝3.2Hz,0.7H),7.80-7.79(d,J＝2.8Hz,0.3H),7.65(s,0.7H),7.63(s,0.3H),7.47-7.46(d,J＝3.2Hz,0.3H),7.43-7.42(d,J＝3.2Hz,0.7H),7.35(br s,0.3H),7.30-7.25(m,1H),7.13-7.10(m,1H),6.94-6.86(m,1H),6.18(s,0.7H),6.04-6.03(d,J＝3.2Hz,0.3H),4.23-4.16(m,2H),4.13-4.05(m,0.7H),3.89-3.83(m,0.3H),3.73(s,1.4H),3.66(s,0.6H),3.61(s,0.5H),3.60(s,2.5H),3.29(s,0.7H),3.22-3.21(m,0.3H),2.50-2.35(m,2H),2.13-2.07(m,0.3H),1.98-1.78(m,5.7H),1.30-1.26(m,3H)。

A stereoisomeric mixture of (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester VII-17-X (130mg, 0.221mmol) was passed through a chiral preparative SFC (column: Chiralpak IG 5 μm 20 × 250 mm; mobile phase: CO₂EtOH, DEA 65, 35, 0.3 at 50 g/min; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100 bar) to give compound VII-17-M (50mg, 38% yield, 100% stereopure) and VII-17-N (60mg, 46% yield, 99.2% stereopure).

VII-17-M chiral assay (column: Chiralpak IG 5 μ M4.6 x 250 mm; mobile phase: CO₂EtOH, DEA 65, 35, 0.3 at 3 g/min; column temperature: 40 ℃; wavelength: 230nm, back pressure: 100 bar, R _T＝3.51min)。

VII-17-N chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO₂EtOH, DEA 65, 35, 0.3 at 3 g/min; column temperature: 40 ℃; wavelength: 230nm, back pressure: 100 bar, R_T＝4.28min)。

Compound VII-18-M:

(trans) -methyl 4- (2-bromo-4-fluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer) intermediates VII-18-X and VII-18-Y:

(trans) -methyl 4- (2-bromo-4-fluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers) and (cis) -methyl 4- (2-bromo-4-fluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers).

The title compound was synthesized by a similar procedure using method B.

Intermediate VII-18-Y:¹H NMR(400MHz,CDCl₃)δ8.25(s,0.7H),7.82(d,J＝3.2Hz,0.7H),7.80(d,J＝3.2Hz,0.3H),7.65(s,0.7H),7.63(s,0.3H),7.46(d,J＝3.2Hz,0.3H),7.42(d,J＝3.2Hz,0.7H),7.41-7.38(m,0.3H),7.32-7.30(m,1H),7.00-6.91(m,1H),6.15(s,0.7H),5.99(d,J＝2.8Hz,0.3H),4.23-4.16(m,2H),4.13-4.07(m,0.7H),3.89-3.84(m,0.3H),3.73(s,1.3H),3.66(s,0.7H),3.61(s,1H),3.60(s,2H),3.30(br s,0.7H),3.22-3.21(m,0.3H),2.43-2.34(m,1.8H),2.13-2.07(m,0.3H),1.96-1.87(m,4.5H),1.83-1.76(m,1.4H),1.30-126(m,3H)。

intermediate VII-18-X:¹H NMR(400MHz,CDCl₃)δ8.16(s,0.5H),7.83(t,J＝3.2Hz,1H),7.59-7.56(m,1H),7.53-7.50(m,0.5H),7.49-7.46(m,0.5H),7.45-7.43(m,0.5H),7.35-7.30(m,2H),7.03-6.91(m,1H),6.17(s,0.5H),6.02(d,J＝2.4Hz,0.5H),4.20(q,J＝7.2Hz,2H),4.10-4.02(m,0.5H),3.86-3.77(m,0.5H),3.62(s,2H),3.60(s,3H),2.95-2.82(m,1H),2.37-2.25(m,1.5H),2.19-2.16(m,1H),2.08-2.01(m,1.5H),1.86-1.75(m,3H),1.70-1.57(m,1H),1.33-1.26(m,3H)。

the stereoisomeric mixture of (trans) -methyl 4- (2-bromo-4-fluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester VII-18-X (560mg, 95% purity, 0.842mmol) was passed through a chiral preparative SFC (column: Chiralpak IF 5 μm 20X 250mm, mobile phase: CO ₂EtOH, DEA 70:30:0.3 at 50 g/min; column temperature: 40 ℃; wavelength: 214 nm; back pressure: 100 bar) to provide the title compound VII-18-M (103mg, 90% pure, 17% yield, 100% stereopure) and VII-18-N (145mg, 90% pure, 25% yield, 99.5% stereopure) as yellow solids.

VII-18-M：LC-MS(ESI)：R_T＝1.92min，C₂₈H₂₈BrFN₄O₅Calculated mass of S631.5, M/z found 632.8[ M + H ]]⁺. Chiral analysis (column: Chiralpak IF 5 μm 4.6 x 250 mm; mobile phase: CO)₂EtOH, DEA 70:30:0.2 at 5 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure:100 bar, R_T＝5.82min)。¹H NMR(400MHz,CDCl₃)δ8.14(s,0.5H),7.83-7.82(m,1H),7.56(s,1H),7.50-7.49(m,0.5H),7.44(d,J＝3.2Hz,1H),7.33-7.28(m,2H),7.03-6.90(m,1H),6.17(s,0.5H),6.02(d,J＝2.8Hz,0.5H),4.20(q,J＝7.2Hz,2H),4.10-4.00(m,0.5H),3.86-3.76(m,0.5H),3.62-3.60(m,5H),2.96-2.83(m,1H),2.37-2.02(m,4H),1.92-1.64(m,4H),1.29(t,J＝7.2Hz,3H)。

VII-18-N：LC-MS(ESI)：R_T＝1.90min，C₂₈H₂₈BrFN₄O₅Calculated mass of S631.5, M/z found 632.8[ M + H ]]⁺. Chiral analysis (column: Chiralpak IF 5 μm 4.6 x 250 mm; mobile phase: CO)₂EtOH, DEA 70:30:0.2 at 5 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar, R_T＝8.02min)。¹H NMR(400MHz,CDCl₃)δ8.15(s,0.5H),7.83-7.82(m,1H),7.56(s,1H),7.50-7.49(m,0.5H),7.44(d,J＝3.2Hz,1H),7.33-7.28(m,2H),7.01-6.91(m,1H),6.17(s,0.5H),6.02(d,J＝2.8Hz,0.5H),4.20(q,J＝7.2Hz,2H),4.10-4.01(m,0.5H),3.86-3.76(m,0.5H),3.62-3.60(m,5H),2.94-2.84(m,1H),2.36-2.02(m,4H),1.93-1.64(m,4H),1.29(t,J＝7.2Hz,3H)。

Compound VII-19-M:

(trans) -methyl 4- (2-bromo-3-fluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer) intermediate VII-19-1:

(trans) -methyl 4- (2-bromo-3-fluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝2.097min，C₂₈H₂₈BrFN₄O₅Calculated mass of S630.1, M/z found 631.0[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.92(s,0.5H),7.88(s,0.5H),7.75-7.72(m,2H),7.34-7.28(m,1H),7.21(d,J＝8.0Hz,1H),7.14-7.07(m,1H),6.20(s,0.5H),6.10(s,0.5H),4.18(q,J＝6.8Hz,2H),4.09-4.03(m,0.5H),3.85-3.81(m,0.5H),3.60-3.58(m,5H),3.00-2.84(m,1H),2.29-2.18(m,2H),2.13-2.06(m,1H),1.88-1.67(m,5H),1.29-1.23(m,3H)。

A stereoisomeric mixture of (trans) -methyl 4- (2-bromo-3-fluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-19-1(352mg, 95% purity, 0.530mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μ M20 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.3 at 12 mL/min; temperature: 30 ℃; wavelength: 214nm) to afford the title compound VII-19-M as a yellow solid (148mg from¹Purity by H NMR 95%, 42% yield) and VII-19-N (144mg, obtained from¹Purity by H NMR 95%, 41% yield).

VII-19-M:¹H NMR(400MHz,DMSO-d₆)δ9.49(br s,0.5H),9.03(s,0.5H),8.00(d,J＝3.2Hz,1.5H),7.94(d,J＝3.2Hz,0.5H),7.85(d,J＝4.8Hz,1H),7.44-7.39(m,1H),7.31-7.25(m,1H),7.21(d,J＝8.0Hz,0.5H),7.16(d,J＝8.0Hz,0.5H),6.06(s,0.5H),5.97(s,0.5H),4.11(q,J＝7.2Hz,2H),3.95-3.90(m,0.5H),3.68-3.62(m,0.5H),3.58(s,2H),3.53(s,1.5H),3.52(s,1.5H),3.00-2.94(m,0.5H),2.84-2.78(m,0.5H),2.18-2.11(m,2H),2.05-2.02(m,0.5H),1.94-1.89(m,2H),1.82-1.76(m,1H),1.70-1.67(m,0.5H),1.63-1.51(m,2H),1.20(t,J＝7.2Hz,3H)。

VII-19-N:¹H NMR(400MHz,DMSO-d₆)δ9.49(br s,0.5H),9.05(s,0.5H),8.00(d,J＝2.8Hz,1.5H),7.95(d,J＝2.8Hz,0.5H),7.86(d,J＝4.8Hz,1H),7.45-7.39(m,1H),7.32-7.25(m,1H),7.21(d,J＝7.6Hz,0.5H),7.16(d,J＝7.6Hz,0.5H),6.06(s,0.5H),5.97(s,0.5H),4.11(q,J＝7.2Hz,2H),3.96-3.90(m,0.5H),3.69-3.63(m,0.5H),3.58(s,2H),3.53(s,2H),3.52(s,1H),3.00-2.94(m,0.5H),2.84-2.78(m,0.5H),2.18-2.10(m,2H),2.06-2.00(m,0.5H),1.94-1.88(m,2H),1.82-1.77(m,1H),1.70-1.67(m,0.5H),1.60-1.51(m,2H),1.20(t,J＝7.2Hz,3H)。

Compound VII-20-N:

(trans) -methyl 4- (2-chloro-3-fluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer) intermediate VII-20-3:

(trans) -methyl 4- (2-chloro-3-fluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝1.89min，C₂₈H₂₈ClFN₄O₅Calculated mass of S586.2, found M/z 586.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.17(s,0.5H),7.83(d,J＝3.2Hz,1H),7.56(s,1H),7.51-7.50(m,0.5H),7.46-7.45(m,0.5H),7.42(s,0.5H),7.23-7.12(m,2H),7.10-7.00(m,1H),6.26(s,0.6H),6.11(s,0.4H),4.20(q,J＝7.2Hz,2H),4.10-4.02(m,0.5H),3.89-3.78(m,0.5H),3.62-3.60(m,5H),2.95-2.87(m,1H),2.36-1.99(m,4H),1.91-1.67(m,3.6H),1.61-1.54(m,0.4H),1.30(t,J＝7.2Hz,3H)。

The stereoisomeric mixture of (trans) -methyl 4- (2-chloro-3-fluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-20-3(400mg, 90% purity, 0.613mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μ M20 250 mm; mobile phase: Hex: EtOH: DEA 50:50:0.3 at 13 mL/min; temperature: 30 ℃ c; wavelength: 230nm) to give the title compound VII-20-M (148mg, 90% purity, 37% yield, 100% stereopurity) and VII-20-N (150mg, 90% purity, 37% yield, 99.7% stereopurity).

VII-20-M chiral analysis (column: Chiralpak IE 5 μ M4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2, at 1mL/min, temperature: 30 ℃; wavelength: 230nm, R_T＝7.675min)。¹H NMR(400MHz,CDCl₃)δ7.83(d,J＝3.2Hz,1H),7.56(s,1H),7.47(br s,1H),7.23-7.13(m,2H),7.11-7.01(m,1H),6.32-6.09(m,1H),4.20(q,J＝7.2Hz,2H),3.98(br s,0.6H),3.86-3.73(m,0.4H),3.60(s,5H),2.93-2.85(m,1H),2.35-2.04(m,4H),2.02-1.72(m,4H),1.31(t,J＝7.2Hz,3H)。

VII-20-N chiral analysis (column): chiralpak IE 5 μm 4.6 × 250 mm; mobile phase: hex EtOH 50 DEA 50:50:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝10.297min)。¹H NMR(400MHz,CDCl₃)δ7.83(d,J＝3.2Hz,1H),7.56(s,1H),7.47(br s,1H),7.21-7.13(m,2H),7.09-7.00(m,1H),6.29-6.10(m,1H),4.20(q,J＝7.2Hz,2H),3.98(br s,0.6H),3.88-3.71(m,0.4H),3.60(s,5H),2.94-2.84(m,1H),2.36-2.07(m,4H),2.04-1.74(m,3H),1.68-1.57(m,1H),1.30(t,J＝7.2Hz,3H)。

Compound VII-21-N:

(trans) -methyl 6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -4- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VII-21-1:

(trans) -methyl 6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -4- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝1.87min，C₂₉H₃₁FN₄O₅Calculated mass of S566.2, found M/z 566.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.12(s,1H),7.80(d,J＝2.8Hz,1H),7.56-7.55(m,1H),7.50(d,J＝2.8Hz,0.2H),7.42(d,J＝2.8Hz,0.8H),7.16-7.02(m,2H),6.90-6.88(m,1H),6.01(s,0.8H),5.91(d,J＝2.4Hz,0.2H),4.21(q,J＝7.2Hz,2H),4.12-4.04(m,1H),3.60(s,5H),2.93-2.87(m,1H),2.54(d,J＝2.0Hz,2.4H),2.40(d,J＝2.0Hz,0.6H),2.35-2.27(m,3H),2.09-1.98(m,1H),1.93-1.65(m,3.5H),1.59-1.55(m,0.5H),1.29(t,J＝7.2Hz,3H)。

The stereoisomeric mixture of (trans) -methyl 6- (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -4- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-21-1(400mg, 90% purity, 0.635mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μ M20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 13 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound VII-21-M as a yellow solid (60mg, 90% purity, 15% yield, 100% stereopure) and VII-21-N (100mg, 90% purity, 25% yield, 99.6% stereopure).

VII-21-M: chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; temperature: 30 ℃; wavelength: 230 nm; R-_T＝9.911min)。¹H NMR(400MHz,CDCl₃)δ8.12(s,1H),7.80(d,J＝2.8Hz,1H),7.56(s,1H),7.50(d,J＝3.2Hz,0.2H),7.42(d,J＝3.2Hz,0.8H),7.16-7.02(m,2H),6.95-6.88(m,1H),6.01(s,0.8H),5.91(d,J＝2.4Hz,0.2H),4.20(q,J＝7.2Hz,2H),4.12-4.04(m,1H),3.60(s,5H),2.93-2.87(m,1H),2.54(d,J＝2.0Hz,2.4H),2.40(d,J＝2.0Hz,0.6H),2.35-2.17(m,3H),2.09-1.98(m,1H),1.93-1.65(m,3.5H),1.59-1.55(m,0.5H),1.29(t,J＝7.2Hz,3H)。

VII-21-N chiral analysis (column: Chiralpak IE 5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2, at 1mL/min, temperature: 30 ℃; wavelength: 230nm, R _T＝12.043min)。¹H NMR(400MHz,CDCl₃)δ8.12(s,1H),7.80(d,J＝2.8Hz,1H),7.56(s,1H),7.50(d,J＝3.2Hz,0.2H),7.42(d,J＝3.2Hz,0.8H),7.16-7.00(m,2H),6.94-6.87(m,1H),6.01(s,0.8H),5.91(d,J＝2.0Hz,0.2H),4.20(q,J＝7.2Hz,2H),4.11-4.03(m,1H),3.60(s,5H),2.94-2.85(m,1H),2.54(d,J＝2.0Hz,2.4H),2.40(d,J＝2.0Hz,0.6H),2.36-2.17(m,3H),2.09-1.98(m,1H),1.93-1.65(m,3.5H),1.58-1.55(m,0.5H),1.29(t,J＝7.2Hz,3H)。

Compound VII-22-S:

(trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VII-22:

methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝2.172min,C₂₉H₂₉ClF₂N₄O₅Calculated mass of S618.2, found M/z 619.1[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.6H),7.83(d,J＝3.2Hz,1H),7.51(d,J＝3.2Hz,0.3H),7.46(d,J＝2.8Hz,0.7H),7.37(s,0.4H),7.10-7.00(m,2H),6.19(s,0.7H),6.05(d,J＝2.8Hz,0.3H),4.21-4.10(m,2H),4.06-4.00(m,0.6H),3.83-3.77(m,0.4H),3.63(s,1H),3.60(s,2H),3.47(s,2H),2.86-2.80(m,1H),2.32-2.30(m,1H),2.28(s,3H),2.16-2.13(m,1H),2.07-1.99(m,2H),1.86-1.62(m,4H),1.28(t,J＝7.2Hz,3H)。

A stereoisomeric mixture of methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (2-ethoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-22(300mg, 90% purity, 0.436mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μm 20mm 250 mm; mobile phase: Hex: EtOH: DEA ═ 75:25:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to afford the title compound VII-22-R as a yellow solid (85mg from¹Purity by H NMR 90%, 28% yield, 96.4% stereopure) and VII-22-S (90mg, obtained from ¹Purity by H NMR 90%, 30% yield, 98.4% stereopure).

VII-22-R:LC-MS(ESI)：R_T＝2.281min，C₂₉H₂₉ClF₂N₄O₅The calculated mass of S is 618.2, found M/z 619.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6mm 250 mm; mobile phase: Hex: EtOH: DEA: 75:25:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝10.938min)。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.6H),7.83(d,J＝3.2Hz,1H),7.51(d,J＝3.2Hz,0.3H),7.46(d,J＝3.2Hz,0.7H),7.38(s,0.4H),7.10-7.01(m,2H),6.19(s,0.7H),6.05(s,0.3H),4.18(q,J＝7.2Hz,2H),4.05-4.00(m,0.7H),3.83-3.77(m,0.3H),3.63(s,1H),3.60(s,2H),3.47(s,2H),2.86-2.80(m,1H),2.31-2.28(m,1H),2.26(s,3H),2.19-1.99(m,2.7H),1.87-1.70(m,4.3H),1.28(t,J＝7.2Hz,3H)。

VII-22-S:LC-MS(ESI)：R_T＝2.241min,C₂₉H₂₉ClF₂N₄O₅Calculated mass of S618.2, found M/z 619.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6mm 250 mm; mobile phase: Hex: EtOH: DEA: 75:25:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝12.525min)。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.6H),7.83(d,J＝3.6Hz,1H),7.51(d,J＝3.2Hz,0.4H),7.46(d,J＝3.2Hz,0.6H),7.38(s,0.4H),7.10-7.00(m,2H),6.19(s,0.6H),6.05(d,J＝2.0Hz,0.4H),4.18(q,J＝6.8Hz,2H),4.06-4.00(m,0.7H),3.83-3.78(m,0.3H),3.63(s,1H),3.60(s,2H),3.47(s,2H),2.86-2.80(m,1H),2.30-2.28(m,1H),2.26(s,3H),2.16-1.98(m,2.5H),1.84-1.64(m,4.5H),1.28(t,J＝6.8Hz,3H)。

Compound VII-23-Y:

(trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) - (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer) intermediates VII-23-M and VII-23-N:

(trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) - (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (a mixture of 2 stereoisomers) and (cis) -ethyl 4- (2-chloro-3, 4-difluorophenyl) - (4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (a mixture of 2 stereoisomers).

The title compound was synthesized by a similar procedure using method B.

VII-23-M：LC-MS(ESI)：R_T＝3.140min,C₂₉H₂₉ClF₂N₄O₅Calculated mass of S618.2, found M/z 619.1[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝2.8Hz,0.6H),8.98(s,0.4H),8.00(d,J＝3.6Hz,0.6H),7.99(s,1H),7.95(d,J＝3.2Hz,0.4H),7.84(d,J＝4.4Hz,1H),7.50-7.43(m,1H),7.23-7.17(m,1H),6.03(s,0.4H),5.93(d,J＝3.6Hz,0.6H),4.13-4.08(m,2H),4.01-3.94(m,2H),3.93-3.86(m,0.4H),3.68-3.61(m,0.6H),3.57(s,2H),3.01-2.92(m,0.4H),2.83-2.76(m,0.6H),2.20-2.10(m,2H),2.06-1.68(m,4H),1.61-1.47(m,2H),1.20(t,J＝7.2Hz,3H),1.10-1.03(m,3H)。

VII-23-N:LC-MS(ESI)：R_T＝3.644min,C₂₉H₂₉ClF₂N₄O₅Calculated mass of S618.2, found M/z 619.1[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.48(d,J＝3.6Hz,0.7H),8.41(s,0.3H),7.97-7.90(m,3H),7.48-7.40(m,1H),7.19-7.14(m,1H),6.03(s,0.3H),5.90(d,J＝3.6Hz,0.7H),4.12-4.04(m,2H),4.01-3.94(m,2H),3.97-3.94(m,0.3H),3.72-3.66(m,1.4H),3.61(s,1.3H),3.28-3.26(m,0.3H),3.19-3.15(m,0.7H),2.36-2.22(m,2H),1.98-1.69(m,4.7H),1.64-1.59(m,0.7H),1.46-1.41(m,0.6H),1.19-1.13(m,3H),1.10-1.04(m,3H)。

A stereoisomeric mixture of (trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -4- (4- (2-ethoxy-2-oxoethyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-23-M (400mg, 0.647mmol) was purified by chiral preparative HPLC (column: chiralpak IE 5 μm20 × 250 mm; mobile phase: hex EtOH DEA 40:60:0.2 at 25 mL/min; temperature: 30 ℃; wavelength: 254nm) to give the title compound VII-23-X (150mg, 38% yield, 99.8% purity, 100% stereopurity) and VII-23-Y (150mg, 38% yield, 99.9% purity, 100% stereopurity) as yellow solids.

VII-23-X:LC-MS(ESI)：R_T＝4.463min,C₂₉H₂₉ClF₂N₄O₅Calculated mass of S618.2, found M/z 618.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 40:60:0.2 at 1.0 mL/min; column temperature: 30 ℃; wavelength: 230nm, R_T＝6.153min)。¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝3.2Hz,0.6H),8.98(s,0.4H),8.01-8.00(m,1.6H),7.95(d,J＝3.2Hz,0.4H),7.85(d,J＝4.4Hz,1H),7.50-7.43(m,1H),7.23-7.17(m,1H),6.03(s,0.4H),5.93(d,J＝3.6Hz,0.6H),4.13-4.08(m,2H),4.01-3.94(m,2H),3.93-3.86(m,0.4H),3.68-3.61(m,0.6H),3.57(s,2H),3.00-2.93(m,0.4H),2.83-2.77(m,0.6H),2.19-2.10(m,2H),2.03-1.50(m,6H),1.20(t,J＝7.2Hz,3H),1.10-1.04(m,3H)。

VII-23-Y:LC-MS(ESI)：R_T＝4.466min,C₂₉H₂₉ClF₂N₄O₅Calculated mass of S618.2, found M/z 618.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 40:60:0.2 at 1.0 mL/min; column temperature: 30 ℃; wavelength: 230nm, R _T＝9.894min)。¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝3.6Hz,0.6H),8.98(s,0.4H),8.01-8.00(m,1.6H),7.95(d,J＝3.6Hz,0.4H),7.85(d,J＝4.0Hz,1H),7.50-7.43(m,1H),7.23-7.17(m,1H),6.03(s,0.4H),5.93(d,J＝3.6Hz,0.6H),4.10(q,J＝7.2Hz,2H),4.01-3.94(m,2H),3.93-3.87(m,0.4H),3.67-3.60(m,0.6H),3.57(s,2H),2.99-2.93(m,0.4H),2.83-2.76(m,0.6H),2.18-2.10(m,2H),2.04-1.67(m,4H),1.61-1.46(m,2H),1.20(t,J＝7.2Hz,3H),1.10-1.03(m,3H)。

Compound VII-24-M:

(trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (3-methoxy-3-oxopropyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VII-24-R:

(trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (3-methoxy-3-oxopropyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝3.193min,C₂₉H₂₉ClF₂N₄O₅Calculated mass of S618.2, M/z Mass found 619.1[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.55-9.54(d,J＝4.0Hz,0.6H),8.98(s,0.4H),8.00-7.95(m,2H),7.71-7.70(d,J＝4.0Hz,1H),7.50-7.43(m,1H),7.22-7.17(m,1H),6.03(s,0.4H),5.93(d,J＝3.6Hz,0.6H),3.99(q,J＝7.2Hz,2H),3.87-3.78(m,0.6H),3.67-3.64(m,0.4H),3.60(s,3H),2.97-2.91(m,0.4H),2.79-2.74(m,0.6H),2.70-2.68(m,2H),2.63-2.59(m,2H),2.16-2.10(m,2H),1.97-1.86(m,2H),1.81-1.66(m,2H)1.57-1.46(m,2H),1.10-1.03(m,3H)。

The stereoisomeric mixture of VII-24-R (396mg, 0.640mmol) was passed through a chiral preparative SFC (column: Chiralpak IE 5 μm 20 × 250 mm; mobile phase: CO₂MeOH 60:40 at 50 g/min; temperature: 30 ℃; wavelength: 230 nm; back pressure: 100 bar) to give the title compound VII-24-M (80mg, 20% yield, 100% stereopure) and VII-24-N (90mg, 23% yield, 100% stereopure) as yellow solids.

VII-24-M:LC-MS(ESI)：R_T＝4.857min,C₂₉H₂₉ClF₂N₄O₅Calculated mass of S618.2, M/z Mass found 619.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: CO)₂EtOH 60:40 at 3.0 g/min; column temperature: 40 ℃; wavelength: 230nm, back pressure: 100 bar, R _T＝3.92min)。¹H NMR(400MHz,CD₃OD)δ7.93(d,J＝3.2Hz,0.6H),7.89(d,J＝2.8Hz,0.4H),7.76-7.74(m,1H),7.55(d,J＝4.8Hz,1H),7.25-7.20(m,2H),6.15(s,0.6H),6.08(s,0.4H),4.06-4.03(m,2H),4.03-4.02(m,0.6H),3.84-3.76(m,0.4H),3.67(s,3H),2.98-2.92(m,0.6H),2.88-2.85(m,0.4H),2.81(t,J＝7.6Hz,2H),2.66(t,J＝7.6Hz,2H),2.29-2.15(m,2H),2.12-1.97(m,2H),1.94-1.79(m,2H),1.76-1.65(m,2H),1.17-1.12(m,3H)。

VII-24-N:LC-MS(ESI)：R_T＝4.860min,C₂₉H₂₉ClF₂N₄O₅Calculated mass of S618.2, M/z Mass found 619.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: CO)₂EtOH 60:40 at 3.0 g/min; column temperature: 40 ℃; wavelength: 230nm, back pressure: 100 bar, R_T＝6.65min)。¹H NMR(400MHz,CD₃OD)δ7.93(d,J＝3.2Hz,0.6H),7.89(d,J＝2.8Hz,0.4H),7.76-7.74(m,1H),7.55(d,J＝4.8Hz,1H),7.27-7.18(m,2H),6.15(s,0.6H),6.08(s,0.4H),4.08-4.04(m,2H),4.03-4.02(m,0.5H),3.85-3.76(m,0.5H),3.67(s,3H),2.98-2.95(m,0.6H),2.89-2.84(m,0.4H),2.81(t,J＝7.6Hz,2H),2.66(t,J＝7.6Hz,2H),2.29-2.15(m,2H),2.12-1.97(m,2H),1.94-1.88(m,2H),1.79-1.65(m,2H),1.17-1.12(m,3H)。

Compound VII-25-N:

(trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (3-ethoxy-2, 2-dimethyl-3-oxopropyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VII-25-7:

(trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (3-ethoxy-2, 2-dimethyl-3-oxopropyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate ester (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝2.10min,C₃₁H₃₃ClF₂N₄O₅Calculated mass of S646.2, found M/z 646.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.6H),7.83(d,J＝3.2Hz,1H),7.51(d,J＝3.2Hz,0.4H),7.46(d,J＝3.2Hz,0.6H),7.38(s,0.4H),7.28(s,1H),7.11-6.99(m,2H),6.19(s,0.6H),6.05(d,J＝2.8Hz,0.4H),4.14(q,J＝6.8Hz,2H),4.04-4.00(m,0.6H),3.85-3.78(m,0.4H),3.63(s,1H),3.60(s,2H),2.90-2.81(m,1H),2.77-2.76(m,2H),2.31-2.07(m,3H),2.05-1.98(m,1H),1.90-1.69(m,3H),1.66-1.52(m,1H),1.28-1.23(m,9H)。

The stereoisomeric mixture of (trans) -methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (3-ethoxy-2, 2-dimethyl-3-oxopropyl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester VII-25-7(500mg, 90% purity, 0.695mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μ M20 × 250mm, mobile phase: Hex: EtOH: DEA ═ 80:20:0.2 at 10 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound VII-25-M as a yellow solid (200mg, 90% pure, 40% yield, 100% stereopure) and VII-25-N (210mg, 90% pure, 42% yield, 100% stereopure).

VII-25-M chiral analysis (column: Chiralpak IE 5 μ M4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2, at 1.0mL/min, temperature: 30 ℃; wavelength: 230nm, R_T＝8.385min)。¹H NMR(400MHz,DMSO-d₆)δ9.60(d,J＝3.6Hz,0.6H),9.06(s,0.4H),8.01(s,1.6H),7.96-7.95(m,0.4H),7.67-7.66(m,1H),7.50-7.43(m,1H),7.24-7.13(m,1H),6.02(s,0.4H),5.93(d,J＝3.6Hz,0.6H),4.06(q,J＝7.2Hz,2H),3.93-3.86(m,0.5H),3.68-3.61(m,0.5H),3.53(s,1.8H),3.52(s,1.2H),2.97-2.89(m,0.5H),2.79-2.72(m,0.5H),2.66(s,2H),2.19-1.45(m,8H),1.20-1.14(m,9H)。

VII-25-N: chiral analysis (column: Chiralpak IE 5 μm 4.6 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＝10.968min)。¹H NMR(400MHz,DMSO-d₆)δ9.60(d,J＝3.2Hz,0.6H),9.06(s,0.4H),8.01(s,1.5H),7.96-7.95(m,0.5H),7.67-7.66(m,1H),7.51-7.43(m,1H),7.26-7.13(m,1H),6.02(s,0.4H),5.93(d,J＝3.6Hz,0.6H),4.06(q,J＝7.2Hz,2H),3.94-3.85(m,0.5H),3.70-3.60(m,0.5H),3.53(s,1.8H),3.52(s,1.2H),3.00-2.89(m,0.5H),2.83-2.72(m,0.5H),2.66(s,2H),2.15-1.46(m,8H),1.20-1.14(m,9H)。

Compound VII-26-8:

(trans) -ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-5-carboxylate (single stereoisomer) intermediates VII-26-5 and VII-26-6:

(trans) -ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-5-carboxylate (mixture of 2 stereoisomers) and (cis) -ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

VII-26-5:¹H NMR(400MHz,DMSO-d₆)δ9.58-9.53(m,0.7H),9.00(s,0.3H),8.02-7.92(m,2H),7.90(d,J＝2.8Hz,1H),7.51-7.44(m,1H),7.24-7.18(m,1H),6.04-6.03(m,0.4H),5.95-5.90(m,0.6H),4.32(q,J＝6.8Hz,2H),4.02-3.96(m,2H),3.94-3.87(m,0.4H),3.72-3.63(m,0.6H),3.15-3.07(m,0.4H),2.98-2.91(m,0.6H),2.23-2.04(m,2H),1.99-1.47(m,6H),1.30(t,J＝6.8Hz,3H),1.10-1.03(m,3H)。

VII-26-6:¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝3.2Hz,0.7H),8.63(s,0.3H),8.01-7.93(m,3H),7.49-7.41(m,1H),7.19-7.16(m,1H),6.04(s,0.3H),5.91(d,J＝3.6Hz,0.7H),4.34(q,J＝7.2Hz,2H),4.01-3.95(m,2H),3.92-3.86(m,0.3H),3.75-3.69(m,0.7H),3.42-3.35(m,0.3H),3.33-3.27(m,0.7H),2.40-2.33(m,2H),1.96-1.75(m,4H),1.70-1.47(m,2H),1.31(t,J＝6.8Hz,3H),1.11-1.05(m,3H)。

The stereoisomeric mixture of (trans) -ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-5-carboxylate VII-26-5(220mg, 95% purity, 0.345mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μm 20 250mm, mobile phase: Hex: EtOH: DEA ═ 70:30:0.3, at 15mL/min, temperature: 30 ℃, wavelength: 230nm) to afford the title compound VII-26-7 as a yellow solid (100mg, obtained from ¹Purity by H NMR 96%, 46% yield, 100% stereopure), VII-26-8(98mg, obtained from¹Purity by H NMR 97%, 45% yield, 98.7% stereopurity).

VII-26-7:LC-MS(ESI)：R_T＝1.98min,C₂₈H₂₇ClF₂N₄O₅Calculated mass of S604.1, M/z found 604.8[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250mm, mobile phase: Hex: EtOH: DEA ═ 70:30:0.2, at 1.0mL/min, temperature: 30 ℃, wavelength: 230nm, R_T＝9.657min)。¹H NMR(400MHz,CD₃OD)δ7.93(d,J＝3.2Hz,0.5H),7.89(d,J＝3.2Hz,0.5H),7.76-7.74(m,2H),7.28-7.19(m,2H),6.15(s,0.6H),6.09(s,0.4H),4.37(q,J＝7.2Hz,2H),4.11-4.02(m,2.6H),3.85-3.78(m,0.4H),3.12-2.93(m,1H),2.36-2.22(m,2H),2.15-1.71(m,6H),1.37(t,J＝6.8Hz,3H),1.17-1.12(m,3H)。

VII-26-8:LC-MS(ESI)：R_T＝1.98min,C₂₈H₂₇ClF₂N₄O₅Calculated mass of S604.1, M/z found 604.8[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250mm, mobile phase: Hex: EtOH: DEA ═ 70:30:0.2, at 1.0mL/min, temperature: 30 ℃ and wavelength: 230nm，R_T＝11.066min)。¹H NMR(400MHz,CD₃OD)δ7.93(d,J＝3.2Hz,0.5H),7.89(d,J＝2.8Hz,0.5H),7.76-7.74(m,2H),7.28-7.19(m,2H),6.15(s,0.6H),6.08(s,0.4H),4.37(q,J＝7.2Hz,2H),4.11-4.02(m,2.5H),3.86-3.77(m,0.5H),3.11-2.92(m,1H),2.36-2.22(m,2H),2.15-1.66(m,6H),1.37(t,J＝7.2Hz,3H),1.17-1.12(m,3H)。

Compound VII-27-R:

(trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (1-ethoxy-2-methyl-1-oxoprop-2-yl) oxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

LC-MS(ESI)：R_T＝2.274min,C₂₉H₂₈ClF₂N₅O₄Calculated mass of S646.2, found M/z 647.1[ M + H ]]⁺。

Compound VII-28-N:

(trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (2-ethoxy-2-oxoethyl) -1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VII-28-R:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (2-ethoxy-2-oxoethyl) -1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

LC-MS(ESI)：R_T＝2.136min,C₂₉H₃₀ClF₂N₅O₄Calculated mass of S617.2, found M/z 618.1[ M + H [ ]]⁺。

The stereoisomeric mixture of VII-28-R (800mg, 1.29mmol) was separated by chiral preparative HPLC (first separation condition: column: Chiralpak IE (5 μ M20 × 250mm), mobile phase: Hex: EtOH: DEA ═ 60:40:0.3 at 11mL/min, temperature: 30 ℃; wavelength: 214 nm; second separation condition: column: Chiralpak IG (5 μ M20 × 250mm), mobile phase: Hex: EtOH: DEA ═ 80:20:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 230nm) to give VII-28-M (184mg, 23% yield, 96.9% stereopurity), VII-28-N (123mg, 15% yield, 99.7% stereopurity), VII-28-P (143mg, 18% yield, 100% stereopurity and VII-120% Q (15 mg, 15% yield), 96.4% stereopure).

VII-28-M chiral analysis (column: Chiralpak IE 5 μ M4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2, at 1mL/min, temperature: 30 ℃; wavelength: 230 nm; R: C ℃; chiral analysis (column: Chiralpak IE 5 μ M4.6:. times.250 mm; mobile phase: Hex: EtOH: DEA:. RTM.: 50: 0.2; temperature _T＝8.072min)。¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝3.6Hz,0.6H),8.93(s,0.4H),8.01-8.00(m,1.6H),7.96(d,J＝3.2Hz,0.4H),7.55(d,J＝5.2Hz,1H),7.51-7.46(m,1H),7.38(s,1H),7.23-7.18(m,1H),6.04(s,0.4H),5.93(d,J＝2.8Hz,0.6H),4.98(d,J＝2.0Hz,2H),4.15-4.10(m,2H),4.01-3.94(m,2H),3.89-3.85(m,0.4H),3.70-3.65(m,0.6H),2.67-2.64(m,0.4H),2.44-2.39(m,0.6H),2.06-1.81(m,5.4H),1.67-1.64(m,0.6H),1.45-1.34(m,2H),1.23-1.19(m,3H),1.10-1.05(m,3H)。

VII-28-N chiral analysis (column: Chiralpak IE 5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.2, at 1mL/min, temperature: 30 ℃; wavelength: 230 nm; R: 1 ℃; chiral analysis: chromatography; chiral chromatography_T＝10.392min)。¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝3.6Hz,0.6H),8.93(s,0.4H),8.01-7.99(m,1.6H),7.96(d,J＝3.2Hz,0.4H),7.55(d,J＝5.2Hz,1H),7.50-7.43(m,1H),7.38(s,1H),7.23-7.18(m,1H),6.04(s,0.4H),5.93(d,J＝3.6Hz,0.6H),4.98(d,J＝2.0Hz,2H),4.14(q,J＝7.2Hz,2H),4.01-3.94(m,2H),3.89-3.80(m,0.4H),3.70-3.62(m,0.6H),2.67-2.61(m,0.5H),2.47-2.40(m,0.5H),2.06-1.80(m,5.4H),1.68-1.63(m,0.6H),1.44-1.34(m,2H),1.21(t,J＝7.2Hz,3H),1.10-1.03(m,3H)。

VII-28-P chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2, at 1mL/min, temperature: 30 ℃; wavelength: 254 nm; R: X; C ℃; chiral analysis: chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 80:20:0.2_T＝10.892min)。¹H NMR(400MHz,DMSO-d₆)δ9.50(br s,0.7H),8.37(s,0.3H),7.99-7.94(m,2H),7.70(s,0.3H),7.66(s,0.7H),7.51(s,1H),7.49-7.41(m,1H),7.21-7.17(m,1H),6.03(s,0.3H),5.91(s,0.7H),5.04(s,2H),4.14(q,J＝7.2Hz,2H),4.01-3.94(m,2H),3.87-3.81(m,0.3H),3.76-3.70(m,0.7H),3.07-3.03(m,0.3H),3.01-2.97(m,0.7H),2.10-1.59(m,7.4H),1.43-1.39(m,0.6H),1.22-1.17(m,3H),1.09-1.06(m,3H)。

VII-28-Q chiral analysis (column: Chiralpak IG 5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2, at 1 mL/min; temperature: 30 ℃; wavelength: 254 nm; RT ═ 13.657 min).¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝3.2Hz,0.7H),8.37(s,0.3H),7.99-7.94(m,2H),7.70(s,0.3H),7.65(s,0.7H),7.50(s,1H),7.49-7.40(m,1H),7.20-7.16(m,1H),6.03(s,0.3H),5.91(d,J＝3.6Hz,0.7H),5.04(s,1.4H),5.03(s,0.6H),4.14(q,J＝7.2Hz,2H),4.00-3.97(m,2H),3.88-3.82(m,0.3H),3.75-3.69(m,0.7H),3.07-3.03(m,0.3H),3.01-2.97(m,0.7H),2.09-1.58(m,7.3H),1.42-1.39(m,0.7H),1.21-1.17(m,3H),1.10-1.06(m,3H)。

Compound VII-29-P:

(trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VII-29-5:

methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

LC-MS(ESI)：R_T＝1.87min，C₂₈H₂₉ClFN₅O₄Calculated mass of S585.2, found M/z 585.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.44(d,J＝3.2Hz,0.6H),8.93(s,0.2H),8.38(s,0.2H),8.01-7.95(m,2H),7.69(s,0.2H),7.63(s,0.5H),7.54-7.53(m,0.3H),7.45-7.31(m,3H),7.24-7.16(m,1H),6.02-6.01(m,0.3H),5.92-5.89(m,0.7H),4.36-4.26(m,2H),3.92-3.66(m,1H),3.59(d,J＝7.6Hz,3H),3.53(s,3H),3.02-2.96(m,1H),2.90-2.84(m,2H),2.12-1.54(m,7H),1.39-1.36(m,1H)。

A methyl groupA stereoisomeric mixture of 4- (2-chloro-4-fluorophenyl) -6- (4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester VII-29-5(350mg, 0.579mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μm 20 250 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.3, at 15 mL/min; temperature: 30 ℃; wavelength: 230nm) to give the title compound group 1(200mg, 29% yield), VII-29-P (40mg, obtained from VII-29-P as a yellow solid ¹Purity by H NMR was 95%, 11% yield, 99.7% stereopure) and VII-29-Q (40mg, purity by NMR was 95%, 11% yield, 99.6% stereopure). Group 1(200mg, 0.34mmol) was isolated by chiral preparative HPLC (column: Chiralpak OJ-H5 μ M50 × 250 mm; mobile phase: MeOH: DEA ═ 100:0.1 at 60 mL/min; temperature: 35 ℃; wavelength: 254nm) to provide the title compound VII-29-M (80mg, 99% purity, 42% yield, 100% stereopurity) and VII-29-N (80mg, 99% purity, 42% yield, 99.9% stereopurity).

VII-29-M:LC-MS(ESI)：R_T＝1.974min，C₂₈H₂₉ClFN₅O₄Calculated mass of S585.2, found M/z 586.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak OJ-H5 μm 4.6 x 250 mm; mobile phase: MeOH: DEA ═ 100:0.2 at 1 mL/min; temperature: 30 ℃ C.; wavelength: 230nm, R: M; (R: g/min); chiral analysis)_T＝5.320min)。¹H NMR(400MHz,CDCl₃)δ8.07(s,0.5H),7.81(d,J＝3.2Hz,0.4H),7.78(d,J＝3.2Hz,0.6H),7.56(s,0.6H),7.49(d,J＝3.2Hz,0.4H),7.47-7.45(m,1H),7.41(d,J＝3.6Hz,0.5H),7.37(s,1H),7.31-7.27(m,0.7H),7.24(s,0.3H),7.14-7.10(m,1H),6.95-6.86(m,1H),6.17(s,0.6H),6.04(d,J＝2.8Hz,0.4H),4.47-4.42(m,2H),4.05-3.99(m,0.6H),3.92-3.85(m,0.4H),3.67(s,3H),3.61-3.59(m,3H),3.11(s,0.6H),3.05(s,0.4H),2.98-2.92(m,2H),2.19-2.14(m,1.6H),2.06-1.80(m,3.4H),1.76-1.69(m,2H),1.60-1.48(m,1H)。

VII-29-N:LC-MS(ESI)：R_T＝1.973min，C₂₈H₂₉ClFN₅O₄Calculated mass of S585.2, found M/z 586.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak OJ-H5 μm 4.6 x 250 mm; mobile phase: MeOH: DEA ═ 100:0.2, to1 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝6.864min)。¹H NMR(400MHz,CDCl₃)δ8.07(s,0.5H),7.81(d,J＝2.8Hz,0.4H),7.78(d,J＝2.8Hz,0.6H),7.56(s,0.6H),7.49(d,J＝2.8Hz,0.4H),7.47-7.45(m,1H),7.41(d,J＝3.2Hz,0.5H),7.37(s,1H),7.31-7.27(m,0.7H),7.24(s,0.3H),7.14-7.10(m,1H),6.95-6.86(m,1H),6.17(s,0.6H),6.04(d,J＝2.8Hz,0.4H),4.47-4.43(m,2H),4.06-3.98(m,0.6H),3.92-3.85(m,0.4H),3.67(s,3H),3.61-3.59(m,3H),3.11(s,0.6H),3.05(s,0.4H),2.97-2.92(m,2H),2.19-2.12(m,1.6H),2.03-1.84(m,3.4H),1.76-1.67(m,2H),1.61-1.48(m,1H)。

VII-29-P:LC-MS(ESI)：R_T＝1.83min，C₂₈H₂₉ClFN₅O₄Calculated mass of S585.2, found M/z 585.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝9.064min)。¹H NMR(400MHz,DMSO-d₆)δ9.44(d,J＝3.2Hz,0.6H),8.92(s,0.4H),8.01-7.98(m,1.6H),7.95(d,J＝3.2Hz,0.4H),7.53(d,J＝5.6Hz,1H),7.45-7.41(m,1H),7.38-7.33(m,2H),7.24-7.19(m,1H),6.02(s,0.4H),5.91(d,J＝3.2Hz,0.6H),4.30-4.26(m,2H),3.93-3.84(m,0.4H),3.69-3.60(m,3.6H),3.52(d,J＝4.8Hz,3H),2.87-2.83(m,2H),2.68-2.55(m,0.6H),2.46-2.43(m,0.4H),2.05-1.74(m,5.4H),1.65-1.61(m,0.6H),1.44-1.30(m,2H)。

VII-29-Q:LC-MS(ESI)：R_T＝1.83min，C₂₈H₂₉ClFN₅O₄Calculated mass of S585.2, found M/z 585.9[ M + H ] ]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R))_T＝12.766min)。¹H NMR(400MHz,DMSO-d₆)δ9.44(d,J＝3.2Hz,0.6H),8.92(s,0.4H),8.01-7.98(m,1.6H),7.95(d,J＝3.2Hz,0.4H),7.53(d,J＝5.6Hz,1H),7.45-7.41(m,1H),7.38-7.33(m,2H),7.24-7.19(m,1H),6.02(s,0.4H),5.91(d,J＝3.2Hz,0.6H),4.30-4.26(m,2H),3.93-3.84(m,0.4H),3.69-3.60(m,3.6H),3.52(d,J＝4.8Hz,3H),2.87-2.83(m,2H),2.68-2.55(m,0.6H),2.46-2.43(m,0.4H),2.05-1.74(m,5.4H),1.65-1.61(m,0.6H),1.44-1.30(m,2H)。

Compound VII-30-10:

(trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (4-methoxy-2-methyl-4-oxobutan-2-yl) -1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediates VII-30-5 and VII-30-6:

(cis) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (4-methoxy-2-methyl-4-oxobutan-2-yl) -1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers) and (trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (4-methoxy-2-methyl-4-oxobutan-2-yl) -1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) cyclohexyl) -2- (thiazole-4-methyl-4-oxobutan-2-yl) ethyl 4- (1-methoxy-2-methyl-4-oxo-butan-2-yl) cyclohexyl) -yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

VII-30-5:LC-MS(ESI)：R_T＝2.327min,C₃₁H₃₄ClF₂N₅O₄Calculated mass of S645.2, found M/z 646.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.08(s,0.7H),7.81(d,J＝3.2Hz,0.3H),7.74(d,J＝3.2Hz,0.7H),7.56(s,0.3H),7.49-7.46(m,2H),7.41(d,J＝3.2Hz,0.7H),7.30-7.28(s,0.3H),7.10-6.97(m,2H),6.18(s,0.7H),6.06(d,J＝2.8Hz,0.3H),4.11-3.97(m,2.8H),3.91-3.83(m,0.2H),3.58(s,0.6H),3.57(s,2.4H),3.15-3.10(m,0.8H),3.07-3.02(m,0.2H),2.96(s,1.6H),2.93(s,0.4H),2.22-2.09(m,2H),2.04-1.92(m,2.7H),1.89-1.81(m,1.3H),1.78(s,4.4H),1.75(s,1.6H),1.74-1.65(m,2H),1.17-1.13(m,3H)。

VII-30-6:LC-MS(ESI)：R_T＝2.167min,C₃₁H₃₄ClF₂N₅O₄Calculated mass of S645.2, found M/z 646.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.19(s,0.8H),7.83(d,J＝3.6Hz,1H),7.52-7.49(m,0.2H),7.46(d,J＝3.2Hz,0.8H),7.43-7.41(m,1H),7.33(s,1.2H),7.13-6.99(m,2H),6.21(s,0.7H),6.08(d,J＝2.0Hz,0.3H),4.12-3.95(m,2.8H),3.83-3.76(m,0.2H),3.58(s,3H),2.89(s,2H),2.66-2.55(m,1H),2.18-1.92(m,4H),1.86-1.75(m,0.7H),1.71-1.68(m,6.3H),1.65-1.63(m,0.4H),1.61-1.46(m,2.6H),1.14(t,J＝6.8Hz,3H)。

The stereoisomeric mixture of (trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (4-methoxy-2-methyl-4-oxobutan-2-yl) -1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-30-6(265mg, 90% purity, 0.369mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IC 5 μm 20: 250 mm; mobile phase: Hex: EtOH: DEA 80:20:0.1, at 60 mL/min; temperature: 35 ℃; wavelength: 214nm) to give the title compound VII-30-9(110mg, is obtained from ¹Purity by H NMR 95%, 44% yield, 99.9% stereopurity) and the title compound VII-30-10(80mg, obtained from¹Purity by H NMR 95%, 32% yield, 99.9% stereopure).

VII-30-9：LC-MS(ESI)：R_T＝2.156min,C₃₁H₃₄ClF₂N₅O₄Calculated mass of S645.2, found M/z 646.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2 at 1 mL/min; wavelength: 230nm, R_T＝13.343min)。¹H NMR(400MHz,CDCl₃)δ8.20(s,0.8H),7.83(d,J＝2.8Hz,1H),7.51(d,J＝3.2Hz,0.3H),7.46(d,J＝2.8Hz,0.7H),7.44(s,0.3H),7.41(s,0.7H),7.33-7.32(m,1.2H),7.13-6.98(m,2H),6.21(s,0.7H),6.08(d,J＝2.0Hz,0.3H),4.11-3.98(m,2.8H),3.83-3.72(m,0.2H),3.58(s,3H),2.90(s,2H),2.67-2.55(m,1H),2.18-2.11(m,2.5H),2.05-1.92(m,2.5H),1.87-1.78(m,1H),1.72(s,6H),1.56-1.47(m,2H),1.16-1.13(m,3H)。

VII-30-10：LC-MS(ESI)：R_T＝2.157min,C₃₁H₃₄ClF₂N₅O₄Calculated mass of S645.2, found M/z 646.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2 at 1 mL/min; wavelength: 230nm, R_T＝15.752min)。¹H NMR(400MHz,CDCl₃)δ8.20(s,0.8H),7.83(d,J＝3.2Hz,1H),7.51(d,J＝2.8Hz,0.3H),7.46(d,J＝3.2Hz,0.7H),7.43(s,0.3H),7.41(s,0.7H),7.33-7.31(m,1.2H),7.13-6.98(m,2H),6.21(s,0.7H),6.08(d,J＝2.0Hz,0.3H),4.13-3.95(m,2.8H),3.84-3.71(m,0.2H),3.58(s,3H),2.89(s,2H),2.66-2.54(m,1H),2.18-2.09(m,2.5H),2.05-1.91(m,2H),1.88-1.75(m,1.5H),1.72(s,1.8H),1.71(s,4.2H),1.61-1.56(m,2H),1.16-1.12(m,3H)。

Compound VII-31:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (4-methoxy-4-oxobutan-2-yl) -1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 8 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

¹H NMR(400MHz,DMSO-d₆)δ9.55-9.53(m,0.5H),8.93(s,0.2H),8.28-8.27(m,0.3H),8.01-7.99(m,1.3H),7.96-7.94(m,0.4H),7.91-7.90(m,0.3H),7.74-7.73(m,0.2H),7.66(s,0.4H),7.59-7.58(m,0.4H),7.49-7.42(m,1.6H),7.32(s,0.4H),7.24-7.16(m,1H),6.04-6.02(m,0.4H),5.93-5.90(m,0.6H),4.78-4.64(m,1H),4.06-3.96(m,2H),3.89-3.82(m,0.4H),3.75-3.65(m,0.6H),3.56-3.53(m,3H),3.02-2.76(m,3H),2.13-1.54(m,7H),1.48-1.32(m,4H),1.10-1.03(m,3H)。

Compound VII-32-N:

(trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Compound VII-32:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (3-methoxy-3-oxopropyl) -1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

LC-MS(ESI)：R_T＝2.803min,C₂₉H₃₀ClF₂N₅O₄Calculated mass of S617.2, found M/z 618.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.19(s,0.3H),8.06(s,0.3H),7.83-7.79(m,1H),7.56-7.36(m,2.5H),7.34-7.26(m,0.4H),7.24(s,0.5H),7.13-6.97(m,2H),6.21(s,0.3H),6.19(s,0.4H),6.08-6.06(m,0.3H),4.44(q,J＝7.2Hz,1H),4.39(q,J＝6.8Hz,1H),4.10-3.99(m,3H),3.70(s,1H),3.67(s,2H),3.11(br s,0.4H),3.04(br s,0.2H),2.96(t,J＝6.4Hz,1H),2.90(t,J＝6.8Hz,1H),2.64-2.55(m,0.4H),2.17-2.10(m,2H),2.03-1.84(m,3H),1.77-1.65(m,2H),1.57-1.46(m,1H),1.16-1.12(m,3H)。

A stereoisomeric mixture of VII-32(770mg, 1.25mmol) was separated by chiral preparative HPLC (first separation conditions: column: Chiralpak IA 5 μm 20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 25 mL/min; temperature: 30 ℃; wavelength: 214nm) to afford VII-32-F (170mg, 22% yield) and VII-32-E (280mg, 36% yield) as yellow solids.

A stereoisomeric mixture of VII-32-F (170mg, 0.28mmol) was separated by chiral preparative HPLC (second separation conditions: column: Chiralpak IE 5 μ M20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 40:60:0.2 at 10 mL/min; temperature: 30 ℃; wavelength: 230nm) to afford VII-32-M (60mg, 35% yield, 100% stereopurity) and VII-32-N (29mg, 29% yield, 100% stereopurity);

compound VII-32-F: LC-MS (ESI): r_T＝2.760min,C₂₉H₃₀ClF₂N₅O₄Calculated mass of S617.2, found M/z 618.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.7H),7.82(d,J＝3.2Hz,1H),7.50(d,J＝2.8Hz,0.3H),7.45(d,J＝3.2Hz,0.7H),7.40(s,0.3H),7.37(s,0.7H),7.32(s,0.3H),7.24(s,1H),7.14-7.09(m,1H),7.07-6.99(m,1H),6.21(s,0.7H),6.08(d,J＝2.4Hz,0.3H),4.38(t,J＝6.4Hz,2H),4.11-3.97(m,2.8H),3.83-3.76(m,0.2H),3.70(s,3H),2.90(t,J＝6.4Hz,2H),2.64-2.55(m,1H),2.17-2.01(m,4H),1.92-1.65(m,1.5H),1.59-1.44(m,2.5H),1.16-1.12(m,3H)。

Compound VII-32-E: LC-MS (ESI): r_T＝4.450min,C₂₉H₃₀ClF₂N₅O₄Calculated mass of S617.2, found M/z 617.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.06(s,0.7H),7.81(d,J＝2.8Hz,0.3H),7.79(d,J＝3.2Hz,0.7H),7.56(s,0.3H),7.50(d,J＝3.2Hz,0.3H),7.47(s,0.7H),7.45(s,0.3H),7.42(d,J＝3.2Hz,0.7H),7.36(s,0.7H),7.28(s,0.3H),7.12-6.97(m,1H),6.19(s,0.7H),6.06(d,J＝2.4Hz,0.3H),4.44(q,J＝6.8Hz,2H),4.11-3.93(m,2.7H),3.90-3.85(m,0.3H),3.67(s,3H),3.11(s,0.7H),3.04(s,0.3H),2.94(q,J＝6.4Hz,2H),2.17-2.12(m,1.5H),2.06-1.83(m,3.5H),1.76-1.61(m,2.5H),1.56-1.48(m,0.5H),1.16-1.12(m,3H)。

Compound VII-32-M: LC-MS (ESI): r_T＝3.872min,C₂₉H₃₀ClF₂N₅O₄Calculated mass of S617.2, found M/z 618.1[ M + H [ ] ]⁺。¹H NMR(400MHz,CDCl₃)δ8.22(s,0.7H),7.87-7.86(m,1H),7.54(d,J＝3.2Hz,0.3H),7.49(d,J＝3.2Hz,0.7H),7.44(s,0.3H),7.42(s,0.7H),7.35(s,0.3H),7.28(s,1H),7.18-7.13(m,1H),7.11-7.03(m,1H),6.25(s,0.7H),6.12(d,J＝3.2Hz,0.3H),4.42(t,J＝6.8Hz,2H),4.15-4.02(m,2.8H),3.88-3.79(m,0.2H),3.74(s,3H),2.94(t,J＝6.8Hz,2H),2.68-2.59(m,1H),2.21-2.02(m,4H),1.96-1.65(m,2H),1.61-1.50(m,2H),1.20-1.16(m,3H)。

Compound VII-32-N: LC-MS (ESI): r_T＝3.876min,C₂₉H₃₀ClF₂N₅O₄Calculated mass of S617.2, found M/z 618.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.22(s,0.7H),7.87-7.86(m,1H),7.54(d,J＝3.2Hz,0.3H),7.49(d,J＝2.8Hz,0.7H),7.44(s,0.3H),7.42(s,0.7H),7.36(s,0.3H),7.28(s,1H),7.18-7.13(m,1H),7.11-7.03(m,1H),6.25(s,0.7H),6.12(d,J＝2.8Hz,0.3H),4.42(t,J＝6.4Hz,2H),4.15-4.02(m,2.8H),3.87-3.80(m,0.2H),3.74(s,3H),2.94(t,J＝6.4Hz,2H),2.68-2.58(m,1H),2.21-2.02(m,4H),1.96-1.66(m,2H),1.60-1.47(m,2H),1.20-1.16(m,3H)。

Compound VII-33-10:

(trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VII-33-8:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B. LC-MS (ESI): r_T＝2.998min,C₃₀H₃₂ClF₂N₅O₄Calculated mass of S631.2, found M/z 632.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.21-8.20(m,0.7H),7.84-7.83(m,1H),7.64(s,0.1H),7.57-7.55(m,0.2H),7.51(d,J＝3.2Hz,0.1H),7.47-7.45(m,1H),7.39-7.34(m,0.3H),7.14(s,0.6H),7.12-6.99(m,2H),6.22-6.21(m,0.7H),6.08(d,J＝2.4Hz,0.3H),4.39(t,J＝7.2Hz,1H),4.31(t,J＝6.8Hz,1H),4.15-3.90(m,3H),3.69(s,1.5H),3.67(s,1.5H),3.06-3.03(m,0.5H),2.99-2.92(m,1H),2.89-2.85(m,1H),2.53-2.47(m,0.5H),2.26(s,0.4H),2.24(s,2.6H),2.19-1.42(m,8H),1.17-1.13(m,3H)。

Intermediates VII-33-9, VII-33-10 and VII-33-11:

(cis) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers), (trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer) and (trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The stereoisomeric mixture of ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (1- (3-methoxy-3-oxopropyl) -3-methyl-1H-pyrazol-4-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-33-8(1.26g, 90% purity, 1.79mmol) was separated by chiral preparative HPLC (conditions: column: Chiralpak IG 5 μm 20 × 250nm, mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 230nm) to provide the title compound VII-33-9(450mg, 36% yield, 90% purity, 97.5% stereopure), VII-33-10 as a yellow solid (220mg, 17% yield, 90% purity, 95.1% stereopure), and VII-33-11 as a yellow solid (210mg, 17% yield, 90% purity, 99.2% stereopure).

VII-33-9：LC-MS(ESI)：R_T＝2.866min,C₃₀H₃₂ClF₂N₅O₄Calculated mass of S631.2, found M/z 632.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.20(s,0.6H),7.84(d,J＝3.2Hz,1H),7.64(s,0.5H),7.56(d,J＝2.8Hz,0.5H),7.46-7.44(m,1H),7.32(s,0.4H),7.13-6.99(m,2H),6.21(s,0.6H),6.08(d,J＝2.8Hz,0.4H),4.39(t,J＝7.2Hz,2H),4.15-3.88(m,3H),3.67(s,3H),3.05-2.99(m,0.7H),2.97-2.92(m,2.3H),2.24(s,3H),2.05-1.70(m,7.4H),1.60-1.41(m,0.6H),1.15(t,J＝7.2Hz,3H)。

VII-33-10：LC-MS(ESI)：R_T＝2.823min,C₃₀H₃₂ClF₂N₅O₄Calculated mass of S631.2, found M/z 632.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)8.19(s,0.8H),7.84(d,J＝3.2Hz,1H),7.51(d,J＝2.8Hz,0.2H),7.46(d,J＝3.2Hz,0.8H),7.33(s,0.2H),7.14-7.10(m,2H),7.07-6.99(m,1H),6.21(s,0.8H),6.08(d,J＝2.4Hz,0.2H),4.31(t,J＝6.4Hz,2H),4.12-4.05(m,2.8H),3.98-3.85(m,0.2H),3.69(s,3H),2.87(d,J＝6.8Hz,2H),2.53-2.47(m,1H),2.26(s,0.7H),2.24(s,2.3H),2.14-1.98(m,4H),1.75-1.41(m,4H),1.14(t,J＝7.2Hz,3H)。

VII-33-11：LC-MS(ESI)：R_T＝2.819min,C₃₀H₃₂ClF₂N₅O₄Calculated mass of S631.2, found M/z 632.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)8.20(s,0.8H),7.84(d,J＝2.8Hz,1H),7.51(d,J＝2.4Hz,0.2H),7.46(d,J＝3.2Hz,0.8H),7.32(s,0.2H),7.14(s,1H),7.12-7.10(m,1H),7.07-6.99(m,1H),6.22(s,0.8H),6.08(s,0.2H),4.31(t,J＝6.8Hz,2H),4.15-3.98(m,2.8H),3.85-3.77(m,0.2H),3.69(s,3H),2.87(d,J＝6.4Hz,2H),2.53-2.47(m,1H),2.26(s,0.7H),2.24(s,2.3H),2.14-1.95(m,4H),1.75-1.42(m,4H),1.14(t,J＝7.2Hz,3H)。

Compound VII-34:

ethyl 6- (4- (1- (3- (tert-butoxycarbonyl) cyclobutyl) -1H-pyrazol-4-yl) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

¹H NMR(300MHz,CDCl₃)δ8.19(br s,0.2H),8.08(br s,0.3H),7.84-7.82(m,0.6H),7.78-7.76(m,0.4H),7.57-7.33(m,3.5H),7.10-6.98(m,2H),6.21-6.19(m,0.7H),6.09-6.05(m,0.3H),5.06-4.93(m,0.4H),4.76-4.64(m,0.6H),4.11-4.02(m,3H),3.15-3.04(m,1H),2.88-2.73(m,4H),2.14-1.89(m,5H),1.78-1.72(m,2H),1.52-1.46(m,11H),1.17-1.12(m,3H)。

Compound VII-35-P:

(trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (3- (methoxycarbonyl) -1-methyl-1H-pyrazol-5-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediates VII-35-X and VII-35-Y:

(cis) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (3- (methoxycarbonyl) -1-methyl-1H-pyrazol-5-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers) and (trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (3- (methoxycarbonyl) -1-methyl-1H-pyrazol-5-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

VII-35-X:LC-MS(ESI)：R_T＝1.81min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z found 604.2[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)9.60(d,J＝3.6Hz,0.8H),8.74(s,0.2H),8.06-7.95(m,2H),7.50-7.43(m,1H),7.24-7.20(m,1H),6.92(s,1H),6.05(s,0.2H),5.93(d,J＝3.2Hz,0.8H),4.01-3.96(m,2H),3.88(s,3H),3.80(s,3H),3.78-3.74(m,1H),3.24-3.22(m,1H),2.14-2.11(m,1H),2.00-1.92(m,3H),1.85-1.76(m,2H),1.67-1.62(m,1H),1.52-1.48(m,1H),1.10-1.05(m,3H)。

VII-35-Y:LC-MS(ESI)：R_T＝1.79min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z found 604.2[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)9.56(d,J＝3.6Hz,0.6H),8.92(s,0.4H),8.01-7.96(m,2H),7.51-7.43(m,1H),7.23-7.20(m,1H),6.60-6.58(m,1H),6.04(s,0.4H),5.94(d,J＝3.6Hz,0.6H),4.01-3.95(m,2H),3.89(s,3H),3.77(s,3H),3.72-3.66(m,1H),2.97-2.91(m,0.5H),2.81-2.75(m,0.5H),2.04-1.85(m,5H),1.82-1.79(m,0.5H),1.71-1.67(m,0.5H),1.52-1.43(m,2H),1.11-1.04(m,3H)。

The stereoisomeric mixture of ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- ((trans) -4- (3- (methoxycarbonyl) -1-methyl-1H-pyrazol-5-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-35-Y (180mg, 90% purity, 0.268mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak ID 5 μm 30: 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.3 at 13 mL/min; temperature: 30 ℃; wavelength: 230nm) to afford VII-35-P (63mg, obtained from VII-35-P as a yellow solid (63mg, obtained from ¹HNMR 95% pure, 37% yield, 100% ee) and VII-35-Q (78mg, obtained from¹Purity of HNMR 97%, 47% yield, 97% ee).

VII-35-P chiral HPLC (column: Chiralpak ID 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0mL/min, temperature: 30 ℃; wavelength: 230nm, R: 1.0mL/min_T＝8.464min)。¹H NMR(300MHz,CDCl₃)8.15(s,0.5H),7.85-7.82(m,1H),7.52-7.46(m,1H),7.34(s,0.5H),7.10-7.01(m,2H),6.62(s,1H),6.21(s,0.6H),6.09(s,0.4H),4.16-4.07(m,2H),4.05-4.00(m,1H),3.94-3.92(m,6H),2.73-2.65(m,1H),2.22-1.99(m,5H),1.91-1.79(m,1H),1.72-1.64(m,2H),1.16-1.11(m,3H)。

VII-35-Q:LC-MS(ESI)：R_T＝1.79min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z found 604.1[ M + H [)]⁺. Chiral HPLC (column): chiralpak ID 5 μm 4.6 × 250 mm; mobile phase: hex EtOH DEA 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝10.400min)。¹H NMR(300MHz,CDCl₃)8.15(s,0.5H),7.85-7.82(m,1H),7.52-7.46(m,1H),7.34(s,0.5H),7.12-7.01(m,2H),6.62(s,1H),6.21(s,0.6H),6.08(s,0.4H),4.13-4.09(m,1H),4.06-4.00(m,2H),3.94-3.92(m,6H),2.74-2.67(m,1H),2.19-2.03(m,5H),1.87-1.80(m,1H),1.73-1.66(m,2H),1.17-1.11(m,3H)。

Compound VII-36-N:

(trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (5- (methoxycarbonyl) -1-methyl-1H-pyrazol-3-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VII-36-R:

(trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (5- (methoxycarbonyl) -1-methyl-1H-pyrazol-3-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

LC-MS(ESI)：R_T＝1.95min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z Mass found 604.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.53(br s,0.5H),8.97(br s,0.5H),8.01-7.98(m,2H),7.50-7.44(m,1H),7.22-7.19(m,1H),6.74(s,1H),5.96(br s,1H),4.03(s,3H),3.98(q,J＝7.2Hz,2H),3.82(s,3H),3.69-3.63(m,0.6H),3.31(s,0.4H),2.77-2.60(m,1H),2.08-2.05(m,2H),1.92-1.85(m,2H),1.80-1.72(m,2H),1.55-1.49(m,2H),1.07(t,J＝7.2Hz,3H)。

A stereoisomeric mixture of VII-36-R (100mg, 0.166mg) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μ M20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 12 mL/min; temperature: 30 ℃; wavelength: 230nm) to give compounds VII-36-M (30mg, 30% yield) and VII-36-N (30mg, 30% yield) as yellow solids.

VII-36-M：¹H NMR(400MHz,DMSO-d₆)δ9.53(br s,0.5H),8.97(br s,0.5H),8.01-7.98(m,2H),7.50-7。44(m,1H),7.22-7.19(m,1H),6.74(s,1H),5.96(br s,1H),4.03(s,3H),3.98(q,J＝7.2Hz,2H),3.82(s,3H),3.69-3.63(m,0.6H),3.31(s,0.4H),2.77-2.60(m,1H),2.08-2.05(m,2H),1.93-1.85(m,2H),1.80-1.72(m,2H),1.55-1.45(m,2H),1.07(t,J＝7.2Hz,3H)。

VII-36-N：¹H NMR(400MHz,DMSO-d₆)δ9.53(br s,0.5H),8.97(br s,0.5H),8.01-7.98(m,2H),7.50-7。44(m,1H),7.22-7.19(m,1H),6.74(s,1H),5.96(br s,1H),4.03(s,3H),3.98(q,J＝7.2Hz,2H),3.82(s,3H),3.69-3.63(m,0.6H),3.31(s,0.4H),2.77-2.60(m,1H),2.08-2.05(m,2H),1.93-1.85(m,2H),1.80-1.72(m,2H),1.55-1.45(m,2H),1.07(t,J＝7.2Hz,3H)。

Compound VII-37-4C:

(trans) -Ethyl 6- (4- (1- (3- (tert-butoxy) -2, 2-dimethyl-3-oxopropyl) -1H-pyrazol-3-yl) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VII-37:

ethyl 6- (4- (1- (3- (tert-butoxy) -2, 2-dimethyl-3-oxopropyl) -1H-pyrazol-3-yl) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

LC-MS(ESI)：R_T＝1.88and 1.91min,C₃₄H₄₀ClF₂N₅O₄Calculated mass of S687.2, found M/z 688.0[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.94-7.93(m,0.3H),7.90-7.85(m,0.7H),7.76-7.72(m,1H),7.54-7.53(m,0.8H),7.47(s,0.3H),7.41(s,0.3H),7.39-7.36(m,0.6H),7.24-7.18(m,2H),6.15-6.13(m,0.6H),6.08-6.06(m,0.4H),4.29-4.27(m,1H),4.22(s,1H),4.08-3.99(m,2.8H),3.87-3.79(m,0.2H),3.12-3.04(m,0.6H),2.69-2.57(m,0.4H),2.26-1.54(m,8H),1.47(s,4H),1.41(s,5H),1.17-1.12(m,9H)。

Ethyl 6- (4- (1- (3- (tert-butoxy) -2, 2-dimethyl-3-oxopropyl) -1H-pyrazoleA stereoisomeric mixture of-3-yl) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-37(290mg, 90% purity, 0.379mmol) was purified by chiral preparative HPLC (first separation conditions: column: chiralpak IE 5 μm 20 × 250 mm; mobile phase: CO 2₂EtOH, DEA 70:30:0.3 at 50 g/min; column temperature: 30 ℃; wavelength: 230 nm; back pressure: 100 bar; second separation conditions: column: chiralpak IE 5 μm 20 × 250 mm; mobile phase: CO 2 ₂EtOH, DEA 70:30:0.3 at 50 g/min; column temperature: 30 ℃; wavelength: 214 nm; back pressure: 100 bar; third separation conditions: column: chiralpak IA 5 μm 20 × 250 mm; mobile phase: CO 2₂EtOH, DEA 70:30:0.3 at 45 g/min; column temperature: 30 ℃; wavelength: 214 nm; back pressure: 100 bar) to provide VII-37-4A (55mg, obtained from¹Purity by H NMR 90%, 19% yield, 100% stereopure), VII-37-4B (68mg, obtained from¹Purity by H NMR 90%, 23% yield, 97.1% stereopure), VII-37-4C (36mg, obtained from¹Purity by H NMR 90%, 12% yield, 100% stereopure) and VII-37-4D (45mg, obtained from¹Purity by H NMR 90%, 16% yield, 93.3% stereopure).

VII-37-4A：LC-MS(ESI)：R_T＝1.93min,C₃₄H₄₀ClF₂N₅O₄Calculated mass of S687.2, found M/z 687.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: CO)₂EtOH, DEA 70:30:0.2 at 3.0 g/min; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100 bar, R_T＝4.05min)。¹H NMR(400MHz,CD₃OD)δ7.88(d,J＝3.2Hz,0.4H),7.86(d,J＝3.2Hz,0.6H),7.75-7.73(m,1H),7.55-7.53(m,1.4H),7.47(s,0.6H),7.24-7.16(m,2H),6.13(s,0.6H),6.06(s,0.4H),4.29-4.27(m,2H),4.08-4.01(m,2.6H),3.88-3.81(m,0.4H),3.15-3.09(m,0.6H),3.07-3.02(m,0.4H),2.26-1.65(m,7.5H),1.50-1.43(m,0.5H),1.41(s,9H),1.17-1.12(m,9H)。

VII-37-4B：LC-MS(ESI)：R_T＝1.92min,C₃₄H₄₀ClF₂N₅O₄Calculated mass of S687.2, found M/z 687.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: CO)₂EtOH, DEA 70:30:0.2 at 3.0 g/min; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100 bar, R _T＝4.77min)。¹H NMR(400MHz,CD₃OD)δ7.88(d,J＝3.2Hz,0.4H),7.86(d,J＝2.8Hz,0.6H),7.75-7.73(m,1H),7.55-7.53(m,1.4H),7.47(s,0.6H),7.24-7.15(m,2H),6.13(s,0.6H),6.06(s,0.4H),4.29-4.27(m,2H),4.08-4.00(m,2.6H),3.89-3.81(m,0.4H),3.15-3.09(m,0.6H),3.06-3.01(m,0.4H),2.25-1.65(m,7.5H),1.50-1.44(m,0.5H),1.41(s,9H),1.17-1.12(m,9H)。

VII-37-4C：LC-MS(ESI)：R_T＝1.88min,C₃₄H₄₀ClF₂N₅O₄Calculated mass of S687.2, found M/z 687.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: CO)₂EtOH, DEA 80:20:0.2 at 3.0 g/min; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100 bar, R_T＝5.03min)。¹H NMR(400MHz,CD₃OD)δ7.94(d,J＝3.2Hz,0.7H),7.90(d,J＝3.2Hz,0.3H),7.76(d,J＝2.8Hz,1H),7.42(s,0.7H),7.39-7.36(m,1.3H),7.24-7.22(m,2H),6.15(s,0.7H),6.08(s,0.3H),4.22(s,2H),4.08-3.99(m,2.7H),3.81-3.73(m,0.3H),2.70-2.53(m,1H),2.18-1.71(m,6.3H),1.62-1.50(m,1.7H),1.47(s,9H),1.17-1.12(m,9H)。

VII-37-4D：LC-MS(ESI)：R_T＝1.89min,C₃₄H₄₀ClF₂N₅O₄Calculated mass of S687.2, found M/z 687.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: CO)₂EtOH, DEA 80:20:0.2 at 3.0 g/min; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100 bar, R_T＝6.37min)。¹H NMR(400MHz,CD₃OD)δ7.94(d,J＝3.2Hz,0.7H),7.90(d,J＝2.8Hz,0.3H),7.76(d,J＝3.2Hz,1H),7.42(s,0.7H),7.39-7.36(m,1.3H),7.26-7.22(m,2H),6.15(s,0.7H),6.08(s,0.3H),4.22(s,2H),4.08-3.98(m,2.7H),3.81-3.74(m,0.3H),2.70-2.54(m,1H),2.17-1.70(m,6.2H),1.62-1.51(m,1.8H),1.47(s,9H),1.18-1.11(m,9H)。

Compound VII-38-N:

(trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (ethoxycarbonyl) -1H-pyrazol-1-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer) intermediates VII-38-X and VII-38-Y:

(cis) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (ethoxycarbonyl) -1H-pyrazol-1-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers) and (trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (ethoxycarbonyl) -1H-pyrazol-1-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers).

The title compound was synthesized as a yellow solid by a similar procedure using method B.

VII-38-X：LC-MS(ESI)：R_T＝4.266min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z found 604.1[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.34(s,0.5H),8.21(s,0.5H),8.08(s,0.5H),8.05(s,0.5H),7.98(s,0.5H),7.83(d,J＝3.2Hz,0.6H),7.80(d,J＝3.2Hz,0.4H),7.47(d,J＝3.2Hz,0.5H),7.43(d,J＝3.2Hz,0.5H),7.35-7.29(m,0.5H),7.12-6.97(m,2H),6.20(s,0.5H),6.08(d,J＝2.4Hz,0.5H),4.55-4.45(m,1H),4.36-4.28(m,2H),4.24-4.13(m,0.5H),4.08-3.97(m,2.5H),2.68-2.44(m,2H),2.19-1.78(m,6H),1.39-1.33(m,3H),1.14(t,J＝7.2Hz,3H)。

VII-38-Y：LC-MS(ESI)：R_T＝4.148min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z found 604.1[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.15(s,0.5H),7.98(s,0.5H),7.95(s,0.5H),7.93(s,1H),7.86-7.82(m,1H),7.52(d,J＝3.2Hz,0.6H),7.47(d,J＝2.8Hz,0.4H),7.34(d,J＝2.0Hz,0.5H),7.13-7.00(m,2H),6.21(s,0.4H),6.09(d,J＝2.8Hz,0.6H),4.34-4.26(m,3H),4.16-3.98(m,2.4H),3.92-3.82(m,0.6H),2.43-2.21(m,2.6H),2.17-2.09(m,1.4H),2.03-1.79(m,3.2H),1.74-1.66(m,0.8H),1.36(t,J＝6.4Hz,3H),1.18-1.11(m,3H)。

A stereoisomeric mixture of (trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (ethoxycarbonyl) -1H-pyrazol-1-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-38-Y (150mg, 97% purity, 0.249mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA 5 μ M20 250 mm; mobile phase: Hex: EtOH: DEA ═ 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃ C; wavelength: 230nm), and then further purified by a C18 column (acetonitrile: water ═ 50% to 71%) to give the title compound VII-38-M (59mg, 96.7% pure, 39% yield, 100% stereopure) and VII-38-N (54mg, 98.6% pure, 36% yield, 96.9% stereopure).

VII-38-M:LC-MS(ESI)：R_T＝4.475min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z found 604.1[ M + H [)]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 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＝10.844min)。¹H NMR(400MHz,CDCl₃)δ8.15(br s,0.5H),8.00-7.95(m,1H),7.93(s,1H),7.85(d,J＝3.2Hz,1H),7.57-7.44(m,1H),7.37-7.32(m,0.5H),7.12-7.00(m,2H),6.21(s,0.5H),6.09(s,0.5H),4.33-4.28(m,3H),4.17-4.10(m,2.5H),3.93-3.82(m,0.5H),2.43-1.74(m,8H),1.35(t,J＝6.8Hz,3H),1.14(t,J＝7.2Hz,3H)。

VII-38-N:LC-MS(ESI)：R_T＝4.471min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z found 604.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 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＝13.803min)。¹H NMR(400MHz,CDCl₃)δ8.15(s,0.5H),7.97(s,0.5H),7.95(s,0.5H),7.93(s,1H),7.83-7.82(m,1H),7.51(d,J＝3.2Hz,0.5H),7.47(d,J＝2.8Hz,0.5H),7.34(br s,0.5H),7.13-6.99(m,2H),6.21(s,0.5H),6.09(d,J＝2.8Hz,0.5H),4.33-4.27(m,3H),4.16-3.99(m,2.5H),3.93-3.82(m,0.5H),2.45-2.03(m,4H),1.97-1.67(m,4H),1.36(t,J＝6.8Hz,3H),1.14(t,J＝6.8Hz,3H)。

Compound VII-39-N and compound VII-39-P:

(cis) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (5- (ethoxycarbonyl) -1H-pyrazol-1-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer) and (trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (5- (ethoxycarbonyl) -1H-pyrazol-1-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer) intermediates VII-39-X and VII-39-Y:

(cis) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (5- (ethoxycarbonyl) -1H-pyrazol-1-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers) and (trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (5- (ethoxycarbonyl) -1H-pyrazol-1-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers).

The title compound was synthesized as a yellow solid by a similar procedure using method B.

VII-39-X：LC-MS(ESI)：R_T＝3.843min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z found 603.9[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝3.6Hz,0.6H),8.55(s,0.4H),8.07(d,J＝2.8Hz,0.4H),8.02-7.97(m,1.6H),7.75(d,J＝2.4Hz,0.4H),7.60(d,J＝2.0Hz,0.6H),7.51-7.40(m,1H),7.26-7.18(m,1H),6.97(d,J＝2.0Hz,0.4H),6.92(d,J＝2.0Hz,0.6H),6.05(s,0.4H),5.94(d,J＝3.6Hz,0.6H),5.51-5.45(m,0.4H),5.28-5.21(m,0.6H),4.31(qd,J＝7.2,2.8Hz,2H),4.10-4.03(m,0.4H),3.98(q,J＝7.2Hz,2H),3.83-3.75(m,0.6H),2.40-2.26(m,2H),2.23-1.99(m,3H),1.95-1.78(m,1.4H),1.74-1.65(m,1H),1.59-1.50(m,0.6H),1.32(t,J＝7.2Hz,3H),1.12-1.03(m,3H)。

VII-39-Y：LC-MS(ESI)：R_T＝4.435min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z found 603.9[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.59(d,J＝3.2Hz,0.6H),9.32(s,0.4H),8.04-7.99(m,1.6H),7.95(d,J＝2.8Hz,0.4H),7.62-7.59(m,1H),7.51-7.43(m,1H),7.25-7.16(m,1H),6.88(d,J＝1.6Hz,1H),6.04(s,0.4H),5.94(d,J＝3.6Hz,0.6H),5.31-5.22(m,0.4H),5.18-5.09(m,0.6H),4.33(q,J＝7.2Hz,2H),4.04-3.93(m,2.4H),3.77-3.68(m,0.6H),2.25-2.15(m,0.4H),2.12-1.88(m,6.4H),1.85-1.79(m,0.6H),1.77-1.71(m,0.6H),1.34(td,J＝7.2,2.0Hz,3H),1.13-1.03(m,3H)。

A racemic mixture of (cis) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (5- (ethoxycarbonyl) -1H-pyrazol-1-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-39-X (390mg, 99.5% purity, 0.639mmol) was passed through a chiral preparative SFC (separation conditions: column: Chiralpak IE 5 μm 20 × 250 mm; mobile phase: CO:. sup. ₂MeOH 75:25 at 50 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar) to provide VII-39-M (160mg, 98.7% pure, 41% yield, 100% stereopure) and VII-39-N (165mg, 98.8% pure, 42% yield, 100% stereopure) as yellow solids.

VII-39-M：LC-MS(ESI)：R_T＝4.170min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z found 603.9[ M + H [)]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH 75:25 at 3.00 g/min; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100 bar, R_T＝6.15min)。¹H NMR(400MHz,DMSO-d₆)δ9.58(d,J＝3.6Hz,0.6H),8.55(s,0.4H),8.07(d,J＝2.8Hz,0.4H),8.02-7.96(m,1.6H),7.74(d,J＝2.0Hz,0.4H),7.60(d,J＝1.6Hz,0.6H),7.50-7.40(m,1H),7.26-7.17(m,1H),6.96(d,J＝2.0Hz,0.4H),6.91(d,J＝2.0Hz,0.6H),6.05(s,0.4H),5.94(d,J＝3.6Hz,0.6H),5.51-5.45(m,0.4H),5.28-5.20(m,0.6H),4.30(qd,J＝7.2,2.4Hz,2H),4.11-4.02(m,0.4H),3.98(q,J＝6.8Hz,2H),3.83-3.74(m,0.6H),2.40-2.26(m,2H),2.22-1.98(m,2.8H),1.95-1.78(m,1.6H),1.74-1.64(m,1H),1.58-1.49(m,0.6H),1.31(t,J＝7.2Hz,3H),1.12-1.02(m,3H)。

VII-39-N：LC-MS(ESI)：R_T＝4.172min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z found 603.9[ M + H [)]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: CO)₂:MeOH＝7525, at 3.00 g/min; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100 bar, R_T＝7.12min)。¹H NMR(400MHz,DMSO-d₆)δ9.58(d,J＝3.6Hz,0.6H),8.55(s,0.4H),8.07(d,J＝3.6Hz,0.4H),8.01-7.97(m,1.6H),7.75(d,J＝2.0Hz,0.4H),7.61(d,J＝2.0Hz,0.6H),7.51-7.40(m,1H),7.25-7.19(m,1H),6.97(d,J＝2.0Hz,0.4H),6.92(d,J＝2.0Hz,0.6H),6.06(s,0.4H),5.94(d,J＝3.6Hz,0.6H),5.51-5.46(m,0.4H),5.28-5.21(m,0.6H),4.31(qd,J＝7.2,2.4Hz,2H),4.11-4.03(m,0.4H),3.98(q,J＝6.8Hz,2H),3.83-3.75(m,0.6H),2.40-2.26(m,2H),2.23-1.98(m,2.8H),1.95-1.78(m,1.6H),1.74-1.64(m,1H),1.59-1.49(m,0.6H),1.31(t,J＝7.2Hz,3H),1.12-1.03(m,3H)。

The racemic mixture of (trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (5- (ethoxycarbonyl) -1H-pyrazol-1-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-39-Y (410mg, 99.5% purity, 0.672mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IG 5 μm 20 250 mm; mobile phase: Hex: IPA: DEA ═ 90:10:0.3 at 15 mL/min; wavelength: 230nm) to afford VII-39-P as a yellow solid (170mg, 99.5% purity, 42% yield, 100% stereopurity) and VII-39-Q (175mg, 99.5% purity, 43% yield, 99.8% stereopurity).

VII-39-P：LC-MS(ESI)：R_T＝3.868min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z found 603.9[ M + H [)]⁺. Chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: Hex: IPA: DEA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R; (R))_T＝9.987min)。¹H NMR(400MHz,DMSO-d₆)δ9.60(d,J＝3.2Hz,0.6H),9.32(s,0.4H),8.04-7.99(m,1.6H),7.95(d,J＝3.6Hz,0.4H),7.63-7.58(m,1H),7.51-7.44(m,1H),7.25-7.16(m,1H),6.88(d,J＝2.0Hz,1H),6.04(s,0.4H),5.94(d,J＝3.6Hz,0.6H),5.32-5.22(m,0.4H),5.18-5.09(m,0.6H),4.33(q,J＝7.2Hz,2H),4.04-3.93(m,2.4H),3.77-3.68(m,0.6H),2.25-2.15(m,0.4H),2.12-1.88(m,6.4H),1.86-1.79(m,0.6H),1.78-1.71(m,0.6H),1.34(td,J＝7.2,2.0Hz,3H),1.13-1.03(m,3H)。

VII-39-Q：LC-MS(ESI)：R_T＝3.980min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z found 603.9[ M + H [)]⁺. Chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: Hex: IPA: DEA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R; (R))_T＝13.321min)。¹H NMR(400MHz,DMSO-d₆)δ9.60(d,J＝3.2Hz,0.6H),9.32(s,0.4H),8.05-7.98(m,1.6H),7.95(d,J＝2.8Hz,0.4H),7.63-7.58(m,1H),7.51-7.44(m,1H),7.26-7.16(m,1H),6.88(d,J＝2.0Hz,1H),6.04(s,0.4H),5.94(d,J＝3.6Hz,0.6H),5.32-5.22(m,0.4H),5.18-5.08(m,0.6H),4.33(q,J＝7.2Hz,2H),4.05-3.93(m,2.4H),3.77-3.67(m,0.6H),2.26-2.14(m,0.4H),2.12-1.88(m,6.4H),1.85-1.79(m,0.6H),1.78-1.71(m,0.6H),1.34(t,J＝7.2Hz,3H),1.13-1.03(m,3H)。

Compound VII-40-M:

(trans) -ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) pyrimidine-5-carboxylate (single stereoisomer) intermediates VII-40-X and VII-40-Y:

(cis) -ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) pyrimidine-5-carboxylate (mixture of 2 stereoisomers) and (trans) -ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) pyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

VII-40-X：LC-MS(ESI)：R_T＝3.614min,C₂₉H₂₈ClF₂N₅O₄Calculated mass of S615.2, M/z found 615.9[ M + H [ ] ]⁺。¹H NMR(400MHz,CDCl₃)δ9.37(s,1.5H),9.28(s,0.5H),8.34(s,1H),7.84(d,J＝3.2Hz,0.8H),7.78(d,J＝3.2Hz,0.2H),7.44(d,J＝2.8Hz,1H),7.11-6.96(m,2H),6.20(s,0.8H),6.05(d,J＝3.2Hz,0.2H),4.47(q,J＝7.2Hz,2H),4.22-4.17(m,0.8H),4.11-4.00(m,2H),3.96-3.91(m,0.2H),3.48(s,0.8H),3.40-3.36(m,0.2H),2.70-2.62(m,0.5H),2.53-2.47(m,1.5H),2.05-1.88(m,5H),1.80-1.78(m,1H),1.45(t,J＝7.2Hz,3H),1.15(t,J＝7.2Hz,3H)。

VII-40-Y：LC-MS(ESI)：R_T＝1.97min,C₂₉H₂₈ClF₂N₅O₄Calculated mass of S615.2, M/z found 616.1[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ9.22(s,2H),8.21(s,0.6H),7.84(d,J＝2.8Hz,1H),7.51(d,J＝2.8Hz,0.4H),7.46(d,J＝3.2Hz,0.6H),7.32(s,0.4H),7.14-6.99(m,2H),6.22(s,0.6H),6.08(d,J＝2.8Hz,0.4H),4.44(q,J＝7.2Hz,2H),4.15-4.01(m,2.8H),3.91-3.85(m,0.2H),3.12-3.05(m,1H),2.29-2.08(m,4H),1.97-1.64(m,4H),1.42(t,J＝7.2Hz,3H),1.15(t,J＝7.2Hz,3H)。

The stereoisomeric mixture of (trans) -ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) pyrimidine-5-carboxylate VII-40-Y (210mg, 95% purity, 0.324mmol) was separated by chiral preparative HPLC (column: Chiralpak ID 5 μ M20 250 mm; mobile phase: Hex: EtOH: DEA 40:60:0.3 at 10 mL/min; temperature: 30 ℃ c; wavelength: 214nm) to provide the title compound VII-40-M (50mg, 95.6% purity, 24% yield, 100% stereopurity) and VII-40-N (55mg, 99.7% purity, 27% yield, 100% stereopurity).

VII-40-M：LC-MS(ESI)：R_T＝4.462min,C₂₉H₂₈ClF₂N₅O₄Calculated mass of S615.2, M/z found 616.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm 4.6 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 ID 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 40:60: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝7.153min)。¹H NMR(400MHz,CDCl₃)δ9.27-9.26(m,2H),8.26(s,0.7H),7.88-7.87(m,1H),7.55(d,J＝2.8Hz,0.3H),7.50(d,J＝3.2Hz,0.7H),7.36(s,0.3H),7.18-7.04(m,2H),6.26(s,0.6H),6.13(d,J＝2.4Hz,0.4H),4.48(q,J＝6.8Hz,2H),4.19-4.05(m,2.5H),3.95-3.89(m,0.5H),3.18-3.10(m,1H),2.33-2.13(m,4H),2.00-1.66(m,4H),1.46(t,J＝6.8Hz,3H),1.22-1.17(m,3H)。

VII-40-N：LC-MS(ESI)：R_T＝3.396min,C₂₉H₂₈ClF₂N₅O₄Calculated mass of S615.2, M/z found 615.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm 4.6 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 ID 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: DEA: 40:60: 0.2; temperature: 230 ℃; wavelength: 230nm_T＝11.243min)。¹H NMR(400MHz,CDCl₃)δ9.26-9.25(m,2H),8.26(s,0.6H),7.88-7.87(m,1H),7.55(d,J＝2.8Hz,0.4H),7.49(d,J＝3.2Hz,0.6H),7.36(s,0.3H),7.18-7.04(m,2H),6.26(s,0.7H),6.12(d,J＝2.4Hz,0.3H),4.48(q,J＝7.2Hz,2H),4.19-4.04(m,2.7H),3.95-3.89(m,0.3H),3.17-3.10(m,1H),2.32-2.13(m,4H),2.01-1.69(m,4H),1.46(t,J＝7.8Hz,3H),1.22-1.17(m,3H)。

Compound VII-41-N:

(trans) -ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) thiazole-4-carboxylate (single stereoisomer) intermediate VII-41-R:

(trans) -Ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) thiazole-4-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

LC-MS(ESI)：R_T＝3.965min,C₂₈H₂₇ClF₂N₄O₄S₂Calculated mass of 620.1, M/z found 621.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.55(d,J＝3.6Hz,0.6H),8.98(s,0.4H),8.42(d,J＝4.8Hz,1H),8.02-8.01(m,1.6H),7.95(d,J＝2.8Hz,0.4H),7.51-7.44(m,1H),7.24-7.18(m,1H),6.05(s,0.4H),5.94(d,J＝3.2Hz,0.6H),4.30(q,J＝7.2Hz,2H),4.02-3.91(m,2.4H),3.73-3.65(m,0.6H),3.27-3.19(m,0.4H),3.13-3.05(m,0.6H),2.27-2.18(m,2H),2.10-1.82(m,3.5H),1.74-1.71(m,0.5H),1.64-1.56(m,2H),1.31(t,J＝7.2Hz,3H),1.10-1.03(m,3H)。

A stereoisomeric mixture of VII-41-R (300mg, 0.48mmol) was separated by chiral preparative HPLC (column: Chiralpak AD 5 μm 20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to give peak 1(122mg, 41% yield, about 90% purity, 100% stereopurity) and peak 2(110mg, 37% yield, about 90% purity, 98.6% stereopurity). Part of peak 1(30mg, 90% pure) and peak 2(30mg, 90% pure) 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: 70% -98% (% B)) to give the title compounds VII-41-M (6.1mg, 20% yield, 98.3% pure, 100% stereopure) and VII-41-N (6.8mg, 23% yield, 99.7% pure, 98.6% stereopure).

VII-41-M：LC-MS(ESI)：R_T＝3.001min，C₂₈H₂₇ClF₂N₄O₄S₂Calculated mass of 620.1, M/z found 621.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak AD-H5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; chiral analysis (column: Chiralpak AD-H5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30 ℃; wavelength_T＝6.075min)。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.2Hz,0.6H),8.99(s,0.4H),8.42(d,J＝5.2Hz,1H),8.02-8.01(m,1.6H),7.96(d,J＝3.2Hz,0.4H),7.51-7.44(m,1H),7.24-7.18(m,1H),6.05(s,0.4H),5.94(d,J＝3.6Hz,0.6H),4.30(q,J＝7.2Hz,2H),4.02-3.91(m,2.4H),3.72-3.66(m,0.6H),3.27-3.19(m,0.4H),3.13-3.05(m,0.6H),2.28-2.18(m,2H),2.08-1.82(m,3.5H),1.75-1.71(m,0.5H),1.65-1.53(m,2H),1.31(t,J＝7.2Hz,3H),1.10-1.03(m,3H)。

VII-41-N：LC-MS(ESI)：R_T＝3.952min,C₂₈H₂₇ClF₂N₄O₄S₂Calculated mass of 620.1, M/z found 621.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak AD-H5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230 nm; R ℃; chiral analysis (column: Chiralpak AD-H5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30: 0.2; temperature: 30 ℃; wavelength_T＝8.428min)。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.6Hz,0.6H),8.98(s,0.4H),8.42(d,J＝3.2Hz,1H),8.02-8.01(m,1.6H),7.95(d,J＝3.6Hz,0.4H),7.51-7.44(m,1H),7.24-7.18(m,1H),6.05(s,0.4H),5.94(d,J＝3.2Hz,0.6H),4.30(q,J＝7.2Hz,2H),4.02-3.90(m,2.4H),3.73-3.65(m,0.6H),3.27-3.20(m,0.4H),3.13-3.06(m,0.6H),2.28-2.18(m,2H),2.08-1.82(m,3.5H),1.75-1.71(m,0.5H),1.67-1.54(m,2H),1.31(t,J＝7.2Hz,3H),1.10-1.05(m,3H)。

Compound VII-42-11:

a mixture of (trans) -methyl 5- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) isoxazole-3-carboxylate (single stereoisomer) and (trans) -ethyl 5- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) isoxazole-3-carboxylate (single stereoisomer)

Intermediates VII-42-9A and VII-42-9B:

(trans) -ethyl 5- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) isoxazole-3-carboxylate (mixture of 2 stereoisomers) and (trans) -methyl 5- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) isoxazole-3-carboxylate (mixture of 2 stereoisomers).

The title compound was synthesized as a yellow solid by a similar procedure using method B. Transesterification is observed when ethanol is used as solvent.

VII-42-9A:LC-MS(ESI)：R_T＝2.03min,C₂₈H₂₇ClF₂N₄O₅Calculated mass of S604.1, M/z found 604.8[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.59(d,J＝3.2Hz,0.6H),9.04(s,0.4H),8.01-7.95(m,2H),7.51-7.44(m,1H),7.23-7.18(m,1H),6.74(d,J＝10.0Hz,1H),6.04(s,0.4H),5.94(d,J＝3.2Hz,0.6H),4.39-4.34(m,2H),4.01-3.94(m,2.5H),3.71-3.65(m,0.5H),3.12-3.06(m,0.4H),2.99-2.92(m,0.6H),2.19-2.12(m,2.3H),2.07-1.78(m,3H),1.73-1.69(m,0.7H),1.60-1.50(m,2H),1.32(t,J＝7.2Hz,3H),1.10-1.03(m,3H)。

VII-42-9B:LC-MS(ESI)：R_T＝2.00min,C₂₇H₂₅ClF₂N₄O₅Calculated mass of S590.1, found M/z 590.8[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.59(s,0.6H),9.04(s,0.4H),8.02-7.96(m,2H),7.51-7.44(m,1H),7.22-7.19(m,1H),6.77-6.74(m,1H),6.03(s,0.4H),5.95(s,0.6H),4.00-3.95(m,2.5H),3.89(s,3H),3.73-3.65(m,0.5H),3.13-3.07(m,0.4H),3.00-2.94(m,0.6H),2.19-2.12(m,2H),1.97-1.72(m,4H),1.61-1.47(m,2H),1.07-1.06(m,3H)。

The stereoisomeric mixture of (trans) -methyl 5- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) isoxazole-3-carboxylate VII-42-9B (200mg, 90% purity, 0.305mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μm20 mm; mobile phase: Hex: EtOH: DEA ═ 50:50:0.3 at 11 mL/min; temperature: 30 ℃ c; wavelength: 230nm) to give compound VII-42-10(45mg, 23% yield, 100% stereopurity) and VII-42-11(65mg, 33% yield, 99.8% stereopure). Transesterification is observed when ethanol is used as solvent.

VII-42-10:LC-MS(ESI)：R_T1.97min and 2.02min, C₂₇H₂₅ClF₂N₄O₅Calculated mass of S590.1 and C₂₈H₂₇ClF₂N₄O₅Calculated mass of S604.1, M/z found 590.8 and 604.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TEA ═ 50:50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IE 5 μm 4.6: 0.2; temperature: 30 ℃; chiral analysis: C _T7.355 and 8.163 min).

VII-42-11:LC-MS(ESI)：R_T1.97min and 2.02min, C₂₇H₂₅ClF₂N₄O₅Calculated mass of S590.1 and C₂₈H₂₇ClF₂N₄O₅Calculated mass of S604.1, M/z found 590.9 and 604.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TEA ═ 50:50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R ℃; chiral analysis (column: Chiralpak IE 5 μm 4.6: 0.2; temperature: 30 ℃; chiral analysis: C_T11.346 and 13.670 min).

Compound VII-43-N:

(trans) -ethyl 3-4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) isoxazole-5-carboxylate (single stereoisomer) intermediate VII-43-R:

(trans) -ethyl 3- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) isoxazole-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

LC-MS(ESI)：R_T＝3.918min,C₂₈H₂₇ClF₂N₄O₅Calculated mass of S604.1, M/z found 605.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝3.2Hz,0.6H),9.02(s,0.4H),8.01(d,J＝3.2Hz,1.6H),7.95(d,J＝3.2Hz,0.4H),7.51-7.46(m,1H),7.38(s,0.4H),7.35(s,0.6H),7.24-7.18(m,1H),6.04(s,0.4H),5.94(d,J＝3.6Hz,0.6H),4.36(q,J＝7.2Hz,2H),3.99(q,J＝7.2Hz,2H),3.93-3.90(m,0.4H),3.74-3.66(m,0.6H),3.04-2.96(m,0.4H),2.87-2.79(m,0.6H),2.10-1.81(m,6H),1.72-1.54(m,2H),1.32(t,J＝7.2Hz,3H),1.11-1.04(m,3H)。

A stereoisomeric mixture of VII-43-R (1.20g, 1.98mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μ M20 × 250mm, mobile phase: Hex: EtOH: DEA ═ 50:50:0.2 at 1.0mL/min, temperature: 30 ℃, wavelength: 214nm) to afford compounds VII-43-M (436mg, 36% yield, 100% stereopurity) and VII-43-N (376mg, 31% yield, 99.8% stereopurity).

VII-43-M:LC-MS(ESI)：R_T＝3.207min,C₂₈H₂₇ClF₂N₄O₅Calculated mass of 604.1, M/z found 605.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 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 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: 50: 0.2; temperature: 230 ℃_T＝6.378min)。¹H NMR(400MHz,DMSO-d₆)δ9.55(d,J＝3.6Hz,0.6H),9.02(s,0.4H),8.01(d,J＝3.2Hz,1.6H),7.95(d,J＝3.2Hz,0.4H),7.51-7.43(m,1H),7.38(s,0.4H),7.35(s,0.6H),7.24-7.18(m,1H),6.04(s,0.4H),5.94(d,J＝3.2Hz,0.6H),4.36(q,J＝7.2Hz,2H),3.99(q,J＝7.2Hz,2H),3.94-3.91(m,0.4H),3.73-3.65(m,0.6H),3.03-2.95(m,0.4H),2.86-2.79(m,0.6H),2.11-1.78(m,6H),1.73-1.53(m,2H),1.32(t,J＝7.2Hz,3H),1.11-1.04(m,3H)。

VII-43-N:LC-MS(ESI)：R_T＝4.047min,C₂₈H₂₇ClF₂N₄O₅Calculated mass of 604.1, M/z found 605.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 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 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: 50: 0.2; temperature: 230 ℃_T＝9.388min)。¹H NMR(400MHz,DMSO-d₆)δ9.55(d,J＝3.6Hz,0.6H),9.02(s,0.4H),8.01(d,J＝3.2Hz,1.6H),7.95(d,J＝3.2Hz,0.4H),7.51-7.43(m,1H),7.38(s,0.4H),7.35(s,0.6H),7.24-7.18(m,1H),6.04(s,0.4H),5.94(d,J＝3.6Hz,0.6H)),4.36(q,J＝7.2Hz,2H),3.99(q,J＝7.2Hz,2H),3.94-3.91(m,0.4H),3.73-3.66(m,0.6H),3.04-2.96(m,0.4H),2.87-2.79(m,0.6H),2.11-1.72(m,6H),1.60-1.53(m,2H),1.32(t,J＝7.2Hz,3H),1.11-1.04(m,3H)。

Compound VII-44-X:

(trans) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (methoxycarbonyl) phenyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers) intermediate VII-44-R:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (methoxycarbonyl) phenyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

LC-MS(ESI)：R_T＝2.17min,2.21min,C₃₀H₂₈ClF₂N₃O₄Calculated mass of S599.2, M/z found 600.2[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.56-9.53(m,0.7H),8.96(s,0.3H),8.02-7.89(m,4H),7.60-7.44(m,3H),7.23-7.19(m,1H),6.05(s,0.4H),5.95-5.93(m,0.6H),4.02-3.95(m,2H),3.85-3.84(m,3.5H),3.75-3.68(m,0.5H),2.93-2.68(m,1H),1.99-1.54(m,8H),1.11-1.05(m,3H)。

Ethyl 4-A stereoisomeric mixture of (2-chloro-3, 4-difluorophenyl) -6- (4- (4- (methoxycarbonyl) phenyl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-44-R (300mg, 0.50mmol) was passed through chiral preparative SFC (separation conditions: column: Chiralpak IA 5 μm 20 x 250 mm; mobile phase: CO ₂MeOH 70:30 at 50 g/min; column temperature: 41.1 ℃; wavelength: 230 nm; back pressure: 100 bar) to afford compounds VII-44-X (mixture of 2 stereoisomers) (200mg, 67% yield) and VII-44-Y (mixture of 2 stereoisomers) (85mg, 28% yield) as yellow solids.

Intermediate VII-44-X: LC-MS (ESI): r_T＝2.07min,C₃₀H₂₈ClF₂N₃O₄Calculated mass of S599.2, M/z found 600.2[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆) δ 9.54(d, J ═ 3.6Hz,0.6H),8.96(s,0.4H),8.02-8.00(m,1.5H),7.96(d, J ═ 2.8Hz,0.5H),7.92-7.89(m,2H),7.51-7.42(m,3H),7.24-7.18(m,1H),6.05(s,0.4H),5.94(d, J ═ 3.2Hz,0.6H),4.02-3.95(m,2.4H),3.84(s,3H),3.75-3.68(m,0.6H),2.86-2.78(m,0.4H),2.72-2.63(m,0.6H),2.03-1.81(m, 5.68, 1.63H), 1.04-1.53 (m, 1.4H), 1.53-1.4H, 1.3H, 1.4H, 1.3H, and 1.5H. Intermediate VII-44-Y: LC-MS (ESI): r_T＝3.121min,C₃₀H₂₈ClF₂N₃O₄Calculated mass of S599.2, M/z found 600.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.56(d,J＝4.0Hz,0.8H),8.52(s,0.2H),7.99-7.93(m,4H),7.60-7.54(m,2H),7.50-7.40(m,1H),7.23-7.20(m,1H),6.04(s,0.2H),5.93(d,J＝3.6Hz,0.8H),4.01-3.94(m,2H),3.86-3.85(m,4H),3.13-3.10(m,0.2H),2.96-2.91(m,0.8H),2.35-2.25(m,2H),2.03-1.59(m,6H),1.10-1.04(m,3H)。

Compound VII-45-R:

(trans) -Ethyl 5- (-4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -1,2, 4-oxadiazole-3-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

LC-MS(ESI)：R_T＝4.364min,C₂₇H₂₆ClF₂N₅O₅Calculated mass of S605.13, found M/z 606.2[ M + H ] ]⁺。¹H NMR(400MHz,CDCl₃)δ8.14(s,0.5H),7.84-7.82(m,1H),7.52(d,J＝2.8Hz,0.5H),7.47(d,J＝3.2Hz,0.5H),7.35(s,0.5H),7.12-7.00(m,2H),6.21(s,0.5H),6.09(d,J＝2.4Hz,0.5H),4.52(q,J＝7.2Hz,2H),4.14-4.00(m,2.5H),3.89-3.82(m,0.5H),3.19-3.12(m,1H),2.41-2.22(m,2.5H),2.15-2.04(m,1.5H),1.97-1.83(m,3H),1.75-1.62(m,1H),1.45(t,J＝7.2Hz,3H),1.17-1.12(m,3H)。

Compound VII-46-P:

methyl 4- (2-chloro-3, 4-difluorophenyl) -6- ((trans) -4- (5- (1- (methoxycarbonyl) cyclopropyl) pyrimidin-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VII-46-Y:

methyl 4- (2-chloro-3, 4-difluorophenyl) -6- ((trans) -4- (5- (1- (methoxycarbonyl) cyclopropyl) pyrimidin-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

LC-MS(ESI)：R_T＝1.92min,C₃₀H₂₈ClF₂N₅O₄Calculated mass of S627.2, M/z found 628.4[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃) δ 8.65(s,0.6H),8.64(s,1.4H),8.24(s,0.7H),7.85-7.83(m,1H),7.52(d, J ═ 3.2Hz,0.3H),7.47(d, J ═ 2.8Hz,0.7H),7.38(d, J ═ 2.4Hz,0.3H),7.12-7.10(m,1H),7.06-6.99(m,1H),6.20(s,0.7H),6.06(d, J ═ 2.4Hz,0.3H),4.13-4.06(m,0.7H),3.87-3.85(m,0.3H),3.67(s,3H),3.64(s,0.9H),3.61(s, 2.06, 1.7H), 3.87-3H, 1.73 (m,1H), 3.73-2.3H, 1H, 1.3.3H), 3.06 (m, 2.06-3H), 3.3H, 1.73 (m,1H), 2.3H). A racemic mixture of methyl 4- (2-chloro-3, 4-difluorophenyl) -6- ((trans) -4- (5- (1- (methoxycarbonyl) cyclopropyl) pyrimidin-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-46-Y (170mg, 0.271mmol) was subjected to chiral preparative HPLC (separation conditions: column: Chiralpak IE 5um 20 × 250 mm; mobile phase: MeOH: IPA: DEA ═ 250 mm) 90:10:0.3 at 10 mL/min; temperature: 30 ℃; wavelength: 214nm) to give VII-46-P as a yellow solid (50mg, obtained from¹H NMR 95% pure, 28% yield, 100% stereopure) and VII-46-Q (50mg, obtained from¹Purity by H NMR 95%, 28% yield, 99.8% stereopure).

VII-46-P:LC-MS(ESI)：R_T＝1.87min,C₃₀H₂₈ClF₂N₅O₄Calculated mass of S627.2, M/z found 628.3[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak ID 5um 4.6 × 250 mm; mobile phase: MeOH: DCM: DEA ═ 90:10:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, Rt ═ 5.543 min).¹H NMR(400MHz,CDCl₃)δ8.65(s,0.6H),8.64(s,1.4H),8.25(s,0.6H),7.84-7.83(m,1H),7.51(d,J＝3.2Hz,0.3H),7.46(d,J＝3.2Hz,0.7H),7.39(br s,0.4H),7.12-7.09(m,1H),7.05-7.01(m,1H),6.20(s,0.7H),6.07(d,J＝2.4Hz,0.3H),4.11-4.06(m,1H),3.67(s,3H),3.64(s,0.9H),3.61(s,2.1H),3.04-2.99(m,1H),2.28-2.21(m,3H),2.11-2.07(m,2H),1.95-1.90(m,2H),1.72-1.70(m,3H),1.26-1.24(m,2H)。

VII-46-Q:LC-MS(ESI)：R_T＝1.87min,C₃₀H₂₈ClF₂N₅O₄Calculated mass of S627.2, M/z found 628.3[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak ID 5um 4.6 × 250 mm; mobile phase: MeOH: DCM: DEA ═ 90:10:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, Rt ═ 9.079 min).¹H NMR(400MHz,CDCl₃)δ8.64(s,2H),8.24(s,0.7H),7.84(d,J＝3.2Hz,1H),7.51(d,J＝2.8Hz,0.3H),7.46(d,J＝3.2Hz,0.7H),7.39(br s,0.3H),7.12-7.09(m,1H),7.05-7.01(m,1H),6.20(s,0.7H),6.07(s,0.3H),4.12-4.06(m,0.7H),3.88-3.83(m,0.3H),3.67(s,3H),3.64(s,0.9H),3.61(s,2.1H),3.05-2.99(m,1H),2.28-2.22(m,3H),2.11-2.08(m,2H),1.97-1.90(m,2H),1.73-1.70(m,3H),1.26-1.24(m,2H)。

Compound VII-47-N:

ethyl 2- ((trans) -4- (6- (2-bromo-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -5-methylpyrimidine-4-carboxylate (single stereoisomer)

Intermediate VII-47-B:

ethyl 2- ((trans) -4- (6- (2-bromo-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -5-methylpyrimidine-4-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

LC-MS(ESI)：R_T＝1.97min,C₂₉H₂₈BrF₂N₅O₄Calculated mass of S659.1, found M/z 660.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.67(s,0.4H),8.66(s,0.6H),8.25(s,0.6H),7.83(d,J＝3.2Hz,1H),7.51(d,J＝3.2Hz,0.4H),7.45(d,J＝3.2Hz,0.6H),7.43(s,0.4H),7.12-7.02(m,2H),6.19(s,0.6H),6.03(d,J＝2.8Hz,0.4H),4.52-4.46(m,2H),4.17-4.07(m,1H),3.63(s,1H),3.61(s,2H),3.12-3.03(m,1H),2.46(s,3H),2.28-2.18(m,2H),2.18-2.04(m,2H),2.03-1.90(m,2H),1.87-1.64(m,2H),1.45(t,J＝6.8Hz,3H)。

A racemic mixture of ethyl 2- ((trans) -4- (6- (2-bromo-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -5-methylpyrimidine-4-carboxylate VII-47-B (127mg, 95% purity, 0.183mmol) was subjected to chiral preparative HPLC (separation conditions: column: Chiralpak IG 5um 30. about.250 mm, mobile phase: CO₂EtOH 70:30 at 60 g/min; column temperature: 40 ℃; wavelength: 230nm, back pressure: 100 bar) to provide VII-47-M (40mg, obtained from¹Purity by H NMR 90%, 30% yield, 99.6% stereopure) and VII-47-N (35mg, obtained from¹Purity by H NMR 90%, 26% yield, 99.6% stereopure).

Intermediate VII-47-M: LC-MS (ESI): r_T＝1.98min,C₂₉H₂₈BrF₂N₅O₄Calculated mass of S659.1, found M/z 660.2[ M + H [)]⁺. Chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO)₂EtOH 70:30 at 3.0 g/min; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100 bar, R_T＝7.78min)。¹H NMR(400MHz,CDCl₃)δ8.66(s,1H),8.24(s,0.6H),7.83(d,J＝3.2Hz,1H),7.52-7.51(m,0.4H),7.45(d,J＝2.8Hz,0.6H),7.42(s,0.4H),7.12-7.04(m,2H),6.19(s,0.7H),6.03(s,0.3H),4.48(q,J＝6.8Hz,2H),4.15-4.08(m,1H),3.63(s,0.5H),3.60(s,2.5H),3.13-3.03(m,1H),2.46(s,3H),2.29-2.06(m,4H),2.03-1.89(m,2H),1.85-1.66(m,2H),1.45(t,J＝6.8Hz,3H)。

Intermediate VII-47-N: LC-MS (ESI): r_T＝1.97min,C₂₉H₂₈BrF₂N₅O₄Calculated mass of S659.1, found M/z 660.2[ M + H [)]⁺. Chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO) ₂EtOH 70:30 at 3.0 g/min; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100 bar, R_T＝8.83min)。¹H NMR(400MHz,CDCl₃)δ8.67(s,0.3H),8.66(s,0.7H),8.24(s,0.6H),7.83(d,J＝2.8Hz,1H),7.51(d,J＝6.4Hz,0.4H),7.46(d,J＝3.2Hz,0.6H),7.43(s,0.4H),7.12-7.03(m,2H),6.19(s,0.7H),6.04(d,J＝2.8Hz,0.3H),4.52-4.46(m,2H),4.17-4.06(m,1H),3.63(s,1H),3.61(s,2H),3.12-3.05(m,1H),2.46(s,3H),2.27-2.11(m,4H),2.08-1.93(m,2H),1.90-1.66(m,2H),1.45(t,J＝7.2Hz,3H)。

Compound VII-48-B:

(trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (4- (2-methoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VII-48:

(trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (4- (2-methoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

LC-MS(ESI)：R_T＝1.86min，C₂₈H₂₈ClFN₄O₅Calculated mass of S586.1, found M/z 586.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.41(d,J＝3.6Hz,0.6H),8.95(s,0.4H),8.00-7.93(m,2H),7.44-7.40(m,1H),7.37-7.32(m,1H),7.24-7.18(m,1H),6.02(s,0.4H),5.91(d,J＝3.6Hz,0.6H),3.90-3.84(m,0.4H),3.65-3.60(m,3.6H),3.53-3.50(m,5H),2.89-2.87(m,0.4H),2.76-2.69(m,0.6H),2.23(s,3H),2.17-2.07(m,2H),1.94-1.77(m,3H),1.68-1.62(m,1H),1.58-1.45(m,2H)。

The racemic mixture of (trans) -methyl 4- (2-chloro-4-fluorophenyl) -6- (4- (4- (2-methoxy-2-oxoethyl) -5-methyloxazol-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-48(180mg, 95% purity, 0.291mmol) was purified by chiral preparative HPLC (separation conditions: superchiral S-AD 5 μm 21 × 250mm, mobile phase: hex: EtOH: formic acid 75:25:0.05, at 20mL/min, temperature: 35 ℃ and wavelength: 220nm) of the sample to be separated, to give compound VII-48-A (65mg, obtained from Yu) as a yellow solid. ¹Purity by H NMR 95%, 36% yield, 98.6% stereopurity) and the title compound VII-48-B (70mg, obtained from¹Purity by H NMR 95%, 39% yield, 96.4% stereopure).

Intermediate VII-48-A: LC-MS (ESI): r_T＝1.84min，C₂₈H₂₈ClFN₄O₅Calculated mass of S586.1, found M/z 587.1[ M + H ]]⁺. Chiral analysis (analysis conditions: column: Chiralpak column: IE 5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2, at 1 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝10.302min)。¹H NMR(400MHz,DMSO-d₆)δ9.44(br s,0.6H),8.97(s,0.4H),7.99(s,1.6H),7.94(s,0.4H),7.43-7.41(m,1H),7.37-7.32(m,1H),7.23-7.19(m,1H),6.02(s,0.4H),5.91(s,0.6H),3.91-3.85(m,0.4H),3.68-3.57(m,3.6H),3.53-3.50(m,5H),2.92-2.86(m,0.4H),2.75-2.69(m,0.6H),2.23(s,3H),2.14-2.07(m,2H),2.01-1.74(m,3.4H),1.68-1.65(m,0.6H),1.59-1.45(m,2H)。

Intermediate VII-48-B: LC-MS (ESI): r_T＝1.84min，C₂₈H₂₈ClFN₄O₅Calculated mass of S586.1, found M/z 587.1[ M + H ]]⁺. Chiral analysis (analysis conditions: column: Chiralpak column: IE 5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2, at 1 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝11.581min)。¹H NMR(400MHz,DMSO-d₆)δ9.43(br s,0.6H),8.97(s,0.4H),7.99(s,1.6H),7.94(s,0.4H),7.43-7.41(m,1H),7.37-7.32(m,1H),7.23-7.19(m,1H),6.02(s,0.4H),5.91(s,0.6H),3.90-3.85(m,0.4H),3.65-3.62(m,3.6H),3.53-3.50(m,5H),2.92-2.86(m,0.4H),2.75-2.69(m,0.6H),2.23(s,3H),2.14-2.07(m,2H),2.01-1.74(m,3.4H),1.68-1.65(m,0.6H),1.59-1.46(m,2H)。

Compound VII-49-a:

methyl 4- (2-chloro-3, 4-difluorophenyl) -6- ((trans) -4- (5- (2-methoxy-2-oxoethyl) pyrimidin-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VII-49:

methyl 4- (2-chloro-3, 4-difluorophenyl) -6- ((trans) -4- (5- (2-methoxy-2-oxoethyl) pyrimidin-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

¹H NMR(400MHz,CDCl₃)δ8.63-8.62(m,1.7H),8.60-8.58(m,0.3H),8.24(br s,0.7H),7.84-7.83(m,1H),7.52-7.51(m,0.3H),7.46-7.45(m,0.7H),7.39-7.37(m,0.3H),7.12-7.09(m,1H),7.05-7.00(m,1H),6.20(s,0.7H),6.06(d,J＝2.4Hz,0.3H),4.10-4.05(m,0.7H),3.87-3.84(m,0.3H),3.75(s,3H),3.64(s,1H),3.62(s,2H),3.61(s,2H),3.07-2.97(m,1H),2.24-2.20(m,3H),2.12-2.07(m,1H),1.94-1.87(m,2H),1.83-1.74(m,1H),1.69-1.64(m,1H)。

A racemic mixture of methyl 4- (2-chloro-3, 4-difluorophenyl) -6- ((trans) -4- (5- (2-methoxy-2-oxoethyl) pyrimidin-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-49(100mg, 95% purity, 0.158mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IG 4.6 μm 20: 250 mm; mobile phase: MeOH: DCM: DEA ═ 90:10:0.3 at 18 mL/min; temperature: 30 ℃; wavelength: 254nm) to give VII-49-A as a yellow solid (40mg from VII-49-A as a yellow solid¹H NMR 95% pure, 40% yield, 100% stereopure) and VII-49-B (40mg, obtained from¹Purity by H NMR 95%, 40% yield,100% stereopure).

Intermediate VII-49-A: LC-MS (ESI): r_T＝1.82min,C₂₈H₂₆ClF₂N₅O₄Calculated mass of S601.1, M/z found 602.3[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG 5um 4.6 x 250 mm; mobile phase: MeOH: DCM: DEA: 90:10:0.2 at 1 mL/min; temperature: 30 ℃ C.; wavelength: 254nm, R: 1.2:. sup._T＝7.300min)。¹H NMR(400MHz,CDCl₃)δ8.63-8.62(m,2H),8.24(s,0.7H),7.84-7.83(m,1H),7.52-7.50(m,0.3H),7.46-7.45(m,0.7H),7.38-7.37(m,0.3H),7.12-7.09(m,1H),7.03-6.98(m,1H),6.20(s,0.7H),6.06(d,J＝2.8Hz,0.3H),4.10-4.05(m,0.7H),3.87-3.84(m,0.3H),3.75(s,3H),3.64(s,1H),3.62(s,2H),3.61(s,2H),3.07-3.04(m,1H),2.28-2.20(m,3H),2.12-2.07(m,1H),1.96-1.89(m,2H),1.84-1.75(m,1H),1.67-1.58(m,1H)。

Intermediate VII-49-B: LC-MS (ESI): r_T＝1.81min,C₂₈H₂₆ClF₂N₅O₄Calculated mass of S601.1, M/z found 602.3[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG 5um 4.6 x 250 mm; mobile phase: MeOH: DCM: DEA: 90:10:0.2 at 1 mL/min; temperature: 30 ℃ C.; wavelength: 254nm, R: 1.2:. sup. _T＝10.123min)。¹H NMR(400MHz,CDCl₃)δ8.63-8.62(m,2H),8.24(br s,0.7H),7.84-7.83(m,1H),7.52-7.50(m,0.3H),7.46-7.45(m,0.7H),7.38-7.37(m,0.3H),7.12-7.09(m,1H),7.03-6.98(m,1H),6.20(s,0.7H),6.06(d,J＝2.8Hz,0.3H),4.10-4.05(m,0.7H),3.87-3.84(m,0.3H),3.75(s,3H),3.64(s,1H),3.62(s,2H),3.61(s,2H),3.07-3.04(m,1H),2.28-2.20(m,3H),2.12-2.07(m,1H),1.96-1.89(m,2H),1.84-1.75(m,1H),1.67-1.58(m,1H)。

Compound VII-50-a:

methyl 4- (2-chloro-4-fluorophenyl) -6- ((trans) -4- (5- (2-methoxy-2-oxoethyl) pyrimidin-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer + acid + ethyl ester)

Intermediate VII-50:

methyl 4- (2-chloro-4-fluorophenyl) -6- ((trans) -4- (5- (2-methoxy-2-oxoethyl) pyrimidin-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B.

¹H NMR(400MHz,CDCl₃)δ8.63(s,0.8H),8.62(s,1.2H),8.22(br s,0.7H),7.84-7.82(m,1H),7.50(d,J＝3.2Hz,0.4H),7.44(d,J＝3.2Hz,0.6H),7.40(br s,0.3H),7.33-7.27(m,1H),7.14-7.12(m,1H),6.96-6.89(m,1H),6.20(s,0.6H),6.06(d,J＝5.2Hz,0.4H),4.09-4.03(m,0.6H),3.87-3.83(m,0.4H),3.75(s,3H),3.63(s,1H),3.62(s,2H),3.61(s,2H),3.07-3.00(m,1H),2.24-2.08(m,4H),1.97-1.88(m,2H),1.82-1.76(m,1H),1.73-1.65(m,1H)。

A racemic mixture of methyl 4- (2-chloro-4-fluorophenyl) -6- ((trans) -4- (5- (2-methoxy-2-oxoethyl) pyrimidin-2-yl) cyclohexyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-50(120mg, 95% purity, 0.195mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA4.6 μm 20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 40:60:0.3 at 10 mL/min; temperature: 30 ℃; wavelength: 254nm) to give VII-50-A (mixture of acid and ethyl ester, 30mg, 25% yield, 100% stereopurity) and VII-50-B (50mg, is obtained from¹Purity by H NMR 95%, 42% yield, 98% stereopurity).

Mixture VII-50-A: chiral analysis (column: Chiralpak IA 5um 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 40:60:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝3.223min，7.171min)。LC-MS(ESI)：R_T＝1.40min,1.83min,C₂₈H₂₇ClFN₅O₄Calculated mass of S584.1, M/z found 570.1[ M + H-14]⁺,598.2[M+H+14]⁺。

Intermediate VII-50-B: LC-MS (ESI): r_T＝1.78min，C₂₈H₂₇ClFN₅O₄Calculated mass of S583.1, found M/z 584.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5um 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 40:60:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝13.619min)。¹H NMR(400MHz,CDCl₃)δ8.63(s,0.8H),8.62(s,1.2H),8.22(br s,0.7H),7.84-7.83(m,1H),7.50(d,J＝6.0Hz,0.4H),7.45(d,J＝3.2Hz,0.6H),7.40(br s,0.3H),7.35-7.31(m,1H),7.14-7.12(m,1H),6.96-6.89(m,1H),6.20(s,0.6H),6.06(d,J＝2.8Hz,0.4H),4.10-4.04(m,0.6H),3.89-3.82(m,0.4H),3.75(s,3H),3.64(s,1H),3.62(s,2H),3.61(s,2H),3.06-2.98(m,1H),2.27-2.08(m,4H),1.97-1.67(m,4H)。

Compound VIII-1:

methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (3, 4-difluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

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)。

The stereoisomeric mixture of VIII-1(600mg, 1.13mmol) was passed through chiral preparative SFC (separation conditions: column: Chiralpak IG 5 μm20 x 250 mm; mobile phase: CO₂50g/min MeOH (DEA) (80: 20: 0.2); the column temperature is 40 ℃; wavelength: 214 nm; back pressure: 100 bar) to provide the title compound VIII-1-a (260mg, 43% yield, 100% stereopure) and VIII-1-B (270mg, 45% yield, 98.6% stereopure) as yellow solids.

VIII-1-A: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: 100 bar, 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)。

VIII-1-B: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 VIII-2:

ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝2.143min，C₂₇H₃₃FN₄O₄Calculated mass of S528.2, found M/z 529.1[ M + H ]]⁺。¹H NMR(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)。

A stereoisomeric mixture of ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VIII-2(3.0g, 85% purity, 4.82mmol) was separated by chiral preparative HPLC (column: Chiralpak IC 5 μm 20mm 250 mm; mobile phase: Hex: EtOH: DEA ═ 98:2:0.3 at 22 mL/min; temperature: 30 ℃; wavelength: 214nm), to provide the title compounds VIII-2-A (950mg, 32% yield, 90% purity, 100% stereopure) and VIII-2-B (650mg, 23% yield, 90% purity, 99.3% stereopure) as yellow solids.

VIII-2-A chiral HPLC (column: Chiralpak IC 5 μm 4.6mm 250 mm; mobile phase: Hex: EtOH: DEA ═ 98:2:0.2, at 1 mL/min; column temperature: 40 ℃; wavelength: 254nm, R: 1 ℃; chiral HPLC, column: Chiralpak IC 5 μm 4.6 mm:, 250 mm; mobile phase: Hex: EtOH: DEA:, 2: 0.2; column temperature_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)。

VIII-2-B chiral HPLC (column: Chiralpak IC 5 μm 4.6mm 250 mm; mobile phase: Hex: EtOH: DEA ═ 98:2:0.2 at 1 mL/min; column temperature: 40 ℃; wavelength: 254nm, R: 1 ℃; chiral HPLC_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 VIII-3:

ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (4-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝2.169min，C₂₇H₃₃FN₄O₄Calculated mass of S528.2, found M/z 529.1[ M + H ]]⁺。¹H NMR(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)。

A stereoisomeric mixture of VIII-3(6.00g, 90% purity, 10.2mmol) was passed through a chiral preparative SFC (column: Chiralpak IG 5 μm 20mm 250 mm; mobile phase: CO₂50g/min MeOH (DEA) (75: 25: 0.3); column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar) to provide the title compounds VIII-3-a (2.70g, 90% pure, 45% yield, 100% stereopure) and VIII-3-B (2.60g, 90% pure, 43% yield, 99.2% stereopure) as yellow solids.

VIII-3-A chiral assay (column: Chiralpak IG 5 μm 4.6mm 250 mm; mobile phase: CO) ₂MeOH: DEA: 75:25:0.2 at 3.00 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar, 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)。

VIII-3-B chiral assay (column: Chiralpak IG 5 μm 4.6mm 250 mm; mobile phase: CO)₂MeOH: DEA: 75:25:0.2 at 3.00 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar, 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 VIII-4:

methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

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)。

A stereoisomeric mixture of methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VIII-4(5.0g, 90% purity, 8.77mmol) was subjected to chiral preparative HPLC (separation conditions: column: Chiralpak IG 5 μm 20 x 250 mm; mobile phase: CO)₂50g/min MeOH (DEA) (75: 25: 0.3); temperature: 30 ℃; wavelength: 230nm) to give the title compounds VIII-4-A (2.2g, 90% pure, 44% yield, 99.1% stereopure) and VIII-4-B (2.0g, 90% pure, 40% yield, 100% stereopure) as yellow solids.

VIII-4-A: chiral analysis: (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH 75:25 at 3 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar, 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)。

VIII-4-B: chiral analysis: (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH 75:25 at 3 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar, 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 VIII-5-B:

methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (4-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VIII-5-2:

methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (4-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B. 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)。

A stereoisomeric mixture of methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (4-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VIII-5-2(2.00g, 3.88mmol) was passed through chiral preparative SFC (column: Chiralpak IG 5 μm20 x 250 mm; mobile phase: CO ₂50g/min MeOH (DEA) (75: 25: 0.3); column temperature: 40 ℃; wavelength: 214 nm; back pressure: 100 bar) was added to the reaction solution to afford the title compound VIII-5-2A (684mg, 34%Yield, 99.3% stereopure) and VIII-5-2B as a yellow solid (607mg, 30% yield, 100% stereopure).

VIII-5-2A: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 IG 5 μm 4.6 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＝3.81min)。

VIII-5-2B: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 IG 5 μm 4.6 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 VIII-6:

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)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝1.55min,C₂₅H₂₈ClFN₄O₄Calculated mass of S534.2M/z found 535.5[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.55(d,J＝3.6Hz,0.8H),9.14(s,0.2H),8.00-7.98(m,1.7H),7.93(d,J＝3.2Hz,0.3H),7.40-7.31(m,2H),7.21-7.15(m,1H),6.07(s,0.2H),5.97(d,J＝3.6Hz,0.8H),4.15-3.98(m,2.2H),3.84-3.76(m,0.8H),3.52(s,2.4H),3.51(s,0.6H),2.82-2.71(m,2H),1.99-1.65(m,4H),1.44(s,9H)。

The stereoisomeric mixture of VIII-6(1.95g, 3.65mmol) was passed through a chiral preparative SFC (column: Chiralpak IG 5 μm 20 × 250 mm; mobile phase: CO ₂MeOH 70:30 at 50 g/min; column temperature: 41.1 ℃; wavelength: 214 nm; back pressure: 100 bar) to provide the title compound VIII-6-A (910mg, 47% yield, 100% stereopure) and VIII-6-B (960mg, 49% yield, 99.1% stereopure).

VIII-6-A:LC-MS(ESI)：R_T＝1.96min,C₂₅H₂₈ClFN₄O₄Calculated mass of S534.2, found value of M/z 535.2[ M + H]⁺. Chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 2.999 g/min; temperature: 40 ℃; wavelength: 230nm, R_T＝2.74min)。

VIII-6-B:LC-MS(ESI)：R_T＝1.96min,C₂₅H₂₈ClFN₄O₄Calculated mass of S534.2, found value of M/z 535.3[ M + H]⁺. Chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 2.999 g/min; temperature: 40.4 ℃; wavelength: 230nm, R_T＝3.60min)。

Compound VIII-7:

methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydro-pyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

The stereoisomeric mixture of VIII-7(7.00g, 13.1mmol) was further separated by chiral preparative HPLC (column: Chiralpak IA 5 μm 20 × 250 mm; mobile phase: Hex: EtOH ═ 90:10 at 23 mL/min; temperature: 30 ℃; wavelength: 230nm) to afford the stereoisomers VIII-7-A (2.44g, 35% yield) and VIII-7-B (1.56g, 22% yield).

VIII-7-A 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)。

VIII-7-B:LC-MS(ESI)：R_T＝2.191min,C₂₅H₂₈ClFN₄O₄Calculated mass of S534.2M/z found 534.9[ M + H]⁺. Chiral HPLC (column: Chiralpak IA 5 μm 4.6 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 VIII-8:

ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝2.01min，C₂₆H₃₀ClFN₄O₄Calculated mass of S548.2, found M/z 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)。

A stereoisomeric mixture of ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VIII-8(2.50g, 4.55mmol) was subjected to chiral preparative HPLC (separation conditions: column: Chiralpak IG 5 μm 20 x 250 mm; mobile phase: CO₂MeOH 70:30 at 50 g/min; temperature: 30 ℃; wavelength: 214 nm; back pressure: 100 bar) to give the compounds VIII-8-A (1.00g, 40% yield, 100% stereopure) and VIII-8-B (1.20g, 48% yield, 99.8% stereopure) as yellow solids.

VIII-8-A: chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 3 g/min; temperature: 30 ℃; wavelength: 230nm, back pressure: 100 bar; r_T＝2.5min)。

VIII-8-B: chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 3 g/min; temperature: 30 ℃; wavelength: 230nm, back pressure: 100 bar; r_T＝3.4min)。

Compound VIII-9:

ethyl 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)

The title compound was synthesized by a similar procedure using method B.

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)。

A stereoisomeric mixture of ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VIII-9(1.00g, 1.82mmol) was passed through chiral preparative SFC (column: Chiralpak IG 5 μm20 x 250 mm; mobile phase: CO₂MeOH 75:25 at 50 g/min; column temperature: 39.8 ℃; wavelength: 214 nm; back pressure: 100 bar) to provide compounds VIII-9-a (410mg, 41% yield, 100% stereopure) and VIII-9-B (450mg, 45% yield, 100% stereopure) as yellow solids.

VIII-9-A chiral assay (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO ₂MeOH 80:20 at 3 g/min; column temperature: 40 ℃; wavelength: 214 nm; back pressure: 100 bar; r_T＝4.69min)。

VIII-9-B chiral assay (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO₂MeOH 80:20 at 3 g/min; column temperature: 40 ℃; wavelength: 214 nm; back pressure: 100 bar; r_T＝5.92min)。

Compound VIII-10:

methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

¹H NMR(400MHz,CDCl₃)δ8.16(br s,0.5H),7.82(d,J＝3.2Hz,1H),7.51(d,J＝2.8Hz,0.5H),7.46(d,J＝3.2Hz,1H),7.10-6.98(m,2H),6.18(s,0.5H),6.06(s,0.5H),4.41-4.16(m,2H),3.97-3.91(m,0.4H),3.74-3.69(m,0.6H),3.61(s,1.2H),3.60(s,1.8H),3.02-2.78(m,2H),2.08-1.80(m,2H),1.73-1.58(m,2H),1.50(s,9H)。

The stereoisomeric mixture of VIII-10(18.0g, 32.6mmol) was passed through a chiral preparative SFC (column: chiralpak IG 5 μm20 x 250 mm; mobile phase: CO₂MeOH 70:30 at 50 g/min; co-solvent: MeOH; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100 bar) to give the title compounds VIII-10-A (8.0g, 40% yield, 100% stereopurity) and VIII-10-B (8.0g, 40%, 100% stereopurity).

VIII-10-A: chiral SFC: (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH: DEA: 70:30:0.2 at 2.999 g/min; column temperature: 39.6 ℃; wavelength: 230nm, back pressure: 100 bar, R_T＝2.37min)。¹H NMR(400MHz,DMSO-d₆)δ9.62(br s,0.7H),9.20(s,0.3H),8.01-7.99(m,1.7H),7.94(d,J＝3.6Hz,0.3H),7.49-7.42(m,1H),7.23-7.15(m,1H),6.03(s,0.3H),5.94(s,0.7H),4.18-3.99(m,2.3H),3.85-3.76(m,0.7H),3.54(s,2H),3.53(s,1H),2.92-2.65(m,2H),1.96-1.51(m,4H),1.44(s,9H)。

VIII-10-B: chiral SFC: (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO) ₂MeOH: DEA: 70:30:0.2 at 2.999 g/min; column temperature: 40 ℃; wavelength: 230nm, back pressure: 100 bar, R_T＝3.44min)。¹H NMR(400MHz,DMSO-d₆)δ9.62(br s,0.7H),9.20(s,0.3H),8.01-7.99(m,1.7H),7.94(d,J＝3.6Hz,0.3H),7.49-7.42(m,1H),7.23-7.15(m,1H),6.03(s,0.3H),5.94(s,0.7H),4.18-3.99(m,2.3H),3.85-3.76(m,0.7H),3.54(s,1H),3.53(s,2H),2.92-2.65(m,2H),1.96-1.51(m,4H),1.44(s,9H)。

Compound VIII-11-6:

ethyl 6- (1- (tert-butoxycarbonyl) -2-methylpiperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B. LC-MS (ESI): RT 2.13min, C₂₇H₃₁ClF₂N₄O₄Calculated mass of S580.2, found M/z 581.0[ M + H [ ]]⁺。¹HNMR(400MHz,DMSO-d₆)δ9.61-9.59(m,1H),8.00-7.98(m,1.7H),7.94(d,J＝3.2Hz,0.3H),7.49-7.43(m,1H),7.21-7.16(m,1H),6.05-6.02(m,0.3H),5.95-5.91(m,0.7H),4.47-4.29(m,1H),4.07-3.94(m,4H),3.02-2.82(m,1H),1.99-1.55(m,3H),1.43(s,9H),1.36-1.23(m,1H),1.18-1.16(m,3H),1.10-1.07(m,3H)。

Compound VIII-12:

ethyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

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)。

A stereoisomeric mixture of VIII-12(13.0g, 22.9mmol) was separated by chiral preparative HPLC (column: Chiralpak IA 5 μm 20 × 250 mm; mobile phase: Hex: EtOH 95:5, 25mL/min, temperature: 30 ℃; wavelength: 214nm) to afford compound VIII-12-A (5g, 38% yield, 99.7% stereopure) and VIII-12-B (5g, 38% yield, 98.4% stereopure).

VIII-12-A:LC-MS(ESI)：R_T＝2.05min,C₂₆H₂₉ClF₂N₄O₄Calculated mass of S566.2, found M/z 567.6[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 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)。

VIII-12-B:LC-MS(ESI)：R_T＝2.05min,C₂₆H₂₉ClF₂N₄O₄Calculated mass of S566.2, found M/z 567.6[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 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 VIII-13:

methyl 4- (4-bromo-2-chlorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝2.13min,C₂₅H₂₈BrClN₄O₄Calculated mass of S594.1, found M/z 594.8[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.13(s,0.4H),7.82(t,J＝2.8Hz,1H),7.56-7.54(m,1H),7.50(d,J＝2.8Hz,0.6H),7.46-7.42(m,1H),7.36-7.31(m,1H),7.19-7.16(m,1H),6.18(s,0.5H),6.04(d,J＝2.4Hz,0.5H),4.35-4.17(m,2.4H),3.97-3.90(m,0.6H),3.61(s,1.5H),3.59(s,1.5H),2.90-2.81(m,2H),1.96-1.62(m,4H),1.50(s,9H)。

A stereoisomeric mixture of VIII-13(1.30g, 90% purity, 1.96mmol) was separated by chiral preparative HPLC (column: Chiralpak AD 5 μm 20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 15 mL/min; column temperature: 40 ℃; wavelength: 214nm) to provide the title compound VIII-13-2a (460mg, 35% yield, purity from HNMR 90%, 100% stereopurity) and VIII-13-2b (480mg, 39% yield, purity from HNMR 95%, 96.2% stereopurity) as yellow solids.

VIII-13-2a：LC-MS(ESI)：R_T＝2.18min,C₂₅H₂₈BrClN₄O₄Calculated mass of S594.1, found M/z 594.8[ M + H ]]⁺. Chiral HPLC (column: Chiralpak AD5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 70:30:0.2 at 1 mL/min; column temperature: 40 ℃; wavelength: 230nm, R ℃; column temperature: 40 ℃; column temperature: R-_T＝4.34min)。¹H NMR(400MHz,CDCl₃)δ8.13(s,0.5H),7.82(t,J＝3.2Hz,1H),7.56(t,J＝2.4Hz,1H),7.50(d,J＝3.2Hz,0.5H),7.45(d,J＝3.2Hz,0.5H),7.43(d,J＝2.4Hz,0.5H),7.36-7.30(m,1H),7.19-7.16(m,1H),6.18(s,0.5H),6.04(d,J＝2.4Hz,0.5H),4.34-4.13(m,2.5H),3.96-3.90(m,0.5H),3.61(s,1.5H),3.59(s,1.5H),2.91-2.82(m,2H),1.96-1.67(m,3H),1.62-1.57(m,1H),1.50(s,9H)。

VIII-13-2b：LC-MS(ESI)：R_T＝2.15min,C₂₅H₂₈BrClN₄O₄Calculated mass of S594.1, found M/z 594.8[ M + H ]]⁺. Chiral HPLC (column: Chiralpak AD5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.2 at 1 mL/min; column temperature: 40 ℃; wavelength: 230nm, R ℃; column temperature: 40 ℃; R-_T＝5.60min)。¹H NMR(400MHz,CDCl₃)δ8.13(s,0.5H),7.82(t,J＝3.6Hz,1H),7.56(t,J＝2.4Hz,1H),7.50(d,J＝3.2Hz,0.5H),7.45(d,J＝2.8Hz,0.5H),7.42(d,J＝2.4Hz,0.5H),7.37-7.31(m,1H),7.19-7.16(m,1H),6.18(s,0.5H),6.04(d,J＝2.4Hz,0.5H),4.35-4.14(m,2.5H),3.96-3.90(m,0.5H),3.61(s,1.5H),3.59(s,1.5H),2.92-2.81(m,2H),2.12-2.04(m,0.5H),1.96-1.64(m,3.5H),1.50(s,9H)。

Compound VIII-14:

methyl 4- (2-bromo-3, 4-difluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝1.96min,C₂₅H₂₇BrF₂N₄O₄Calculated mass 596.1 of S, M/z found 599.3[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.58(d,J＝3.2Hz,0.7H),9.16(s,0.3H),8.00-7.98(m,1.7H),7.93-7.92(m,0.3H),7.51-7.36(m,1H),7.23-7.12(m,1H),6.00(s,0.3H),5.92(d,J＝3.6Hz,0.7H),4.16-4.02(m,2.3H),3.82-3.76(m,0.7H),3.52(s,2.1H),3.51(s,0.9H),2.78(br s,2H),1.97-1.50(m,4H),1.44(s,9H)。

The stereoisomeric mixture of VIII-14(950mg, 1.59mmol) was passed through a chiral preparative SFC (column: Chiralpak IG 5 μm 20 × 250 mm; mobile phase: CO₂50g/min MeOH (DEA) (70: 30: 0.2); column temperature: 41.1 ℃; wavelength: 214 nm; back pressure: 100 bar) to provide the title compounds VIII-14-a (450mg, 47% yield, 100% stereopure) and VIII-14-B (460mg, 48% yield, 100% stereopure) as yellow solids.

VIII-14-A:LC-MS(ESI)：R_T＝1.85min,C₂₅H₂₇BrF₂N₄O₄Calculated mass 596.1 of S, M/z found 597.5[ M + H ]⁺. Chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH: DEA: 70:30:0.2 at 2.999 g/min; temperature: 40 ℃; wavelength: 230nm, R_T＝2.72min)。¹H NMR(400MHz,DMSO-d₆)δ9.52(br s,0.7H),9.15(s,0.3H),8.00-7.92(m,2H),7.51-7.45(m,1H),7.23-7.13(m,1H),6.01(s,0.3H),5.92(s,0.7H),4.14-3.99(m,2.3H),3.82-3.76(m,0.7H),3.52(s,3H),2.86-2.71(m,2H),1.96-1.50(m,4H),1.44(s,9H)。

VIII-14-B:LC-MS(ESI)：R_T＝1.85min,C₂₅H₂₇BrF₂N₄O₄Calculated mass 596.1 of S, M/z found 597.5[ M + H]⁺. Chiral analysis (column: Chiralpak IG 5 μm 4.6 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)。¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝3.6Hz,0.7H),9.15(s,0.3H),8.00-7.92(m,2H),7.51-7.44(m,1H),7.23-7.12(m,1H),6.01(s,0.3H),5.92(d,J＝3.2Hz,0.7H),4.16-3.99(m,2.3H),3.82-3.75(m,0.7H),3.52-3.51(m,3H),2.92-2.71(m,2H),1.96-1.49(m,4H),1.44(s,9H)。

Compound VIII-15:

methyl 4- (2-bromo-3-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

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)。

A stereoisomeric mixture of methyl 4- (2-bromo-3-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VIII-15(6.40g, 107mmol) was passed through chiral preparative SFC (column: Chiralpak IG 5 μm 20 x 250 mm; mobile phase: CO₂MeOH 70:30 at 50 g/min; column temperature: 30 ℃; wavelength: 214nm, back pressure: 100 bar) to provide the title compounds VIII-15-a (2.60g, 38% yield, 100% stereopure) and VIII-15-B (2.90g, 38% yield, 99.5% stereopure) as yellow solids.

VIII-15-A chiral assay (column: Chiralpak IG 5 μm 4.6 x 250 mm; CO)₂MeOH 70:30 at 3.0 g/min; column temperature: 40 ℃; wavelength: 254nm, back pressure: 100 bar, 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)。

VIII-15-B chiral assay (column: Chiralpak IG 5 μm 4.6 x 250 mm; CO)₂MeOH 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 VIII-16-2B:

methyl 4- (2-bromo-4-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VIII-16-1:

methyl 4- (2-bromo-4-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝2.207min，C₂₅H₂₈BrFN₄O₄Calculated mass of S578.1, found M/z 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)。

A stereoisomeric mixture of methyl 4- (2-bromo-4-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VIII-16-1(5.00g, 8.65mmol) was separated by chiral SFC (column: Chiralpak IG 5 μm 20 x 250 mm; mobile phase: CO2: MeOH ═ 70:30, at 50g/min, temperature: 30 ℃; wavelength: 214nm, back pressure: 100 bar) to give VIII-16-2A (1.6g, 32% yield, 100% stereopurity) as a yellow solid and VIII-16-2B (1.8g, 36% yield, 100% stereopurity) as a yellow solid.

VIII-16-2A chiral HPLC analysis (column: Chiralpak IG 5 μm 4.6 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)。

VIII-16-2B chiral HPLC analysis (column: Chiralpak IG 5 μm 4.6 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 VIII-17:

ethyl-6- (1- (tert-butoxycarbonyl) pyrrolidin-3-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 4 stereoisomers)

The title compound was synthesized by a similar procedure using method B.

LC-MS(ESI)：R_T＝2.144min,C₂₅H₂₇ClF₂N₄O₄Calculated mass of S552.1, M/z found 553.1[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.27(s,0.3H),7.77-7.73(m,1H),7.46-7.35(m,1.7H),7.09-6.97(m,2H),6.15(s,0.3H),6.06-6.01(m,0.7H),4.76-4.65(m,0.3H),4.47-4.40(m,0.7H),4.04-3.95(m,2H),3.71-3.31(m,4H),2.39-1.99(m,2H),1.47-1.42(m,9H),1.10-1.04(m,3H)。

Compound VIII-18-2:

ethyl 6- (1- (tert-butoxycarbonyl) azetidin-3-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B. LC-MS (ESI): r_T＝1.657min,C₂₄H₂₅ClF₂N₄O₄Calculated mass of S538.1, M/z found 539.1[ M + H [ ].]⁺。¹H NMR(400MHz,CDCl₃)δ8.57(s,0.1H),7.85-7.83(m,1H),7.54(d,J＝2.8Hz,0.9H),7.47-7.45(m,1H),7.10-7.07(m,2H),6.21(s,0.1H),6.10(d,J＝2.8Hz,0.9H),4.89-4.85(m,0.1H),4.64-4.56(m,0.9H),4.40-4.25(m,3H),4.17-4.13(m,1H),4.06(q,J＝7.2Hz,2H),1.49(s,9H),1.13(t,J＝7.2Hz,3H)。

Compound VIII-19-4:

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)

The title compound was synthesized as a yellow solid by a similar procedure using method B. LC-MS (ESI): r_T＝1.56min，C₂₃H₂₄ClFN₄O₄Calculated mass of S506.1, M/z found 507.4[ M + H [ ]]⁺。

A stereoisomeric mixture of VIII-19-4(9.00g, 17.8mmol) was separated by chiral preparative HPLC (column: Chiralpak IC 5um 20 × 250mm, mobile phase: MeOH: EtOH ═ 70:30, at 20mL/min, temperature: 30 ℃, wavelength: 214nm) to afford compounds VIII-19-4A (3.5g, 39% yield, 100% ee) and VIII-19-4B (3.58g, 40% yield, 99.4% ee).

Compound VIII-19-4A: LC-MS (ESI): r_T＝1.55min，C₂₃H₂₄ClFN₄O₄Calculated mass of S506.1, M/z found 507.6[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IC 5 μm 4.6 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 VIII-19-4B: LC-MS (ESI): r_T＝1.56min，C₂₃H₂₄ClFN₄O₄Calculated mass of S506.1, M/z found 507.6[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IC 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH ═ 70:30, at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝7.158min)；¹H NMR(400MHz,DMSO-d₆)δ9.66-9.65(d,J＝2.8Hz,1H),8.04-8.02(m,2H),7.42-7.38(m,2H),7.21(dt,J＝8.8,3.2Hz,1H),5.94(d,J＝2.8Hz,1H),4.48-4.41(m,1H),4.13-3.97(m,4H),3.52(s,3H),1.42(s,9H)。

Compound VIII-20-6B:

methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (5- (4- (ethoxycarbonyl) piperidin-1-yl) pyrimidin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer) intermediate VIII-20-6:

Methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (5- (4- (ethoxycarbonyl) piperidin-1-yl) pyrimidin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B. LC-MS (ESI): r_T＝1.933min,C₃₂H₃₅ClFN₇O₄Calculated mass of S667.2, found M/z 668.1[ M + H ]]+。¹H NMR(400MHz,CDCl₃)8.15(s,1H),8.14(s,1H),7.80(d,J＝3.2Hz,0.5H),7.76(d,J＝3.2Hz,0.5H),7.46(d,J＝3.2Hz,0.5H),7.42(d,J＝3.2Hz,0.5H),7.33-7.29(m,1H),7.14-7.11(m,1H),6.97-6.89(m,1H),6.20(s,0.5H),6.07(d,J＝2.4Hz,0.5H),4.91-4.75(m,2H),4.30-4.24(m,0.5H),4.17(q,J＝7.2Hz,2H),4.05-3.99(m,0.5H),3.62(s,1.5H),3.61(s,1.5H),3.38-3.32(m,2H),3.05-2.93(m,2H),2.75-2.69(m,2H),2.42-2.36(m,1H),2.06-2.03(m,3H),1.96-1.89(m,3H),1.79-1.69(m,2H),1.27(t,J＝7.2Hz,3H)。

A racemic mixture of methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (5- (4- (ethoxycarbonyl) piperidin-1-yl) pyrimidin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VIII-20-6(200mg, 90% pure, 0.269mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE 5um 20. about.250 mm; mobile phase: MeOH: DCM: DEA ═ 80:20:0.3 at 14 mL/min; temperature: 30 ℃ C.; wavelength: 254nm) to give VIII-20-6A as a yellow solid (90mg, 90% pure from 1H NMR), 45% yield, 100% stereopure) and VIII-20-6B (80mg, 90% purity from 1H NMR, 40% yield, 99.7% stereopure).

VIII-20-6A: chiral analysis (column: Chiralpak IE 5 μm 4.6 × 250 mm; mobile phase: MeOH: DCM: DEA: 80:20:0.2 at 1 mL/min; temperature: 30 ℃ C.; wavelength: 254nm, R: 1 mL/min; chiral analysis of chiral molecules: 4.6: (chiral molecules: 250) and (chiral molecules: 1 g/min; chiral molecules: 1 g _T＝8.560min)。1H NMR(400MHz,CDCl₃)δ8.15(s,1H),8.14(s,1H),7.81(d,J＝3.2Hz,0.5H),7.76(d,J＝3.2Hz,0.5H),7.47(d,J＝3.2Hz,0.5H),7.43(d,J＝3.2Hz,0.5H),7.32-7.29(m,1H),7.15-7.12(m,1H),6.97-6.89(m,1H),6.20(s,0.5H),6.07(d,J＝2.8Hz,0.5H),4.90-4.75(m,2H),4.31-4.25(m,0.5H),4.17(q,J＝7.2Hz,2H),4.05-3.99(m,0.5H),3.63(s,1.5H),3.61(s,1.5H),3.39-3.33(m,2H),2.98-2.94(m,2H),2.76-2.69(m,2H),2.43-2.37(m,1H),2.08-2.02(m,3H),1.96-1.89(m,3H),1.79-1.70(m,2H),1.28(t,J＝7.2Hz,3H)。

VIII-20-6B: chiral analysis (column: Chiralpak IE 5 μm 4.6 × 250 mm; mobile phase: MeOH: DCM: DEA: 80:20:0.2 at 1 mL/min; temperature: 30 ℃ C.; wavelength: 254nm, R: 1 mL/min; chiral analysis of chiral molecules: 4.6: (chiral molecules: 250) and (chiral molecules: 1 g/min; chiral molecules: 1 g_T＝12.299min)。1H NMR(400MHz,CDCl₃)δ8.18(s,1H),8.17(s,1H),7.84(d,J＝4.0Hz,0.5H),7.78(d,J＝4.0Hz,0.5H),7.50(d,J＝4.0Hz,0.5H),7.46(d,J＝4.0Hz,0.5H),7.36-7.31(m,1H),7.19-7.14(m,1H),7.01-6.91(m,1H),6.23(s,0.5H),6.10(d,J＝3.2Hz,0.5H),4.93-4.82(m,2H),4.34-4.26(m,0.5H),4.20(q,J＝9.6Hz,2H),4.08-4.02(m,0.5H),3.65(s,1.5H),3.64(s,1.5H),3.41-3.29(m,2H),3.00-2.95(m,2H),2.84-2.72(m,2H),2.46-2.39(m,1H),2.11-1.91(m,6H),1.78-1.69(m,2H),1.31(t,J＝9.6Hz,3H)。

Compound VIII-21-B:

ethyl 4- (2-bromo-3-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VIII-21:

ethyl 4- (2-bromo-3-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B. LC-MS (ESI): r_T＝2.11min,C₂₆H₃₀BrFN₄O₄Calculated mass of S592.1, found M/z 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)。

The racemic mixture of VIII-21(7.60g, 95% purity, 12.2mmol) was passed through chiral preparative SFC (separation conditions: column: Chiralpak IG 5 μm 20 × 250 mm; mobile phase: CO)₂MeOH 75:25 at 50 g/min; column temperature: 40 ℃; wavelength: 254 nm; back pressure: 100 bar) to provide the title compound VIII-21-a as a yellow solid (3.20g, 95% pure, 42% yield, 100% stereopure) and VIII-21-B as a yellow solid (3.20g, 95% pure, 42% yield, 99.3% stereopure).

VIII-21-A：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 IG 5 μm 20 × 250 mm; mobile phase: CO)₂MeOH 75:25 at 3.0 g/min; column temperature: 40 ℃; wavelength: 254 nm; back pressure: 100 bar, 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)。

VIII-21-B：LC-MS(ESI)：R_T＝2.249min,C₂₆H₃₀BrFN₄O₄Calculated mass of S592.1, found M/z 593.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak IG 5 μm 20 × 250 mm; mobile phase: CO)₂MeOH 75:25 at 3.0 g/min; column temperature: 40 ℃; wavelength: 254 nm; back pressure: 100 bar, 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 VIII-22-2:

ethyl 4- (2-bromo-4-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate VIII-22:

ethyl 4- (2-bromo-4-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B. LC-MS (ESI): r_T＝2.06min，C₂₆H₃₀BrFN₄O₄Calculated mass of S592.1, found M/z 595.5[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.10(s,0.4H),7.86-7.80(m,1H),7.53-7.49(m,0.6H),7.47-7.44(m,0.4H),7.42-7.38(m,0.6H),7.35-7.30(m,2H),7.05-6.92(m,1H),6.20(s,0.4H),6.06(d,J＝1.2Hz,0.6H),4.39-4.16(m,2.4H),4.11-3.89(m,2.6H),2.97-2.76(m,2H),2.14-1.70(m,3H),1.61-1.56(m,1H),1.52(s,9H),1.18-1.09(m,3H)。

A racemic mixture of ethyl 4- (2-bromo-4-fluorophenyl) -6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VIII-22(820mg, 90% purity, 1.24mmol) was subjected to chiral preparative HPLC (column: Chiralpak IG 5 μm 30mm 250 mm; mobile phase: CO ₂MeOH 70:30 at 55 g/min; column temperature: 40 ℃; wavelength: 214nm, back pressure: 100 bar) to provide the titled solid as a yellow solidCompound VIII-22-1(380mg, from¹Purity by H NMR 90%, 46% yield, 100% stereopure) and VIII-22-2(370mg, from¹Purity by H NMR 90%, 45% yield, 99.8% stereopure).

VIII-22-1：LC-MS(ESI)：R_T＝2.128min,C₂₆H₃₀BrFN₄O₄Calculated mass of S592.1, found M/z 593.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 3 g/min; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100 bar, R_T＝3.09min)。¹H NMR(400MHz,CDCl₃)δ8.08(br s,0.4H),7.82-7.80(m,1H),7.49(d,J＝2.8Hz,0.6H),7.43(d,J＝3.2Hz,0.4H),7.38(s,0.6H),7.33-7.28(m,2H),7.01-6.93(m,1H),6.18(s,0.4H),6.05(d,J＝2.4Hz,0.6H),4.37-4.14(m,2.4H),4.08-4.00(m,2H),3.95-3.89(m,0.6H),2.91-2.79(m,2H),2.07-1.81(m,2.6H),1.74-1.68(m,0.4H),1.64-1.58(m,1H),1.50(s,9H),1.15-1.10(m,3H)。

VIII-22-2：LC-MS(ESI)：R_T＝2.128min,C₂₆H₃₀BrFN₄O₄Calculated mass of S592.1, found M/z 593.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: CO)₂MeOH 70:30 at 3 g/min; column temperature: 40 ℃; wavelength: 230 nm; back pressure: 100 bar, R_T＝4.32min)。¹H NMR(400MHz,CDCl₃)δ8.08(br s,0.4H),7.82-7.80(m,1H),7.49(d,J＝3.2Hz,0.6H),7.43(d,J＝3.2Hz,0.4H),7.38(s,0.6H),7.33-7.28(m,2H),7.01-6.93(m,1H),6.18(s,0.4H),6.05(d,J＝2.4Hz,0.6H),4.36-4.14(m,2.4H),4.08-4.00(m,2H),3.95-3.89(m,0.6H),2.91-2.79(m,2H),2.07-1.81(m,2.6H),1.73-1.68(m,0.4H),1.64-1.58(m,1H),1.50(s,9H),1.14-1.10(m,3H)。

Compound VIII-23-B:

methyl 6- (1- (5- (3- (tert-butoxy) -3-oxopropyl) pyridin-2-yl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer) intermediate VIII-23:

methyl 6- (1- (5- (3- (tert-butoxy) -3-oxopropyl) pyridin-2-yl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid by a similar procedure using method B. LC-MS (ESI): r_T＝1.99min，C₃₂H₃₅ClFN₅O₄Calculated mass of S639.2, found M/z 640.1[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.5H),8.07(s,1H),7.81(d,J＝2.8Hz,0.5H),7.77(d,J＝3.2Hz,0.5H),7.48-7.29(m,3.5H),7.15-7.12(m,1H),6.98-6.89(m,1H),6.70-6.66(m,1H),6.20(s,0.5H),6.07(d,J＝2.8Hz,0.5H),4.49-4.20(m,2.5H),4.03-3.95(m,0.5H),3.62(s,1.5H),3.61(s,1.5H),3.00-2.89(m,2H),2.82-2.77(m,2H),2.52-2.47(m,2H),2.30-2.20(m,0.5H),2.12-2.06(m,1H),2.00-1.94(m,1H),1.88-1.72(m,1.5H),1.44(s,9H)。

A racemic mixture of methyl 6- (1- (5- (3- (tert-butoxy) -3-oxopropyl) pyridin-2-yl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VIII-23(220mg, 95% purity, 0.326mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μm 20 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.3 at 10 mL/min; temperature: 30 ℃; wavelength: 254nm) to give the title compound VIII-23-A (89mg, obtained from¹Purity by H NMR 95%, 40% yield, 100% stereopure) and VIII-23-B as a yellow solid (80mg, obtained from¹Purity by H NMR 95%, 36% yield, 99.9% stereopure).

VIII-23-A:LC-MS(ESI)：R_T＝1.86min，C₃₂H₃₅ClFN₅O₄Calculated mass of S639.2, found M/z 640.0[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5um 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝7.100min)。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.5H),8.07(s,1H),7.81(d,J＝3.2Hz,0.5H),7.77(d,J＝2.8Hz,0.5H),7.47(d,J＝3.2Hz,0.5H),7.43-7.29(m,3H),7.15-7.12(m,1H),6.98-6.89(m,1H),6.69-6.66(m,1H),6.20(s,0.5H),6.07(d,J＝2.4Hz,0.5H),4.49-4.33(m,2H),4.27-4.21(m,0.5H),4.02-3.95(m,0.5H),3.62(s,1.5H),3.61(s,1.5H),2.99-2.88(m,2H),2.82-2.77(m,2H),2.52-2.47(m,2H),2.30-2.20(m,0.5H),2.12-1.72(m,3.5H),1.44(s,9H)。

VIII-23-B:LC-MS(ESI)：R_TCalculated mass 639.2 for C32H35ClFN5O4S, found M/z 640.0[ M + H ] 1.85min]⁺. Chiral analysis (column: Chiralpak IE 5um 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 50:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 254nm, R _T＝11.757min)。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.5H),8.07(s,1H),7.81(d,J＝3.2Hz,0.5H),7.77(d,J＝3.2Hz,0.5H),7.47(d,J＝3.2Hz,0.5H),7.43-7.29(m,3H),7.15-7.12(m,1H),6.98-6.89(m,1H),6.69-6.66(m,1H),6.20(s,0.5H),6.07(d,J＝2.4Hz,0.5H),4.49-4.33(m,2H),4.27-4.21(m,0.5H),4.03-3.95(m,0.5H),3.62(s,1.5H),3.61(s,1.5H),2.99-2.88(m,2H),2.82-2.77(m,2H),2.52-2.47(m,2H),2.30-2.20(m,0.5H),2.13-1.72(m,3.5H),1.44(s,9H)。

Part VI: preparation of Free Amine (FA) products having the formula IX

Free amine 1: (exemplified by method D)

Methyl 4- (3, 4-difluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA1, single stereoisomer)

To a solution of methyl 6- (1- (tert-butoxycarbonyl) piperidin-4-yl) -4- (3, 4-difluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VIII-1-B (270mg, 0.510mmol) in dichloromethane (3mL) was added trifluoroacetic acid (3mL) at room temperature. After stirring at room temperature for 0.5 h, the mixture was concentrated under reduced pressure to give a residue, which was dissolved in ethyl acetate (50mL) and washed three times with saturated aqueous sodium bicarbonate solution (25mL), three times with water (25mL) and three times with brine (25mL), over Na₂SO₄The solid was dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (220mg, 100% yield). LC-MS (ESI): r_T＝1.896min，C₂₁H₂₂F₂N₄O₂The calculated mass of S is 432.1, found M/z 432.9[ M + H ]]⁺。

Spectroscopic analysis of free amines having the general formula IX

Free amine 2:

ethyl 4- (3-fluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA2, single stereoisomer)

The title compound was synthesized from compound VIII-2-B by a similar procedure using method D.

LC-MS(ESI)：R_T＝1.53min，C₂₂H₂₅FN₄O₂Calculated mass of S428.2, found 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)。

Free amine 3: ethyl 4- (4-fluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA3, single stereoisomer)

The title compound was synthesized from compound VIII-3-B by a similar procedure using method D.

LC-MS(ESI)：R_T＝1.536min，C₂₂H₂₅FN₄O₂Calculated mass of S428.2, found 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)。

Free amine 4: methyl 4- (3-fluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA4, single stereoisomer)

The title compound was synthesized from compound VIII-4-A by a similar procedure using method D.

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)。

Free amine 5: methyl 4- (4-fluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA5, single stereoisomer)

The title compound was synthesized from compound VIII-5-2B by a similar procedure using method D.

LC-MS(ESI)：R_T＝1.38min，C₂₁H₂₃FN₄O₂Calculated mass of S414.2, found 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)。

Free amine 6: methyl 4- (2-chloro-3-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA6, single stereoisomer)

The title compound was synthesized from compound VIII-6-B by a similar procedure using method D.

¹H NMR(300MHz,DMSO-d₆)8.01(s,2H),7.38-7.18(m,3H),6.00(s,0.8H),5.76-5.74(m,0.2H),3.83-3.74(m,1H),3.53-3.48(m,3H),3.29-3.18(m,2H),2.86-2.71(m,2H),2.06-1.59(m,4H)。

Free amine 7: methyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA7, single stereoisomer)

The title compound was synthesized from compound VIII-7-B by a similar procedure using method D.

LC-MS(ESI)：R_T＝1.444min,C₂₀H₂₁Cl₂FN₄O₂Calculated mass of S470.1, found 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)。

Free amine 8: ethyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA8, single stereoisomer)

The title compound was synthesized from compound VIII-8-B by a similar procedure using method D.

LC-MS(ESI)：R_T＝1.897min，C₂₁H₂₂ClFN₄O₂Calculated mass of S448.1, found M/z 449.1[ M + H ]]⁺。

Free amine 9: ethyl 4- (2-chloro-3-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA9, single stereoisomer)

The title compound was synthesized from compound VIII-9-B by a similar procedure using method D.

¹H NMR(300MHz,CDCl₃) Δ 8.33(s,0.5H),7.86-7.78(m,1H),7.58-7.38(m,1.5H),7.20-6.96(m,3H),6.24(s,0.4H),6.10(s,0.6H),4.10-3.95(m,3H),3.56-3.39(m,2H),3.08-2.85(m,2H),2.38-2.15(m,1H),2.15-2.08(m,1H),1.92-1.74(m,2H),1.16-1.06(m, 3H). Free amine 10: methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA10, single stereoisomer)

The title compound was synthesized from compound VIII-10-B by a similar procedure using method D.

¹H NMR(400MHz,CDCl₃)δ8.40(s,0.4H),7.85-7.78(m,1H),7.53(d,J＝2.8Hz,1H),7.44(d,J＝3.2Hz,0.6H),7.12-6.96(m,2H),6.18(s,0.4H),6.07(s,0.6H),4.32-4.17(m,1H),4.07-3.92(m,2H),3.61(s,2H),3.60(s,1H),3.39-3.29(m,1H),3.11-2.85(m,2H),2.45-2.17(m,1.4H),2.04-1.81(m,2.6H)。

Free amine 11: ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (2-methylpiperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA11, mixture of 4 stereoisomers)

The title compound was synthesized from compound VIII-11-6 by a similar procedure using method D.

LC-MS(ESI)：RT＝1.774min，C₂₂H₂₃ClF₂N₄O₂The calculated mass of S is 480.1, found M/z 481.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.01(d,J＝6.8Hz,2H),7.50-7.42(m,1H),7.24-7.18(m,1H),5.96(d,J＝10.8Hz,1H),4.13-4.04(m,1H),4.00-3.94(m,2H),3.67-3.53(m,1H),3.16-2.95(m,2H),2.12-1.92(m,2H),1.82-1.76(m,0.6H),1.66-1.61(m,1H),1.55-1.50(m,0.4H),1.25-1.23(m,3H),1.07(t,J＝7.2Hz,3H)。

Free amine 12: ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA12, single stereoisomer)

The title compound was synthesized from compound VIII-12-B by a similar procedure using method D.

LC-MS(ESI)：R_T＝1.55min,C₂₁H₂₁ClF₂N₄O₂Calculated mass of S466.1, found M/z 467.1[ M + H ]]⁺。

Free amine 13: methyl 4- (4-bromo-2-chlorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA13, single stereoisomer)

The title compound was synthesized from compound VIII-13-2b by a similar procedure using method D.

LC-MS(ESI)：R_T＝1.61min,C₂₀H₂₀BrClN₄O₂Calculated mass of S494.0, M/z found 494.7[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.26(s,0.6H),7.83-7.79(m,1H),7.56-7.55(m,1H),7.50(d,J＝3.2Hz,0.4H),7.44(d,J＝3.2Hz,0.8H),7.37(d,J＝2.0Hz,0.2H),7.35-7.30(m,1H),7.21-7.17(m,1H),6.17(s,0.6H),6.04(s,0.4H),4.18-4.12(m,0.6H),3.97-3.91(m,0.4H),3.61(s,1H),3.59(s,2H),3.30-3.20(m,2H),2.90-2.79(m,2H),2.19-2.13(m,0.5H),1.98-1.86(m,2.5H),1.83-1.62(m,2H)。

Free amine 14: methyl 4- (2-bromo-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA14, single stereoisomer)

The title compound was synthesized from compound VIII-14-B by a similar procedure using method D.

LC-MS(ESI)：R_T＝1.64min,C₂₀H₁₉BrF₂N₄O₂Calculated mass of S496.0, M/z found 497.4[ M +1 [ ]]⁺。

Free amine 15: methyl 4- (2-bromo-3-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA15, single stereoisomer)

The title compound was synthesized from compound VIII-15-B by a similar procedure using method D.

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),7.11-7.02(m,2H),6.24(s,0.2H),6.14-6.09(m,0.8H),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)。

Free amine 16: methyl 4- (2-bromo-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA16, single stereoisomer)

The title compound was synthesized from compound VIII-16-2B by a similar procedure using method D.

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)。

Free amine 17: ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (pyrrolidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA17, mixture of 4 stereoisomers)

The title compound was synthesized from compound VIII-17 by a similar procedure using method D.

LC-MS(ESI)：R_T＝1.531min,C₂₀H₁₉ClF₂N₄O₂Calculated mass of S452.1, M/z found 453.0[ M + H]⁺。¹H NMR(300MHz,CDCl₃)δ10.45-10.33(m,1H),7.84(s,1H),7.41(s,1H),7.12-7.02(m,2H),6.17-6.15(m,1H),4.67(br s,1H),4.15-4.01(m,2H),3.36-3.19(m,2H),3.01-2.94(m,2H),2.46-2.10(m,1.5H),1.99-1.77(m,1.5H),1.15-1.10(m,3H)。

Free amine 18: ethyl 6- (azetidin-3-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA18, mixture of 2 stereoisomers)

The title compound was synthesized from compound VIII-18-2 by a similar procedure using method D.

LC-MS(ESI)：R_T＝1.555min,C₁₉H₁₇ClF₂N₄O₂Calculated mass of S438.1, found M/z 439.0[ M + H ]]⁺。

Free amine 19: methyl 6- (azetidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA19, mixture of 2 stereoisomers)

The title compound was synthesized from compound VIII-19-4 by a similar procedure using method D.

LC-MS(ESI)：R_T＝1.32min，C₁₈H₁₆ClFN₄O₂Calculated mass of S406.1, M/z found 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),7.22-7.17(m,1H),5.98(s,1H),4.58(s,1H),3.96-3.88(m,4H),3.51(s,3H)。

Free amine 19-1B: methyl 6- (azetidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ester hydrochloride (FA19-1B, single stereoisomer)

To a suspension of methyl 6- (1- (tert-butoxycarbonyl) azetidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VIII-19-4B (3.58g, 7.07mmol) in methanol (35mL) was added 4M hydrochloride salt in methanol (35mL, 14mmol), which was stirred at room temperature for 1.5 hours. The mixture was concentrated to give a residue which was purified by silica gel chromatography (dichloromethane: methanol ═ 10:1) to give the title compound as a yellow solid (2.76g, 98% yield).¹H NMR(400MHz,DMSO-d₆)δ9.37(br s,2H),8.08(d,J＝2.8Hz,1H),8.04(d,J＝2.8Hz,1H),7.49-7.46(m,2H),7.42(dd,J＝8.8,2.4Hz,1H),7.19(td,J＝11.2,2.4Hz,1H),5.95(s,1H),4.58-4.49(m,1H),4.33-4.04(m,4H),3.52(s,3H)。

Free amine 20: ethyl 4- (2-bromo-3-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA20, single stereoisomer)

The title compound was synthesized from compound VIII-21-B by a similar procedure using method D.

LC-MS(ESI)：R_T＝1.58min,C₂₁H₂₂BrFN₄O₂Calculated mass of S492.1, M/z found 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)。

Free amine 21: ethyl 4- (2-bromo-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (FA21, single stereoisomer)

The title compound was synthesized from compound VIII-22-2 by a similar procedure using method D.

¹H NMR(400MHz,CDCl₃)δ8.22(br s,0.5H),7.82(d,J＝3.2Hz,0.5H),7.79(d,J＝3.2Hz,0.5H),7.49(d,J＝2.8Hz,0.5H),7.42(d,J＝3.2Hz,0.5H),7.38(br s,0.5H),7.33-7.28(m,2H),7.02-6.93(m,1H),6.18(s,0.5H),6.05(s,0.5H),4.19-4.13(m,0.5H),4.08-4.00(m,2H),3.97-3.92(m,0.5H),3.36-3.20(m,2H),2.92-2.79(m,2H),2.23-2.17(m,0.6H),1.91-1.83(m,2H),1.77-1.66(m,1.4H),1.15-1.10(m,3H)。

Part VII: preparation of Building Block (BB) of the general formula X for the coupling step

Building block 1: ethyl 2- (2-chloropyrimidin-5-yl) acetate (BB1)

Building block 2: methyl 2-chloro-5-methylpyrimidine-4-carboxylate (BB2)

To a solution of 2-chloro-5-methylpyrimidine-4-carboxylic acid BB2-1(500mg, 95% purity, 2.75mmol) in methanol (10mL) at 0 ℃ under nitrogen was added thionyl chloride (662mg, 99% purity, 5.51 mmol). After stirring at 0 ℃ for 30 minutes and at room temperature for 2 hours, the mixture was diluted with ethyl acetate (200 mL). The mixture was washed three times with saturated aqueous sodium bicarbonate solution (40 ml). The organic layer was dried over Na2SO4 (solid) and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (415mg, 99% purity, 80% yield). LC-MS (ESI): r _T＝0.837min,C₇H₇ClN₂O₂Calculated mass of 186.0, found M/z 187.0[ M + H ]]⁺.¹H NMR(300MHz,DMSO-d₆)δ8.64(s,1H),3.89(s,3H),2.39(s,3H)。

Building block 3: methyl 2-bromothiazole-5-carboxylate (BB3)

Building block 4: ethyl 2-chloro-5-methylpyrimidine-4-carboxylate (BB4)

Round bottom flask a was filled with ethyl 2-oxopropionate (27.0g, 232.6mmol) and the flask was cooled to-10 ℃. Acetic acid (80mL) was added while maintaining the temperature below-5 ℃. 30% aqueous hydrogen peroxide (26.4mL, 258.4mmol) was added dropwise to maintain the temperature at-5 ℃. Another flask B was filled with 2-chloro-5-methylpyrimidine BB4-1(10.0g, 77.8mmol), toluene (80mL), and water (40 mL). After flask B was cooled to-10 deg.C, sulfuric acid (12.4mL, 228.2mmol) was added followed by ferrous sulfate heptahydrate (64.8g, 233.1 mmol). The peroxide solution was added to flask B over 1 hour while maintaining the temperature at 0 ℃ to-5 ℃. After the addition, the reaction mixture was stirred for a further 30 minutes. It was then poured into ice water (1L). The mixture was extracted three times with ethyl acetate (500 mL). The combined organic layers were washed with 0.5M aqueous hydrogen sulfate (500mL) and brine (500mL) over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by C18 column (acetonitrile: water 30% to 90%) to give the title compound as a yellow solid (8.50g, 95% purity, 52% yield). LC-MS (ESI): r _T＝2.04min,C₈H₉ClN₂O₂Calculated mass of 200.0, M/z measured mass of 200.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.63(s,1H),4.48(q,J＝7.2Hz,2H),2.51(s,3H),1.44(t,J＝7.2Hz,3H)。

Building block 5: 1-methyl-1H-pyrazole-4-carboxylic acid (BB5)

Intermediate BB 5-2:

ethyl 1-methyl-1H-pyrazole-4-carboxylate

To a solution of ethyl 1H-pyrazole-4-carboxylate BB5-1(5.00g, 35.7mmol) in tetrahydrofuran (20mL) at 0 ℃ under nitrogen was added 60% wt. sodium hydride in mineral oil (2.50g, 62.5 mmol). The reaction mixture was stirred at room temperature for 1 hour and then iodomethane (10.0g, 70.5mmol) was added. After stirring at 60 ℃ for 6 hours, the reaction mixture was cooled, quenched with water (40mL), and quenched with EtOHEthyl acetate (60mL) was extracted three times. The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried and concentrated to give the title compound as a colorless oil (5.6g, from¹Purity of H NMR 80%, 83% yield).¹H NMR(300MHz,CDCl₃)δ7.83(s,2H),4.26-4.19(m,2H),3.87(s,3H),1.36-1.26(m,3H)。

Building block 5:

1-methyl-1H-pyrazole-4-carboxylic acid

To a solution of ethyl 1-methyl-1H-pyrazole-4-carboxylate BB5-2(3.0g, 80% purity, 15.6mmol) in ethanol (10mL) was added sodium hydroxide (1.0g, 25mmol) in water (30mL) at room temperature. After refluxing overnight, the reaction mixture was cooled, acidified with 1M aqueous hydrochloric acid (20mL) to pH 3 and extracted three times with ethyl acetate (40 mL). The combined organic layers were washed three times with water (20mL) and Na ₂SO₄(solid) dried and concentrated to provide the title compound as a white solid (1.8g, 92% yield). LC-MS (ESI): RT ═ 0.24min, C₅H₆N₂O₂Calculated mass of 126.1, M/z found 127.3[ M + H ]]⁺.¹H NMR(300MHz,DMSO-d₆)δ12.2(br s,1H),8.20(s,1H),7.77(s,1H),3.86(s,3H)。

Building block 6: ethyl 2-chlorooxazole-4-carboxylate (BB6)

Building block 7: 2-chloropyrimidine-5-carboxylic acid (BB7)

Building block 8: ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (BB8)

Building block 9: ethyl 2- (2-chloropyrimidin-4-yl) acetate (BB9)

Sodium hydride (1.22g, 60% wt. in mineral oil, 30.5mmol) was added portionwise to a solution of ethyl 3-oxobutyrate (1.96g, 98% purity, 14.8mmol) in tetrahydrofuran (100mL) at a temperature between 0 and 5 ℃. The reaction mixture was stirred and allowed to slowly warm to room temperature. Then adding 2, 4-dichloropyrimidine in portionsPyridine BB9-1(2.00g, 95% purity, 12.7mmol) and the reaction stirred at 70 ℃ for 4 h. After cooling to room temperature, the reaction mixture was poured into ice-water (80mL) and extracted twice with ethyl acetate (100 mL). The combined organic layers were passed over Na₂SO₄(solid) was dried, filtered and concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to give the title compound BB9(700mg, 90% purity, 25% yield) as a colorless oil. ¹H NMR(400MHz,CDCl₃)δ8.59-8.57(m,1H),7.33-7.32(m,0.7H),7.27-7.26(m,0.3H),4.23-4.16(m,2H),3.99(s,0.5H),3.82-3.81(m,1.5H),1.30-1.23(m,3H)。

Building block 10: ethyl 2-chlorooxazole-5-carboxylate (BB10)

Building block 11: ethyl 2-bromothiazole-4-carboxylate (BB11)

Building block 12: ethyl 2- (2-chloro-4-methylpyrimidin-5-yl) acetate (BB12)

Intermediate BB 12-2:

2- (2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) acetic acid

To a solution of uracil BB12-1(23.0g, 205mmol) in glacial acetic acid (800mL) was added benzoyl peroxide (100g, 413mmol) at room temperature. After stirring overnight at 80 ℃ and cooling to room temperature, the mixture was concentrated under reduced pressure to remove volatiles, and the residue was washed with ethyl acetate (200mL) to give the title compound (22g, from¹The purity of the H NMR was 35% (including unreacted BB12-1), 22% yield). LC-MS (ESI): r_T＝0.22min，C₆H₆N₂O₄Calculated mass of 170.0, found value of M/z 168.9[ M-H ]]^-。¹H NMR(400MHz,DMSO-d₆)δ12.28(br s,1H),11.12(s,1H),10.76(s,1H),7.36(s,1H),3.14(s,2H)。

Intermediate BB 12-3:

ethyl 2- (2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) acetate

To a solution of 2- (2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) acetic acid BB12-2(22.0g, 35% pure, 45.3mmol) in ethanol (220mL) was added sulfuric acid (concentrated, 4.0g, 40.8mmol) at room temperature. After stirring overnight at 90 ℃ and cooling to room temperature, the mixture was concentrated under reduced pressure to remove volatiles, and the residue was washed with ethyl acetate (150mL) to give the title compound (19g, from ¹Purity by H NMR 35%, 74% yield).¹H NMR(400MHz,DMSO-d₆)δ11.14(s,1H),10.78(s,1H),7.38(s,1H),4.04(q,J＝7.2Hz,2H),3.21(s,2H),1.17(t,J＝7.2Hz,3H)。

Intermediate BB 12-4:

ethyl 2- (2, 4-dichloropyrimidin-5-yl) acetate

A mixture of ethyl 2- (2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) acetate BB12-3(19.0g, 35% pure, 33.6mmol) in phosphorus oxychloride (300mL) was stirred at 110 ℃ for 3 hours. It was cooled to room temperature and concentrated under reduced pressure to remove volatiles, and the residue was dissolved in ethyl acetate (500 mL). Ice water (200mL) was added, followed by extraction three times with ethyl acetate (200 mL). The combined organic layers were washed with brine (100mL) and over 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 (4.40g, obtained from¹Purity of H NMR 90%, 51% yield). LC-MS (ESI): r_T＝1.50min,C₈H₈Cl₂N₂O₂Calculated Mass 234.0, M/z found 232.9[ M-H [ ]]^-。¹H NMR(300MHz,CDCl₃)δ8.81(s,1H),4.13(q,J＝7.2Hz,2H),3.90(s,2H),1.19(t,J＝7.2Hz,3H)。

Building block 12:

ethyl 2- (2-chloro-4-methylpyrimidin-5-yl) acetate

To a solution of ethyl 2- (2, 4-dichloropyrimidin-5-yl) acetate BB12-4(100mg, 90% purity, 0.383mmol) in 1, 4-dioxane (2mL) at room temperature under nitrogen at room temperature2,4, 6-trimethyl-1, 3,5,2,4, 6-trioxatriboran (98.0mg, 0.781mmol), potassium carbonate (159mg, 1.15mmol) and tetrakis (triphenylphosphine) palladium (44mg, 0.038mmol) were added. After stirring at 90 ℃ overnight, cooled to room temperature, the reaction mixture was poured into water (10mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and over Na ₂SO₄(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 90%) to give the title compound as a brown oil (27.0mg, 95% purity, 31% yield). LC-MS (ESI): r_T＝0.89min，C₉H₁₁ClN₂O₂Calculated Mass of 214.1, M/z found 214.9[ M + H [ ]]⁺。¹H NMR(300MHz,DMSO-d₆)δ8.53(s,1H),4.11(q,J＝7.2Hz,2H),3.84(s,2H),2.41(s,3H),1.19(t,J＝7.2Hz,3H)。

Building block 13: ethyl 2, 5-dichloropyrimidine-4-carboxylate (BB13)

Round bottom flask a was filled with ethyl 2-oxopropionate (4.70g, 40.5mmol) and the flask cooled to-10 ℃ and acetic acid (13mL) was added while maintaining the temperature below-5 ℃. 33% aqueous hydrogen peroxide (1.3mL, 42.4mmol) was added dropwise to maintain the temperature below-5 ℃. Another flask B was filled with 2, 5-dichloropyrimidine BB13-1(2.00g, 13.2mmol), toluene (13mL), and water (7 mL). After cooling the flask to-15 deg.C, sulfuric acid (2.2mL, 41.3mmol) was added followed by ferrous sulfate heptahydrate (11.2g, 40.3 mmol). To flask B was added a peroxide solution, which had been prepared in flask a over 1 hour while maintaining the temperature below-10 ℃, the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice water (200mL) and neutralized to pH about 7 with 1M aqueous sodium hydroxide solution and filtered. The filter cake was washed twice with dichloromethane (200 mL). The filtrates were combined and the aqueous layer was separated and extracted twice with dichloromethane (200 mL). The combined organic layers were washed with water (200mL), brine (b) 200mL) over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (petroleum ether: ethyl acetate 100:1 to 50:1) to provide the title compound as a colourless oil (300mg, 96% purity, 10% yield). LC-MS (ESI): r_T＝1.682min,C₇H₆Cl₂N₂O₂Calculated mass of 220.0, M/z found 221.0[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.73(s,1H),4.49(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H)。

Building block 14: (cis) -tert-butyl 3- (2-chloropyrimidin-5-yl) -3-hydroxycyclobutanecarboxylate (BB14)

To a solution of tert-butyl 3-oxocyclobutanecarboxylate BB14-1(2.00g, 98% purity, 11.5mmol) and 5-bromo-2-chloropyrimidine BB14-2(2.27g, 98% purity, 1.50mmol) in anhydrous tetrahydrofuran (120mL) at-78 deg.C under a nitrogen atmosphere was added dropwise 2.5M n-butyllithium in hexane (4.8mL, 12.0mmol) over 25 minutes. After stirring at-78 ℃ for 1 hour, the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The resulting mixture was warmed to room temperature, diluted with water (80mL) and extracted twice with ethyl acetate (80 mL). The combined organic layers were washed with brine (100mL) 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 ═ 10:1 to 5:1) to give the title compound (1.40g, 90% purity, 38% yield) as a pale yellow solid. LC-MS (ESI): r _T＝1.51min，C₁₃H₁₇ClN₂O₃Calculated mass of 284.1, found M/z 284.8[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.76(s,2H),4.37(br s,1H),3.01-2.94(m,1H),2.87-2.81(m,2H),2.60-2.55(m,2H),1.50(s,9H)。

Building block 15: ethyl 2-chloro-4- (trifluoromethyl) thiazole-5-carboxylate (BB15)

Building block 16: ethyl 5-bromo-1, 3, 4-thiadiazole-2-carboxylate (BB16)

Building block 18: methyl 2-fluoroisonicotinic acid methyl ester (BB18)

To a solution of 2-fluoroisonicotinic acid BB18-1(400mg, 2.84mmol) in methanol (3mL) and dichloromethane (9mL) at 0 deg.C was added dropwise 2M diazomethane (1.5mL, 3.00mmol) in tetrahydrofuran. After stirring at room temperature for 2 hours, the mixture was poured into water (10mL) and the reaction mixture was extracted three times with dichloromethane (10 mL). The combined organic layers were 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 as a yellow oil (140mg, 26% yield).¹H NMR(400MHz,DMSO-d₆)δ8.47(d,J＝5.2Hz,1H),7.82-7.79(m,1H),7.60-7.59(m,1H),3.92(s,3H)。

Building block 19: methyl 6-fluoronicotinate (BB19)

Building block 20: methyl 6-fluoropyridine formate (BB20)

Building block 21: methyl 6-chloropyrimidine-4-carboxylate (BB21)

The building block 22: 5-chloropyrazine-2-carboxylic acid (BB22)

Building block 23: 2-chloropyrimidine-4-carboxylic acid (BB23)

Building block 24: ethyl 2-bromo-5-methyloxazole-4-carboxylate (BB24)

Building block 25: ethyl 2-chlorooxazole-5-carboxylate (BB25)

Building block 26: 2- (2-ethoxy-2-oxoacetamido) acetic acid (BB26)

Intermediate BB 26-2:

ethyl 2- ((2- (tert-butoxy) -2-oxoethyl) amino) -2-oxoacetate

To a solution of tert-butyl 2-amino acetate hydrochloride BB26-1(2.00g, 11.7mmol) and triethylamine (3.02g, 29.2mmol) in dichloromethane (30mL) was added dropwise oxalyl chloride monoethyl ester (1.6mL, 14.0mmol) at 0 ℃. After the addition, the mixture was stirred at room temperature for 3 hours. It was then diluted with dichloromethane (50mL) and washed twice with 1M aqueous hydrochloric acid (40mL), with saturated aqueous sodium bicarbonate (40mL) and brine (40mL), over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give the title compound (2.10g, obtained from¹Purity by H NMR 95%, 74% yield). LC-MS (ESI): r_T＝1.49min,C₁₀H₁₇NO₅Calculated mass of 231.1, M/z found 176.0[ M + H-56 ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.52(br s,1H),4.37(q,J＝7.2Hz,2H),4.02(d,J＝5.6Hz,2H),1.49(s,9H),1.39(t,J＝7.2Hz,3H)。

Building block 26:

2- (2-ethoxy-2-oxoacetamido) acetic acid

To a solution of ethyl 2- ((2- (tert-butoxy) -2-oxoethyl) amino) -2-oxoacetate BB26-2(2.10g, 95% purity, 8.63mmol) in dichloromethane (21mL) was added trifluoroacetic acid (7 mL). After stirring at room temperature overnight, the mixture was concentrated to give the title compound as a brown oil (2.10g, from ¹Purity by H NMR 70%, 97% yield). LC-MS (ESI): r_T＝0.32min,C₆H₉NO₅Calculated mass of 175.0, M/z found 176.1[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ7.72(s,1H),4.38(q,J＝7.2Hz,2H),4.20(d,J＝5.6Hz,2H),1.39(t,J＝7.2Hz,3H)。

Building block 27: methyl 6-chloro-4-methylpyridazine-3-carboxylate (BB27)

A mixture of methyl 4, 6-dichloropyridazine-3-carboxylate BB27-1(400mg, 95% purity, 1.84mmol), methylboronic acid (135mg, 98% purity, 2.21mmol) and potassium carbonate (768mg, 99% purity, 5.50mmol) in tetrahydrofuran (10mL) was degassed with nitrogen for 10 minutes. Tetrakis (triphenylphosphine) palladium (0) (112mg, 95% pure, 0.092mmol) and silver oxide (1.10g, 95% pure, 4.51mmol) were then added and the solution was further degassed with nitrogen for an additional 5 minutes. The vial was sealed and the reaction was heated at 80 ℃ overnight under nitrogen atmosphere. The mixture was then cooled to room temperature and concentrated. The obtained residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to obtain the title compound BB27(30mg, 74% purity, 6% yield) and methyl 4-chloro-6-methylpyridazine-3-carboxylate BB27-2(53mg, 53% purity, 8% yield) as a yellow oil.

BB27：¹H NMR(400MHz,CDCl₃)δ7.46(s,1H),4.04(s,3H),2.59(s,3H)。

BB27-2：¹H NMR(400MHz,CDCl₃)δ7.48(s,1H),4.04(s,3H),2.77(s,3H)。

Building block 28: methyl 6-chloro-2-methylpyrimidine-4-carboxylate (BB28)

Intermediate BB 28-2:

6-chloro-2-methylpyrimidin-4-ol

To a 13M aqueous sulfuric acid solution (25mL, 32.5mmol) at 0 deg.C was added 4, 6-dichloro-2-methylpyrimidine BB28-1(4.00g, 97% purity, 23.8mmol) in portions over 20 minutes. After stirring at 0 ℃ for 1.5 h and at room temperature overnight, the reaction mixture was poured into 6M aqueous sodium hydroxide (80mL) in an ice bath. The resulting solid was then collected by filtration, washed with warm water (100mL) and dried under high vacuum to provide the desired product as a white solid (3.00g, from ¹Purity by H NMR 95%, 83% yield).¹H NMR(400MHz,DMSO-d₆)δ12.87(br s,1H),6.34(s,1H),2.30(s,3H)。

Intermediate BB 28-3:

methyl 6-hydroxy-2-methylpyrimidine-4-carboxylate

Reacting 6-chloro-2-methylpyrimidine-4Alcohol BB28-2(2.50g, 95% purity, 16.4mmol), N-diisopropylethylamine (3.30g, 25.5mmol) and [1,1' -bis (diphenylphosphino) ferrocene]A suspension of dichloropalladium (II) (605mg, 0.827mmol) in methanol (10mL) and N, N-dimethylformamide (10mL) was heated at 100 ℃ under a carbon monoxide atmosphere (5MPa) for 16 h. The resulting solid was then collected by filtration, washed with methanol (30mL), followed by diethyl ether (60mL) and dried under vacuum to give the title compound (2.10g, from¹Purity by H NMR 95%, 72% yield).¹H NMR(400MHz,DMSO-d₆)δ12.85(br s,1H),6.72(s,1H),3.82(s,3H),2.33(s,3H)。

Building block 28:

methyl 6-chloro-2-methylpyrimidine-4-carboxylate

A mixture of methyl 6-hydroxy-2-methylpyrimidine-4-carboxylate BB28-3(300mg, 95% purity, 1.70mmol) in phosphoryl trichloride (10mL) was stirred at 110 ℃ for 30 minutes. The mixture was then cooled to room temperature and concentrated to give a residue which was purified by preparative TLC (petroleum ether: ethyl acetate ═ 8:1) to give the title compound (60mg, from ca) as a colourless oil¹Purity of H NMR 96%, 18% yield). ¹H NMR(400MHz,DMSO-d₆)δ7.96(s,1H),3.92(s,3H),2.70(s,3H)。

Building blocks 29 and 30:

methyl 5-chloro-3-methylpyrazine-2-carboxylate (BB29) and methyl 6-chloro-3-methylpyrazine-2-carboxylate (BB30)

Intermediate BB 29-2:

methyl 3-methylpyrazine-2-carboxylate

To a solution of 3-methylpyrazine-2-carboxylic acid BB29-1(1.0g, 7.10mmol) in methanol (30mL) was added concentrated aqueous hydrochloric acid (0.5mL, 6mmol) at room temperature. After stirring at 85 ℃ overnight, the mixture was concentrated under reduced pressure to give a residue, which was dissolved in ethyl acetate (5mL) and washed with saturated aqueous sodium bicarbonateWashed twice (15 mL). The combined aqueous layers were then extracted twice with ethyl acetate (60 mL). The combined organic layers were washed twice with water (30mL) and brine (30mL) over anhydrous Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a white solid (850mg, 85% purity, 67% yield). LC-MS (ESI): r_T＝0.738min,C₇H₈N₂O₂Calculated mass of 152.1, M/z found 153.0[ M + H ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.64-8.61(m,1H),8.55-8.51(m,1H),4.05-4.00(m,3H),2.90-2.85(m,3H)。

Intermediate BB 29-3:

mixture of 3- (methoxycarbonyl) -2-methylpyrazine 1-oxide and 2- (methoxycarbonyl) -3-methylpyrazine 1-oxide

To a solution of methyl 3-methylpyrazine-2-carboxylate BB29-2(100mg, 85% pure, 0.560mmol) in chloroform (4mL) at room temperature was added m-chloroperoxybenzoic acid (168mg, 85% pure, 0.83 mmol). After 3 hours at 70 ℃, the mixture was diluted with water (10mL), then basified to pH 8 to 9 with saturated aqueous sodium bicarbonate and extracted twice with dichloromethane (30 mL). The combined organic layers were washed twice with water (10mL) and brine (10mL), over Na ₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to leave a residue, which was purified by silica gel column chromatography (dichloromethane: methanol ═ 10:1) to give the title compound (90mg, 90% purity, 87% yield) as a white solid. LC-MS (ESI): r_T＝0.541min,C₇H₈N₂O₃Calculated mass of 168.1, found value of M/z 169.0[ M + H ]]⁺。

Building blocks 29 and 30:

methyl 5-chloro-3-methylpyrazine-2-carboxylate (BB29) and methyl 6-chloro-3-methylpyrazine-2-carboxylate (BB30)

To a solution of a mixture of 3- (methoxycarbonyl) -2-methylpyrazine 1-oxide and 2- (methoxycarbonyl) -3-methylpyrazine 1-oxide BB29-3(680mg, 90% purity, 3.64mmol) in N, N-dimethylformamide (10mL) at room temperaturePhosphorus trichloride (1mL) was added. After stirring at 100 ℃ for 1 hour, the reaction mixture was cooled and 1M aqueous sodium carbonate solution (10mL) was added slowly at 0 ℃ and then extracted twice with ethyl acetate (50 mL). The combined organic layers were washed twice with water (30mL) and brine (30mL), over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to leave a residue, which was purified by silica gel column chromatography (ethyl acetate: methanol ═ 10:1) to give a white solid, which was purified by chiral preparative HPLC (column: Chiralpak ID 5 μm 20mm x 250 mm; mobile phase: CO:. fig. ₂MeOH 70:30 at 50 g/min; temperature: 40 ℃; wavelength: 230nm) to provide the title compound BB29(250mg, 95% pure, 39% yield, 100% stereopure) and BB30(300mg, 95% pure, 46% yield, 98.9% stereopure) as yellow solids.

BB29 chiral HPLC (column: Chiralpak ID 5 μm 4.6 x 250 mm; mobile phase: CO₂MeOH 70:30 at 3 g/min; temperature: 40 ℃; wavelength: 280nm, R_T＝3.17min)。¹H NMR(400MHz,CDCl₃)δ8.74(s,1H),3.91(s,3H),2.71(s,3H)。

BB 30: chiral HPLC (column: Chiralpak ID 5 μm 4.6 x 250 mm; mobile phase: CO₂MeOH 70:30 at 3 g/min; temperature: 40 ℃; wavelength: 280nm, R_T＝4.31min)。¹H NMR(400MHz,CDCl₃)δ8.91(s,1H),3.92(s,3H),2.73(s,3H)。

Building block 31: ethyl 2-chloro-6-methylpyrimidine-4-carboxylate (BB31)

Intermediate BB 31-3:

ethyl 2-hydroxy-6-methylpyrimidine-4-carboxylate:

to a solution of ethyl 2, 4-dioxovalerate BB31-1(5.00g, 31.6mmol) and urea BB31-2(1.90g, 31.6mmol) in ethanol (40mL) at room temperature was added concentrated aqueous hydrochloric acid (4.3 mL). After stirring at 90 ℃ for 16 hours, the reaction mixture was cooled to room temperature and was then hydrogenated with 10M saturated hydrogenAqueous sodium solution was adjusted to PH 7-8 and concentrated to give a residue which was purified by C18 column (acetonitrile: water ═ 1% to 25%) to give the title compound BB31-3 as a yellow solid (650mg, 11% yield). ¹H NMR(400MHz,DMSO-d₆)δ6.47(s,1H),4.31(q,J＝7.2Hz,2H),2.26(s,3H),1.30(t,J＝7.2Hz,3H)。

Building block 31:

ethyl 2-chloro-6-methylpyrimidine-4-carboxylate:

a mixture of ethyl 2-hydroxy-6-methylpyrimidine-4-carboxylate BB31-3(550mg, 3.02mmol) in phosphorus oxychloride (10mL) was stirred at 115 ℃ for 1 hour. It was then allowed to cool to room temperature and the solvent was removed under reduced pressure to give a residue, which was basified to pH 8-9 with saturated aqueous sodium bicarbonate (20mL) 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 ═ 10:1 to 1:3) to give the title compound (85mg, 14% yield) as a yellow solid.¹H NMR(400MHz,CDCl₃)δ7.80(s,1H),4.49(q,J＝7.2Hz,2H),2.65(s,3H),1.44(t,J＝7.2Hz,3H)。

Building block 32: tert-butyl 6-chloro-4- ((4-methoxybenzyl) oxy) nicotinate (BB32)

Intermediate BB 32-2:

tert-butyl 4, 6-dichloronicotinate

To a solution of 4, 6-dichloronicotinic acid BB32-1(10.0g, 0.05mol) in tetrahydrofuran (100mL) at room temperature were added di-tert-butyl dicarbonate (22.7g, 0.10mol) and 4-dimethylaminopyridine (1.20g, 0.01 mol). After stirring at 70 ℃ for 3 hours, 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: 30:1 to 20:1) to give the title compound (11.0g, 89% yield) as a colorless oil Rate). LC-MS (ESI): r_T＝1.84min,C₁₀H₁₁C_l2NO₂Calculated mass of 247.0, found M/z 247.9[ M + H]⁺。¹H NMR(300MHz,CDCl₃)δ8.76(s,1H),7.44(s,1H),1.61(s,9H)。

Building block 32:

tert-butyl 6-chloro-4- ((4-methoxybenzyl) oxy) nicotinate

To a solution of (4-methoxyphenyl) methanol (2.80g, 20.3mmol) in N, N-dimethylformamide (35mL) at 0 ℃ under nitrogen atmosphere was added in portions 60% wt. sodium hydride in mineral oil (970mg, 24.3 mmol). After stirring at 0 ℃ for 1 hour, tert-butyl 4, 6-dichloronicotinate BB32-2(5.00g, 20.2mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. It was then quenched with ice (50g) and extracted twice 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 (petroleum ether: ethyl acetate ═ 20:1 to 10:1) to provide a crude product, which was further purified by C18 column (acetonitrile: water ═ 30% to 70%) to give the title compound (2.50g, 35% yield) as a white solid. LC-MS (ESI): r_T＝1.83min,C₁₈H₂₀ClNO₄Calculated mass of 349.1, found M/z 349.9[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.62(s,1H),7.38-7.36(m,2H),6.95-6.91(m,3H),5.11(s,2H),3.83(s,3H),1.50(s,9H)。

Building block 33: tert-butyl 6-chloro-5-fluoronicotinic acid methyl ester (BB33)

Intermediate BB 33-2:

6-chloro-5-fluoronicotinic acid

To a solution of 2-chloro-3-fluoro-5-methylpyridine BB33-1(1.00g, 6.86mmol) in water (5mL) and pyridine (5mL) was added potassium permanganate (2.20g, 13.7mmol) at room temperature. After stirring at 100 ℃ under nitrogen atmosphere for 4 hours, the mixture is stirred The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a white solid (700mg, 58% yield). LC-MS (ESI): r_T＝0.30min,C₆H₃ClFNO₂Calculated mass of 175.0, M/z found 174.0[ M-H [)]^-。¹H NMR(400MHz,CD₃OD)δ8.70(d,J＝1.2Hz,1H),8.06(dd,J＝8.8,1.6Hz,1H)。

Building block 33:

tert-butyl 6-chloro-5-fluoronicotinate

To a solution of 6-chloro-5-fluoronicotinic acid BB33-2(600mg, 3.43mmol) in tert-butanol (20mL) was added 4-dimethylaminopyridine (126mg, 1.03mmol) and di-tert-butyl dicarbonate (1.50g, 6.86mmol) at room temperature. After stirring at 80 ℃ overnight, the reaction mixture was cooled to room temperature 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 50:1) to give the title compound (300mg, 38% yield) as a white solid. LC-MS (ESI): r_T＝1.80min,C₁₀H₁₁ClFNO₂Calculated mass of 231.1, M/z found 232.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.73(d,J＝1.6Hz,1H),8.27(dd,J＝8.4,2.0Hz,1H),1.57(s,9H)。

Building block 34: methyl 2-chloro-3-fluoroisonicotinic acid methyl ester (BB34)

To a solution of 2-chloro-3-fluoroisonicotinic acid BB34-1(200mg, 95% purity, 1.08mmol) in dichloromethane (3mL) was added methanol (1mL) and 0.6M (diazomethyl) trimethylsilane (0.6mL, 0.360mmol) in dichloromethane dropwise at 0 ℃. After stirring at 0 ℃ for 1 hour, the mixture was quenched with acetic acid (0.5mL) and concentrated in vacuo. The residue was then partitioned between water (10mL) and dichloromethane (1BB 34-1). The combined organic layers were washed with brine (10mL) and dried over anhydrous Na ₂SO₄(solid) dried, filtered and concentrated to give the title compound (205mg, from¹Purity of H NMR 90%, yield 90%).¹H NMR(300MHz,CDCl₃)δ8.30(d,J＝4.8Hz,1H),7.70(t,J＝4.8Hz,1H),4.00-3.97(m,3H)。

Building block 35: ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate (BB35)

Intermediate BB 35-3:

2-chloro-4- (1-ethoxyvinyl) -5-fluoropyrimidine

To a solution of 2, 4-dichloro-5-fluoropyrimidine BB35-1(500mg, 3.00mmol) and tributyl (1-ethoxyvinyl) tin BB35-2(1.08g, 3.00mmol) in N, N-dimethylformamide (5mL) at room temperature under a nitrogen atmosphere was added tetrakis (triphenylphosphine) palladium (347mg, 0.300 mmol). The mixture was stirred at 90 ℃ for 2 hours. The other batch (500mg) was combined for work-up. The mixture was cooled to room temperature and poured into water (30 mL). It was extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with water (20mL), 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 ═ 50:1 to 10:1) to give the title compound (1.7g, obtained from¹Purity of H NMR 60%, 86% yield by¹0.3 equivalent of SnBu for H NMR₃Cl)。¹H NMR(400MHz,CDCl₃)δ8.47(d,J＝2.8Hz,1H),5.31(d,J＝2.8Hz,1H),4.73(d,J＝2.8Hz,1H),3.97(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H)。

Building block 35:

ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate

To a solution of 2-chloro-4- (1-ethoxyvinyl) -5-fluoropyrimidine BB35-3(1.70g, 60% purity, 5.03mmol) in dioxane (50mL) and water (30mL) was added sodium periodate (1.61g, 7.53mmol) and potassium permanganate (0.32g, 2.03mmol) at room temperature. The mixture was stirred at room temperature for 4 hours. Insoluble solids are then filtered off from the mixture and the filtrate is taken up in ethyl acetate (C)30mL) was extracted three times. 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 ═ 30:1 to 8:1) to give the title compound (700mg, 94.5% purity, 64% yield) as a colorless oil. LC-MS (ESI): r_T＝1.521min,C₇H₆ClFN₂O₂Calculated mass of 204.0, M/z found 205.0[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.70(d,J＝1.6Hz,1H),4.51(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H)。

Building block 36: ethyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate (BB36)

Intermediate BB 36-2:

ethyl 2-hydroxy-4, 6-dimethyl-1, 2-dihydropyrimidine-5-carboxylate

To a solution of ethyl acetoacetate BB36-1(20.0g, 0.154mol), acetaldehyde (7.50g, 0.170mol), and urea (10.2g, 0.170mol) in absolute ethanol (50mL) was added acetic acid (30 drops) at room temperature. After stirring overnight at 95 ℃ under nitrogen, the mixture was allowed to cool to room temperature and diluted with water (200 mL). The precipitate that appeared was collected by filtration and washed with water (200mL), followed by a mixed solvent of petroleum ether (167mL) and ethyl acetate (33mL) to give the desired product as a white solid (11.4g, 36% yield). LC-MS (ESI): r _T＝1.65min，C₉H₁₄N₂O₃Calculated mass of 198.1, M/z found 199.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.98(s,1H),7.21(s,1H),4.13-4.03(m,3H),2.16(s,3H),1.19(t,J＝7.6Hz,3H),1.10(d,J＝6.0Hz,3H)。

Intermediate BB 36-3:

ethyl 2-hydroxy-4, 6-dimethylpyrimidine-5-carboxylate

To a solution in concentrated nitric acid (20mL) and water (8mL) at 0 deg.C in portionsEthyl 2-hydroxy-4, 6-dimethyl-1, 2-dihydropyrimidine-5-carboxylate BB36-2(5.00g, 25.3mmol) was added. After stirring at 0 ℃ for 1 h, the reaction mixture was basified to pH about 6 by sodium bicarbonate (about 15g, 17.9 mmol). The aqueous solution was extracted four times with a mixed solvent of dichloromethane and methanol (v/v ═ 20/1, 50 mL). The combined organic layers were concentrated to give the desired product as a yellow solid (3.00g, 61% yield). LC-MS (ESI): r_T＝1.22min，C₉H₁₂N₂O₃Calculated mass of 196.1, found value of M/z 197.0[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.13(br s,1H),4.26(q,J＝6.8Hz,2H),2.35(s,6H),1.29(t,J＝6.8Hz,3H)。

Intermediate BB 36-4:

ethyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate

A mixture of ethyl 2-hydroxy-4, 6-dimethylpyrimidine-5-carboxylate BB36-3(3.00g, 15.3mmol) in phosphorus oxychloride was stirred at 90 ℃ under nitrogen for 2 days. After cooling to room temperature, the mixture was concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 15:1) to give the desired product as a pale yellow oil (1.60g, 49% yield). LC-MS (ESI): r_T＝2.12min，C₉H₁₁ClN₂O₂Calculated Mass of 214.1, M/z found 214.9[ M + H [ ] ]⁺。¹H NMR(400MHz,CDCl₃)δ4.47-4.44(m,2H),2.56(s,6H),1.44-1.40(m,3H)。

Building block 36:

2-chloro-4, 6-dimethylpyrimidine-5-carboxylic acid

To a solution of ethyl 2-chloro-4, 6-dimethylpyrimidine-5-carboxylate BB36-4(100mg, 0.443mmol) in water (4mL) and tetrahydrofuran (1mL) was added sodium hydroxide (22mg, 0.550mmol) at room temperature. After stirring at room temperature for 16 h, the mixture was concentrated under reduced pressure to give the crude title compound as a white solid (110mg, 60% purity, 80% yield), which was used in the next step without further purification. LC-MS (ESI): r_T＝0.27min，C₇H₇ClN₂O₂Calculated mass of 186.0 (m/z found value of 186.9 [)M+H]⁺。

Building block 37: ethyl 2-chloro-5, 6-dimethylpyrimidine-4-carboxylate (BB37)

Intermediate BB 37-2:

2, 4-dichloro-6- (1-ethoxyvinyl) -5-methylpyrimidine

To a solution of 2,4, 6-trichloro-5-methylpyrimidine BB37-1(5.50g, 27.9mmol) in N, N-dimethylformamide (30mL) under a nitrogen atmosphere were added tributyl (1-ethoxyvinyl) stannyl (10.0g, 27.7mmol) and bis (triphenylphosphine) palladium (II) chloride (410mg, 5.61 mmol). After stirring at 100 ℃ for 8 hours under nitrogen, the reaction mixture was cooled to room temperature, diluted with water (30mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed with brine (30mL) and Na ₂SO₄(solid) dried, filtered and concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give the desired compound (4.00g, from¹Purity of H NMR 90%, 55% yield).¹H NMR(400MHz,CDCl₃)δ4.78(d,J＝3.2Hz,1H),4.57(d,J＝3.2Hz,1H),3.93(q,J＝6.8Hz,2H),2.40(s,3H),1.39(t,J＝6.8Hz,3H)。

Intermediate BB 37-3:

ethyl 2, 6-dichloro-5-methylpyrimidine-4-carboxylate

A suspension of sodium periodate (1.34g, 8.49mmol) in water (5mL) was sonicated until a clear solution was obtained. A solution of 2, 4-dichloro-6- (1-ethoxyvinyl) -5-methylpyrimidine BB37-2(5.50g, 90% purity, 21.2mmol) in 1, 4-dioxane (25mL) and potassium permanganate (9.28g, 43.4mmol) was then added at room temperature. After stirring at room temperature under a nitrogen atmosphere for 2 hours, the reaction mixture was diluted with water (60mL) and extracted twice with ethyl acetate (60 mL). The combined organic layers were washed with brine (60mL) and Na₂SO₄(solid) drying, filtration and concentration to give a residue which is passed over silicaPurification by gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) was performed to give the title compound (4.00g, obtained from¹Purity of H NMR 90%, 72% yield).¹H NMR(400MHz,CDCl₃)δ4.46(q,J＝6.8Hz,2H),2.47(s,3H),1.41(t,J＝6.8Hz,3H)。

Building block 37:

ethyl 2-chloro-5, 6-dimethylpyrimidine-4-carboxylate

To a solution of ethyl 2, 6-dichloro-5-methylpyrimidine-4-carboxylate BB37-3(2.00g, 90% purity, 7.66mmol) and methylboronic acid (460mg, 7.69mmol) in 1, 4-dioxane (10mL) was added tetrakis (triphenylphosphine) palladium (890mg, 0.770mmol) and anhydrous potassium carbonate (3.20g, 23.2mmol) at room temperature. After stirring overnight at 110 ℃ under nitrogen, the reaction mixture was cooled to room temperature, diluted with water (20mL) and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried, filtered and concentrated to give a residue which was purified by C18 column (acetonitrile: water 40% to 70%) to give the title compound (600mg, from water) as a white solid¹Purity of H NMR 90%, 33% yield).¹H NMR(400MHz,CDCl₃)δ4.45(q,J＝7.2Hz,2H),2.58(s,3H),2.38(s,3H),1.43(t,J＝7.2Hz,3H)。

Building block 38: ethyl 2-chloro-5-ethylpyrimidine-4-carboxylate (BB38)

Intermediate BB 38-2:

ethyl 5-bromo-2-chloropyrimidine-4-carboxylate

Round bottom flask a was filled with ethyl 2-oxopropionate (5.40g, 98% pure, 45.6mmol) and the flask was cooled to-10 ℃. Acetic acid (20mL) was added while maintaining the temperature below-5 ℃. 30% aqueous hydrogen peroxide (4.7mL, 46.0mmol) was added dropwise to maintain the temperature at-5 ℃. Another flask B was filled with 5-bromo-2-chloropyrimidine (3.0g, 98% purity, 15.2mmol), toluene (20mL), and water (10 mL). The flask was cooled to-10 deg.C Thereafter, sulfuric acid (2.5mL, 46.0mmol) was added followed by ferrous sulfate heptahydrate (13.2g, 98% purity, 46.5 mmol). To flask B was added a peroxide solution, which had been prepared in flask a over 1 hour while maintaining the temperature at-10 ℃. After the addition, the reaction mixture was stirred for a further 30 minutes. It was then poured into ice water (100mL), neutralized to pH about 7 with 1N aqueous sodium hydroxide and filtered through celite. The celite was washed with dichloromethane (200 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were washed with 0.5M aqueous sodium bisulfite (200mL) and brine (200mL) over Na₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a residue which was purified by silica gel chromatography (petroleum ether: ethyl acetate 100:1 to 50:1) to give the title compound as a colourless oil (850mg, 90% purity, 19% yield) and 5-bromo-2-chloropyrimidine (1.5g, 90% purity, 46% yield) was recovered as a white solid. LC-MS (ESI): r_T＝1.39min,C₇H₆BrClN₂O₂Calculated mass of 263.9,265.9, M/z found 265.0,267.0[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.85(s,1H),4.50(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H)。

Intermediate BB 38-3:

ethyl 2-chloro-5-vinylpyrimidine-4-carboxylate

To a mixture of ethyl 5-bromo-2-chloropyrimidine-4-carboxylate BB38-2(300mg, 90% purity, 1.02mmol), 4,5, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborolan (160mg, 98% purity, 1.02mmol) and potassium phosphate (661mg, 98% purity, 3.05mmol) in toluene (9mL) and water (3mL) was added palladium acetate (24mg, 99% purity, 0.106mmol) and tricyclohexylphosphine (61mg, 95% purity, 0.207mmol) under a nitrogen atmosphere. After stirring at 85 ℃ under nitrogen for 16 h, the mixture was diluted with water (20 mL). The organic phase was separated and the aqueous layer was extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na ₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a residue, and the residue was subjected to silica gel column chromatography (petroleum ether: acetic acid)Ethyl ester 100:1 to 10:1) to give the title compound as a white solid (100mg, 90% purity, 41.6% yield). LC-MS (ESI): r_T＝1.67min,C₉H₉ClN₂O₂Calculated mass of 212.0, M/z found 212.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.89(s,1H),7.17-7.10(m,1H),5.84(d,J＝17.6Hz,1H),5.61(d,J＝11.2Hz,1H),4.48(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H)。

Building block 38:

ethyl 2-chloro-5-ethylpyrimidine-4-carboxylate

To a solution of ethyl 2-chloro-5-vinylpyrimidine-4-carboxylate BB38-3(100mg, 90% purity, 0.423mmol) in ethanol (5mL) under a nitrogen atmosphere was added platinum dioxide (25mg, 99% purity, 0.109 mmol). After stirring at 20 ℃ for 1 hour under a hydrogen atmosphere with a balloon, the reaction mixture was filtered and the filtrate was concentrated to give the title compound as a black solid (90mg, 90% purity, 89.1% yield). LC-MS (ESI): r_T＝1.677min,C₉H₁₁ClN₂O₂Calculated mass of 214.1, M/z found 215.0[ M + H ]]⁺。

Building block 39: methyl 3- (2-Chloropyrimidin-5-yl) propionate (BB39)

Intermediate BB 39-2:

methyl 3- (2-chloropyrimidin-5-yl) acrylate

A suspension of 5-bromo-2-chloropyrimidine BB39-1(5.0g, 26mmol), methyl acrylate (2.6g, 31mmol), triethylamine (5.7g, 57mmol), wt. palladium acetate (4 mmol%, 243mg) and tris (m-tolyl) phosphine (8 mmol%, 630mg) in N, N-dimethylformamide (30mL) was stirred at 130 ℃ for 4 hours. After cooling to room temperature, the mixture was quenched with water (300mL) and extracted twice with ethyl acetate (100 mL). The combined organic layers were concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 12:1 to 10:1) to give yellow Title compound as a colored solid (600mg, 12% yield).¹H NMR(300MHz,CDCl₃)δ8.76(s,2H),7.59(d,J＝15.9Hz,1H),6.58(d,J＝16.2Hz,1H),3.84(s,3H)。

Building block 39:

methyl 3- (2-chloropyrimidin-5-yl) propionate

To a solution of methyl 3- (2-chloropyrimidin-5-yl) acrylate BB39-2(150mg, 0.758mmol) in ethyl acetate (20mL) and dichloromethane (2mL) was added 10% wt. palladium on charcoal (100mg) at room temperature. After stirring at room temperature under a hydrogen atmosphere overnight, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (15mg, 10% yield).¹H NMR(300MHz,CDCl₃)δ8.63(s,0.5H),8.52(s,1.5H),3.68(s,3H),2.95(d,J＝7.2Hz,2H),2.67(d,J＝7.2Hz,2H)。

Building block 40: methyl 6-chloro-2-methoxypyrimidine-4-carboxylate (BB40)

The building block 41: methyl 6-fluoro-3-methoxypyrazine-2-carboxylate (BB41)

To a solution of methyl 3, 6-difluoropyrazine-2-carboxylate BB41-1(400mg, 2.30mmol) in methanol (4mL) at-20 ℃ was added sodium methoxide (122mg, 2.26mmol), and the reaction was stirred at 0 ℃ for 1 hour. At 0 ℃, the mixture was quenched with saturated aqueous ammonium chloride solution (30mL) and then extracted twice with ethyl acetate (30 mL). The combined organic layers were washed with brine (20mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1 to 5:1) to give the title compound (80mg, 18% yield, 96% purity) as a white solid. LC-MS (ESI): r _T＝1.34min,C₇H₇FN₂O₃Calculated mass of 186.0, M/z found 186.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.10(d,J＝8.4Hz,1H),4.09(s,3H),3.99(s,3H)。

Building block 42: methyl 2-chloro-6-methoxypyrimidine-4-carboxylate (BB42)

To a solution of methyl 2, 6-dichloropyrimidine-4-carboxylate BB42-1(1.00g, 4.83mmol) in methanol (20mL) was added potassium carbonate (669mg, 4.84mmol) at room temperature. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (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 the title compound as a white solid (200mg, 21% yield). LC-MS (ESI): r_T＝1.53min,C₇H₇ClN₂O₃Calculated mass of 202.0, M/z found 203.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.45(s,1H),4.02(s,3H),3.90(s,3H)。

Building block 43: mixtures of ethyl 2-chloro-4-methoxypyrimidine-5-carboxylate and ethyl 4-chloro-2-methoxypyrimidine-5-carboxylate (BB43)

To a solution of ethyl 2, 4-dichloropyrimidine-5-carboxylate BB43-1(1.00g, 99% purity, 5.52mmol) in methanol (10mL) was added sodium methoxide (488mg, 96% purity, 8.67mmol) at room temperature. After stirring at this temperature for 2 hours, the mixture was concentrated under reduced pressure to give a residue, which was partitioned between ethyl acetate (15mL) and water (15 mL). The aqueous layer was separated and extracted twice with ethyl acetate (15 mL). The combined organic layers were passed over Na ₂SO₄(solid) dried, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 100:1 to 10:1) to give the title compound as a white solid (640mg, 65% yield by¹1:1 for H NMR).¹H NMR(400MHz,CDCl₃)δ9.01(s,1H),8.86(s,1H),4.44-4.36(m,4H),4.14(s,3H),4.10(s,3H),1.43-1.37(m,6H)。

Building block 44: methyl tert-butyl 6-chloro-5-fluoropicolinate (BB44)

To a solution of 6-chloro-5-fluoropicolinic acid BB44-1(200mg, 1.09mmol, 96% purity) in t-butanol (4mL) was added 4-dimethylaminopyridine (500mg, 2.25mmol, 98% purity) and di-tert-butyl dicarbonate (150mg, 1.20mmol, 98% purity) at room temperature. After stirring overnight at 50 ℃ under a nitrogen atmosphere, the mixture was washed with water (10mL) and extracted twice with ethyl acetate (20 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 25:1 to 20:1) to give the title compound as a white solid (180mg, 90% purity, 64% yield).¹H NMR(300MHz,CDCl₃)δ8.03-7.99(m,1H),7.58-7.53(m,1H),1.63(s,9H)。

Building block 45: ethyl 2-chloro-5-ethylpyrimidine-4-carboxylate (BB45)

Intermediate BB 45-1:

ethyl 2-chloro-5- (prop-1-en-2-yl) pyrimidine-4-carboxylate

To a mixture of ethyl 5-bromo-2-chloropyrimidine-4-carboxylate BB38-2(300mg, 90% purity, 1.02mmol), 4,5, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborolan (175mg, 98% purity, 1.02mmol) and potassium phosphate (661mg, 98% purity, 3.05mmol) in toluene (9mL) and water (3mL) under a nitrogen atmosphere was added palladium acetate (23mg, 99% purity, 0.101mmol) and tricyclohexylphosphine (60mg, 95% purity, 0.203 mmol). At 85 ℃ under nitrogen atmosphereAfter stirring for 16 hours, the reaction mixture was diluted with water (20mL) 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 silica gel column chromatography (petroleum ether: ethyl acetate 100:1 to 20:1) to give the title compound as a white solid (90mg, 90% purity, 35% yield). LC-MS (ESI): r_T＝1.63min,C₁₀H₁₁ClN₂O₂Calculated mass of 226.1, M/z found 226.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.62(s,1H),5.33(s,1H),5.07(s,1H),4.43(q,J＝7.2Hz,2H),2.11(s,3H),1.39(t,J＝7.2Hz,3H)。

Building block 45:

ethyl 2-chloro-5-ethylpyrimidine-4-carboxylate

To a solution of ethyl 2-chloro-5- (prop-1-en-2-yl) pyrimidine-4-carboxylate BB45-1(90mg, 90% pure, 0.357mmol) in ethanol (5mL) under nitrogen was added platinum dioxide (20mg, 99% pure, 0.087 mmol). After stirring at 20 ℃ under a balloon hydrogen atmosphere for 1 hour, the reaction mixture was filtered and the filtrate was concentrated to give the title compound as a black solid (75mg, 95% purity, 87% yield). LC-MS (ESI): r _T＝1.65min,C₁₀H₁₃ClN₂O₂Calculated mass of 228.1, M/z found 229.1[ M + H ]]⁺。

Building block 46: ethyl 2- (2-chloropyrimidin-5-yl) -2-methylpropionate (BB46)

To a mixture of 60% wt. sodium hydride (50mg, 1.25mmol) in N, N-dimethylformamide (3mL) in mineral oil was slowly added a solution of methyl iodide (156mg, 1.10mmol) and ethyl 2- (2-chloropyrimidin-5-yl) acetate BB46-1(100mg, 0.498mmol) in N, N-dimethylformamide (3mL) under nitrogen at 0 ℃. After stirring at 0 ℃ for 3 hours, the reaction mixture was quenched with water (10mL) and then withEthyl acetate (20mL) was extracted three times. The combined organic layers were washed with water (5mL), brine (5mL), 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 (65mg, obtained from¹Purity of H NMR 90%, 51% yield). LC-MS (ESI): r_T＝1.18min，C₁₀H₁₃ClN₂O₂Calculated mass of 228.1, M/z found 229.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.63(s,2H),4.16(q,J＝7.2Hz,2H),1.64(s,6H),1.23(t,J＝7.2Hz,3H)。

Building block 47: methyl 2-chloro-4- (methoxymethyl) thiazole-5-carboxylate (BB47)

Intermediate BB 47-2:

methyl 2-chloro-4-methoxy-3-oxobutanoate

To a solution of methyl 4-methoxy-3-oxobutyrate BB47-1(2.0g, 98% purity, 13.4mmol) in dichloromethane (20mL) was added sulfonyl chloride (1.2 mL). After stirring overnight at room temperature under nitrogen, the mixture was concentrated under reduced pressure to give a residue, which was dissolved in ethyl acetate (100 mL). The solution was washed with water (50mL) and brine (50mL) over Na ₂SO₄The (solid) was dried, filtered and concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound (1.6g, 98.5% purity, 65% yield) as a yellow oil. LC-MS (ESI): r_T＝1.11min,C₆H₉ClO₄Calculated mass of 180.6, M/z found 181.1[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ5.03(s,1H),4.24(s,2H),3.80(s,3H),3.39(s,3H)。

Intermediate BB 47-3:

methyl 2-amino-4- (methoxymethyl) thiazole-5-carboxylate

A mixture of methyl 2-chloro-4-methoxy-3-oxobutyrate BB47-2(1.6g, 98.5% pure, 8.73mmol) and thiourea (671mg, 99% pure, 8.73mmol) in ethanol (15mL) was stirred at 80 ℃ under nitrogen overnight. The mixture was then cooled to room temperature and concentrated under reduced pressure to give a residue, which was diluted with saturated aqueous sodium bicarbonate solution (20 mL). The resulting solid was collected by filtration and recrystallized from water (5mL) and ethanol (5mL) to give the title compound (1.18g, 91.9% purity, 61.4% yield). LC-MS (ESI): r_T＝0.35min，C₇H₁₀N₂O₃Calculated mass of S202.2, M/z found 203.2[ M + H ]]⁺。¹H NMR(300MHz,CD₃OD)δ4.64(s,2H),3.78(s,3H),3.38(s,3H)。

Building block 47:

methyl 2-chloro-4- (methoxymethyl) thiazole-5-carboxylate

To a suspension of tert-butyl nitrite (74mg, 95% purity, 0.628mmol), cuprous chloride (57mg, 97% purity, 0.554mmol) in acetonitrile (1mL) was added methyl 2-amino-4- (methoxymethyl) thiazole-5-carboxylate BB47-3(100mg, 91.9% purity, 0.454 mmol). After stirring at room temperature under nitrogen for 2 hours and at 70 ℃ for 1 hour, the mixture was cooled to room temperature and filtered. The filtrate was poured into 6N aqueous hydrochloric acid (10mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with MgSO ₄The (solid) was dried and concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound as a yellow oil (78mg, 99% purity, 77% yield). LC-MS (ESI): r_T＝1.54min,C₇H₈ClNO₃Calculated mass of S221.7, M/z found 222.0[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ4.85(s,2H),3.90(s,3H),3.49(s,3H)。

Building block 48: methyl 2-chloro-5- (trifluoromethyl) isonicotinate (BB48)

Building block 49: 6-chloro-4- (trifluoromethyl) nicotinic acid (BB49)

Building block 50: tert-butyl 2-chloro-6- (trifluoromethyl) isonicotinate (BB50)

A mixture of 2-chloro-6- (trifluoromethyl) isonicotinic acid BB50-1(300mg, 1.26mmol, 95% purity), di-tert-butyl dicarbonate (410mg, 1.88mmol) and N, N-lutidine-4-amine (170mg, 1.39mmol) in 2-methylpropan-2-ol (9mL) was stirred at 50 ℃ overnight. The solvent was removed and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate 100:1 to 30:1) to give the title product as a white solid (120mg, 33% yield, 99% purity).¹H NMR(400MHz,CDCl₃)δ8.08(s,1H),8.01(s,1H),1.62(s,9H)。

Building block 51: benzoyl chloride (BB51)

Building block 52: 5-methyl isoxazole-4-carbonyl chloride (BB52)

Building block 53: 1H-pyrazole-4-carbonyl chloride (BB53)

A mixture of 1H-pyrazole-4-carboxylic acid BB51-1(641mg, 5.72mmol) in thionyl chloride (5mL) was stirred at 85 ℃ under nitrogen overnight. The mixture was then concentrated to give the title compound as a white solid (680mg, 91% yield), which was used directly in the next step.

Building block 54: 2-chloro-5-methylpyrimidine-4-carboxylic acid (BB54)

Building block 55: (trans) -3- (2-Chloropyrimidin-5-yl) -3-hydroxycyclobutanecarboxylic acid (BB55)

To a mixture of (trans) -tert-butyl 3- (2-chloropyrimidin-5-yl) -3-hydroxycyclobutanecarboxylate BB14(150mg, 0.530mmol) in dry dichloromethane (15mL) at room temperature was added trifluoroacetic acid (0.5mL) and triethylsilane (565mg,4.86 mmol). After stirring at room temperature for 2 hours, 30 ℃ for 4 hours and at 50 ℃ overnight under nitrogen, trifluoroacetic acid (4mL) was added. The mixture obtained is stirred at 40 ℃ for a further 6 hours. It was then cooled to room temperature and concentrated to give a residue, which was dissolved in saturated aqueous sodium bicarbonate (0.5 mL). The aqueous solution was extracted three times with ethyl acetate (3 mL). The combined organic layers were concentrated to give the title compound as a yellow solid (100mg, 83% yield). LC-MS (ESI): r_T＝0.554min，C₉H₉ClN₂O₃Calculated mass of 228.0, M/z found 229.0[ M + H [ ]]⁺。

Building block 56: methyl 2-fluoro-5-isonicotinic acid methyl ester (BB56)

Building block 57: ethyl 2-chloro-5- (dimethylamino) pyrimidine-4-carboxylate (BB57)

Intermediate BB 57-2:

ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate

To a round bottom flask was added ethyl 2-oxopropionate (7.01g, 60.4mmol) and the mixture was cooled to-10 ℃. To the same flask was added acetic acid (10mL) with an internal temperature below-5 ℃. A30% wt. aqueous solution of hydrogen peroxide (5.17g, 45.6mmol) was added dropwise to maintain the internal temperature below-5 ℃. To another round-bottomed flask containing toluene (25mL) and cooled to-10 deg.C was added 2-chloro-5-fluoropyrimidine BB57-1(2g, 15.1mmol), concentrated sulfuric acid (2.5mL, 46.0mmol), and iron sulfate heptahydrate (15.12g, 45.3mmol) with an internal temperature below-5 deg.C. To this mixture was added a peroxide solution under nitrogen at-10 ℃ over 0.5 hours. The mixture was stirred at-10 ℃ for 0.5 h and warmed to room temperature. After stirring at room temperature overnight, the mixture was quenched with water (25mL) at 0 deg.C, poured into saturated sodium bicarbonate solution (300mL) and extracted three times with ethyl acetate (60 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (50mL) and brine (50mL) over Na ₂SO₄(solid) dried and filtered. Filtering the filtrateConcentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:1 to 20:1) to give the title compound (997mg, obtained from¹Purity of H NMR 90%, 29% yield). LC-MS (ESI): r_T＝1.41min,C₇H₆ClFN₂O₂Calculated mass of 204.0, M/z found 204.9[ M + H ]]+。¹H NMR(400MHz,DMSO-d₆)δ9.16(d,J＝2.4Hz,1H),4.42(q,J＝6.8Hz,2H),1.31(t,J＝7.2Hz,3H)。

Building block 57:

ethyl 2-chloro-5- (dimethylamino) pyrimidine-4-carboxylate

To a solution of ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate BB57-2(200mg, 90% purity, 0.88mmol) in ethyl acetate (1mL) was added 33% wt. aqueous dimethylamine (0.2mL, 0.996 mmol). The mixture was stirred at 0 ℃ for 1 hour and then warmed to room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated to give a residue, which was purified by preparative TLC (petroleum ether: ethyl acetate ═ 8:1) to provide the title compound (180mg, obtained from r. sp.) as a yellow oil¹Purity by H NMR 95%, 85% yield). LC-MS (ESI): r_T＝1.45min,C₉H₁₂ClN₃O₂Calculated mass of 229.1, M/z found 230.0[ M + H [)]+。¹H NMR(400MHz,DMSO-d₆)δ8.55(s,1H),4.37(q,J＝7.2Hz,2H),2.91(s,6H),1.32(t,J＝7.2Hz,3H)。

Building block 58: ethyl 5- (bis (2, 4-dimethoxybenzyl) amino) -2-chloropyrimidine-4-carboxylate (BB58)

Sodium hydride (528mg, 60% wt. in mineral oil, 13.2mmol) was added to tetrahydrofuran (50mL) and stirred for 3 minutes at 0 deg.C, then bis (2, 4-dimethoxybenzyl) amine (1.47g, 95% purity, 4.4mmol) was added and stirring continued for 15 minutes, then ethyl 2-chloro-5-fluoropyrimidine-4-carboxylate BB57-2(1.0g, 95% purity, 4.6mmol) was added and the resulting mixture stirred for 3 hours at 0 deg.C . At 0 ℃, the mixture was quenched with ice water (40mL) and then extracted twice with ethyl acetate (50mL), the organic phases were combined, washed with water (50mL) and brine (50mL), over 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 (900mg, obtained from¹Purity by H NMR 95%, 37% yield). LC-MS (ESI): r_T＝1.971min,C₂₅H₂₈ClN₃O₆Calculated mass 501.2, M/z found 502.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.32(s,1H),7.10(d,J＝8.4Hz,2H),6.51(d,J＝2.0Hz,2H),6.47(dd,J＝8.0Hz,2.0Hz,2H),4.27(q,J＝7.2Hz,2H),4.23(s,4H),3.75-3.72(m,6H),3.62(s,6H),1.25(t,J＝7.2Hz,3H)。

Building block 59: methyl 2-bromo-5-nitroisonicotinate (BB59)

To a solution of 2-bromo-5-nitroisonicotinic acid BB59-1(100mg, 0.405mmol) and sodium carbonate (130mg, 1.23mmol) in N, N-dimethylformamide (2mL) at 0 deg.C was added iodomethane (173mg, 1.22 mmol). After stirring at 0 ℃ for 2 hours, the mixture was poured into ethyl acetate (20mL) and water (10 mL). The aqueous layer was then extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with brine (120mL) and Na₂SO₄(solid) dried and filtered. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1 to 5:1) to give the title compound (85mg, obtained from¹Purity by H NMR 95%, 76% yield). ¹H NMR(400MHz,DMSO-d₆)δ9.19(s,1H),8.24(s,1H),3.92(s,3H)。

Building block 60: ethyl 2-chloro-5-methoxypyrimidine-4-carboxylate (BB60)

Section VIII: coupling of dihydropyrimidines of the formula XI

Compound XI-1-B: (exemplified by method E)

Methyl 4- (3, 4-difluoro-2-methylphenyl) -6- (1- (5- (2-ethoxy-2-oxoethyl) pyrimidin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

To a solution of ethyl 2- (2-chloropyrimidin-5-yl) acetate BB1(45mg, 0.213mmol) and methyl 4- (3, 4-difluoro-2-methylphenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate FA1(100mg, 93% purity, 0.220mmol) in 1, 4-dioxane (3mL) was added triethylamine (112mg, 1.11mmol) at room temperature. After stirring at 100 ℃ for 5 hours under nitrogen and cooling to room temperature, 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 Na₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by C18 column (acetonitrile: water 75% to 85%) to give the title compound as a yellow solid (78mg, 56% yield). LC-MS (ESI): r_T＝1.98min,C₂₉H₃₀F₂N₆O₄Calculated mass 596.2 of S, M/z found 597.0[ M + H ]⁺。¹H NMR(400MHz,CDCl₃)δ8.26(d,J＝2.4Hz,2H),8.11(s,0.8H),7.79-7.75(m,1H),7.48(d,J＝3.2Hz,0.2H),7.41(d,J＝3.2Hz,0.8H),7.13-7.05(m,0.2H),6.96-6.86(m,2H),5.95(s,0.8H),5.86(d,J＝2.0Hz,0.2H),5.04-4.86(m,2H),4.38-4.30(m,0.8H),4.20-4.17(m,2H),3.98-3.92(m,0.2H),3.62(s,3H),3.45(s,1.6H),3.43(s,0.4H),3.09-2.97(m,2H),2.58(d,J＝2.4Hz,2.4H),2.43(d,J＝2.0Hz,0.6H),2.14-2.09(m,1H),1.98-1.89(m,1H),1.81-1.68(m,2H),1.26(q,J＝7.2Hz,3H)。

Spectroscopic analysis of dihydropyrimidines of the general formula XI

Compound XI-3-S:

ethyl 6- (1- (5- (2-ethoxy-2-oxoethyl) pyrimidin-2-yl) piperidin-4-yl) -4- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB1 and FA2 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.00min，C₃₀H₃₃FN₆O₄Calculated mass of S592.2, found M/z 593.0[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.27-8.26(m,2H),8.07(s,0.7H),7.78-7.74(m,1H),7.46(d,J＝3.2Hz,0.3H),7.39(d,J＝3.2Hz,0.7H),7.19-7.03(m,2.3H),6.95-6.88(m,1H),6.03(s,0.8H),5.93(d,J＝2.0Hz,0.2H),5.03-4.86(m,2H),4.37-4.32(m,0.8H),4.20-4.11(m,2.2H),4.09-4.01(m,2H),3.44(s,1.5H),3.43(s,0.5H),3.08-2.97(m,2H),2.54(s,2.3H),2.40(s,0.7H),2.15-2.09(m,1H),2.01-1.95(m,1H),1.82-1.66(m,2H),1.28(t,J＝7.2Hz,3H),1.15-1.10(m,3H)。

Compound XI-4-B:

methyl 2- (4- (5- (ethoxycarbonyl) -6- (4-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB2 and FA3 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.137min，C₂₉H₃₁FN₆O₄Calculated mass of S578.2, found M/z 579.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.50(d,J＝3.6Hz,0.8H),9.09(s,0.2H),8.45(s,0.2H),8.43(s,0.8H),8.01-7.88(m,2H),7.29-7.25(m,0.8H),7.17-7.14(m,0.2H),7.06-6.96(m,2H),5.81(s,0.2H),5.69(d,J＝3.2Hz,0.8H),4.88-4.73(m,2H),4.00-3.98(m,2.1H),3.93-3.88(m,3.9H),2.95-2.85(m,2H),2.67-2.55(m,3H),2.18(s,3H),1.99-1.77(m,3H),1.63-1.60(m,1H),1.10-1.06(m,3H)。

Compound XI-5-B:

methyl 2- (4- (6- (3-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB2 and FA4 by a similar procedure using method E.

¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝3.6Hz,0.8H),9.24(s,0.2H),8.45(s,0.2H),8.44(s,0.8H),7.98(d,J＝3.2Hz,0.8H),7.95(d,J＝3.2Hz,0.8H),7.93(d,J＝3.2Hz,0.2H),7.90(d,J＝2.8Hz,0.2H),7.23-7.14(m,2H),7.07-6.99(m,1H),5.86(s,0.2H),5.74(d,J＝3.2Hz,0.8H),4.89-4.74(m,2H),4.27-4.20(m,0.2H),3.94-3.91(m,0.8H),3.88(s,0.8H),3.87(s,2.2H),3.54(s,0.8H),3.53(s,2.2H),2.99-2.86(m,2H),2.45(d,J＝1.2Hz,0.8H),2.39(d,J＝1.6Hz,2.2H)2.18(s,3H),1.95-1.77(m,3H),1.64-1.60(m,1H)。

Compound XI-6-B:

methyl 6- (1- (5- (2-ethoxy-2-oxoethyl) pyrimidin-2-yl) piperidin-4-yl) -4- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB1 and FA4 by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.65min，C₂₉H₃₁FN₆O₄Calculated mass of S578.2, found M/z 578.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝3.6Hz,0.8H),9.18(s,0.2H),8.29-8.27(m,2H),7.97-7.88(m,2H),7.23-7.13(m,2H),7.07-7.00(m,1H),5.87(s,0.2H),5.74(d,J＝3.2Hz,0.8H),4.92-4.77(m,2H),4.24-4.19(m,0.2H),4.10(q,J＝7.2Hz,2H),3.93-3.88(m,0.8H),3.54(s,2H),3.53(s,3H),2.94-2.85(m,2H),2.46(s,0.7H),2.39(s,2.3H),1.92-1.58(m,4H),1.20(t,J＝7.2Hz,3H)。

Compound XI-9-B:

methyl 4- (2-chloro-3-fluorophenyl) -6- (1- (5- (2-ethoxy-2-oxoethyl) pyrimidin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB1 and FA6 by a similar procedure using method E.

¹H NMR(400MHz,DMSO-d₆)δ9.58(d,J＝3.2Hz,0.7H),9.22(s,0.3H),8.29(s,0.8H),8.28(s,1.2H),7.99-7.90(m,2H),7.41-7.29(m,2H),7.32-7.17(m,1H),6.08(s,0.3H),5.99(d,J＝3.6Hz,0.7H),4.90-4.77(m,2H),4.22-4.18(m,0.3H),4.13-4.07(m,2H),3.95-3.89(m,0.7H),3.55(s,3H),3.53(s,2H),2.97-2.86(m,2H),2.04-1.06(m,4H),1.20(t,J＝7.2Hz,3H)。

Compound XI-10-1:

methyl 2- (4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB3 and FA6 by a similar procedure using method E.

¹H NMR(400MHz,DMSO-d₆)δ9.64(d,J＝4.0Hz,0.8H),9.38(s,0.2H),8.00-7.96(m,1.7H),7.92(d,J＝2.8Hz,0.3H),7.90(s,1H),7.41-7.30(m,2H),7.23-7.21(m,0.7H),7.18-7.16(m,0.3H),6.07(s,0.2H),5.99(d,J＝3.6Hz,0.8H),4.19-4.08(m,2.2H),3.93-3.87(m,0.8H),3.76(s,3H),3.54(s,2.2H),3.53(s,0.8H),3.27-3.19(m,2H),2.24-1.99(m,1H),1.94-1.90(m,1H),1.87-1.67(m,2H)。

Compound XI-13-S:

methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (4- (2-ethoxy-2-oxoethyl) pyrimidin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB9 and FA7 by a similar procedure using method E.

¹H NMR(400MHz,DMSO-d₆)δ9.50(d,J＝3.6Hz,0.7H),9.21(s,0.3H),8.33-8.31(m,1H),7.98(d,J＝3.2Hz,0.7H),7.95-7.93(m,1H),7.90(d,J＝3.2Hz,0.3H),7.44-7.31(m,2H),7.24-7.19(m,1H),6.59-6.57(m,1H),6.02(s,0.3H),5.93(d,J＝4.0Hz,0.7H),4.93-4.79(m,2H),4.20-4.09(m,2.3H),3.93-3.88(m,0.7H),3.66(s,2H),3.54(s,2H),3.53(s,1H),2.93-2.83(m,2H),2.06-1.99(m,0.3H),1.91-1.70(m,3H),1.62-1.58(m,0.7H),1.22-1.18(m,3H)。

Compound XI-14-A:

ethyl 2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidin-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB4 and FA7 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.00min，C₂₈H₂₈ClFN₆O₄Calculated mass of S598.2, found M/z 599.0[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.28(d,J＝4.0Hz,1H),8.13(s,0.5H),7.81(d,J＝3.2Hz,0.5H),7.77(d,J＝3.2Hz,0.5H),7.47(d,J＝3.2Hz,0.5H),7.42-7.41(m,1H),7.32-7.29(m,1H),7.15-7.12(m,1H),6.97-6.89(m,1H),6.20(s,0.5H),6.07(d,J＝2.8Hz,0.5H),5.03-4.87(m,2H),4.43(q,J＝7.2Hz,2H),4.33-4.27(m,0.5H),4.07-4.01(m,0.5H),3.63(s,1.6H),3.61(s,1.4H),3.06-2.95(m,2H),2.28(s,1.5H),2.26(s,1.5H),2.17-2.13(m,0.8H),2.01-1.92(m,1.6H),1.80-1.68(m,1.6H),1.42(t,J＝7.2Hz,3H)。

Compound XI-15-S:

methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (5- (2-ethoxy-2-oxoethyl) pyrimidin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB1 and FA7 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.01min,C₂₈H₂₈ClFN₆O₄Calculated mass of S598.2, found M/z 598.8[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.27(s,1H),8.26(s,1H),8.13(br s,0.5H),7.81(d,J＝3.2Hz,0.5H),7.77(br s,0.5H),7.47(d,J＝3.2Hz,0.5H),7.42(s,1H),7.32-7.29(m,1H),7.15-7.12(m,1H),6.97-6.89(m,1H),6.21(s,0.5H),6.07(d,J＝3.2Hz,0.5H),5.03-4.85(m,2H),4.35-4.28(m,0.5H),4.20-4.03(m,2.5H),3.63(s,1.5H),3.61(s,1.5H),3.45(s,1H),3.43(s,1H),3.08-2.96(m,2H),2.20-2.09(m,1H),2.01-1.94(m,1.5H),1.81-1.67(m,1.5H),1.28(t,J＝8.8Hz,3H)。

Compound XI-16-B:

ethyl 2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4-methylpyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB8 and FA7 by a similar procedure using method E.

LC-MS(ESI)：R_T＝4.252min,C₂₈H₂₈ClFN₆O₄Calculated mass of S598.2, found M/z 598.9[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝3.6Hz,0.7H),9.29(s,0.3H),8.77(s,0.3H),8.76(s,0.7H),7.98(d,J＝2.8Hz,0.7H),7.95-7.93(m,1H),7.90(d,J＝3.2Hz,0.3H),7.45-7.41(m,1H),7.38-7.30(m,1H),7.24-7.19(m,1H),6.02(s,0.3H),5.93(d,J＝3.6Hz,0.7H),5.06-4.91(m,2H),4.25(q,J＝7.2Hz,2.2H),4.00-3.91(m,0.8H),3.55(s,2H),3.53(s,1H),3.05-2.96(m,2H),2.60(s,1H),2.59(s,2H),1.99-1.64(m,4H),1.30(t,J＝7.2Hz,3H)。

Compound XI-18-S:

ethyl 2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) oxazole-4-carboxylic acid ester (single stereoisomer)

The title compound was synthesized from compounds BB6 and FA7 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.051min，C₂₆H₂₅ClFN₅O₅Calculated mass of S573.1, found M/z 573.9[ M + H ] ]⁺。¹H NMR(400MHz,CDCl₃)δ8.13(s,0.3H),7.83-7.79(m,2H),7.49(d,J＝3.2Hz,0.7H),7.44(s,1H),7.30-7.28(m,1H),7.14(d,J＝8.0Hz,1H),6.98-6.89(m,1H),6.20(s,0.3H),6.07(s,0.7H),4.40-4.31(m,4H),4.28-4.25(m,0.4H),4.02-3.96(m,0.6H),3.61(s,3H),3.19-3.08(m,2H),2.26-1.69(m,4H),1.37(t,J＝6.8Hz,3H)。

Compound XI-19-2:

methyl 2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB3 and FA7 by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.63min，C₂₅H₂₃ClFN₅O₄S₂Calculated mass of 575.1, M/z found 575.8[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.57(d,J＝3.6Hz,0.8H),9.35(s,0.2H),8.00-7.96(m,2H),7.92-7.90(m,1H),7.45-7.42(m,1H),7.39-7.31(m,1H),7.24-7.20(m,1H),6.02(s,0.2H),5.93(d,J＝3.6Hz,0.8H),4.19-4.08(m,2.2H),3.93-3.87(m,0.8H),3.76(s,3H),3.54(s,2.4H),3.53(s,0.6H),3.27-3.18(m,2H),2.08-1.67(m,4H)。

Compound XI-21-B:

ethyl 4- (2-chloro-4-fluorophenyl) -6- (1- (5- (2-ethoxy-2-oxoethyl) pyrimidin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB1 and FA8 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.10min，C₂₉H₃₀ClFN₆O₄Calculated mass of S612.2, found M/z 613.1[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ8.52(br s,2H),7.93(br s,1H),7.69(br s,1H),7.41-7.34(m,1H),7.17-7.16(m,1H),7.05-6.97(m,1H),6.25(br s,1H),5.23-5.09(m,2H),4.38-4.29(m,1H),4.22(q,J＝7.2Hz,2H),4.14-4.05(m,2H),3.57(br s,2H),3.42-3.28(m,2H),2.17-2.07(m,2H),2.01-1.95(m,2H),1.31(t,J＝7.2Hz,3H),1.17-1.14(m,3H)。

Compound XI-23-B:

ethyl 4- (2-chloro-3-fluorophenyl) -6- (1- (5- (2-ethoxy-2-oxoethyl) pyrimidin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB1 and FA9 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.02min，C₂₉H₃₀ClFN₆O₄Calculated mass of S612.2, found M/z 613.0[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ8.52(br s,2H),8.01(br s,1H),7.87(br s,1H),7.32-7.27(m,0.7H),7.24-7.15(m,2.3H),6.39(br s,1H),5.25-5.13(m,2H),4.46-4.36(m,1H),4.21(q,J＝6.4Hz,2H),4.11-4.07(m,2H),3.59(s,2H),3.37-3.24(m,2H),2.47-2.25(m,2H),2.19-2.09(m,1H),1.99-1.96(m,1H),1.29(t,J＝7.2Hz,3H),1.16(t,J＝7.2Hz,3H)。

Compound XI-24-B:

(cis) -methyl 6- (1- (5- (3- (tert-butoxycarbonyl) -1-hydroxycyclobutyl) pyrimidin-2-yl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB14 and FA10 by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.73min,C₃₃H₃₅ClF₂N₆O₅Calculated mass of S700.2, M/z found 701.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.64(d,J＝3.6Hz,0.7H),9.24(s,0.3H),8.50(s,0.6H),8.48(s,1.4H),7.99-7.91(m,2H),7.50-7.43(m,1H),7.22-7.16(m,1H),6.03(s,0.3H),5.94(d,J＝3.2Hz,0.7H),5.77(s,0.5H),5.75(s,0.5H),4.91-4.80(m,2H),4.22-4.16(m,0.3H),3.95-3.89(m,0.7H),3.55(s,2H),3.54(s,1H),2.95-2.87(m,2H),2.67-2.59(m,3H),2.45-2.41(m,2H),2.06-1.60(m,4H),1.41(s,9H)。

Compound XI-25-B:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) oxazole-5-carboxylic acid ester (single stereoisomer)

The title compound was synthesized from compounds BB10 and FA10 by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.86min,C₂₆H₂₄ClF₂N₅O₅Calculated mass of S591.1, found M/z 591.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.15(s,0.4H),7.83-7.80(m,1H),7.58(s,0.6H),7.56(s,0.4H),7.51(d,J＝3.2Hz,0.6H),7.46(d,J＝3.2Hz,0.6H),7.43(s,0.4H),7.09-7.05(m,2H),6.19(s,0.3H),6.08(d,J＝2.4Hz,0.7H),4.48-4.30(m,4.4H),4.07-4.01(m,0.6H),3.62(s,2H),3.61(s,1H),3.25-3.14(m,2H),2.25-2.10(m,1H),2.02-1.72(m,3H),1.36(t,J＝6.4Hz,3H)。

Compound XI-26-B:

ethyl 5-chloro-2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB13 and FA10 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.237min,C₂₇H₂₄Cl₂F₂N₆O₄Calculated mass of S636.1, M/z found 639.0[ M + H [ ]]⁺。

Compound XI-28-6:

methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (5- (2-ethoxy-2-oxoethyl) -4-methylpyrimidin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB12 and FA10 by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.79min,C₂₉H₂₉ClF₂N₆O₄Calculated mass of S630.2, M/z found 630.8[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.63(d,J＝4.0Hz,0.7H),9.28(s,0.3H),8.11-8.10(m,1H),8.01-7.91(m,2H),7.50-7.42(m,1H),7.24-7.14(m,1H),6.02(s,0.3H),5.94(d,J＝3.6Hz,0.7H),4.94-4.79(m,2H),4.22-4.15(m,0.3H),4.09(q,J＝6.8Hz,2H),3.94-3.87(m,0.7H),3.57(s,2H),3.55(s,2.1H),3.53(s,0.9H),2.94-2.81(m,2H),2.26(s,0.9H),2.25(s,2.1H),2.10-2.01(m,0.3H),1.96-1.69(m,3H),1.63-1.59(m,0.7H),1.20(t,J＝6.8Hz,3H)。

Compound XI-29-S:

methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (5- (2-ethoxy-2-oxoethyl) pyrimidin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB1 and FA10 by a similar procedure using method E.

¹H NMR(400MHz,CDCl₃)δ8.27-8.26(m,2H),8.16(s,1H),7.82-7.81(m,0.4H),7.78-7.77(m,0.6H),7.48-7.47(m,0.4H),7.44-7.43(m,0.6H),7.10-6.99(m,2H),6.20(s,0.6H),6.07-6.06(m,0.4H),5.04-4.86(m,2H),4.35-4.28(m,0.6H),4.20-4.04(m,2.4H),3.63(s,1.3H),3.61(s,1.7H),3.45(s,1.2H),3.43(s,0.8H),3.07-2.96(m,2H),2.20-2.08(m,0.7H),2.05-1.91(m,1.3H),1.79-1.67(m,2H),1.29-1.26(m,3H)。

Compound XI-30-B:

methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB3 and FA10 by a similar procedure using method E.

¹H NMR(400MHz,DMSO-d₆)δ9.68(d,J＝3.2Hz,0.8H),9.41(s,0.2H),8.01-7.96(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.90(s,1H),7.49-7.43(m,1H),7.24-7.20(m,0.7H),7.17-7.14(m,0.3H),6.02(s,0.2H),5.94(d,J＝3.6Hz,0.8H),4.18-4.08(m,2.1H),3.94-3.87(m,0.9H),3.76(s,3H),3.54(s,2.2H),3.53(s,0.8H),3.28-3.19(m,2H),2.27-2.04(m,1H),1.99-1.89(m,1H),1.86-1.68(m,2H)。

Compound XI-31-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4- (trifluoromethyl) thiazole-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB15 and FA10 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.824min,C₂₇H₂₃ClF₅N₅O₄S₂Calculated Mass of 675.1, M/z found 675.8[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.67(d,J＝3.6Hz,0.7H),9.42(s,0.3H),8.01-7.92(m,2H),7.49-7.42(m,1H),7.24-7.14(m,1H),6.03(s,0.3H),5.95(d,J＝4.0Hz,0.7H),4.25(q,J＝7.2Hz,2H),4.20-4.02(m,2.3H),3.94-3.86(m,0.7H),3.54(s,2.1H),3.53(s,0.9H),3.29-3.21(m,2H),2.29-1.83(m,3H),1.76-1.69(m,1H),1.26(t,J＝7.2Hz,3H)。

Compound XI-32-B:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB11 and FA10 by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.86min，C₂₆H₂₄ClF₂N₅O₄S₂Calculated mass of 607.1, M/z found 608.3[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.64(d,J＝3.2Hz,0.7H),9.30(s,0.3H),8.00-7.96(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.70(s,1H),7.49-7.42(m,1H),7.24-7.15(m,1H),6.03(s,0.3H),5.94(d,J＝3.6Hz,0.7H),4.24(q,J＝7.2Hz,2H),4.16-3.98(m,2.3H),3.90-3.83(m,0.7H),3.54(s,2H),3.53(s,1H),3.20-3.06(m,2H),2.10-1.65(m,4H),1.28(t,J＝7.2Hz,3H)。

Compound XI-33-B:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) oxazole-4-carboxylic acid ester (single stereoisomer)

The title compound was synthesized from compounds BB6 and FA10 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.077min,C₂₆H₂₄ClF₂N₅O₅Calculated mass of S591.1, found M/z 592.0[ M + H ]]⁺。

Compound XI-34-10F:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) -2-methylpiperidin-1-yl) pyrimidine-5-carboxylate (mixture of 2 stereoisomers)

Intermediate XI-34-10:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) -2-methylpiperidin-1-yl) pyrimidine-5-carboxylate (mixture of 4 stereoisomers)

The title compound was synthesized from compounds BB7 and FA11 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.18min,C₂₉H₂₉ClF₂N₆O₄Calculated mass of S630.2, M/z found 630.8[ M + H [)]⁺。¹H NMR(300MHz,DMSO-d₆)δ9.65-9.61(m,0.8H),9.28-9.07(m,0.2H),8.81(s,2H),7.97-7.95(m,2H),7.51-7.41(m,1H),7.26-7.15(m,1H),6.05-5.92(m,1H),5.37-5.18(m,1H),4.91-4.76(m,1H),4.27-4.25(m,3H),4.03-3.98(m,2H),3.19-3.07(m,1H),1.95-1.62(m,4H),1.28-1.24(m,6H),1.10-1.06(m,3H)。

A stereoisomeric mixture of XI-34-10(550mg, 0.87mmol) was separated by preparative HPLC (separation conditions: column: Chiralpak IA 20 mm. about.250 mm 5um mobile phase: Hex-EtOH-DEA-40-60-0.3, flow rate: 22 mL/min; wavelength: 230nm) to give compounds groups 1XI-34-10A and XI-34-10B (240mg, 43% yield, 100% de) as yellow solids and groups 2XI-34-10F (140mg, 25% yield, 98.8% de) as yellow solids. Group 1 was separated by preparative HPLC (separation conditions: column: Chiralpak IE 4.6 mm. times.250 mm 5 um; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 12 ml/min; wavelength: 230nm) to give the title compounds XI-34-10A (100mg, 41% yield, 100% de) and XI-34-10B (100mg, 41% yield, 99.8% de) as yellow solids.

XI-34-10A：LC-MS(ESI)：R_T＝2.28min，C₂₉H₂₉ClF₂N₆O₄The calculated mass of S was 630.2, found value of M/z 630.9[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IE 4.6 mm. about.250 mm 5 um; mobile phase: Hex-EtOH-DEA-70-30-0.2 at 1.0 mL/min; wavelength: 230nm, R_T＝10.865min)。¹H NMR(400MHz,CD₃OD)δ8.82(s,0.8H),8.81(s,1.2H),7.86(s,0.4H),7.85(s,0.4H),7.70(s,0.6H),7.69(s,0.4H),7.27-7.21(m,2H),6.18(s,0.4H),6.11(s,0.6H),5.44-5.33(m,1H),5.01-4.90(m,1H),4.68-4.60(m,0.4H),4.36-4.30(m,2.6H),4.10-4.04(m,2H),3.25-3.13(m,1H),2.21-1.83(m,3.4H),1.71-1.68(m,0.6H),1.38-1.35(m,6H),1.17-1.12(m,3H)。

XI-34-10B：LC-MS(ESI)：R_T＝2.31min,C₂₉H₂₉ClF₂N₆O₄Calculated mass of S630.2, M/z found 630.9[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IE 4.6 mm. about.250 mm 5 um; mobile phase: Hex-EtOH-DEA-70-30-0.2 at 1.0 mL/min; wavelength: 230nm, R_T＝14.122min)。¹H NMR(400MHz,CD₃OD)δ8.82(s,0.8H),8.81(s,1.2H),7.86-7.85(m,1H),7.69-7.68(m,1H),7.25-7.22(m,2H),6.16(s,0.4H),6.09(s,0.6H),5.42-5.28(m,1H),5.02-4.90(m,1H),4.67-4.60(m,0.4H),4.35-4.30(m,2.6H),4.11-4.04(m,2H),3.27-3.16(m,1H),2.11-1.81(m,3.4H),1.65-1.60(m,0.6H),1.37-1.31(m,6H),1.17-1.12(m,3H)。

XI-34-10F：LC-MS(ESI)：R_T＝2.18min，C₂₉H₂₉ClF₂N₆O₄The calculated mass of S is 630.2, M/z found 630.8[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IA 4.6 mm. about.250 mm 5 um; mobile phase: Hex-EtOH-DEA-40-60-0.2 at 1.0 mL/min; wavelength: 230nm, R_T10.549 and 11.719 min).¹H NMR(400MHz,CD₃OD)δ8.81(s,2H),7.85(d,J＝3.2Hz,1H),7.69(d,J＝3.2Hz,1H),7.25-7.21(m,2H),6.12(d,J＝7.6Hz,1H),5.41-5.31(m,1H),5.00-4.91(m,1H),4.60-4.45(m,1H),4.33(d,J＝7.2Hz,2H),4.10-4.05(m,2H),3.25-3.14(m,1H),2.20-1.72(m,4H),1.38-1.32(m,6H),1.16-1.13(m,3H)。

Compounds XI-35-5R and XI-35-5S:

ethyl 6- (1- (4- (tert-butoxycarbonyl) phenyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer) and ethyl 6- (1- (4- (tert-butoxycarbonyl) phenyl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

By a similar procedure using method B to give the racemic product (180mg) as a yellow solid, it was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA 5 μm 20 × 250 mm; mobile phase: Hex: IPA: DEA ═ 70:30:0.3 at 22 mL/min; column temperature: 30 ℃; wavelength: 214nm) to give the title compounds XI-35-5R (58mg, 31% yield, 100% ee) and XI-35-5S (48mg, 26% yield, 100% ee) as a yellow solid.

XI-35-5R: chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R-_T＝10.261min)。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝3.6Hz,0.8H),9.02(s,0.2H),8.00-7.93(m,2H),7.76-7.73(m,2H),7.50-7.43(m,1H),7.25-7.18(m,1H),7.02-6.99(m,2H),6.05(s,0.3H),5.95(d,J＝3.2Hz,0.7H),4.12-3.97(m,4H),3.88-3.82(m,1H),2.92-2.82(m,2H),2.06-1.89(m,2H),1.82-1.77(m,1H),1.68-1.63(m,1H),1.52(s,9H),1.11-1.04(m,3H)。

XI-35-5S: chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA ═ 60:40:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R-_T＝16.394min)。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝3.6Hz,0.7H),9.02(s,0.3H),8.00-7.93(m,2H),7.76-7.73(m,2H),7.50-7.44(m,1H),7.25-7.18(m,1H),7.02-6.99(m,2H),6.05(s,0.3H),5.95(d,J＝3.6Hz,0.7H),4.12-3.97(m,4H),3.88-3.81(m,1H),2.94-2.82(m,2H),2.06-1.88(m,2.2H),1.82-1.79(m,1H),1.66-1.63(m,0.8H),1.52(s,9H),1.11-1.04(m,3H)。

Compound XI-36-S:

ethyl-6- (1- (5- (tert-butoxycarbonyl) -4- ((4-methoxybenzyl) oxy) pyridin-2-yl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB32 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.11min,C₃₉H₄₀ClF₂N₅O₆Calculated mass of S779.2, found M/z 779.8[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ9.62(d,J＝3.6Hz,0.8H),9.12(d,J＝4.0Hz,0.2H),8.40(s,0.3H),8.39(s,0.7H),8.00-7.93(m,2H),7.45-7.43(m,3H),7.25-7.20(m,1H),6.99-6.96(m,2H),6.48(s,0.3H),6.45(s,0.7H),6.04(s,0.3H),5.95(d,J＝3.2Hz,0.7H),5.15(s,2H),4.73-4.57(m,2H),4.03-3.92(m,3H),3.75(s,3H),2.98-2.88(m,2H),1.94-1.76(m,3.2H),1.67-1.60(m,0.8H),1.41(s,9H),1.10(t,J＝7.2Hz,3H)。

Compound XI-37-2:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (6- (methoxycarbonyl) pyridin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB20 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.676min,C₂₈H₂₆ClF₂N₅O₄Calculated mass of S601.1, M/z found 601.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝3.6Hz,0.7H),9.15(s,0.3H),7.99-7.91(m,2H),7.71-7.67(m,1H),7.51-7.43(m,1H),7.30-7.28(m,1H),7.25-7.18(m,1H),7.13(d,J＝8.8Hz,1H),6.04(s,0.3H),5.95(d,J＝3.6Hz,0.7H),4.65-4.51(m,2H),4.21-4.12(m,0.3H),4.03-3.98(m,2H),3.93-3.87(m,0.7H),3.84(s,3H),2.95-2.82(m,2H),2.06-1.63(m,4H),1.11-1.05(m,3H)。

Compound XI-38-3:

ethyl 6- (1- (4- (tert-butoxycarbonyl) -6- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB50 and FA12 by a similar procedure using method E.

¹H NMR(400MHz,DMSO-d₆)δ9.62(br s,0.7H),9.24(s,0.3H),7.99-7.90(m,2H),7.50-7.44(m,2H),7.25-7.17(m,2H),6.04(s,0.3H),5.95(br s,0.7H),4.64-4.50(m,2H),4.25-4.18(m,0.3H),4.03-3.93(m,2.7H),3.04-2.94(m,2H),2.13-1.84(m,3H),1.77-1.67(m,1H),1.57(s,9H),1.11-1.05(m,3H)。

Compound XI-39-S:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (4- (methoxycarbonyl) -5- (trifluoromethyl) pyridin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB48 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝4.322min,C₂₉H₂₅ClF₅N₅O₄Calculated mass of S669.1, found M/z 669.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝3.2Hz,0.6H),9.32(s,0.4H),8.50(s,1H),7.99-7.90(m,2H),7.50-7.43(m,1H),7.24-7.15(m,2H),6.04(s,0.3H),5.95(d,J＝3.2Hz,0.7H),4.71-4.58(m,2H),4.26-4.20(m,0.3H),4.03-3.95(m,2.7H),3.87(s,3H),3.07-2.98(m,2H),2.12-1.66(m,4H),1.11-1.04(m,3H)。

Compound XI-40-B:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (3-fluoro-4- (methoxycarbonyl) pyridin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB34 and FA12 by a similar procedure using method E.

1H NMR(300MHz,CDCl3)δ8.28(s,0.5H),8.18-8.12(m,1H),7.85-7.78(m,1H),7.52-7.48(m,1H),7.46-7.43(m,0.5H),7.38-7.30(m,1H),7.16-7.01(m,2H),6.22(s,0.5H),6.10(s,0.5H),4.26-4.08(m,2H),4.00-3.95(m,3H),3.33-3.18(m,3H),3.12-2.90(m,1H),2.39-2.17(m,2H),2.04-1.80(m,3H),1.18-1.13(m,3H)。

Compound XI-41-B:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (4- (methoxycarbonyl) pyridin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB18 and FA12 by a similar procedure using method E.

¹H NMR(400MHz,DMSO-d₆)δ9.62(br s,0.7H),9.13(s,0.3H),8.30(d,J＝5.2Hz,1H),7.99-7.91(m,2H),7.51-7.43(m,1H),7.27-7.18(m,2H),7.03(d,J＝4.8Hz,1H),6.04(s,0.3H),5.95(s,0.7H),4.60-4.46(m,2H),4.20-4.13(m,0.3H),4.01-3.97(m,2H),3.96-3.90(m,0.7H),3.88(s,3H),2.99-2.86(m,2H),2.07-1.63(m,4H),1.11-1.05(m,3H)。

Compound XI-42-3B:

ethyl 6- (1- (6- (tert-butoxycarbonyl) -2-chloropyridin-3-yl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB44 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝7.814min,C₃₁H₃₁Cl₂F₂N₅O₄Calculated mass of S677.1, found M/z 677.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.64(d,J＝3.2Hz,0.8H),9.07(s,0.2H),8.02-8.00(m,1.7H),7.97-7.94(m,1.3H),7.69-7.65(m,1H),7.51-7.45(m,1H),7.26-7.22(m,1H),6.06(s,0.2H),5.96(d,J＝3.2Hz,0.8H),4.02-3.96(m,2.2H),3.85-3.79(m,0.8H),3.64-3.56(m,2H),2.86-2.78(m,2H),2.22-1.83(m,3.3H),1.70-1.67(m,0.7H),1.55(s,9H),1.11-1.05(m,3H)。

Compound XI-43-1:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (5- (methoxycarbonyl) pyridin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB19 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.126min,C₂₈H₂₆ClF₂N₅O₄Calculated mass of S601.1, M/z found 602.0[ M + H [)]⁺。

Compound XI-45-B:

ethyl 6- (1- (5- (tert-butoxycarbonyl) -3-fluoropyridin-2-yl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB33 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.940min,C₃₁H₃₁ClF₃N₅O₄Calculated mass of S661.2, found M/z 662.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.60(d,J＝3.6Hz,0.7H),9.13(s,0.3H),8.50-8.49(m,1H),7.99-7.91(m,2H),7.77-7.72(m,1H),7.50-7.43(m,1H),7.24-7.17(m,1H),6.04(s,0.3H),5.95(d,J＝3.2Hz,0.7H),4.55-4.39(m,2H),4.22-4.16(m,0.2H),4.03-3.91(m,2.8H),3.10-3.01(m,2H),2.16-1.76(m,3.5H),1.68-1.64(m,0.5H),1.53(s,9H),1.11-1.04(m,3H)。

Compound XI-46-S:

methyl 6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4-methylpyridazine-3-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB27 and FA12 by a similar procedure using method E.

¹H NMR(300MHz,CDCl₃)δ8.11(br s,0.3H),7.82-7.77(m,1H),7.49-7.44(m,1H),7.34(br s,0.7H),7.10-7.04(m,2H),6.71-6.67(m,1H),6.21(s,0.5H),6.09(s,0.5H),4.80-4.67(m,2H),4.47-4.33(m,0.5H),4.18-4.06(m,2.5H),3.98(s,1H),3.97(s,2H),3.21-3.12(m,2H),2.55(s,3H),2.13-2.09(m,1H),2.04-1.98(m,1.5H),1.83-1.73(m,1.5H),1.14(t,J＝7.2Hz,3H)。

Compound XI-47-3:

Ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (5-methoxy-6- (methoxycarbonyl) pyrazin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB41 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝4.167min,C₂₈H₂₇ClF₂N₆O₅Calculated mass of S632.1, found M/z 632.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝3.6Hz,0.7H),9.11(s,0.3H),8.21(s,0.3H),8.19(s,0.7H),8.00-7.92(m,2H),7.50-7.43(m,1H),7.25-7.17(m,1H),6.04(s,0.3H),5.95(d,J＝3.2Hz,0.7H),4.43-4.27(m,2H),4.16-4.09(m,0.3H),4.02-3.95(m,2H),3.90-3.83(m,6.7H),2.95-2.80(m,2H),2.08-1.64(m,4H),1.11-1.05(m,3H)。

Compound XI-48-B:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (6- (methoxycarbonyl) -5-methylpyrazin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB30 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.858min,C₂₈H₂₇ClF₂N₆O₄Calculated mass of S616.1, found M/z 617.0[ M [ ]+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.24(s,1H),8.15(s,0.5H),7.82(d,J＝3.2Hz,0.5H),7.78(d,J＝3.2Hz,0.5H),7.49(d,J＝3.2Hz,0.5H),7.44(d,J＝3.2Hz,0.5H),7.35(s,0.5H),7.11-7.00(m,2H),6.22(s,0.5H),6.10(d,J＝2.4Hz,0.5H),4.60-4.44(m,2H),4.34-4.28(m,0.5H),4.10-3.97(m,2.5H),3.96(s,3H),3.10-2.98(m,2H),2.66(s,1.5H),2.65(s,1.5H),2.24-1.96(m,3H),1.86-1.75(m,1H),1.15(t,J＝7.2Hz,3H)。

Compound XI-49-B:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (5- (methoxycarbonyl) -6-methylpyrazin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB29 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.127min,C₂₈H₂₇ClF₂N₆O₄Calculated mass of S616.2, found M/z 617.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.11(s,0.3H),8.06(s,1H),7.82-7.78(m,1H),7.49-7.44(m,1H),7.36(s,0.7H),7.10-7.00(m,2H),6.22(s,0.4H),6.11(d,J＝2.8Hz,0.6H),4.79-4.62(m,2H),4.40-4.35(m,0.4H),4.15-4.01(m,2.6H),3.95-3.94(m,3H),3.17-3.06(m,2H),2.75(s,3H),2.20-2.12(m,1H),2.06-2.02(m,0.8H),2.00-1.96(m,0.7H),1.84-1.72(m,1.5H),1.15(t,J＝7.2Hz,3H)。

Compound XI-50-S:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) oxazole-5-carboxylic acid ester (single stereoisomer)

The title compound was synthesized from compounds BB10 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝4.410min,C₂₇H₂₆ClF₂N₅O₅Calculated mass of S605.1, found M/z 605.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.89-7.87(m,1H),7.73(d,J＝3.2Hz,1H),7.61(s,1H),7.26-7.22(m,2H),6.16(s,0.3H),6.10(s,0.7H),4.36-4.26(m,4.2H),4.09-4.02(m,2.8H),3.26-3.19(m,2H),2.18-1.92(m,3.3H),1.75-1.72(m,0.7H),1.34(t,J＝6.8Hz,3H),1.16-1.11(m,3H)。

Compound XI-52-S:

methyl 6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -2-methoxypyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB40 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.004min,C₂₈H₂₇ClF₂N₆O₅Calculated mass of S632.1, found M/z 633.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.12(s,0.4H),7.86(d,J＝2.8Hz,0.6H),7.83(d,J＝3.2Hz,0.4H),7.53(d,J＝3.2Hz,0.6H),7.48(d,J＝2.8Hz,0.4H),7.39(br s,0.6H),7.13-7.04(m,3H),6.26(s,0.4H),6.14(d,J＝2.4Hz,0.6H),4.88-4.60(m,2H),4.19-4.07(m,3H),4.05(s,1.4H),4.04(s,1.6H),4.01(s,1.4H),4.00(s,1.6H),3.22-3.07(m,2H),2.19-2.12(m,1H),2.04-1.95(m,2H),1.82-1.71(m,1H),1.18(t,J＝7.2Hz,3H)。

Compound XI-53-S:

methyl 6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -2-methylpyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB28 and FA12 by a similar procedure using method E.

¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝3.6Hz,0.7H),9.31(s,0.3H),7.99-7.90(m,2H),7.50-7.42(m,1H),7.24-7.15(m,2H),6.03(s,0.3H),5.94(d,J＝3.6Hz,0.7H),4.73-4.56(m,2H),4.27-4.20(m,0.3H),4.04-3.94(m,2.7H),3.86(s,3H),3.03-2.93(m,2H),2.44(s,3H),2.11-2.01(m,0.3H),1.99-1.65(m,3.7H),1.11-1.04(m,3H)。

Compound XI-54-S:

methyl 6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB21 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.966min,C₂₇H₂₅ClF₂N₆O₄Calculated mass of S602.1, M/z found 603.1[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝3.6Hz,0.7H),9.27(s,0.3H),8.61-8.60(m,1H),7.98-7.90(m,2H),7.50-7.37(m,2H),7.24-7.15(m,1H),6.04(s,0.3H),5.95(d,J＝3.2Hz,0.7H),4.61(br s,1.6H),4.26-4.20(m,0.4H),4.03-3.93(m,3H),3.88(s,1H),3.87(s,2H),3.07-2.98(m,2H),2.14-1.66(m,4H),1.11-1.04(m,3H)。

Compound XI-56-B:

Ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5, 6-dimethylpyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB37 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.18min,C₃₀H₃₁ClF₂N₆O₄Calculated mass of S644.2, found M/z 644.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.13(s,0.6H),7.82-7.77(m,1H),7.50-7.48(m,0.4H),7.44-7.43(m,0.6H),7.33(s,0.4H),7.12-7.01(m,2H),6.21(s,0.6H),6.09(d,J＝2.4Hz,0.4H),4.47-4.40(m,2H),4.32-4.24(m,1H),4.11-3.98(m,2H),3.04-2.88(m,2H),2.40(s,3H),2.16(s,3H),2.09-1.81(m,6H),1.42(t,J＝6.8Hz,3H),1.15(t,J＝7.2Hz,3H)。

Compound XI-57-S:

methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -6-methoxypyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB42 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝4.179min,C₂₈H₂₇ClF₂N₆O₅Calculated mass of S632.1, found M/z 632.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.60(d,J＝3.6Hz,0.7H),9.23(s,0.3H),7.99-7.90(m,2H),7.50-7.43(m,1H),7.25-7.17(m,1H),6.53(s,0.3H),6.52(s,0.7H),6.04(s,0.3H)，5.95(d,J＝3.6Hz,0.7H),4.94-4.83(m,2H),4.25-4.18(m,0.3H),4.03-3.93(m,2.7H),3.92(s,3H),3.85(s,3H),3.00-2.90(m,2H),2.09-1.65(m,4H),1.12-1.05(m,3H)。

Compound XI-58-S:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -6-methylpyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB31 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝4.338min,C₂₉H₂₉ClF₂N₆O₄Calculated mass of S630.2, M/z found 630.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.12(s,0.5H),7.81(d,J＝2.8Hz,0.4H),7.76(d,J＝2.8Hz,0.6H),7.47(d,J＝3.2Hz,0.4H),7.43(d,J＝2.8Hz,0.6H),7.33(d,J＝2.4Hz,0.5H),7.14-6.98(m,3H),6.22(s,0.6H),6.10(d,J＝2.8Hz,0.4H),5.19-4.99(m,2H),4.44-4.36(m,2H),4.33-4.28(m,0.6H),4.13-4.00(m,2.4H),3.09-2.95(m,2H),2.43(s,1.2H),2.42(s,1.8H),2.25-1.90(m,2.5H),1.81-1.66(m,1.5H),1.42(t,J＝7.2Hz,3H),1.17-1.13(m,3H)。

Compound XI-59-B:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-isopropylpyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB45 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.569min,C₃₁H₃₃ClF₂N₆O₄Calculated mass of S658.2, M/z found 658.9[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.42(d,J＝1.2Hz,1H),8.13(s,0.6H),7.81(d,J＝3.2Hz,0.4H),7.78(d,J＝3.6Hz,0.6H),7.48(d,J＝2.8Hz,0.4H),7.43(d,J＝2.8Hz,0.6H),7.34(d,J＝2.4Hz,0.4H),7.12-6.98(m,2H),6.22(s,0.6H),6.09(d,J＝2.4Hz,0.4H),5.05-4.85(m,2H),4.43(q,J＝7.2Hz,2H),4.35-4.27(m,0.6H),4.13-3.99(m,2.4H),3.11-2.91(m,3H),2.18-2.03(m,1H),1.97-1.91(m,1H),1.79-1.65(m,2H),1.42(t,J＝7.2Hz,3H),1.27-1.24(m,6H),1.15(t,J＝7.2Hz,3H)。

Compound XI-60-B:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-ethylpyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB38 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.851min,C₃₀H₃₁ClF₂N₆O₄Calculated mass of S644.2, found M/z 644.9[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.31(d,J＝2.8Hz,1H),8.13(s,0.6H),7.81(d,J＝2.8Hz,0.4H),7.78(d,J＝3.2Hz,0.6H),7.48(d,J＝3.2Hz,0.4H),7.43(d,J＝2.8Hz,0.6H),7.34(d,J＝2.4Hz,0.4H),7.12-7.00(m,2H),6.22(s,0.6H),6.09(d,J＝2.8Hz,0.4H),5.04-4.87(m,2H),4.43(q,J＝7.2Hz,2H),4.34-4.27(m,0.6H),4.13-3.99(m,2.4H),3.06-2.93(m,2H),2.67-2.60(m,2H),2.20-1.95(m,2.5H),1.80-1.68(m,1.5H),1.42(t,J＝7.2Hz,3H),1.22-1.13(m,6H)。

Compound XI-61-B:

ethyl 5-chloro-2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB13 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.275min,C₂₈H₂₆Cl₂F₂N₆O₄Calculated mass of S650.1, M/z found 651.0[ M + H [ ]]⁺。¹H NMR(300MHz,CDCl₃)δ8.34(d,J＝4.8Hz,1H),8.10(s,0.5H),7.81-7.78(m,1H),7.48(d,J＝2.8Hz,0.5H),7.43(d,J＝3.2Hz,0.5H),7.33(s,0.5H),7.12-7.01(m,2H),6.21(s,0.5H),6.09(d,J＝2.7Hz,0.5H),5.01-4.83(m,2H),4.49-4.42(m,2H),4.38-4.22(m,0.5H),4.11-3.98(m,2.5H),3.09-2.95(m,2H),2.14-1.88(m,2.5H),1.80-1.65(m,1.5H),1.43(t,J＝7.2Hz,3H),1.14(t,J＝7.2Hz,3H)。

Compound XI-62-B:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-fluoropyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB35 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.08min，C₂₈H₂₆ClF₃N₆O₄The calculated mass of S is 634.1, found M/z 634.8[ M + H [ ] ]⁺。¹H NMR(400MHz,CDCl₃)δ8.36(s,1H),8.11(s,0.4H),7.84-7.75(m,1H),7.52-7.41(m,1H),7.33(s,0.6H),7.14-7.00(m,2H),6.22(s,0.6H),6.10(s,0.4H),5.02-4.82(m,2H),4.45(q,J＝7.2Hz,2H),4.35-4.28(m,0.6H),4.11-3.99(m,2.4H),3.11-2.96(m,2H),2.18-2.09(m,1H),2.01-1.90(m,1.4H),1.80-1.65(m,1.6H),1.43(t,J＝7.2Hz,3H),1.15(t,J＝6.8Hz,3H)。

Compound XI-64-B:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4-methyloxazole-5-carboxylic acid ester (single stereoisomer)

The title compound was synthesized from compounds BB25 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.605min,C₂₈H₂₈ClF₂N₅O₅Calculated mass of S619.2, found value of M/z 620.1[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.63(d,J＝3.2Hz,0.7H),9.29(s,0.3H),8.00-7.91(m,2H),7.50-7.42(m,1H),7.24-7.16(m,1H)6.04(s,0.3H),5.95(d,J＝3.6Hz,0.7H),4.26-4.11(m,4.3H),4.02-3.95(m,2H),3.90-3.82(m,0.7H),3.16-3.06(m,2H),2.30-2.29(m,3H),2.23-1.80(m,3H),1.72-1.64(m,1H),1.29-1.23(m,3H),1.10-1.04(m,3H)。

Compound XI-66-N:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (5- (3-methoxy-3-oxopropyl) pyrimidin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB39 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.407min,C₂₉H₂₉ClF₂N₆O₄Calculated mass of S630.2, M/z found 631.2[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆) δ 9.58(d, J ═ 3.6Hz,0.7H),9.12(s,0.3H),8.27(d, J ═ 4.8Hz,2H),7.98-7.90(m,2H),7.50-7.43(m,1H),7.24-7.17(m,1H),6.04(s,0.3H),5.94(d, J ═ 3.6Hz,0.7H),4.88-4.74(m,2H),4.19-4.13(m,0.3H),4.02-3.93(m,2H),3.90-3.87(m,0.7H),3.59(s,3H),2.93-2.82(m,2H),2.70-2.59(m,4H),2.05-1.70(m, 3.70H), 1.1H (m,1H), 1.11-1H), 1.9.1H, 1H, 4.9.13 (m, 1H). Compound XI-67-B:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (5- (1-ethoxy-2-methyl-1-oxoprop-2-yl) pyrimidin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB46 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.90min,C₃₁H₃₃ClF₂N₆O₄Calculated mass of S658.2, M/z found 659.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝3.2Hz,0.7H),9.20(s,0.3H),8.37(s,0.8H),8.36(m,1.2H),7.99-7.91(m,2H),7.50-7.43(m,1H),7.24-7.15(m,1H),6.04(s,0.3H),5.94(d,J＝3.2Hz,0.7H),4.92-4.77(m,2H),4.21-4.15(m,0.3H),4.11-4.06(m,2H),4.02-3.97(m,2H),3.95-3.87(m,0.7H),2.97-2.85(m,2H),2.08-1.61(m,4H),1.50(s,6H),1.70-1.04(m,6H)。

Compound XI-68-B:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methyloxazole-4-carboxylic acid ester (single stereoisomer)

The title compound was synthesized from compounds BB24 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.178min,C₂₈H₂₈ClF₂N₅O₅Calculated mass of S619.2, found value of M/z 620.1[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.62(d,J＝3.6Hz,0.8H),9.16(s,0.2H),8.00-7.92(m,2H),7.50-7.43(m,1H),7.24-7.16(m,1H),6.04(s,0.3H),5.94(d,J＝3.6Hz,0.7H),4.26-4.20(m,2H),4.08-3.95(m,4.3H),3.84-3.78(m,0.7H),3.07-2.94(m,2H),2.48(s,3H),2.13-1.61(m,4H),1.27(t,J＝6.8Hz,3H),1.10-1.04(m,3H)。

Compound XI-69-B:

ethyl-4- (2-chloro-3, 4-difluorophenyl) -6- (1- (5- (2-ethoxy-2-oxoethyl) pyrimidin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB1 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝4.550min,C₂₉H₂₉ClF₂N₆O₄Calculated mass of S630.2, M/z found 630.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.59(d,J＝3.6Hz,0.7H),9.16(s,0.3H),8.28-8.27(m,2H),7.98-7.90(m,2H),7.50-7.42(m,1H),7.24-7.16(m,1H),6.04(s,0.3H),5.94(d,J＝3.2Hz,0.7H),4.91-4.76(m,2H),4.20-4.14(m,0.3H),4.10(q,J＝6.8Hz,2H),4.00(q,J＝6.8Hz,2H),3.95-3.88(m,0.7H),3.54(s,2H),2.93-2.84(m,2H),2.04-1.71(m,3.3H),1.63-1.60(m,0.7H),1.20(t,J＝6.8Hz,3H),1.11-1.04(m,3H)。

Compound XI-70-N:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) oxazole-4-carboxylic acid ester (single stereoisomer)

The title compound was synthesized from compounds BB6 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝4.433min,C₂₇H₂₆ClF₂N₅O₅Calculated mass of S605.1, found M/z 606.1[ M + H ] ]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH 70:30 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230 nm; R_T＝8.799min)。¹H NMR(400MHz,DMSO-d₆)δ9.60(s,0.7H),9.18(s,0.3H),8.30(d,J＝5.2Hz,1H),8.00-7.97(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.50-7.43(m,1H),7.24-7.17(m,1H),6.04(s,0.3H),5.95(s,0.7H),4.24(q,J＝7.2Hz,2H),4.14-3.95(m,4.3H),3.86-3.81(m,0.7H),3.12-3.01(m,2H),2.18-1.70(m,3H),1.66-1.63(m,1H),1.27(t,J＝7.2Hz,3H),1.11-1.04(m,3H)。

Compounds XI-72-X and XI-72-S:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4-methoxypyrimidine-5-carboxylate (single stereoisomer) and ethyl 4- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -2-methoxypyrimidine-5-carboxylate (single stereoisomer).

The title compound was synthesized from compounds BB43 and FA12 by a similar procedure using method E.

XI-72-X：¹H NMR(400MHz,DMSO-d₆)δ9.63-9.62(m,0.7H),9.13(s,0.3H),8.51-8.48(m,1H),8.01-7.97(m,1.7H),7.93-7.92(m,0.3H),7.50-7.42(m,1H),7.25-7.16(m,1H),6.04(s,0.3H),5.96-5.95(s,0.7H),4.30-4.11(m,4H),4.05-3.89(m,6H),3.12-3.02(m,2H),2.13-1.76(m,3.3H),1.68-1.65(m,0.7H),1.34-1.30(m,3H),1.12-1.05(m,3H)。

XI-72-S：¹H NMR(400MHz,DMSO-d₆)δ9.62-9.61(m,0.7H),9.28(s,0.3H),8.66-8.65(m,1H),7.99-7.94(m,1.7H),7.91-7.90(m,0.3H),7.50-7.43(m,1H),7.25-7.16(m,1H),6.04(s,0.3H),5.96-5.95(m,0.7H),5.02-4.85(m,2H),4.20(q,J＝7.2Hz,2.3H),4.04-3.93(m,5.7H),3.06-2.97(m,2H),2.16-1.67(m,4H),1.28-1.23(m,3H),1.11-1.04(m,3H)。

Compound XI-73-S:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4-methylpyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB8 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝4.640min,C₂₉H₂₉ClF₂N₆O₄Calculated mass of S630.2, M/z found 631.2[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝3.2Hz,0.7H),9.26(s,0.3H),8.77-8.76(m,1H),7.99-7.90(m,2H),7.50-7.42(m,1H),7.24-7.16(m,1H),6.04(s,0.3H),5.95(d,J＝3.2Hz,0.7H),5.04-4.91(m,2H),4.28-4.22(m,2.3H),4.03-3.92(m,2.7H),3.04-2.96(m,2H),2.60-(s,1H),2.59(s,2H),2.10-1.66(m,4H),1.30(t,J＝7.2Hz,3H),1.11-1.04(m,3H)。

Compound XI-75-S:

ethyl 5- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -1,3, 4-thiadiazole-2-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB16 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.212min，C₂₆H₂₅ClF₂N₆O₄S₂Calculated mass of 622.1, M/z found 623.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆(one drop D)₂O))δ7.99-7.96(m,1.7H),7.91-7.90(m,0.3H),7.49-7.42(m,1H),7.24-7.17(m,1H),6.04(s,0.3H),5.95(s,0.7H),4.38-4.33(m,2H),4.20-4.06(m,2H),4.02-3.97(m,2H),3.95-3.87(m,1H),3.40-3.29(m,2H),2.33-1.85(m,3H),1.79-1.69(m,1H),1.32(t,J＝6.8Hz,3H),1.10-1.03(m,3H)。

Compound XI-76-B:

ethyl 5- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-2-carboxylate (single stereoisomer)

Intermediate XI-76-B1:

ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (2- (2-ethoxy-2-oxoacetamido) acetyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate

To a solution of 2- (2-ethoxy-2-oxoacetamido) acetic acid BB26(122mg, 70% purity, 0.488mmol) and N, N-diisopropylethylamine (215mg, 1.63mmol) in N, N-dimethylformamide (4mL) was added o- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (205mg, 0.528 mmol). The mixture was stirred at room temperature for 30 min, then (S) -ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate FA12(200mg, 95% purity, 0.407mmol) was added. After stirring at room temperature overnight, the mixture was poured into water (30mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were washed with water (30mL) and brine (30mL) and washed with Na ₂SO₄(solid) dried and filtered. The filtrate was concentrated to give a residue which was purified by silica gel chromatography (petroleum ether: ethyl acetate ═ 2:1 to 2:3) to give the title compound (130mg, 90% purity, 46% yield) as a yellow solid. LC-MS (ESI): r_T＝1.45min,C₂₇H₂₈ClF₂N₅O₆Calculated mass of S623.1, found M/z 624.0[ M + H ]]⁺。

Compound XI-76-B:

ethyl 5- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-2-carboxylate

To a solution of ethyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (2- (2-ethoxy-2-oxoacetamido) acetyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate XI-76-B1(130mg, 90% purity, 0.187mmol) in toluene (2mL) was added 2, 4-bis (4-methoxyphenyl) -1,3,2, 4-dithiadiphosphetanyl ring 2, 4-disulfide (lawesen's reagent, 83mg, 0.205mmol) at room temperature under nitrogen atmosphere. At 110After stirring for 3 hours at deg.C and then cooling to room temperature, the mixture was concentrated under reduced pressure to remove volatiles, then poured into brine (10mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were passed over 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 50% to 100%) to give the title compound as a yellow solid (70mg, 98% purity, 59% yield). ¹H NMR(400MHz,DMSO-d₆)δ9.64(d,J＝4.0Hz,0.7H),9.18(m,0.3H),8.00-7.92(m,2H),7.50-7.44(m,1H),7.33-7.32(m,1H),7.25-7.17(m,1H),6.04(s,0.3H),5.95(d,J＝3.2Hz,0.7H),4.29(q,J＝3.2Hz,0.7H),4.02-3.95(m,2H),3.87-3.72(m,3H),3.19-3.04(m,2H),2.33-1.75(m,3.3H),1.69-1.65(m,0.7H),1.29(t,J＝7.2Hz,3H),1.10-1.04(m,3H)。

Compound XI-77-S:

methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4- (methoxymethyl) thiazole-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB47 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝4.022min，C₂₈H₂₈ClF₂N₅O₅S₂Calculated mass 651.1, M/z found 652.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.64(d,J＝3.6Hz,0.8H),9.32(s,0.2H),8.00-7.91(m,2H),7.50-7.43(m,1H),7.25-7.16(m,1H),6.04(s,0.2H),5.95(d,J＝3.2Hz,0.8H),4.59(s,2H),4.16-4.06(m,2H),4.02-3.97(m,2H),3.95-3.87(m,1H),3.74(s,3H),3.32(s,2.4H),3.31(s,0.6H),3.24-3.15(m,2H),2.25-2.20(m,0.2H),2.09-1.68(m,3.8H),1.11-1.04(m,3H)。

Compound XI-78-S:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB3 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.944min，C₂₇H₂₆ClF₂N₅O₄S₂Calculated mass 621.1, M/z found 622.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.64(d,J＝3.2Hz,0.7H),9.31(s,0.3H),8.00-7.91(m,2H),7.87(s,1H),7.50-7.43(m,1H),7.25-7.16(m,1H),6.04(s,0.3H),5.95(d,J＝3.2Hz,0.7H),4.25-4.08(m,4.2H),4.02-3.86(m,2.8H),3.26-3.17(m,2H),2.25-1.84(m,3H),1.77-1.68(m,1H),1.26(t,J＝7.2Hz,3H),1.11-1.04(m,3H)。

Compound XI-79-S:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4- (trifluoromethyl) thiazole-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB15 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.656min,C₂₈H₂₅ClF₅N₅O₄S₂Calculated mass of 689.1, M/z found 690.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.65(d,J＝3.2Hz,0.7H),9.35(s,0.3H),8.00-7.92(m,2H),7.50-7.43(m,1H),7.25-7.12(m,1H)6.04(s,0.3H),5.95(d,J＝3.2Hz,0.7H),4.28-4.02(m,4.3H),4.00-3.87(m,2.7H),3.27-3.20(m,2H),2.27-1.85(m,3H),1.76-1.70(m,1H),1.26(t,J＝7.2Hz,3H),1.11-1.03(m,3H)。

Compound XI-80-S:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB11 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.84min，C₂₇H₂₆ClF₂N₅O₄S₂Calculated mass of 621.1, M/z found 622.3[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.63(d,J＝4.0Hz,0.7H),9.22(s,0.3H),8.00-7.96(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.70(s,1H),7.50-7.43(m,1H),7.25-7.17(m,1H),6.04(s,0.3H),5.95(d,J＝3.2Hz,0.7H),4.24(q,J＝7.2Hz,2H),4.13-3.95(m,4.3H),3.91-3.82(m,0.7H),3.17-3.04(m,2H),2.10-1.65(m,4H),1.28(t,J＝7.2Hz,3H),1.01-1.04(m,3H)。

Compound XI-81-B:

ethyl 2- (4- (6- (4-bromo-2-chlorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidin-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB4 and FA13 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.17min,C₂₈H₂₈BrClN₆O₄Calculated mass of S658.1, found M/z 658.7[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.29-8.28(m,1H),8.14(s,0.5H),7.81(d,J＝3.2Hz,0.5H),7.77(d,J＝3.2Hz,0.5H),7.56(s,1H),7.47(d,J＝3.2Hz,0.5H),7.43(d,J＝2.8Hz,1H),7.38-7.32(m,1H),7.21-7.18(m,1H),6.19(s,0.5H),6.05(d,J＝2.4Hz,0.5H),5.00-4.87(m,2H),4.43(q,J＝7.2Hz,2H),4.33-4.27(m,0.5H),4.07-4.02(m,0.5H),3.63(s,1.5H),3.61(s,1.5H),3.06-2.98(m,2H),2.28(s,1.5H),2.27(s,1.5H),2.19-2.05(m,1H),1.98-1.89(m,1.4H),1.78-1.67(m,1.6H),1.43(t,J＝7.2Hz,3H)。

Compound XI-82-B:

methyl 2- (4- (6- (2-bromo-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB3 and FA14 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.064min,C₂₅H₂₂BrF₂N₅O₄S₂Calculated mass of 637.0, M/z found 637.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.67(d,J＝3.2Hz,0.7H),9.40(s,0.3H),8.00-7.95(m,2H),7.90(s,1H),7.53-7.46(m,1H),7.25-7.21(m,0.7H),7.16-7.13(m,0.3H),6.01(s,0.3H),5.94(d,J＝3.6Hz,0.7H),4.18-4.08(m,2.5H),3.93-3.87(m,0.5H),3.76(s,3H),3.54(s,2H),3.53(s,1H),3.28-3.18(m,2H),2.07-1.97(m,1.5H),1.92-1.84(m,1.5H),1.77-1.64(m,1H)。

Compound XI-83-B:

methyl 2- (4- (6- (2-bromo-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB3 and FA15 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.033min，C₂₅H₂₃BrFN₅O₄S₂Calculated mass of 619.0, found value of M/z 620.0[ M + H [) ]⁺。¹H NMR(400MHz,CDCl₃)δ8.14(s,0.2H),7.92-7.91(m,1H),7.83(d,J＝3.2Hz,0.8H),7.79(d,J＝3.2Hz,0.2H),7.53(s,0.8H),7.50(d,J＝3.2Hz,0.8H),7.45(d,J＝3.2Hz,0.2H),7.25-7.20(m,1H),7.13-7.01(m,2H),6.27(s,0.2H),6.12(d,J＝2.8Hz,0.8H),4.37-4.19(m,2H),4.16-4.06(m,1H),3.85(s,0.6H),3.84(s,2.4H),3.61(s,2.4H),3.60(s,0.6H),3.34-3.22(m,2H),2.32-2.22(m,1H),2.16-2.02(m,2H),1.93-1.77(m,1H)。

Compound XI-84-N:

methyl 2- (4- (6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB3 and FA16 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.745min，C₂₅H₂₃BrFN₅O₄S₂Calculated mass of 619.0, M/z found 619.7[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.12(s,1H),7.91-7.90(m,1H),7.83-7.79(m,1H),7.50(d,J＝3.2Hz,1.7H),7.44(d,J＝2.8Hz,0.3H),7.34-7.32(m,1H),7.03-6.93(m,1H),6.18(s,0.2H),6.05(d,J＝2.4Hz,0.8H),4.35-4.15(m,2.2H),4.10-4.04(m,0.8H),3.85(s,0.5H),3.84(s,2.5H),3.62(s,2.5H),3.61(s,0.5H),3.33-3.21(m,2H),2.31-2.21(m,0.8H),2.15-1.97(m,2H),1.91-1.76(m,1.2H)。

Compound XI-85-M:

ethyl 2- (3- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) pyrrolidin-1-yl) oxazole-4-carboxylic acid ester (single stereoisomer)

Compound XI-85:

ethyl 2- (3- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) pyrrolidin-1-yl) oxazole-4-carboxylic acid ester (mixture of 4 stereoisomers)

The title compound was synthesized from compounds BB6 and FA17 by a similar procedure using method E.

LC-MS(ESI)：R_T＝4.271min,C₂₆H₂₄ClF₂N₅O₅Calculated mass of S591.1, found M/z 591.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ8.08-8.01(m,1H),7.87-7.86(m,1H),7.71-7.69(m,1H),7.28-7.23(m,2H),6.17(s,0.2H),6.11(d,J＝4.8Hz,0.8H),4.62-4.59(m,1H),4.34-4.28(m,2H),4.09-4.00(m,2.4H),3.88-3.62(m,3.6H),2.45-2.39(m,1H),2.33-2.28(m,1H),1.36-1.28(m,3H),1.14(t,J＝7.2Hz,3H)。

A stereoisomeric mixture of ethyl-2- (3- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) pyrrolidin-1-yl) oxazole-4-carboxylate XI-85(800mg, 90% purity, 1.20mmol) was separated by chiral preparative HPLC (column: Chiralpak IF 5 μ M20 250 mm; mobile phase: Hex: EtOH: DEA 70:30:0.3 at 13 mL/min; temperature: 30 ℃; wavelength: 214nm) to provide the title compound XI-85-M (150mg, 99.2% purity, 19% yield, 100% stereopurity) as a yellow solid and group 1(XI-85-N, Sigma), Mixture of XI-85-P and XI-85-Q, 600 mg). Group 1(600mg, 0.960mmol) was separated by chiral preparative HPLC (column: Chiralpak IG 5 μm 20 × 250 mm; mobile phase: Hex: EtOH: DEA ═ 70:30:0.3 at 15 mL/min; temperature: 30 ℃; wavelength: 214nm) to provide the title compounds XI-85-N (130mg, 99.5% purity, 16% yield, 100% stereopurity), XI-85-P (150mg, 99.4% purity, 19% yield, 100% stereopurity) and XI-85-Q (130mg, 99.2% purity, 16% yield, 100% stereopurity) as yellow solids.

XI-85-M：LC-MS(ESI)：R_T＝3.806min,C₂₆H₂₄ClF₂N₅O₅Calculated mass of S591.1, found M/z 592.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IF 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 70:30:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R); temperature: 30 ℃; and_T＝8.999min)。¹H NMR(400MHz,DMSO-d₆)δ9.73(d,J＝3.6Hz,0.9H),9.42(s,0.1H),8.33(s,0.1H),8.28(s,0.9H),8.00-7.93(m,2H),7.50-7.43(m,1H),7.27-7.23(m,1H),6.05(s,0.1H),5.96(d,J＝3.2Hz,0.9H),4.47-4.43(m,1H),4.23(q,J＝7.2Hz,2H),3.99(q,J＝7.2Hz,2H),3.84-3.67(m,3H),3.56-3.53(m,1H),2.23-2.18(m,2H),1.26(t,J＝7.2Hz,3H),1.09-1.02(m,3H)。

XI-85-N：LC-MS(ESI)：R_T＝3.805min,C₂₆H₂₄ClF₂N₅O₅calculated mass of S591.1, found M/z 592.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IF 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 70:30:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R); temperature: 30 ℃; and_T＝7.434min)。¹H NMR(400MHz,DMSO-d₆)δ9.72(d,J＝3.2Hz,0.8H),9.41(s,0.2H),8.33(s,0.2H),8.27(s,0.8H),8.00-7.94(m,2H),7.45(q,J＝8.8Hz,1H),7.27-7.23(m,1H),6.05(s,0.1H),5.96(d,J＝3.2Hz,0.9H),4.47-4.43(m,1H),4.21(q,J＝7.2Hz,2H),3.98(q,J＝6.8Hz,2H),3.84-3.66(m,3H),3.54(q,J＝7.2Hz,1H),2.22-2.17(m,2H),1.26(t,J＝7.2Hz,3H),1.09-1.02(m,3H)。

XI-85-P：LC-MS(ESI)：R_T＝3.786min,C₂₆H₂₄ClF₂N₅O₅calculated mass of S591.1, found M/z 592.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 70:30:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R); temperature: 30 ℃; and_T＝14.636min)。¹H NMR(400MHz,DMSO-d₆)δ9.72(s,0.8H),9.44(s,0.2H),8.34(s,0.2H),8.27(s,0.8H),8.00-7.94(m,2H),7.53-7.46(m,1H),7.28-7.24(m,1H),6.07(s,0.2H),5.98(s,0.8H),4.47-4.44(m,1H),4.22(q,J＝6.8Hz,2H),3.99(q,J＝7.6Hz,2H),3.80-3.54(m,4H),2.34-2.29(m,2H),1.28(t,J＝6.8Hz,3H),1.11-1.05(m,3H)。

XI-85-Q：LC-MS(ESI)：R_T＝3.792min,C₂₆H₂₄ClF₂N₅O₅calculated mass of S591.1, found M/z 592.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: DEA: 70:30:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230nm, R; (R); temperature: 30 ℃; and_T＝16.379min)。¹H NMR(400MHz,DMSO-d₆)δ9.72(m,0.8H),9.44(s,0.2H),8.33(s,0.2H),8.26(s,0.8H),7.99-7.93(m,2H),7.52-7.45(m,1H),7.27-7.22(m,1H),6.06(s,0.1H),5.97(s,0.9H),4.48-4.44(m,1H),4.21(q,J＝6.8Hz,2H),3.97(q,J＝7.2Hz,2H),3.78-3.53(m,4H),2.33-2.27(m,2H),1.26(t,J＝7.2Hz,3H),1.09-1.02(m,3H)。

compound XI-86-N:

ethyl 2- (3- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) azetidin-1-yl) oxazole-4-carboxylate (single stereoisomer) intermediate XI-86-R:

ethyl-2- (3- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) azetidin-1-yl) oxazole-4-carboxylic acid ester (mixture of 2 stereoisomers)

The title compound was synthesized from compounds BB6 and FA18 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.189min,C₂₅H₂₂ClF₂N₅O₅Calculated mass of S577.1, found M/z 578.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.82(s,0.9H),9.48(s,0.1H),8.37(s,0.1H),8.32(s,0.9H),8.02-8.00(m,1.8H),9.48(d,J＝3.2Hz,0.2H),7.48-7.42(m,1H),7.31-7.28(m,1H),6.05(s,0.1H),5.97(s,0.9H),4.93-4.88(m,0.1H),4.71-4.64(m,0.9H),4.37-4.34(m,3H),4.30-4.21(m,3H),3.99(q,J＝7.2Hz,2H),1.26(t,J＝7.2H,3H),1.08(t,J＝7.2H,3H)。

A stereoisomeric mixture of ethyl 2- (3- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) azetidin-1-yl) oxazole-4-carboxylate XI-86-R (300mg, 96% purity, 0.498mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IE 5 μ M20 mm; mobile phase: Hex: EtOH ═ 70:30, 15 mL/min; wavelength: 214nm) to give compound XI-86-M (90mg, 99.8% purity, 31% yield, 100% stereopurity) and XI-86-N (80mg, 99.5% purity), 28% yield, 98.6% stereopure).

XI-86-M：LC-MS(ESI)：R_T＝4.130min,C₂₅H₂₂ClF₂N₅O₅Calculated mass of S577.1, found M/z 578.1[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH ═ 70:30, at 1.0 mL/min; column temperature: 30 ℃; wavelength: 230nm, R_T＝16.261min)。¹H NMR(400MHz,DMSO-d₆)δ9.83(s,1H),8.33(s,1H),8.00-8.02(m,2H),7.42-7.49(m,1H),7.28-7.32(m,1H),5.97(s,1H),4.64-4.69(m,1H),4.35-4.37(m,3H),4.21-4.31(m,3H),3.98(q,J＝7.2Hz,2H),1.27(t,J＝7.2Hz,3H),1.08(t,J＝6.8Hz,3H)。

XI-86-N：LC-MS(ESI)：R_T＝4.135min,C₂₅H₂₂ClF₂N₅O₅Calculated mass of S577.1, found M/z 578.1[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH ═ 70:30, at 1.0 mL/min; column temperature: 30 ℃; wavelength: 230nm, R_T＝18.383min)。¹H NMR(400MHz,DMSO-d₆)δ9.82(d,J＝3.2Hz,0.9H),9.49(s,0.1H),8.38(0.1H),8.33(s,0.9H),,8.02-7.95(m,2H),7.49-7.42(m,1H),7.31-7.28(m,1H),6.05(s,0.1H),5.97(d,J＝3.2Hz,0.9H),4.91(s,0.1H),4.71-4.63(m,0.9H),4.37-4.34(m,3H),4.30-4.21(m,3H),3.98(q,J＝7.2Hz,2H),1.26(t,J＝7.2Hz,3H),1.08(t,J＝7.2Hz,3H)。

Compound XI-87-S:

methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (4- (methoxycarbonyl) -5-methylpyridin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB56 and FA7 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.028min,C₂₈H₂₇ClFN₅O₄Calculated mass of S583.1, measured value of M/z 584.1[ M + H]⁺。

Compound XI-88-4:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5- (dimethylamino) pyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB57 and FA10 by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.99min,C₂₉H₃₀ClF₂N₇O₄Calculated mass of S645.2, found M/z 645.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.62(s,0.7H),9.32(s,0.3H),8.51(s,0.3H),8.49(s,0.7H),7.99-7.91(m,2H),7.49-7.45(m,1H),7.23-7.14(m,1H),6.02(s,0.3H),5.94(s,0.7H),4.78-4.66(m,2H),4.34(q,J＝6.8Hz,2H),4.22-4.16(m,0.3H),3.92-3.87(m,0.7H),3.54(s,3H),2.96-2.82(m,2H),2.65(s,6H),2.08-1.60(m,4H),1.30(t,J＝6.8Hz,3H)。

Compound XI-89-2:

ethyl 5- (bis (2, 4-dimethoxybenzyl) amino) -2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB58 and FA10 by a similar procedure using method E.

¹H NMR(400MHz,CDCl₃)δ8.16(s,0.6H),8.04(s,0.6H),8.03(s,0.4H),7.81(d,J＝3.2Hz,0.4H),7.78(d,J＝3.2Hz,0.6H),7.49(d,J＝3.2Hz,0.4H),7.43(d,J＝3.2Hz,0.6H),7.40(d,J＝2.0Hz,0.4H),7.31-7.28(m,2H),7.11-6.98(m,2H),6.43(d,J＝8.4Hz,2H),6.39-6.38(m,2H),6.19(s,0.6H),6.06(d,J＝2.4Hz,0.4H),4.95-4.73(m,2H),4.37(q,J＝7.6Hz,2H),4.32-4.22(m,0.6H),4.11(s,2.4H),4.10(s,1.6H),4.05-3.96(m,0.4H),3.78(s,6H),3.71(s,6H),3.62(s,1.8H),3.60(s,1.2H),2.99-2.87(m,2H),2.18-2.03(m,0.5H),2.01-1.97(m,0.5H),1.96-1.86(m,1.5H),1.78-1.64(m,1.5H),1.35(t,J＝7.6Hz,3H)。

Compound XI-90-3:

methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (4- (methoxycarbonyl) -5-nitropyridin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB59 and FA10 by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.81min,C₂₇H₂₃ClF₂N₆O₆Calculated mass of S632.1, found M/z 633.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.99(s,1H),8.13(s,0.3H),7.83-7.79(m,1H),7.50(d,J＝3.2Hz,0.7H),7.45(s,1H),7.11-7.00(m,2H),6.62-6.10(m,1H),6.20(s,0.3H),6.08(d,J＝2.0Hz,0.7H),4.91-4.53(m,2H),4.44-4.37(m,0.3H),4.20-4.14(m,0.7H),3.96(s,3H),3.63(s,3H),3.25-3.15(m,2H),2.21-1.69(m,4H)。

Compound XI-91-1:

ethyl 2- (4- (6- (3, 4-difluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB4 and FA1 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.04min,C₂₉H₃₀ClF₂N₆O₄Calculated mass 596.2 of S, M/z found 597.0[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ8.28(s,1H),8.10(s,0.8H),7.78-7.75(m,1H),7.47(s,0.2H),7.40(d,J＝3.2Hz,0.8H),7.10(br s,0.2H),7.04(br s,0.2H),6.96-6.86(m,1.8H),5.95(s,0.8H),5.86(s,0.2H),5.04-4.88(m,2H),4.42(q,J＝7.2Hz,2H),4.32(t,J＝12.4Hz,1H),3.61(s,3H),3.07-2.98(m,2H),2.57(s,2.5H),2.43(s,0.5H),2.28(s,3H),2.11-2.08(m,1H),1.97-1.94(m,1H),1.82-1.68(m,2H),1.42(t,J＝7.2Hz,3H)。

Compound XI-92-1:

ethyl 2- (4- (6- (3, 4-difluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methoxypyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB60 and FA1 by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.69min,C₂₉H₃₀F₂N₆O₅Calculated mass of S612.2, found M/z 613.2[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ8.26(s,1H),8.11(s,0.8H),7.79(d,J＝3.2Hz,0.2H),7.76(d,J＝3.2Hz,0.8H),7.48(d,J＝3.2Hz,0.2H),7.41(d,J＝3.2Hz,0.8H),7.12-7.08(m,0.2H),7.03(s,0.2H),6.96-6.86(m,1.8H),5.94(s,0.8H),5.86(d,J＝2.0Hz,0.2H),4.95-4.77(m,2H),4.44(q,J＝7.2Hz,2H),4.34-4.26(m,1H),3.87(s,2.4H),3.86(s,0.6H),3.61(s,3H),3.07-2.91(m,2H),2.57(d,J＝2.4Hz,2.4H),2.43(d,J＝2.4Hz,0.6H),2.12-2.05(m,1H),1.97-1.88(m,1H),1.82-1.65(m,2H),1.42(t,J＝7.2Hz,3H)。

Compound XI-93-3:

ethyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-ethoxypyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB60 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.86min，C₃₀H₃₁ClF₂N₆O₅The calculated mass of S was 660.2, found value of M/z 661.2[ M + H [)]⁺。¹H NMR(400MHz,CDCl₃)δ8.25(s,1H),8.14(s,0.6H),7.79(s,1H),7.49-7.41(m,1H),7.33(br s,0.4H),7.12-7.00(m,2H),6.22(s,0.6H),6.09(br s,0.4H),4.97-4.79(m,2H),4.45(q,J＝6.8Hz,2H),4.33-4.22(m,0.6H),4.08-4.04(m,4.4H),3.05-2.93(m,2H),2.15-1.90(m,2.4H),1.81-1.67(m,1.6H),1.43-1.38(m,6H),1.15(t,J＝7.2Hz,3H)。

Compound XI-94-1:

ethyl 2- (4- (6- (2-bromo-3-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5- (dimethylamino) pyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB57 and FA20 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.06min,C₃₀H₃₃BrFN₇O₄Calculated mass of S685.1,687.1, found M/z 688.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.33(s,0.5H),8.32(s,0.5H),8.11(s,0.5H),7.80(d,J＝2.8Hz,0.5H),7.77(d,J＝3.2Hz,0.5H),7.46(d,J＝2.8Hz,0.5H),7.42-7.40(m,1H),7.25-7.18(m,1H),7.16-7.14(m,1H),7.07-6.99(m,1H),6.28(s,0.5H),6.13(d,J＝2.4Hz,0.5H),4.97-4.81(m,2H),4.44(q,J＝7.2Hz,2H),4.35-4.26(m,0.5H),4.09-3.98(m,2.5H),3.04-2.90(m,2H),2.74(s,3H),2.73(s,3H),2.24-2.06(m,1H),2.02-1.94(m,1.5H),1.81-1.68(m,1.5H),1.41(t,J＝7.2Hz,3H),1.12(t,J＝7.2Hz,3H)。

Compound XI-95S:

ethyl 2- (4- (6- (2-bromo-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidin-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB4 and FA15 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.124min,C₂₈H₂₈BrFN₆O₄Calculated mass of S642.1,644.1, found M/z 645.0[ M + H ]]⁺。

Compound XI-96-1:

ethyl 2- (4- (6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidin-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB4 and FA16 by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.81min,C₂₈H₂₈BrFN₆O₄Calculated mass of S642.1, found M/z 643.0,645.0[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.28(d,J＝3.6Hz,1H),8.12(s,0.5H),7.80(d,J＝3.2Hz,0.5H),7.76(d,J＝3.2Hz,0.5H),7.47-7.44(m,1H),7.41(d,J＝3.2Hz,0.5H),7.34-7.28(m,2H),7.02-6.93(m,1H),6.18(s,0.5H),6.03(d,J＝2.4Hz,0.5H),5.03-4.87(m,2H),4.42(q,J＝7.2Hz,2H),4.34-4.28(m,0.5H),4.08-4.01(m,0.5H),3.62(s,2H),3.61(s,1H),3.07-2.95(m,2H),2.28(s,1.4H),2.26(s,1.6H),2.22-2.13(m,1H),2.01-1.93(m,1.5H),1.81-1.65(m,1.5H),1.42(t,J＝7.2Hz,3H)。

Compound XI-97-1:

ethyl 2- (4- (6- (2-bromo-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5- (dimethylamino) pyrimidine-4-carboxylate (single stereoisomer)

The title compound was synthesized from compounds BB57 and FA21 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.051min,C₃₀H₃₃BrFN₇O₄The calculated mass of S is 685.1, found M/z 686.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.40(d,J＝3.6Hz,0.6H),9.14(s,0.4H),8.50(s,0.4H),8.49(s,0.6H),7.98-7.89(m,2H),7.57(dd,J＝8.4Hz,2.4Hz,1H),7.39-7.32(m,1H),7.29-7.22(m,1H),6.01(s,0.3H),5.92(d,J＝3.6Hz,0.7H),4.81-4.64(m,2H),4.40-4.34(m,2H),4.22-4.13(m,0.4H),4.06-3.95(m,2H),3.93-3.84(m,0.6H),2.88-2.82(m,2H),2.65(s,6H),1.99-1.61(m,4H),1.34-1.30(m,3H),1.12-1.07(m,3H)。

Part IX: the dihydropyrimidines of formula VII and formula XI are hydrolyzed to the final products of formula I and formula II, respectively.

Compounds I-1-C: (exemplified by method C)

(trans) -2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid (single stereoisomer)

To a solution of (trans) -methyl 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylate VII-1-X (120mg, 0.198mmol, 95% purity) in tetrahydrofuran (2mL), methanol (2mL) and water (1mL) at 0 ℃ was added lithium hydroxide monohydrateSubstance (17.0mg, 0.397 mmol). After stirring at 0 ℃ for 2 h, the mixture was diluted with water (10mL) and acidified to pH 5 to 6 with 1M aqueous hydrochloride solution. The aqueous layer was 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 preparative HPLC (column: Waters 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: 5% -70% (% B)) to give the title compound as a yellow solid (69.5mg, 61% yield, 98.4% purity). LC-MS (ESI): r _T＝3.683min,C₂₅H₂₁ClF₂N₄O₅Calculated mass of S562.1, found M/z 562.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ8.26(s,1H),7.92(d,J＝2.8Hz,1H),7.75(d,J＝3.2Hz,1H),7.26-7.18(m,2H),6.11(s,1H),4.10-3.74(m,1H),3.60(s,3H),3.03-2.90(m,1H),2.33-2.18(m,2H),2.10-1.66(m,6H)。

Similarly using the above-described analogous procedure for ester hydrolysis, the following acids can be prepared: these are shown in table 2 below, in which the corresponding esters are referred to, which are listed with reference to their compound number ("Cpd. #").

Table 2:

spectroscopic analysis of the final products having the general formula I and the general formula II

Compounds I-2-D:

(trans) -2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid (single stereoisomer)

From compound VII-2-Y.

The title compound was synthesized by a similar procedure using method C. LC-MS (ESI): r_T＝3.558min,C₂₆H₂₃ClF₂N₄O₅Calculated mass of S576.1, found M/z 577.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 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＝11.206min)。¹H NMR(400MHz,CD₃OD)δ8.23(s,1H),7.92(d,J＝2.8Hz,1H),7.75(d,J＝3.2Hz,1H),7.27-7.22(m,2H),6.12(s,1H),4.08-3.77(m,3H),3.03-2.90(m,1H),2.34-2.17(m,2H),2.12-1.66(m,6H),1.15(t,J＝7.2Hz,3H)

Compounds I-3-D:

trans-2- (4- (6- (3-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-3-H by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.430min，C₂₆H₂₅FN₄O₅Calculated mass of S524.2, M/z found 524.9[ M + H [ ] ]⁺. Chiral HPLC (column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: Hex: IPA: TFA: 80:20:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝14.346min)。¹HNMR(400MHz,CD₃OD)δ8.33(s,1H),7.93(d,J＝3.6Hz,1H),7.76(d,J＝2.8Hz,1H),7.17-7.13(m,2H),6.98-6.93(m,1H),5.96(s,1H),4.06-3.89(m,1H),3.63(s,3H),3.05-2.98(m,1H),2.50(s,3H),2.33-2.27(m,2H),2.15-1.75(m,6H)。

Compound I-4-B:

(trans) -2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-4-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝4.127min,C₂₅H₂₂ClFN₄O₅Calculated mass of S544.1, found M/z 544.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.17-8.83(m,1H),8.36(s,1H),8.01-7.93(m,2H),7.44-7.41(m,1H),7.36-7.34(m,1H),7.24-7.22(m,1H),6.02(s,0.4H),5.92(s,0.6H),3.97-3.85(m,0.4H),3.72-3.60(m,0.6H),3.54(s,1.8H),3.53(s,1.2H),3.06-2.94(m,0.4H),2.89-2.78(m,0.6H),2.25-2.09(m,2H),2.02-1.76(m,3H),1.73-1.52(m,3H)。

Compound I-5-B

(trans) -2- (4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-5-Q by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.127min,C₂₅H₂₂ClFN₄O₅Calculated Mass of S544.1M/z found 545.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝3.2Hz,0.6H),9.05(s,0.4H),8.04-7.99(m,1.6H),7.98-7.91(m,1.4H),7.42-7.28(m,2H),7.24-7.16(m,1H),6.08(s,0.4H),5.98(d,J＝3.2Hz,0.6H),3.97-3.87(m,0.4H),3.72-3.61(m,0.6H),3.53(s,1.2H),3.52(s,1.8H),2.98-2.91(m,0.4H),2.83-2.72(m,0.6H),2.23-2.09(m,2H),2.07-1.99(0.4H),1.98-1.85(m,2H),1.84-1.74(m,1H),1.71-1.65(m,0.6H),1.64-1.46(m,2H)。

Compound I-6-B:

(trans) -2- (4- (6- (4-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-6-Q by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.099min，C₂₆H₂₅FN₄O₅Calculated mass of S524.15, found M/z 525.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(s,0.7H),8.97(s,0.3H),8.03-7.90(m,3H),7.32-7.24(m,0.7H),7.19-7.12(m,0.3H),7.08-6.92(m,2H),5.81(s,0.3H),5.71-5.64(m,0.7H),3.98-3.88(m,0.3H),3.69-3.59(m,0.7H),3.53(s,3H),2.99-2.89(m,0.3H),2.83-2.71(m,0.7H),2.59(s,1H),2.50(s,2H),2.24-2.08(m,2H),2.06-1.75(m,3H),1.71-1.46(m,3H)。

Compound I-7-B:

(trans) -2- (4- (6- (2-chloro-3, 4-difluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -5- (methoxycarbonyl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-7-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.399min,C₂₇H₂₁ClF₄N₄O₅Calculated mass of HCl 629.4, found M/z 592.9[ M-HCl + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.94(br s,1H),8.67(s,1H),8.62(s,1H),8.16-8.09(m,1H),7.53-7.46(m,1H),7.24-7.21(m,1H),6.06(s,1H),4.02-3.84(m,1H),3.54(s,3H),2.93-2.84(m,1H),2.25-2.12(m,2H),1.96-1.89(m,2H),1.85-1.76(m,2H),1.66-1.51(m,2H)。

Compound I-8-B:

2- (3- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) bicyclo [1.1.1] pent-1-yl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-8-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.618min,C₂₄H₁₇ClF₂N₄O₅Calculated mass of S546.1, found M/z 546.8[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak IA 5 μm 4.6 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＝11.842min)。¹H NMR(400MHz,CD₃OD)δ8.31(s,1H),7.92(d,J＝3.2Hz,1H),7.76(d,J＝3.2Hz,1H),7.27-7.19(m,2H),6.10(s,1H),3.62(s,3H),2.72(s,6H)。

compound I-9-B:

(trans) -2- (4- (6- (2-chloro-3-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compounds VII-9-F by a similar procedure using method C.

LC-MS(ESI)：R_T＝2.974min,C₂₆H₂₄ClFN₄O₅Calculated mass of S558.1, M/z found 559.1[ M + H [ ] ]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.50(br s,0.6H),8.98(s,0.4H),8.63(s,0.6H),8.62(s,0.4H),8.04-7.92(m,2H),7.42-7.28(m,2H),7.25-7.17(m,1H),6.09(s,0.4H),5.98(s,0.6H),4.03-3.93(m,2H),3.92-3.88(m,0.3H),3.70-3.60(m,0.7H),3.07-3.01(m,0.4H),2.92-2.83(m,0.6H),2.25-2.12(m,2H),2.07-1.87(m,2.5H),1.85-1.77(m,1H),1.74-1.69(m,0.5H),1.66-1.49(m,2H),1.11-1.00(m,3H)。

Compound I-10-C:

(trans) -2- (4- (6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-10-P by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.590min,C₂₆H₂₄ClFN₄O₅Calculated mass of S558.1, M/z found 558.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; chiral analysis of chiral molecules (column: Chiralpak IE 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: TFA: 80:20: 0.2; temperature: 254_T＝19.068min)。¹H NMR(400MHz,DMSO-d₆)δ8.96(br s,1H),8.33(s,1H),8.01-8.00(m,1.5H),7.95(d,J＝2.8Hz,0.5H),7.44-7.41(m,1H),7.38-7.35(m,1H),7.25-7.20(m,1H),6.03(s,0.4H),5.93(s,0.6H),4.02-3.96(m,2H),3.91-3.87(m,0.3H),3.70-3.61(m,0.7H),3.01-2.95(m,0.4H),2.86-2.79(m,0.6H),2.20-2.13(m,2H),2.05-1.71(m,4H),1.64-1.48(m,2H),1.11-1.04(m,3H)。

Compound I-11-B:

(trans) -2- (4- (5- (ethoxycarbonyl) -6- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-11-Q by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.668min，C₂₇H₂₇FN₄O₅Calculated mass of S538.2, found M/z 538.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 254 nm; R; (R))_T＝11.136min)。¹H NMR(400MHz,CD₃OD)δ8.30(s,1H),7.90(d,J＝3.2Hz,1H),7.73(d,J＝3.2Hz,1H),7.17-7.08(m,2H),6.97-6.89(m,1H),5.93(s,1H),4.05(q,J＝7.2Hz,2H),4.01-3.81(m,1H),3.04-2.92(m,1H),2.47(s,3H),2.34-2.21(m,2H),2.14-2.03(m,1H),2.01-1.85(m,3H),1.84-1.68(m,2H),1.14(t,J＝7.2Hz,3H)。

Compound I-12-C:

(trans) -2- (4- (5- (ethoxycarbonyl) -6- (4-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-12-P by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.345min,C₂₇H₂₇FN₄O₅Calculated mass of S538.2, found M/z 539.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak OJ-H5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: TFA ═ 60:40:0.2, at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝6.430min)。¹H NMR(400MHz,DMSO-d₆)δ9.47(br s,0.7H),8.90(s,0.3H),8.36(s,1H),7.99-7.98(m,1.7H),7.93-7.92(m,0.3H),7.29-7.25(m,0.7H),7.18-7.15(m,0.3H),7.07-6.97(m,2H),5.82(s,0.3H),5.68(s,0.7H),4.01-3.84(m,2.3H),3.68-3.60(m,0.7H),3.02-2.96(m,0.3H),2.86-2.80(m,0.7H),2.56(s,0.7H),2.52(m,2.3H),2.20-2.13(m,2H),2.02-1.80(m,3H),1.71-1.48(m,3H),1.10-1.06(m,3H)。

Compound I-13-C:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohex-1-en-1-yl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-13-P by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.177min,C₂₆H₂₁ClF₂N₄O₅Calculated mass of S574.1, measured value of M/z 575.0[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; temperature: 30 ℃; temperature: R-_T＝10.796min)。¹H NMR(400MHz,DMSO-d₆)δ8.42(s,1H),8.01-7.93(m,2H),7.51-7.45(m,1H),7.26-7.20(m,1H),6.86-6.82(m,1H),6.07(s,0.3H),5.97(s,0.7H),4.12(br s,0.3H),4.01-3.90(m,2.7H),2.78-2.65(m,2H),2.44-2.33(m,2H),2.07-1.82(m,2H),1.08-1.01(m,3H)。

Compounds I-13-D:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohex-1-en-1-yl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compounds VII-13-Q by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.176min,C₂₆H₂₁ClF₂N₄O₅Calculated mass of S574.1, measured value of M/z 575.0[ M + H [)]⁺. Chiral HPLC (column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; temperature: 30 ℃; temperature: R- _T＝14.955min)。¹H NMR(400MHz,DMSO-d₆)δ8.43(s,1H),8.01-7.94(m,2H),7.53-7.47(m,1H),7.29-7.25(m,1H),6.83-6.81(m,1H),6.05(s,0.2H),5.96(s,0.8H),4.13(br s,0.3H),4.00-3.89(m,2.7H),2.75-2.57(m,2H),2.49-2.23(m,2H),2.07-1.99(m,2H),1.08-1.01(m,3H)。

Compound I-14-B:

(trans) -2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -5-methyloxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-14-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.572min,C₂₇H₂₅ClF₂N₄O₅Calculated mass of S590.1, found M/z 591.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 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＝10.076min)。¹H NMR(400MHz,DMSO-d₆)δ8.01-8.00(m,1.6H),7.95(d,J＝2.8Hz,0.4H),7.50-7.43(m,1H),7.22-7.18(m,1H),6.04(s,0.4H),5.93(s,0.6H),4.02-3.87(m,2.4H),3.68-3.62(m,0.6H),2.98-2.91(m,0.4H),2.81-2.75(m,0.6H),2.53(s,3H),2.19-1.55(m,8H),1.11-1.04(m,3H)。

Compound I-15-A:

(trans) -2- ((4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) methyl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-15-M by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.367min,C₂₇H₂₅ClF₂N₄O₅Calculated mass of S590.1, found M/z 591.0[ M + H ]]⁺. Chiral analysis (Chiralpak IA 5 μm 4.6 × 250 mm; mobile phase: Hex: IPA: TFA: 80:20:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝10.887min)。¹H NMR(400MHz,DMSO-d₆)δ8.93(s,1H),8.34(br s,1H),7.99-7.97(m,1.5H),7.94-7.93(m,0.5H),7.49-7.42(m,1H),7.21-7.15(m,1H),6.02(s,0.5H),5.91(s,0.5H),4.00-3.93(m,2H),3.86-3.79(m,0.5H),3.62-3.56(m,0.5H),2.69-2.67(m,2H),1.99-1.56(m,7H),1.21-1.04(m,5H)。

Compound I-16-B:

(trans) -2- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazol-4-yl) acetic acid (single stereoisomer)

The title compound was synthesized from compound VII-16-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.406min,C₂₆H₂₃ClF₂N₄O₅Calculated mass of S576.1, found M/z 577.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; chiral analysis of chiral molecules: (column: Chiralpak IE 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: 50: TFA: 0_T＝7.928min)。¹H NMR(400MHz,DMSO-d₆)δ8.01-7.95(m,2H),7.77(s,1H),7.49-7.43(m,1H),7.22-7.14(m,1H),6.02(s,0.4H),5.93(s,0.6H),3.94-3.87(m,0.5H),3.69-3.61(m,0.5H),3.53(s,3H),3.38(s,2H),2.99-2.92(m,0.5H),2.82-2.74(m,0.5H),2.18-2.10(m,2H),2.04-1.67(m,4H),1.61-1.48(m,2H)。

Compound I-17-A:

(trans) -2- (2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazol-4-yl) acetic acid (single stereoisomer)

The title compound was synthesized from compound VII-17-M by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.287min，C₂₆H₂₄ClFN₄O₅Calculated mass of S558.1, M/z found 558.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 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＝9.850min)。¹H NMR(400MHz,DMSO-d₆)δ9.47(br s,0.6H),9.01(s,0.4H),8.00(s,1.6H),7.94(d,J＝3.2Hz,0.4H),7.81(d,J＝4.0Hz,1H),7.45-7.41(m,1H),7.38-7.33(m,1H),7.25-7.20(m,1H),6.02(s,0.4H),5.92(s,0.6H),3.92-3.87(m,0.3H),3.67-3.61(m,0.7H),3.54(s,2.5H),3.52(s,0.5H),3.45(s,2H),3.00-2.93(m,0.4H),2.82-2.76(m,0.6H),2.17-2.10(m,2H),2.01-1.76(m,3.4H),1.69-1.51(m,2.6H)。

Compound I-18-A:

(trans) -2- (2- (4- (6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazol-4-yl) acetic acid (single stereoisomer)

The title compound was synthesized from compound VII-18-M by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.438min，C₂₆H₂₄BrFN₄O₅Calculated mass of S602.1, M/z found 602.8[ M + H [)]⁺。¹H NMR(400MHz,CD₃OD)δ8.31-8.29(m,2H),7.78(s,1H),7.61-7.55(m,2H),7.30-7.26(m,1H),6.35(s,1H),4.00-3.89(m,1H),3.70(s,3H),3.61(s,2H),3.05-2.93(m,1H),2.33-2.29(m,2H),2.18-1.92(m,4H),1.85-1.66(m,2H)。

Compound I-19-B:

(trans) -2- (2- (4-6- (2-bromo-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazol-4-yl) acetic acid (single stereoisomer)

The title compound was synthesized from compound VII-19-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.310min，C₂₆H₂₄BrFN₄O₅Calculated mass of S602.1, M/z found 605.1[ M + H]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 60:40:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝9.644min)。¹H NMR(400MHz,DMSO-d₆)δ9.49(s,0.5H),9.02(s,0.5H),8.00(d,J＝2.8Hz,1.5H),7.94(d,J＝3.2Hz,0.5H),7.81(d,J＝4.0Hz,1H),7.44-7.39(m,1H),7.31-7.15(m,2H),6.06(s,0.5H),5.96(s,0.5H),3.96-3.88(m,0.5H),3.70-3.63(m,0.5H),3.53(s,1.5H),3.52(s,1.5H),3.44(s,2H),3.01-2.93(m,0.5H),2.84-2.78(m,0.5H),2.17-2.10(m,2H),2.01-1.95(m,0.5H),1.88-1.82(m,2H),1.78-1.76(m,1H),1.71-1.67(m,0.5H),1.61-1.51(m,2H)。

Compound I-20-B:

(trans) -2- (2- (4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazol-4-yl) acetic acid (single stereoisomer)

The title compound was synthesized from compound VII-20-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.104min，C₂₆H₂₄ClFN₄O₅Calculated mass of S558.1, M/z found 559.2[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.96(d,J＝2.4Hz,1H),7.82(br s,1H),7.72(s,1H),7.34-7.28(m,1H),7.25-7.23(m,1H),7.19-7.15(m,1H),6.19(s,1H),4.01-3.88(m,1H),3.60(s,3H),3.58(s,2H),2.98-2.89(m,1H),2.31-2.19(m,2H),2.11-1.85(m,4H),1.83-1.69(m,2H)。

Compound I-21-B:

(trans) -2- (2- (4- (6- (3-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazol-4-yl) acetic acid (single stereoisomer)

The title compound was synthesized from compound VII-21-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.336min，C₂₇H₂₇FN₄O₅Calculated mass of S538.6, found M/z 539.9[ M + H ] ]⁺。¹H NMR(400MHz,CD₃OD)δ7.93(d,J＝3.6Hz,1H),7.76(d,J＝2.8Hz,1H),7.73(s,1H),7.21-7.12(m,2H),6.98-6.91(m,1H),5.96(s,1H),4.10-3.84(m,1H),3.62(s,3H),3.58(s,2H),3.02-2.90(m,1H),2.50(s,3H),2.38-2.19(m,2H),2.15-2.05(m,1H),2.03-1.70(m,5H)。

Compound I-22-B:

(trans) -2- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -5-methyloxazol-4-yl) acetic acid (single stereoisomer)

The title compound was synthesized from compound VII-22-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.540min,C₂₇H₂₅ClF₂N₄O₅Calculated mass of S590.1, found M/z 591.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6mm 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝9.844min)。¹H NMR(400MHz,DMSO-d₆)δ9.07(br s,1H),8.01(s,1.6H),7.95(d,J＝3.2Hz,0.4H),7.50-7.44(m,1H),7.22-7.15(m,1H),6.02(s,0.4H),5.92(s,0.6H),3.93-3.87(m,0.5H),3.66-3.60(m,0.5H),3.54(s,1.6H),3.53(s,1.4H),3.36(s,2H),2.91-2.86(m,0.5H),2.75-2.69(m,0.5H),2.22(s,3H),2.15-1.49(m,8H)。

Compound I-23-B:

(trans) -2- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazol-4-yl) acetic acid (single stereoisomer)

The title compound was synthesized from compound VII-23-Y by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.341min,C₂₇H₂₅ClF₂N₄O₅Calculated mass of S590.1, found M/z 591.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 50:0.2 at 1.0 mL/min; column temperature: 30 ℃; wavelength: 230nm, R_T＝8.867min)。¹H NMR(400MHz,DMSO-d₆)δ9.59-9.51(m,0.6H),8.99(br s,0.4H),8.01-8.00(m,1.6H),7.95(d,J＝3.6Hz,0.4H),7.82(d,J＝4.4Hz,1H),7.50-7.43(m,1H),7.22-7.17(m,1H),6.03(s,0.4H),5.93(m,0.6H),4.01-3.95(m,2H),3.93-3.87(m,0.4H),3.67-3.61(m,0.6H),3.47(s,2H),3.00-2.92(m,0.4H),2.82-2.75(m,0.6H),2.19-2.10(m,2H),2.04-1.67(m,4H),1.61-1.47(m,2H),1.10-1.04(m,3H)。

Compound I-24:

(trans) -3- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazol-4-yl) propanoic acid (mixture of 2 stereoisomers)

The title compound was synthesized from compounds VII-24-R by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.880min,C₂₈H₂₇ClF₂N₄O₅Calculated mass of S604.1, M/z measured value 605.2[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.91(s,1H),7.75(s,1H),7.55(s,1H),7.22(d,J＝5.2Hz,2H),6.15(s,0.4H)6.08(s,0.6H),4.06-4.02(m,2H),3.80(s,1H),3.05-3.02(m,1H),2.95-2.79(m,2H),2.63-2.61(m,2H),2.24-2.00(m,4H),2.00-1.75(m,4H),1.14(t,J＝6.8Hz,3H)。

Compound I-24-A:

(trans) -3- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazol-4-yl) propionic acid (single stereoisomer)

The title compound was synthesized from compound VII-24-M by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.663min,C₂₈H₂₇ClF₂N₄O₅Calculated mass of S604.1, M/z Mass found 605.1[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IG 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; chiral analysis of the chiral structure of the protein_T＝11.811min)。¹H NMR(400MHz,CD₃OD)δ7.91(s,1H),7.75(d,J＝2.8Hz,1H),7.55(s,1H),7.24-7.22(m,2H),6.14(s,0.6H),6.09(s,0.4H),4.05(q,J＝7.2Hz,2H),4.02-3.98(m,0.6H),3.84-3.75(m,0.4H),2.98-2.87(m,1H),2.80(t,J＝7.6Hz,2H),2.61(t,J＝7.6Hz,2H),2.28-2.15(m,2H),2.08-1.97(m,2H),1.89-1.79(m,2H),1.76-1.67(m,2H),1.14(t,J＝7.2Hz,3H)。

Compound I-25-B:

(trans) -3- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazol-4-yl) -2, 2-dimethylpropanoic acid (single stereoisomer)

The title compound was synthesized from compound VII-25-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.045min,C₂₉H₂₉ClF₂N₄O₅Calculated mass of S618.2, found M/z 619.0[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.92(br s,1H),7.76-7.75(m,1H),7.52(s,1H),7.27-7.17(m,2H),6.16-6.04(m,1H),4.12-3.97(m,0.5H),3.88-3.72(m,0.5H),3.60(s,3H),3.00-2.82(m,1H),2.76(s,2H),2.29-1.98(m,4H),1.95-1.60(m,4H),1.21(s,6H)。

Compound I-26-B:

(trans) -2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-26-8 by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.782min,C₂₆H₂₃ClF₂N₄O₅Calculated mass of S576.1, found M/z 576.9[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝3.2Hz,1H),7.76(d,J＝2.8Hz,1H),7.57(s,1H),7.27-7.22(m,2H),6.12(s,1H),4.05(q,J＝7.2Hz,2H),3.95-3.93(m,1H),3.05-2.97(m,1H),2.33-2.26(m,2H),2.09-2.01(m,1H),1.97-1.71(m,5H),1.14(t,J＝7.2Hz,3H)。

Compound I-27-B:

(trans) -2- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazol-4-yl) -2-methylpropanoic acid (single stereoisomer)

Intermediate I-27-R:

(trans) -2- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazol-4-yl) -2-methylpropanoic acid (mixture of 2 stereoisomers)

The title compound was synthesized from compounds VII-27-R by a similar procedure using method C.

LC-MS(ESI)：RT＝3.929min，C₂₉H₂₉ClF₂N₄O₅The calculated mass of S is 618.2, measured m/zValue 619.2[ M + H]+。¹H NMR(400MHz,DMSO-d₆)δ12.21(br s,1H),9.57(s,0.5H),8.98(s,0.5H),8.02-8.00(m,1.5H),7.96-7.45(m,0.5H),7.83-7.82(m,1H),7.51-7.44(m,1H),7.22-7.17(m,1H),6.04(s,0.4H),5.93(s,0.6H),4.01-3.94(m,2H),3.90-3.87(m,0.4H),3.68-3.61(m,0.6H),2.98-2.92(m,0.4H),2.82-2.76(m,0.6H),2.17-2.09(m,2H),2.03-1.66(m,4H),1.60-1.50(m,2H),1.41(s,6H),1.10-1.03(m,3H)。

A stereoisomeric mixture of (trans) -2- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) oxazol-4-yl) -2-methylpropanoic acid I-27-R (190mg, 0.292mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA 5 μm20 mm; mobile phase: Hex: EtOH: TFA ═ 85:15:0.2 at 10 ml/min; temperature: 30 ℃; wavelength: 254nm) to afford the title compound I-27-a (40mg, 95.4% purity, 21% yield) and I-27-B (35mg, 97.9% purity, 19% yield).

I-27-A：LC-MS(ESI)：R_T＝4.290min,C₂₉H₂₉ClF₂N₄O₅Calculated mass of S618.2, found M/z 619.0[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; temperature: 30 ℃; and_T＝7.612min)。¹H NMR(400MHz,DMSO-d₆)δ8.99(s,1H),8.01(s,1.3H),7.96-7.95(m,0.7H),7.76(s,1H),7.51-7.44(m,1H),7.22-7.18(m,1H),6.03(s,0.4H),5.93(s,0.6H),3.99-3.86(m,2.4H),3.68-3.61(m,0.6H),3.00-2.90(m,0.5H),2.85-2.76(m,0.5H),2.18-2.11(m,2H),2.06-1.66(m,4H),1.61-1.49(m,2H),1.38(s,6H),1.10-1.03(m,3H)。

I-27-B：LC-MS(ESI)：R_T＝4.304min,C₂₉H₂₉ClF₂N₄O₅calculated mass of S618.2, found M/z 619.0[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; temperature: 30 ℃; and_T＝8.661min)。¹H NMR(400MHz,DMSO-d₆)δ8.99(s,1H),8.00(s,1.4H),7.96-7.95(m,0.6H),7.80(s,1H),7.51-7.44(m,1H),7.23-7.17(m,1H),6.03(s,0.4H),5.93(s,0.6H),4.01-3.86(m,2.4H),3.68-3.62(m,0.6H),2.97-2.92(m,0.5H),2.84-2.74(m,0.5H),2.17-2.08(m,2H),2.02-1.66(m,4H),1.60-1.50(m,2H),1.40(s,6H),1.10-1.03(m,3H)。

compound I-28-B:

(trans) -2- (4- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -1H-pyrazol-1-yl) acetic acid (single stereoisomer)

The title compound was synthesized from compound VII-28-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.381min,C₂₇H₂₆ClF₂N₅O₄Calculated mass of S589.1, found M/z 590.2[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IE (5 μm 4.6 x 250mm), mobile phase: Hex: EtOH: TFA ═ 80:20:0.2 at 1.0mL/min, temperature: 30 ℃; wavelength: 254nm, R_T＝18.729min)。¹H NMR(400MHz,DMSO-d₆)δ8.95(br s,1H),8.02-7.99(m,1.6H),7.96(d,J＝2.8Hz,0.4H),7.51-7.44(m,2H),7.26(s,1H),7.23-7.17(m,1H),6.03(s,0.4H),5.92(s,0.6H),4.58(s,2H),4.00-3.95(m,2H),3.94-3.87(m,0.3H),3.69-3.63(m,0.7H),2.65-2.58(m,0.6H),2.50-2.45(m,0.4H),2.05-1.79(m,5.4H),1.66-1.63(m,0.6H),1.43-1.34(m,2H),1.10-1.05(m,3H)。

Compound I-29-C:

(trans) -3- (4- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -1H-pyrazol-1-yl) propionic acid (single stereoisomer)

The title compound was synthesized from compound VII-29-P by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.400min，C₂₇H₂₇ClFN₅O₄Calculated mass of S571.2, found M/z 572.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IC 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝10.246min)。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝2.8Hz,1H),7.75(d,J＝3.2Hz,1H),7.49(s,1H),7.42-7.38(m,2H),7.24-7.22(m,1H),7.07-7.02(m,1H),6.11(s,1H),4.36(t,J＝6.4Hz,2H),3.93(br s,1H),3.59(s,3H),2.84(t,J＝6.4Hz,2H),2.67-2.57(m,1H),2.15-1.74(m,6H),1.59-1.45(m,2H)。

Compounds I-30-D:

(trans) -3- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -1H-pyrazol-1-yl) -3-methylbutyric acid (single stereoisomer)

The title compound was synthesized from compound VII-30-10 by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.905min,C₃₀H₃₂ClF₂N₅O₄Calculated mass of S631.2, found M/z 632.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA ═ 70:30:0.2 at 1 mL/min; wavelength: 254nm, R_T＝9.296min)。¹H NMR(400MHz,CD₃OD)δ7.86-7.78(m,1H),7.66(d,J＝3.2Hz,1H),7.51(s,1H),7.30(s,1H),7.17-7.08(m,2H),6.05(s,0.7H),5.98(s,0.3H),4.00-3.87(m,2.7H),3.75-3.63(m,0.3H),2.77(s,2H),2.62-2.43(m,1H),2.11-1.64(m,6H),1.60(s,6H),1.53-1.34(m,2H),1.04(t,J＝7.2Hz,3H)。

Compound I-31:

3- (4- (4- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -1H-pyrazol-1-yl) butanoic acid (mixture of 8 stereoisomers)

The title compound was synthesized from compound VII-31 by a similar procedure using method C.

LC-MS(ESI)：R_T4.309 and 4.456min, C₂₉H₃₀ClF₂N₅O₄Calculated mass of S617.2, found M/z 618.0[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.93-7.92(m,0.5H),7.87(d,J＝3.2Hz,0.5H),7.75(d,J＝3.2Hz,0.5H),7.72(d,J＝2.8Hz,0.5H),7.68(s,0.5H),7.57-7.49(m,1H),7.39(s,0.5H),7.24-7.19(m,2H),6.14-6.05(m,1H),4.85-4.74(m,1H),4.07-4.01(m,2.7H),3.93-3.79(m,0.3H),3.13-3.06(m,0.5H),2.98-2.87(m,1H),2.83-2.72(m,1H),2.66-2.57(m,0.5H),2.21-1.69(m,7H),1.58-1.56(m,2H),1.50(d,J＝6.8Hz,2H),1.16-1.12(m,3H)。

Compound I-32-B:

3- (4- ((trans) -4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -1H-pyrazol-1-yl) propionic acid (single stereoisomer)

The title compound was synthesized from compound VII-32-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.261min,C₂₈H₂₈ClF₂N₅O₄Calculated mass of S603.2, M/z found 603.9[ M + H [)]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1.0mL/min, temperature: 30 ℃; wavelength: 230nm, R_T＝19.003min)。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝2.8Hz,1H),7.75(d,J＝3.2Hz,1H),7.49(s,1H),7.39(s,1H),7.26-7.22(m,2H),6.13(s,1H),4.36(t,J＝7.2Hz,2H),4.04(q,J＝7.2Hz,3H),2.82(t,J＝6.8Hz,2H),2.68-2.56(m,1H),2.13-1.70(m,6H),1.60-1.46(m,2H),1.13(t,J＝7.2Hz,3H)。

Compound I-33-C:

(trans) -3- (4- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -3-methyl-1H-pyrazol-1-yl) propionic acid (single stereoisomer)

The title compound was synthesized from compound VII-33-10 by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.668min,C₂₉H₃₀ClF₂N₅O₄Calculated mass of S617.2, found M/z 618.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: Hex: IPA: TFA: 80:20:0.2 at 1mL/min, temperature: 30 ℃ C.; wavelength: 254nm, R_T＝8.339min)。¹H NMR(400MHz,CD₃OD)δ7.92(s,1H),7.75(d,J＝3.2Hz,1H),7.37(s,1H),7.26-7.22(m,2H),6.13(s,1H),4.28(t,J＝6.8Hz,2H),4.07-4.02(m,2.5H),3.97-3.73(m,0.5H),2.79(t,J＝6.4Hz,2H),2.62-2.45(m,1H),2.22(s,3H),2.03-1.73(m,6H),1.59-1.41(m,2H),1.14(t,J＝6.8Hz,3H)。

Compound I-34:

3- (4- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -1H-pyrazol-1-yl) cyclobutanecarboxylic acid (mixture of 4 stereoisomers)

To a solution of ethyl 6- (4- (1- (3- (tert-butoxycarbonyl) cyclobutyl) -1H-pyrazol-4-yl) cyclohexyl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate VII-34(50mg, 95% purity, 0.069mmol) in dichloromethane (1mL) was added trifluoroacetic acid (1mL) at room temperature. After stirring at room temperature under a nitrogen atmosphere for 12 hours, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by a C18 column (acetonitrile: water (0.1% hydrochloric acid) ═ 5% to 95%) to give the title compound (41mg, 99.8% purity, 94% yield) as a yellow solid. LC-MS (ESI): r _T＝3.602min,C₃₀H₃₀ClF₂N₅O₄Calculated mass of S629.2, M/z found 630.2[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ8.30-8.27(m,0.1H),8.21-8.18(m,0.9H),8.11-8.10(m,1H),7.76(s,0.6H),7.64(s,0.4H),7.60(s,0.3H),7.57(s,0.3H),7.50(s,0.2H),7.47(s,0.2H),7.38-7.27(m,2H),6.29(s,0.4H),6.24(s,0.6H),5.11-5.02(m,0.5H),4.80-4.73(m,0.5H),4.14-4.08(m,2H),3.99-3.89(m,1H),3.20-3.10(m,1H),3.04-2.97(m,0.5H),2.88-2.83(m,0.5H),2.78-2.66(m,4H),2.27-2.15(m,2H),2.01-1.85(m,4H),1.80-1.77(m,0.5H),1.71-1.68(m,0.5H),1.61-1.45(m,1H),1.17(t,J＝7.2Hz,3H)。

Compound I-35-C:

(trans) -5- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -1-methyl-1H-pyrazole-3-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-35-P by a similar procedure using method C.

LC-MS(ESI)：R_T＝2.531min,C₂₇H₂₆ClF₂N₅O₄Calculated mass of S589.1, found M/z 589.9[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; temperature: 30 ℃; temperature: R-_T＝11.982min)。¹H NMR(400MHz,DMSO-d₆)8.02-7.97(m,2H),7.51-7.44(m,1H),7.23-7.19(m,1H),6.43(s,1H),6.04(s,0.4H),5.94(s,0.6H),4.01-3.97(m,2H),3.85(s,3H),3.72-3.67(s,1H),2.94-2.88(m,0.5H),2.78-2.68(m,0.5H),2.05-1.85(m,5H),1.82-1.79(m,0.4H),1.71-1.68(m,0.6H),1.47-1.41(m,2H),1.11-1.04(m,3H)。

Compound I-36-B:

(trans) -3- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -1-methyl-1H-pyrazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-36-N by a similar procedure using compound I-34.

LC-MS(ESI)：R_T＝3.373min,C₂₇H₂₆ClF₂N₅O₄Calculated mass of S589.1, M/z Mass found 590.0[ M + H ]]⁺. Chiral analysis: (column: Chiralpak IA 5 μm 4.6 × 250 mm; mobile phase: Hex: IPA: TFA: 80:20:0.2 at 1.0 mL/min; column temperature: 30 ℃; wavelength: 254nm, R; (light: red);)_T＝12.684min)。¹H NMR(400MHz,DMSO-d₆)δ9.54(br s,0.6H),8.96(s,0.4H),8.02-7.99(m,1.5H),7.96-7.95(m,0.5H),7.51-7.44(m,1H),7.23-7.18(m,1H),6.57(s,1H),6.04(s,0.4H),5.93(s,0.6H),4.01(s,3H),4.00-3.92(m,2H),3.90-3.87(m,0.4H),3.69-3.63(m,0.6H),2.75-2.67(m,0.6H),2.62-2.58(m,0.4H),2.08-1.99(m,2H),1.96-1.85(m,2H),1.82-1.65(m,2H),1.53-1.40(m,2H),1.10-1.04(m,3H)。

Compound I-37-C:

(trans) -3- (4- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -1H-pyrazol-1-yl) -2, 2-dimethylpropanoic acid (single stereoisomer)

The title compound was synthesized from compound VII-37-4C by a similar procedure using compound I-34.

LC-MS(ESI)：R_T＝3.883min,C₃₀H₃₂ClF₂N₅O₄Calculated mass of S631.2, found M/z 632.3[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 85:15:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; chiral analysis of chiral molecules (column: Chiralpak IE 5 μm 4.6: 0 mm; mobile phase: Hex: EtOH: TFA: 85:15: 0.2; temperature: 254_T＝15.769min)。¹H NMR(400MHz,CD₃OD)δ7.96-7.89(m,1H),7.76(d,J＝3.2Hz,1H),7.45(s,1H),7.37(s,1H),7.27-7.20(m,2H),6.15(s,0.7H),6.08(s,0.3H),4.27(s,2H),4.07-3.98(m,2.7H),3.86-3.72(m,0.3H),2.71-2.54(m,1H),2.20-1.68(m,6H),1.62-1.42(m,2H),1.17-1.12(m,9H)。

Compound I-38-B:

(trans) -1- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -1H-pyrazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-38-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝4.469min,C₂₆H₂₄ClF₂N₅O₄Calculated mass of S575.1, found M/z 575.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 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＝10.027min)。¹H NMR(400MHz,CD₃OD)δ8.20(s,1H),7.96-7.88(m,2H),7.76(d,J＝2.8Hz,1H),7.24-7.22(m,2H),6.15-6.10(m,1H),4.41-4.27(m,1H),4.12-4.03(m,2.5H),3.89-3.81(m,0.5H),2.29-1.85(m,8H),1.15(t,J＝7.2Hz,3H)。

Compound I-39-B:

(cis) -1- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -1H-pyrazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-39-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.547min,C₂₆H₂₄ClF₂N₅O₄Calculated mass of S575.1, found M/z 576.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 90:10:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R ℃; chiral analysis of the chiral structure of the protein _T＝9.103min)。¹H NMR(400MHz,DMSO-d₆+D₂O)δ8.08(d,J＝3.2Hz,0.6H),7.99(d,J＝3.2Hz,0.4H),7.97(d,J＝3.2Hz,0.4H),7.96(d,J＝2.8Hz,0.6H),7.58(d,J＝1.6Hz,0.6H),7.50-7.41(m,1.4H),7.25-7.19(m,1H),6.74(d,J＝2.0Hz,0.4H),6.70(d,J＝1.6Hz,0.6H),6.05(s,0.6H),5.95(s,0.4H),5.79-5.73(m,0.6H),5.43-5.36(m,0.4H),4.15-4.03(m,0.6H),3.98(q,J＝7.2Hz,2H),3.81-3.73(m,0.4H),2.37-2.26(m,2H),2.24-2.15(m,1H),2.10-2.01(m,1H),1.99-1.75(m,2.6H),1.72-1.62(m,1H),1.56-1.47(m,0.4H),1.10-1.05(m,3H)。

Compound I-39-C:

(trans) -1- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -1H-pyrazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-39-P by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.091min,C₂₆H₂₄ClF₂N₅O₄Calculated mass of S575.1, found M/z 575.9[ M + H ]]⁺. Chiral analysis (column: Chiralpak IF 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 95:5:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝16.725min)。¹H NMR(400MHz,DMSO-d₆+D₂O)δ8.03-7.99(m,1H),7.97(d,J＝3.6Hz,0.6H),7.92(d,J＝2.8Hz,0.4H),7.50-7.42(m,2H),7.25-7.18(m,1H),6.66(d,J＝1.6Hz,1H),6.04(s,0.4H),5.95(s,0.6H),5.51-5.42(m,0.4H),5.40-5.32(m,0.6H),4.04-3.90(m,2.4H),3.74-3.69(m,0.6H),2.12-1.79(m,7.4H),1.76-1.68(m,0.6H),1.13-1.03(m,3H)。

Compound I-40-A:

(trans) -2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) pyrimidine-5-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-40-M by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.422min,C₂₇H₂₄ClF₂N₅O₄Calculated mass of S587.1, found M/z 587.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.55(br s,0.4H),9.09(s,2H),9.03(s,0.6H),8.02-7.95(m,2H),7.51-7.44(m,1H),7.24-7.18(m,1H),6.04(s,0.5H),5.94(s,0.5H),4.02-3.95(m,2.4H),3.75-3.68(m,0.6H),3.11-3.05(m,0.5H),2.95-2.88(m,0.5H),2.16-2.13(m,2.4H),1.96-1.83(m,3H),1.74-1.67(m,2.6H),1.11-1.04(m,3H)。

Compound I-41-B:

(trans) -2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) thiazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-41-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.684min,C₂₆H₂₃ClF₂N₄O₄S₂Calculated mass of 592.1, M/z found 593.0[ M + H ] ]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 230 nm; R; (R); chiral analysis; (column: Chiralpak IE 5 μm 4.6: 0.2; mobile phase: Hex: EtOH: TFA: 70:30:0_T＝9.361min)。¹H NMR(400MHz,CD₃OD)δ8.12(s,1H),7.92(d,J＝3.2Hz,1H),7.75(d,J＝3.6Hz,1H),7.27-7.20(m,2H),6.13(s,1H),4.05(q,J＝7.2Hz,2H),4.03-3.93(m,1H),3.23-3.15(m,1H),2.36-2.30(m,2H),2.15-1.87(m,4H),1.80-1.72(m,2H),1.15(t,J＝7.2Hz,3H)。

Compound I-42-B:

(trans) -5- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) isoxazole-3-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-42-11 by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.704min,C₂₆H₂₃ClF₂N₄O₅Calculated mass of S576.1, found M/z 577.1[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)δ7.84(d,J＝2.8Hz,1H),7.48(d,J＝2.4Hz,1H),7.09-7.01(m,2H),6.46(s,1H),6.16(s,1H),4.07-4.02(m,3H),2.99-2.93(m,1H),2.30-2.25(m,2H),2.15-2.10(m,1H),2.01-1.94(m,1H),1.88-1.81(m,1H),1.72-1.65(m,3H),1.13(t,J＝6.8Hz,3H)。

Compound I-43-B:

(trans) -4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) isoxazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-43-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.246min,C₂₆H₂₃ClF₂N₄O₅Calculated mass of S576.1, found M/z 576.9[ M + H [ ]]⁺. Chiral analysis: (column: Chiralpak IA 5 μm 4.6 × 250 mm; mobile phase: Hex: IPA: TFA: 80:20:0.2 at 1.0 mL/min; column temperature: 30 ℃ C.; wavelength: 230nm, R;. degree.C.; column temperature: 250 nm; rate: 1.0 mL/min; rate: 0.2; rate: 4.6;)_T＝10.178min)。¹H NMR(400MHz,CD₃OD)δ7.92(d,J＝3.2Hz,1H),7.75(d,J＝3.2Hz,1H),7.25-7.22(m,2H),6.81(s,1H),6.13(s,1H),4.05(q,J＝7.2Hz,2H),4.01-3.92(m,1H),2.94-2.87(m,1H),2.21-2.05(m,3H),2.01-1.82(m,3H),1.75-1.61(m,2H),1.14(t,J＝7.2Hz,3H)。

Compound I-44-A:

(trans) -4- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) benzoic acid (single stereoisomer)

Intermediate I-44-E:

(trans) -4- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) benzoic acid (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid from compound VII-44-X by a similar procedure using method C. LC-MS (ESI): r_T＝3.922min,C₂₉H₂₆ClF₂N₃O₄Calculated mass of S585.1, found M/z 586.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.99(br s,1H),8.02-8.01(m,1.6H),7.96(d,J＝3.2Hz,0.4H),7.89-7.86(m,2H),7.51-7.44(m,1H),7.40-7.36(m,2H),7.24-7.19(m,1H),6.05(s,0.4H),5.94(s,0.6H),4.02-3.96(m,2.5H),3.75-3.69(m,0.5H),2.83-2.76(m,0.4H),2.69-2.63(m,0.6H),2.04-1.81(m,5.5H),1.73-1.70(m,0.5H),1.62-1.51(m,2H),1.11-1.05(m,3H)。

A stereoisomeric mixture of (trans) -4- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) benzoic acid I-44-E (95mg, 95% purity, 0.154mmol) was separated by chiral preparative HPLC (separation conditions: column: Chiralpak IA 5 μm 20 250 mm; mobile phase: Hex: EtOH: TFA 80:20:0.3, at 15 mL/min; temperature: 30 ℃; wavelength: 254nm) and further purified by a C18 column (acetonitrile: water 75% to 25%) to give the title compound I-44-a as a yellow solid (19mg, 20% yield, 98.7% pure, 100% stereopure) and I-44-B (19.0mg, 21% yield, 97.7% pure, 95.2% stereopure).

I-44-A：LC-MS(ESI)：R_T＝3.948min,C₂₉H₂₆ClF₂N₃O₄Calculated mass of S585.1, found M/z 586.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R _T＝9.681min)。¹H NMR(400MHz,DMSO-d₆)δ12.81(br s,1H),9.58(br s,0.6H),9.00(s,0.4H),8.03-8.01(m,1.6H),7.97-7.96(m,0.4H),7.90-7.87(m,2H),7.51-7.39(m,3H),7.24-7.19(m,1H),6.05(s,0.4H),5.94(d,J＝2.0Hz,0.6H),4.03-3.93(m,2.4H),3.76-3.69(m,0.6H),2.85-2.78(m,0.4H),2.71-2.65(m,0.6H),2.08-1.85(m,5.5H),1.73-1.70(m,0.5H),1.64-1.50(m,2H),1.11-1.05(m,3H)。

I-44-B：LC-MS(ESI)：R_T＝3.942min,C₂₉H₂₆ClF₂N₃O₄Calculated mass of S585.1, found M/z 586.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝11.272min)。¹H NMR(400MHz,DMSO-d₆)δ12.77(br s,1H),9.57(s,0.6H),9.00(s,0.4H),8.03-8.01(m,1.6H),7.97-7.96(m,0.4H),7.91-7.87(m,2H),7.51-7.40(m,3H),7.24-7.19(m,1H),6.05(s,0.4H),5.94(d,J＝2.8Hz,0.6H),4.02-3.93(m,2.4H),3.76-3.68(m,0.6H),2.84-2.78(m,0.4H),2.71-2.65(m,0.6H),2.07-1.81(m,5.5H),1.75-1.69(m,0.5H),1.63-1.51(m,2H),1.11-1.05(m,3H)。

Compound I-45:

(trans) -5- (-4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -1,2, 4-oxadiazole-3-carboxylic acid (mixture of 2 stereoisomers)

The title compound was synthesized from compounds VII-45-R by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.070min,C₂₅H₂₂ClF₂N₅O₅Calculated mass of S577.1, found M/z 577.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.91(dd,J＝4.0,3.2Hz,1H),7.75(t,J＝2.8Hz,1H),7.26-7.18(m,2H),6.12(s,0.5H),6.11(s,0.5H),4.08-4.02(m,2H),3.97-3.91(m,0.5H),3.89-3.84(m,0.5H),3.18-3.12(m,0.5H),2.47-2.41(m,0.5H),2.36-2.30(m,1H),2.08-1.93(m,3H),1.91-1.74(m,3H),1.68-1.56(m,1H),1.16-1.12(m,3H)。

Compound I-46-C:

1- (2- ((trans) -4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) pyrimidin-5-yl) cyclopropanecarboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-46-P by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.557min,C₂₉H₂₆ClF₂N₅O₄Calculated mass of S613.1, M/z found 614.2[ M + H [)]⁺. Chiral analysis (column: Chiralpak IA 5um 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA 50:50:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 280nm, Rt 6.186 min).¹H NMR(400MHz,CD₃OD)δ8.74(s,2H),7.95(s,1H),7.78(d,J＝2.8Hz,1H),7.26(d,J＝4.8Hz,2H),6.16(s,1H),4.14-4.07(m,0.7H),3.89-3.85(m,0.3H),3.63(s,3H),3.07-3.00(m,1H),2.20-2.15(m,3H),2.06-2.01(m,1H),1.95-1.88(m,4H),1.68(dd,J＝7.2Hz,4.0Hz,2H),1.32(dd,J＝7.2Hz,4.0Hz,2H)。

Compounds I-47-D:

2- ((trans) -4- (6- (2-bromo-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -5-methylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound VII-47-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝2.830min,C₂₇H₂₄BrF₂N₅O₄Calculated mass of S631.1, M/z found 632.1[ M + H [)]⁺。¹H NMR(400MHz,CD₃OD)δ8.77(s,0.1H),8.66(s,0.9H),7.91(d,J＝3.2Hz,0.9H),7.87(d,J＝3.2Hz,0.1H),7.74(d,J＝3.2Hz,0.9H),7.70(d,J＝3.2Hz,0.1H),7.31-7.16(m,2H),6.11(s,0.9H),6.09(s,0.1H),4.09-3.91(m,1H),3.60(s,3H),3.08-2.93(m,1H),2.48(s,0.3H),2.43(s,2.7H),2.20-2.05(m,3H),1.99-1.78(m,5H)。

Compound I-48-B:

(trans) -2- (2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) -5-methyloxazol-4-yl) acetic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound VII-48-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.986min，C₂₇H₂₆ClFN₄O₅Calculated mass of S572.1, found M/z 573.1[ M + H ]]⁺. Chiral analysis (analytical conditions: column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA ═ 80:20:0.2, at 1 mL/min; temperature: 30 ℃; wavelength: 254nm, R_T＝8.870min)。¹H NMR(400MHz,CD₃OD)δ7.94(br s,1H),7.78-7.77(m,1H),7.43-7.40(m,1H),7.26-7.24(m,1H),7.09-7.05(m,1H),6.16(s,0.6H),6.09(s,0.4H),4.10-3.98(m,0.5H),3.87-3.75(m,0.5H),3.62(s,3H),3.43(s,2H),2.93-2.85(m,1H),2.29-2.13(m,5H),2.02-1.69(m,6H)。

Compound I-49-A:

2- (2- ((trans) -4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) pyrimidin-5-yl) acetic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound VII-49-a by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.485min,C₂₇H₂₄ClF₂N₅O₄Calculated mass of S587.1, found M/z 588.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.05(br s,1H),8.62(s,1H),8.61(s,1H),8.02-8.00(m,1.5H),7.95-7.94(m,0.5H),7.47-7.41(m,1H),7.25-7.14(m,1H),6.03(s,0.5H),5.94(s,0.5H),3.98-3.91(m,0.5H),3.73-3.68(m,0.5H),3.57(s,2H),3.54(s,1.5H),3.53(s,1.5H),3.03-2.98(m,0.5H),2.88-2.82(m,0.5H),2.10-1.69(m,8H)。

Compound I-50-A:

2- (2- ((trans) -4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) cyclohexyl) pyrimidin-5-yl) acetic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound VII-50-a by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.361min，C₂₇H₂₅ClFN₅O₄Calculated mass of S569.1, found M/z 570.2[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5um 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1 mL/min; temperature: 30 ℃; wavelength: 254nm, R; (R); chiral analysis_T＝8.867min)。¹H NMR(400MHz,DMSO-d₆)δ9.41(br s,0.5H),9.00(br s,0.5H),8.64(s,1H),8.63(s,1H),8.01-8.00(m,1.5H),7.94-7.93(m,0.5H),7.43-7.32(m,2H),7.24-7.20(m,1H),6.03(s,0.4H),5.92(s,0.6H),3.98-3.88(m,0.5H),3.73-3.70(m,0.5H),3.63(s,2H),3.54(s,1.5H),3.53(s,1.5H),3.05-2.99(m,0.5H),2.86-2.79(m,0.5H),2.14-1.64(m,8H)。

Compound II-1-B:

2- (2- (4- (6- (3, 4-difluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-5-yl) acetic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-1-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.839min,C₂₇H₂₆F₂N₆O₄Calculated mass of S568.2, found M/z 569.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.42(br s,1H),9.58(s,0.8H),9.24(s,0.2H),8.27(s,0.4H),8.26(s,1.6H),7.98(d,J＝3.2Hz,0.8H),7.94-7.93(m,1H),7.89(d,J＝3.2Hz,0.2H),7.27-7.17(m,1H),7.13-7.09(m,0.8H),6.98-6.95(m,0.2H),5.82(s,0.2H),5.70(s,0.8H),4.91-4.76(m,2H),4.24-4.17(m,0.2H),3.94-3.87(m,0.8H),3.54(s,3H),3.45(s,2H),2.97-2.84(m,2H),2.44(d,J＝1.6Hz,3H),2.07-1.59(m,4H)。

Compound II-2-B:

2- (4- (5- (ethoxycarbonyl) -6- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compounds BB2 and FA2 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.905min，C₂₈H₂₉FN₆O₄Calculated mass of S564.2, found M/z 565.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.53(d,J＝2.8Hz,0.8H),9.10(s,0.2H),8.30-8.29(m,1H),7.97-7.88(m,2H),7.23-7.14(m,2H),7.07-7.01(m,1H),5.87(s,0.2H),5.74(d,J＝2.8Hz,0.8H),4.90-4.76(m,2H),4.22-4.15(m,0.2H),3.99(q,J＝7.2Hz,2H),3.92-3.87(m,0.8H),2.92-2.82(m,2H),2.45(s,0.6H),2.40(s,2.4H),2.13(s,3H),2.01-1.59(m,4H),1.08(t,J＝7.2Hz,3H)。

Compound II-3-B:

2- (2- (4- (5- (ethoxycarbonyl) -6- (3-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-5-yl) acetic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-3-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.142min，C₂₈H₂₉FN₆O₄Calculated mass of S564.2, found M/z 565.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.52(br s,0.7H),9.12(s,0.3H),8.28-8.26(m,2H),7.97-7.88(m,2H),7.23-7.13(m,2H),7.07-7.01(m,1H),5.87(s,0.2H),5.75(s,0.8H),4.91-4.77(m,2H),4.21-4.16(m,0.2H),3.99(q,J＝7.2Hz,2H),3.93-3.87(m,0.8H),3.42(s,2H),2.93-2.84(m,2H),2.45(s,0.7H),2.40(s,2.3H),2.09-1.59(m,4H),1.10-1.05(m,3H)。

Compound II-4-B:

2- (4- (5- (ethoxycarbonyl) -6- (4-fluoro-2-methylphenyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-4-B by a similar procedure using method C.

LC-MS (ESI): RT 3.299min, calculated mass 564.2 for C28H29FN6O4S, found M/z 565.1[ M + H ] +. 1H NMR (400MHz, DMSO-d6) δ 13.33(s,1H),9.53(s,0.8H),9.10(s,0.2H),8.39(s,0.2H),8.38(s,0.8H),7.97-7.93(m,1.7H),7.92-7.88(m,0.3H),7.29-7.25(m,0.8H),7.17-7.14(m,0.2H),7.07-6.99(m,2H),5.82(s,0.2H),5.69(d, J ═ 2.8Hz,0.8H),4.91-4.76(m,2H),4.21-4.15(m,0.2H),4.00-3.98(m,2H), 3.93-3.93 (m), 0.91-4.2H), 1.84 (m,2H), 1.07-6.2H), 1.2H, 5.2H, 3.2H, 3.98(m, 3.93-3.8H), 3.84 (m, 1.2H), 1.2H, 1..

Compound II-5-B:

6- (4- (6- (3-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -3-methylpyridinecarboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-5-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝4.362min,C₂₇H₂₇FN₆O₄Calculated mass of S550.2, M/z Mass found 551.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.54(d,J＝3.6Hz,0.8H),9.18(s,0.2H),8.37(s,0.2H),8.36(s,0.8H),7.97-7.88(m,2H),7.21-7.14(m,2H),7.07-7.00(m,1H),5.87(s,0.2H),5.75(d,J＝3.2Hz,0.8H),4.90-4.76(m,2H),4.25-4.19(m,0.2H),3.94-3.88(m,0.8H),3.54(s,3H),2.94-2.85(m,2H),2.46(s,0.8H),2.39(s,2.2H),2.17(s,3H),2.04-1.78(m,3H),1.71-1.59(m,1H)。

Compound II-6-B:

2- (2- (4- (6- (3-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-5-yl) acetic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-6-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝4.064min，C₂₇H₂₇FN₆O₄Calculated mass of S550.2, found M/z 551.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.56(br s,0.8H),9.22(s,0.2H),8.27-8.26(m,2H),7.97-7.88(m,2H),7.23-7.13(m,1.8H),7.07-7.00(m,1.2H),5.87(s,0.2H),5.74(s,0.8H),4.92-4.77(m,2H),4.25-4.19(m,0.2H),3.94-3.88(m,0.8H),3.54(s,3H),3.44(s,2H),2.94-2.85(m,2H),2.45(s,0.6H),2.39(s,2.4H),2.07-1.59(m,4H)。

Compound II-7-B:

2- (4- (6- (4-fluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compounds BB2 and FA5 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.973min,C₂₇H₂₇FN₆O₄Calculated mass of S550.2, M/z found 551.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.52(d,J＝3.2Hz,0.8H),9.06(s,0.2H),8.15-8.10(m,1H),7.98-7.86(m,2H),7.30-7.26(m,0.8H),7.18-7.13(m,0.2H),7.06-6.94(m,2H),5.81(s,0.2H),5.69(d,J＝3.2Hz,0.8H),4.90-4.72(m,2H),4.20-4.13(m,0.2H),3.91-3.81(m,0.8H),3.54(s,3H),2.89-2.76(m,2H),2.04(s,3H),1.94-1.71(m,3H),1.60-1.53(m,1H)。

Compound II-8-B:

2- (4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound BB2-1 and FA6 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.920min，C₂₆H₂₄ClFN₆O₄Calculated mass of S570.1, found M/z 571.0[ M + H ] ]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.57(s,0.7H),9.20(s,0.3H),8.33(s,0.3H),8.32(s,0.7H),7.98-7.94(m,1.7H),7.90(d,J＝3.2Hz,0.3H),7.41-7.29(m,2H),7.23-7.15(m,1H),6.05(s,0.3H),5.95(s,0.7H),4.88-4.76(m,2H),4.22-4.16(m,0.3H),3.94-3.88(m,0.7H),3.54(s,2.1H),3.53(s,0.9H),2.93-2.83(m,2H),2.14(s,3H),2.03-1.59(m,4H)。

Compound II-9-B:

2- (2- (4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-5-yl) acetic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-9-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.242min,C₂₆H₂₄ClFN₆O₄Calculated mass of S570.1, M/z Mass found 571.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.57(s br,0.7H),9.23(s,0.3H)8.27(s,0.6H),8.26(s,1.4H),7.98-7.90(m,2H),7.41-7.29(m,2H),7.23-7.16(m,1H),6.08(s,0.3H),5.98(s,0.7H),4.91-4.76(m,2H),4.22-4.16(m,0.3H),3.95-3.88(m,0.7H),3.54(s,2.1H),3.53(s,0.9H),3.43(s,2H),2.96-2.85(m,2H),2.05-1.60(m,4H)。

Compound II-10-B:

2- (4- (6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-10-1 by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.167min,C₂₄H₂₁ClFN₅O₄S₂Calculated mass of 561.1, M/z Mass found value of 562.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(br s,0.5H),9.38(s,0.5H),8.00-7.96(m,1.7H),7.92-7.91(d，J＝3.2Hz,0.3H),7.71(s,1H),7.41-7.32(m,2H),7.23-7.21(m,0.7H),7.18-7.16(m,0.3H),6.07(s,0.2H),5.99(s,0.8H),4.20-4.05(m,2.3H),3.93-3.85(m,0.7H),3.54(s,2.2H),3.53(s,0.8H),3.22-3.13(m,2H),2.28-1.90(m,2H),1.85-1.69(m,2H)。

Compound II-11-X:

methyl 6- (1- (1H-pyrazole-4-carbonyl) piperidin-4-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

To a solution of 1H-pyrazole-4-carbonyl chloride BB53(225mg, 1.73mmol) in acetonitrile (15mL) was added N, N-dimethylpyridin-4-amine (210mg, 1.73mmol), methyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate FA7(150mg, 0.345mmol), and pyridine (0.54 mL). 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 extracted three times with ethyl acetate (10 mL). The combined organic layers were washed with brine (10mL) and Na ₂SO₄(solid) dried and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was further purified by C18 column (acetonitrile: water ═ 45% to 95%) to give the title compound as a yellow solid (76mg, 98.6% purity, 42% yield). LC-MS (ESI): r_T＝7.739min，C₂₄H₂₂ClFN₆O₃Calculated mass of S528.1, M/z found 529.2[ M + H]⁺。¹H NMR(400MHz,CDCl₃)δ8.18(s,0.3H),7.88-7.87(m,2H),7.83-7.81(m,1H),7.51(d,J＝2.8Hz,0.7H),7.48(d,J＝2.0Hz,0.7H),7.45(d,J＝3.2Hz,0.3H),7.30-7.28(m,1H),7.18-7.12(m,1H),7.01-6.91(m,1H),6.20(s,0.3H),6.08(d,J＝2.4Hz,0.7H),5.01-4.65(m,1H),4.48-4.33(m,0.4H),4.19-4.03(m,0.6H),3.62(s,3H),3.45-2.81(m,2H),2.23-1.96(m,4H),1.87-1.55(m,2H)。

Compound II-12-B:

methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (1-methyl-1H-pyrazole-4-carbonyl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

To a solution of methyl 4- (2-chloro-4-fluorophenyl) -6- (piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate FA7(50mg, 0.115mmol) in dichloromethane (10mL) was added 1-methyl-1H-pyrazole-4-carboxylic acid BB5(20mg, 0.159mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (40mg, 0.209mmol), and 4-dimethylaminopyridine (4mg, 0.033mmol) at room temperature. After stirring at room temperature overnight, the resulting mixture was diluted with water (15mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed three times with water (20mL) and Na₂SO₄(solid) dried and concentrated. The residue was purified by C18 column (acetonitrile: water ═ 70% to 80%) to give the desired compound as a yellow solid (50mg, 80% yield). LC-MS (ESI): r _T＝2.788min,C₂₅H₂₄ClFN₆O₃The calculated mass of S is 542.1, found M/z 542.9[ M + H ]]+。¹H NMR(400MHz,CDCl₃)δ8.14(s,0.3H),7.83-7.81(m,1H),7.75-7.73(m,1H),7.67-7.66(m,1H),7.51-7.50(m,0.7H),7.45(s,1H),7.30-7.28(m,1H),7.15-7.12(m,1H),6.97-6.87(m,1H),6.20(s,0.3H),6.07(s,0.7H),5.00-4.36(m,2H),4.33-4.27(m,0.3H),4.13-4.05(m,0.7H),3.94(s,3H),3.61-3.60(m,3H),3.50-2.75(m,2H),2.21-1.88(m,3H),1.81-1.70(m,1H)。

Compound II-13-A:

2- (2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-4-yl) acetate (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-13-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.269min，C₂₆H₂₄ClFN₆O₄Calculated mass of S570.1, found M/z 571.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.50(br s,0.7H),9.15(br s,0.3H),8.14(d,J＝5.2Hz,1H),7.95-7.92(m,2H),7.43-7.35(m,2H),7.24-7.19(m,1H),6.53-6.52(m,1H),6.01(br s,0.3H),5.93(s,0.7H),4.97-4.83(m,2H),4.19-4.11(m,0.3H),3.93-3.86(m,0.7H),3.54(s,3H),3.18(s,2H),2.87-2.77(m,2H),1.97-1.76(m,3.2H),1.62-1.58(m,0.8H)。

Compound II-14-A:

2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-14-A by a similar procedure using method C.

LC-MS(ESI)：R_T＝1.39min，C₂₆H₂₄ClFN₆O₄Calculated mass of S570.1, found M/z 571.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 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＝8.514min)。¹H NMR(400MHz,DMSO-d₆)δ13.42(br s,1H),9.47(d,J＝3.6Hz,0.7H),9.15(s,0.3H),8.40(s,0.3H),8.39(s,0.7H),7.98-7.89(m,2H),7.43-7.32(m,2H),7.24-7.17(m,1H),6.02(s,0.3H),5.93(d,J＝3.6Hz,0.7H),4.88-4.76(m,2H),4.21-4.15(m,0.3H),3.94-3.88(m,0.7H),3.55(s,2H),3.53(s,1H),2.95-2.86(m,2H),2.19(s,3H),1.93-1.60(m,4H)。

Compound II-15-A:

2- (2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-5-yl) acetic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-15-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝2.712min,C₂₆H₂₄ClFN₆O₄Calculated mass of S570.1, found M/z 571.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆Adding one drop of D₂O)δ8.26(s,0.6H),8.25(s,1.4H),7.97-7.94(m,1H),7.89-7.85(m,1H),7.43-7.33(m,2H),7.23-7.17(m,1H),6.01(s,0.3H),5.94(s,0.7H),4.88-4.74(m,2H),4.19-4.11(m,0.3H),3.94-3.87(m,0.7H),3.55(s,2.1H),3.53(s,0.9H),3.43(s,2H),2.95-2.86(m,2H),2.01-1.59(m,4H)。

Compound II-16-B:

2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4-methylpyrimidine-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-16-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.874min,C₂₆H₂₄ClFN₆O₄Calculated mass of S570.1, found M/z 570.9[ M + H]⁺。¹H NMR(400MHz,CD₃OD)δ8.79(s,1H),7.87(d,J＝2.8Hz,1H),7.70(d,J＝2.8Hz,1H),7.42-7.38(m,1H),7.25-7.22(m,1H),7.09-7.02(m,1H),6.15(s,0.4H),6.08(s,0.6H),5.19-5.00(m,2H),4.38-4.28(m,0.3H),4.12-4.03(m,0.7H),3.61(s,3H),3.12-2.98(m,2H),2.65(s,3H),2.10-1.68(m,4H)。

Compound II-17-B:

2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidine-5-carboxylic acid (single stereoisomer)

The title compound was synthesized from compounds BB7 and FA7 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.263min，C₂₅H₂₂ClFN₆O₄Calculated mass of S556.1, found M/z 557.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.75(br s,1H),9.50(s,0.7H),9.26(s,0.3H),8.80-8.79(m,2H),7.98-7.89(m,2H),7.43-7.31(m,2H),7.24-7.20(m,1H),6.02(s,0.3H),5.94(s,0.7H),5.02-4.89(m,2H),4.26-4.20(m,0.3H),3.99-3.93(m,0.7H),3.55(s,2H),3.54(s,1H),3.09-3.00(m,2H),2.14-1.66(m,4H)。

Compound II-18-B:

2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-18-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.226min，C₂₄H₂₁ClFN₅O₅Calculated mass of S545.1, found M/z 546.1[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.89(s,2H),7.72(d,J＝3.2Hz,1H),7.42-7.38(m,1H),7.23(dd,J＝8.8,2.4Hz,1H),7.07-7.03(m,1H),6.09(s,1H),4.28-4.18(m,2.4H),4.02-3.94(m,0.6H),3.64(s,0.5H),3.60(s,2.5H),3.17-3.06(m,2H),2.19-2.02(m,2H),1.92-1.70(m,2H)。

Compound II-19-A:

2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-19-2 by a similar procedure using method C.

LC-MS(ESI)：R_T＝2.059min，C₂₄H₂₁ClFN₅O₄S₂Calculated mass of 561.1, M/z found 562.2[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.97(m,1.6H),7.92-7.91(m,0.4H),7.50(s,1H),7.44-7.32(m,2H),7.24-7.19(m,1H),6.02(s,0.2H),5.93(s,0.8H),4.12-4.01(m,2.2H),3.89-3.84(m,0.8H),3.54(s,2.1H),3.53(s,0.9H),3.15-3.06(m,2H),2.08-1.63(m,4H)。

Compound II-20-B:

2- (4- (6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compounds BB54 and FA8 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.999min,C₂₇H₂₆ClFN₆O₄Calculated mass of S584.1, M/z found 584.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.51(d,J＝3.2Hz,0.7H),9.13(s,0.3H),8.35-8.33(m,1H),7.98-7.90(m,2H),7.45-7.33(m,2H),7.25-7.20(m,1H),6.03(s,0.3H),5.94(d,J＝3.6Hz,0.7H),4.89-4.76(m,2H),4.20-4.14(m,0.3H),4.00(q,J＝7.2Hz,2H),3.94-3.88(m,0.7H),2.92-2.83(m,2H),2.15(s,3H),2.02-1.60(m,4H),1.11-1.05(m,3H)。

Compound II-21-B:

2- (2- (4- (6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-5-yl) acetic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-21-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.311min，C₂₇H₂₆ClFN₆O₄Calculated mass of S584.1, M/z found 585.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.49(s,0.7),9.13(s,0.3H),8.27-8.25(m,2H),7.97-7.93(m,2H),7.44-7.33(m,2H),7.26-7.18(m,1H),6.03(s,0.3H),5.94(s,0.7H),4.92-4.74(m,2H),4.22-4.13(m,0.4H),4.02-3.86(m,2.6H),3.42(s,2H),2.97-2.80(m,2H),2.07-1.56(m,4H),1.11-1.05(m,3H)。

Compound II-22-B:

2- (4- (6- (2-chloro-3-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound BB2-1 and FA9 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.279min，C₂₇H₂₆ClFN₆O₄Calculated mass of S584.1, M/z found 585.0[ M + H [ ] ]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.54(s,0.7H),9.10(s,0.3H),8.26(s,1H),7.98-7.90(m,2H),7.39-7.31(m,2H),7.23-7.18(m,1H),6.09(s,0.3H),5.99(s,0.7H),4.88-4.76(m,2H),4.02-3.87(m,3H),2.90-2.81(m,2H),2.12(s,3H),1.91-1.72(m,3H),1.63-1.59(m,1H),1.10-1.03(m,3H)。

Compound II-23-B:

2- (2- (4- (6- (2-chloro-3-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-5-yl) acetic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-23-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.312min，C₂₇H₂₆ClFN₆O₄Calculated mass of S584.1, M/z found 585.1[ M + H [ ]]⁺。¹H NMR(400MHz,CD₃OD)δ8.18(s,2H),7.77(d,J＝2.8Hz,1H),7.60(d,J＝3.2Hz,1H),7.24-7.13(m,2H),7.08-7.03(m,1H),6.07(br s,1H),4.98-4.82(m,1H),4.75-4.66(m,1H),4.26-3.93(m,3H),3.38(s,2H),2.96-2.85(m,2H),2.05-1.55(m,4H),1.04(t,J＝7.2Hz,3H)。

Compound II-24-B:

(cis) -3- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-5-yl) -3-hydroxycyclobutanecarboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-24-B by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.322min,C₂₉H₂₇ClF₂N₆O₅Calculated mass of S644.1, found M/z 644.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.50-8.49(m,1.9H),8.40-8.39(m,0.1H),7.99-7.91(m,2H),7.50-7.43(m,1H),7.22-7.16(m,1H),6.03(s,0.3H),5.94(s,0.7H),4.94-4.80(m,2H),4.23-4.16(m,0.3H),3.95-3.89(m,0.7H),3.55(s,2.1H),3.54(s,0.9H),2.95-2.87(m,2H),2.67-2.60(m,3H),2.45-2.39(m,2H),2.07-1.60(m,4H)。

Compound II-25-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) oxazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-25-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.769min,C₂₄H₂₀ClF₂N₅O₅Calculated mass 563.1 of S, found value of M/z 564.2[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.34(br s,1H),8.00-7.97(m,1.7H),7.92-7.91(m,0.3H),7.49-7.43(m,2H),7.24-7.14(m,1H),6.02(s,0.3H),5.94(s,0.7H),4.20-4.10(m,2.2H),3.88-3.83(m,0.8H),3.54(s,3H),3.13-3.04(m,2H),2.20-2.12(m,0.2H),2.01-1.81(m,2.8H),1.72-1.63(m,1H)。

Compound II-26-B:

5-chloro-2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-26-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.347min,C₂₅H₂₀Cl₂F₂N₆O₄Calculated mass of S608.1, found M/z 609.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆+ one drop D₂O)δ8.42(s,1H),7.97-7.88(m,2H),7.47-7.40(m,1H),7.23-7.12(m,1H),6.00(s,0.4H),5.93(s,0.6H),4.83-4.67(m,2H),4.23-4.13(m,0.3H),3.96-3.85(m,0.7H),3.53(s,3H),3.00-2.87(m,2H),2.05-1.60(m,4H)。

Compound II-27-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compounds FA10 and BB2-1 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.064min,C₂₆H₂₃ClF₂N₆O₄Calculated mass of S588.1, found M/z 588.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ13.39(brs,1H),9.59(s,0.7H),9.22(s,0.3H),8.40(s,0.3H),8.39(s,0.7H),7.97(d,J＝3.2Hz,0.7H),7.94(d,J＝5.2Hz,1H),7.90(d,J＝3.2Hz,0.3H),7.49-7.41(m,1H),7.23-7.14(m,1H),6.02(s,0.3H),5.94(d,J＝3.6Hz,0.7H),4.90-4.74(m,2H),4.24-4.14(m,0.3H),3.96-3.86(m,0.7H),3.55(s,2H),3.54(s,1H),2.99-2.84(m,2H),2.19(s,3H),2.07-1.58(m,4H)。

Compound II-28-B:

2- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4-methylpyrimidin-5-yl) acetic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-28-6 by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.414min,C₂₇H₂₅ClF₂N₆O₄Calculated mass of S602.1, found M/z 603.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.08-8.06(m,1H),7.99-7.90(m,2H),7.50-7.42(m,1H),7.24-7.14(m,1H),6.02(s,0.3H),5.94(s,0.7H),4.94-4.79(m,2H),4.22-4.16(m,0.3H),3.94-3.86(m,0.7H),3.55(s,2.1H),3.54(s,0.9H),3.43(s,2H),2.93-2.80(m,2H),2.26(s,0.9H),2.25(s,2.1H),2.09-1.59(m,4H)。

Compound II-29-B:

2- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-5-yl) acetic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-29-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.349min,C₂₆H₂₃ClF₂N₆O₄Calculated mass of S588.1, M/z found 589.0[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.91(d,J＝3.2Hz,1H),7.75(d,J＝3.6Hz,1H),7.37(s,1H),7.32-7.24(m,2H),6.19(s,0.3H),6.13(s,0.7H),4.88-4.84(m,2H),4.50-4.45(m,0.3H),4.24-4.16(m,0.7H),4.13-4.06(m,2H),3.31-3.27(m,2H),2.64(s,3H),2.18-1.97(m,3.3H),1.90-1.87(m,0.7H),1.20-1.15(m,3H)。

Compound II-30-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-30-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.253min,C₂₄H₂₀ClF₂N₅O₄S₂Calculated mass of 579.1, M/z Mass found value of 580.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.62(br s,1H),9.67(d,J＝3.2Hz,0.8H),9.41(s,0.2H),8.01-7.96(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.80(s,1H),7.49-7.43(m,1H),7.24-7.14(m,1H),6.03(s,0.2H),5.94(d,J＝3.6Hz,0.8H),4.20-4.04(m,2.3H),3.93-3.86(m,0.7H),3.55(s,2.2H),3.53(s,0.8H),3.25-3.15(m,2H),2.25-1.90(m,2H),1.89-1.66(m,2H)。

Compound II-31-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4- (trifluoromethyl) thiazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-31-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.317min,C₂₅H₁₉ClF₅N₅O₄S₂647.1, found M/z 648.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.67(s,0.7H),9.44(s,0.3H),8.01-7.92(m,2H),7.50-7.43(m,1H),7.25-7.14(m,2H),6.03(s,0.3H),5.94(s,0.7H),4.21-3.98(m,2.3H),3.92-3.85(m,0.7H),3.55(s,2.1H),3.53(s,0.9H),3.24-3.13(m,2H),2.30-1.82(m,3H),1.75-1.67(m,1H)。

Compound II-32-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-32-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.348min，C₂₄H₂₀ClF₂N₅O₄S₂Calculated mass of 579.1, found value of M/z 580.0[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.91-7.85(m,1H),7.72(d,J＝3.2Hz,1H),7.49(s,1H),7.25-7.18(m,2H),6.16(s,0.3H),6.08(s,0.7H),4.29-4.10(m,2.4H),4.03-3.92(m,0.6H),3.60(s,3H),3.21-3.14(m,2H),2.26-1.91(m,3.3H),1.78-1.70(m,0.7H)。

Compound II-33-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-33-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.836min,C₂₄H₂₀ClF₂N₅O₅Calculated mass 563.1 of S, found value of M/z 563.9[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.30(s,0.3H),8.18(s,0.7H),8.00-7.99(m,1.6H),7.95-7.93(m,0.4H),7.51-7.42(m,1H),7.27-7.16(m,1H),6.03(s,0.3H),5.94(s,0.7H),4.16-3.99(m,2H),3.91-3.78(m,1H),3.54(s,2H),3.53(s,1H),3.12-2.96(m,2H),2.14-1.61(m,4H)。

Compound II-34-F:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) -2-methylpiperidin-1-yl) pyrimidine-5-carboxylic acid (mixture of 2 stereoisomers)

The title compound was synthesized as a yellow solid from compound XI-34-10F by a similar procedure using method D.

LC-MS(ESI)：R_T＝3.337min,C₂₇H₂₅ClF₂N₆O₄The calculated mass of S was 602.1, found value of M/z 602.9[ M + H [ ]]⁺,¹H NMR(400MHz,DMSO-d₆)δ8.79(s,0.4H),8.78(s,1.6H),7.99-7.92(m,2H),7.52-7.44(m,1H)，7.26-7.15(m，1H),6.06(s,0.1H),6.03(s,0.1H),5.97(s,0.4H),5.94(s,0.4H),5.36-5.21(m,1H),4.90-4.77(m,1H),4.53-4.46(m,0.3H),4.26-4.21(m,0.7H),4.05-4.00(m,2H),3.13-3.06(m,1H),2.12-1.66(m,4H),1.27-1.24(m,3H),1.12-1.07(m,3H)。

Compound II-35-A:

4- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) benzoic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-35-5R by a similar procedure using method D.

LC-MS(ESI)：R_T＝3.148min,C₂₈H₂₅ClF₂N₄O₄Calculated mass of S586.1, found M/z 587.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm 4.6 × 250 mm; mobile phase: Hex: EtOH: TFA 75:25:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength:230nm，R_T＝8.375min)。¹H NMR(400MHz,DMSO-d₆)δ7.99-7.96(m,1.7H),7.93-7.92(d,J＝2.8Hz,0.3H),7.78(d,J＝8.8Hz,2H),7.50-7.44(m,1H),7.24-7.19(m,1H),7.01(d,J＝8.8Hz,2H),6.05(s,0.3H),5.95(s,0.7H),4.13-3.97(m,4.2H),3.89-3.80(m,0.8H),2.95-2.82(m,2H),2.10-1.88(m,2.3H),1.82-1.79(m,1H),1.66-1.62(m,0.7H),1.11-1.04(m,3H)。

compound II-36-B:

6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4-hydroxynicotinic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-36-S by a similar procedure using method D.

LC-MS(ESI)：R_T＝3.231min,C₂₇H₂₄ClF₂N₅O₅Calculated Mass of S603.1M/z found 603.9[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.64(d,J＝3.2Hz,0.7H),9.20(s,0.3H),8.20-8.19(m,1H),8.00-7.97(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.50-7.43(m,1H),7.26-7.20(m,1H),7.19-7.00(m,0.7H),6.09(s,0.3H),6.07(s,0.7H),6.04(s,0.3H),5.94(d,J＝2.8Hz,0.7H),4.30-4.14(m,2.3H),4.02-3.95(m,2H),3.91-3.85(m,0.7H),3.02-2.94(m,2H),2.11-1.74(m,3H),1.69-1.63(m,1H),1.10-1.06(m,3H)。

Compound II-37-B:

6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) picolinic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-37-2 by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.474min,C₂₇H₂₄ClF₂N₅O₄Calculated mass of S587.1, found M/z 587.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.99-7.91(m,2H),7.68-7.64(m,1H),7.51-7.44(m,1H),7.28-7.18(m,2H),7.10-7.06(m,1H),6.05(s,0.3H),5.95(s,0.7H),4.68-4.53(m,2H),4.19-4.12(m,0.2H),4.03-3.96(m,2H),3.92-3.87(m,0.8H),2.94-2.80(m,2H),2.06-1.87(m,4H),1.12-1.05(m,3H)。

Compound II-38-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -6- (trifluoromethyl) isonicotinic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-38-3 by a similar procedure using method D.

LC-MS(ESI)：R_T＝2.938min,C₂₈H₂₃ClF₅N₅O₄Calculated mass of S655.1, found M/z 656.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(br s,0.6H),9.25(s,0.4H),7.99-7.90(m,2H),7.51-7.43(m,2H),7.30(s,0.6H),7.29(s,0.4H),7.25-7.17(m,1H),6.04(s,0.3H),5.95(s,0.7H),4.60-4.49(m,2H),4.25-4.17(m,0.4H),4.03-3.92(m,2.6H),3.05-2.89(m,2H),2.13-1.82(m,3H),1.76-1.66(m,1H),1.11-1.05(m,3H)。

Compound II-39-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5- (trifluoromethyl) isonicotinic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-39-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝2.728min,C₂₈H₂₃ClF₅N₅O₄Calculated mass of S655.1, found M/z 656.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆+D₂O)δ8.41(s,1H),7.98-7.88(m,2H),7.48-7.42(m,1H),7.24-7.18(m,1H),7.01-7.00(m,1H),6.04(s,0.3H),5.96(s,0.7H),4.68-4.55(m,2H),4.23-4.17(m,0.3H),4.03-3.91(m,2.7H),3.04-2.95(m,2H),2.04-1.64(m,4H),1.11-1.05(m,3H)。

Compound II-40-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -3-fluoroisonicotinic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-40-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝4.321min,C₂₇H₂₃ClF₃N₅O₄Calculated mass of S605.1, found M/z 605.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ8.05(d,J＝4.8Hz,1H),7.91(d,J＝3.2Hz,1H),7.75(d,J＝3.2Hz,1H),7.26-7.24(m,2H),7.18-7.16(m,1H),6.13(s,1H),4.21-4.14(m,3H),4.07(q,J＝7.2Hz,2H),3.08-2.98(m,2H),2.23-2.06(m,2H),1.98-1.95(m,1H),1.83-1.79(m,1H),1.15(t,J＝7.2Hz,3H)。

Compound II-41-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) isonicotinic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-41-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.589min,C₂₇H₂₄ClF₂N₅O₄Calculated mass of S587.1, M/z Mass found 587.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.59(br s,0.7H),9.11(s,0.3H),8.24(d,J＝5.2Hz,1H),7.99-7.91(m,2H),7.51-7.44(m,1H),7.26-7.21(m,2H),7.02(d,J＝4.8Hz,1H),6.04(s,0.3H),5.95(s,0.7H),4.58-4.44(m,2H),4.18-4.12(m,0.3H),4.03-3.96(m,2H),3.93-3.87(m,0.7H),2.96-2.83(m,2H),2.04-1.62(m,4H),1.11-1.05(m,3H)。

Compound II-42-B:

6-chloro-5- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) picolinic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-42-3B by a similar procedure using method D.

¹H NMR(400MHz,DMSO-d₆)δ8.02-8.00(m,1.7H),7.96-7.93(m,1.3H),7.64-7.61(m,1H),7.51-7.45(m,1H),7.25-7.21(m,1H),6.06(s,0.3H),5.95(s,0.7H),4.02-3.96(m,2.2H),3.84-3.78(m,0.8H),3.61-3.53(m,2H),2.84-2.76(m,2H),2.23-1.82(m,3.3H),1.69-1.66(m,0.7H),1.11-1.05(m,3H)。

Compound II-43-B:

6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) nicotinic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-43-1 by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.394min,C₂₇H₂₄ClF₂N₅O₄Calculated mass of S587.1, found M/z 587.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.60(br s,0.7H),9.19(br s,0.3H),8.65(s,1H),8.00-7.90(m,3H),7.54-7.44(m,1H),7.27-7.15(m,1H),6.90-6.88(m,1H),6.04(s,0.3H),5.94(s,0.7H),4.72-4.53(m,2H),4.24-4.14(m,0.2H),4.05-3.92(m,2.8H),3.03-2.89(m,2H),2.01-1.62(m,4H),1.13-1.02(m,3H)。

Compound II-44-B:

6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4- (trifluoromethyl) nicotinic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compounds FA12 and BB49 by a similar procedure using method D.

LC-MS(ESI)：R_T＝3.719min,C₂₈H₂₃ClF₅N₅O₄Calculated mass of S655.1, found M/z 656.1[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.24(br s,1H),8.70(s,0.4H),8.69(s,0.6H),7.98-7.90(m,2H),7.50-7.42(m,1H),7.24-7.12(m,2H)6.04(s,0.3H),5.95(s,0.7H),4.77-4.58(m,2H),4.27-4.18(m,0.3H),4.03-3.95(m,2.7H),3.07-2.98(m,2H),2.16-1.82(m,3H),1.76-1.64(m,1H),1.11-1.04(m,3H)。

Compound II-45-B:

6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-fluoronicotinic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-45-B by a similar procedure using method D.

LC-MS(ESI)：R_T＝3.468min,C₂₇H₂₃ClF₃N₅O₄Calculated mass of S605.1, found M/z 606.1[ M + H ]]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; column temperature: 30 ℃; wavelength: 230 nm; R_T＝5.833min)。¹H NMR(400MHz,DMSO-d₆)δ9.17(s,1H),8.52(s,1H),7.99-7.91(m,2H),7.78(dd,J＝14.4,1.6Hz,1H),7.50-7.43(m,1H),7.24-7.17(m,1H),6.04(s,0.3H),5.95(s,0.7H),4.55-4.39(m,2H),4.21-4.16(m,0.3H),4.03-3.90(m,2.7H),3.10-3.01(m,2H),2.18-1.75(m,3.5H),1.67-1.64(m,0.5H),1.11-1.05(m,3H)。

Compound II-46-B:

6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4-methylpyridazine-3-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-46-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.397min,C₂₇H₂₅ClF₂N₆O₄Calculated mass of S602.1, found M/z 603.2[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.88(d,J＝2.8Hz,1H),7.72(d,J＝2.8Hz,1H),7.31(s,1H),7.27-7.21(m,2H),6.12(br s,1H),4.72-4.64(m,2H),4.41-4.31(m,0.3H),4.18-4.13(m,0.7H),4.07(q,J＝7.2Hz,2H),3.22-3.13(m,2H),2.58(s,3H),2.18-1.79(m,4H),1.15(t,J＝7.2Hz,3H)。

Compound II-47-B:

6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -3-methoxypyrazine-2-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-47-3 by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.677min,C₂₇H₂₅ClF₂N₆O₅Calculated mass of S618.1, M/z found 619.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.62(s,0.7H),9.10(s,0.3H),8.05-7.92(m,3H),7.51-7.44(m,1H),7.25-7.18(m,1H),6.04(s,0.3H),5.95(s,0.7H),4.41-4.24(m,2H),4.14-3.95(m,2.4H),3.87-3.81(m,3.6H),2.91-2.76(m,2H),2.08-1.63(m,4H),1.11-1.05(m,3H)。

Compound II-48-B:

6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -3-methylpyrazine-2-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-48-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.071min,C₂₇H₂₅ClF₂N₆O₄Calculated mass of S602.1, found M/z 603.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(s,0.7H),9.18(s,0.3H),8.39(s,0.3H),8.37(s,0.7H),7.99-7.91(m,2H),7.51-7.44(m,1H),7.24-7.17(m,1H),6.04(s,0.3H),5.95(s,0.7H),4.60-4.45(m,2H),4.20-4.14(m,0.3H),4.03-3.96(m,2H),3.92-3.86(m,0.7H),2.93-2.84(m,2H),2.48(s,3H),2.09-1.63(m,4H),1.11-1.05(m,3H)。

Compound II-49-B:

5- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -3-methylpyrazine-2-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-49-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝4.115min,C₂₇H₂₅ClF₂N₆O₄Calculated mass of S602.1, M/z found 602.9[ M + H]⁺。¹H NMR(400MHz,CD₃OD)δ7.94(br s,1H),7.77(d,J＝3.2Hz,1H),7.61(d,J＝3.2Hz,1H),7.12-7.11(m,2H),6.03-5.95(m,1H),4.70-4.50(m,2H),4.29-4.18(m,0.4H),4.00-3.93(m,2.6H),3.02-2.95(m,2H),2.63(s,3H),2.00-1.75(m,3.4H),1.70-1.64(m,0.6H),1.04(t,J＝7.2Hz,3H)。

Compound II-50-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) oxazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid by a similar procedure using method C. LC-MS (ESI): r_T＝3.054min,C₂₅H₂₂ClF₂N₅O₅Calculated mass of S577.1, found M/z 577.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.62(br s,0.7H),9.27(s,0.3H),8.00-7.91(m,2H),7.58-7.54(m,1H),7.50-7.43(m,1H),7.25-7.18(m,1H),6.04(s,0.3H),5.95(s,0.7H),4.22-4.12(m,2.3H),4.02-3.95(m,2H),3.89-3.83(m,0.7H),3.16-3.06(m,2H),2.22-1.64(m,4H),1.11-1.04(m,3H)。

Compound II-51-B:

5- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrazine-2-carboxylic acid (single stereoisomer)

The title compound was synthesized from compounds BB22 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.325min,C₂₆H₂₃ClF₂N₆O₄The calculated mass of S is 588.1, found M/z 588.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝3.6Hz,0.7H),9.25(s,0.3H),8.67(s,1H),8.43(s,0.4H),8.41(s,0.6H),7.98-7.90(m,2H),7.50-7.42(m,1H),7.24-7.16(m,1H),6.04(s,0.4H),5.95(s,0.6H),4.76-4.60(m,2H),4.27-4.20(m,0.3H),4.03-3.93(m,2.7H),3.11-3.00(m,2H),2.07-1.68(m,4H),1.11-1.04(m,3H)。

Compound II-52-B:

6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -2-methoxypyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid by a similar procedure using method C. LC-MS (ESI): r_T＝3.417min,C₂₇H₂₅ClF₂N₆O₅Calculated mass of S618.1, M/z found 618.9[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.26(br s,1H),7.98-7.91(m,2H),7.50-7.43(m,1H),7.19-7.16(m,1H),6.96-6.94(m,1H),6.04(s,0.3H),5.95(s,0.7H),4.70-4.43(m,2H),4.25-4.17(m,0.5H),4.03-3.91(m,2.5H),3.84(s,3H),3.03-2.94(m,2H),2.13-1.73(m,3H),1.64-1.60(m,1H),1.11-1.04(m,3H)。

Compound II-53-B:

6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -2-methylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid by a similar procedure using method C. LC-MS (ESI): r_T＝3.647min,C₂₇H₂₅ClF₂N₆O₄Calculated mass of S602.1, M/z found 603.1[ M + H [)]⁺。¹H NMR(400MHz,CD₃OD)δ7.91(d,J＝3.2Hz,1H),7.75(d,J＝3.6Hz,1H),7.37(s,1H),7.32-7.24(m,2H),6.19(s,0.3H),6.13(s,0.7H),4.88-4.84(m,2H),4.50-4.45(m,0.3H),4.24-4.16(m,0.7H),4.13-4.06(m,2H),3.31-3.27(m,2H),2.64(s,3H),2.18-1.97(m,3.3H),1.90-1.87(m,0.7H),1.20-1.15(m,3H)。

Compound II-54-B:

6- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid by a similar procedure using method C. LC-MS (ESI): r_T＝3.373min,C₂₆H₂₃ClF₂N₆O₄Calculated mass of S588.1M/z found 588.9[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.27(s,1H),8.57(d,J＝3.2Hz,1H),7.98-7.90(m,2H),7.50-7.43(m,1H),7.31-7.29(m,1H),7.24-7.16(m,1H),6.04(s,0.3H),5.95(s,0.7H),4.61(br s,1.6H),4.27-4.20(m,0.4H),4.03-3.93(m,3H),3.08-3.00(m,2H),2.12-1.67(m,4H),1.11-1.04(m,3H)。

Compound II-55-B:

(trans) -3- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-5-yl) -3-hydroxycyclobutanecarboxylic acid (single stereoisomer)

The title compound was synthesized from compounds BB55 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.604min,C₃₀H₂₉ClF₂N₆O₅Calculated mass of S658.2, M/z found 659.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.50(s,0.6H),8.49(s,1.4H),7.99-7.95(m,1.7H),7.91(s,0.3H),7.50-7.43(m,1H),7.24-7.17(m,1H),6.04(s,0.3H),5.94(s,0.7H),4.94-4.80(m,2H),4.22-4.14(m,0.3H),3.98(q,J＝7.2Hz,2H),3.95-3.89(m,0.7H),2.95-2.86(m,2H),2.68-2.62(m,4H),2.45-2.43(m,1H),1.93-1.61(m,4H),1.11-1.04(m,3H)。

Compound II-56-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5, 6-dimethylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound XI-56-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.331min,C₂₈H₂₇ClF₂N₆O₄Calculated mass of S616.2, found M/z 617.1[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.90(d,J＝3.2Hz,1H),7.74(d,J＝3.2Hz,1H),7.31-7.23(m,2H),6.15(s,1H),5.05-4.95(m,2H),4.24-4.13(m,1H),4.09(q,J＝7.2Hz,2H),3.04-2.92(m,2H),2.44(s,3H),2.26(s,3H),2.05-1.75(m,4H),1.18(t,J＝7.2Hz,3H)。

Compound II-57-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -6-methoxypyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-57-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.541min,C₂₇H₂₅ClF₂N₆O₅Calculated mass of S618.1, M/z found 619.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.21(br s,1H),7.99-7.90(m,2H),7.50-7.43(m,1H),7.24-7.17(m,1H),6.41(s,0.4H),6.40(s,0.6H),6.04(s,0.4H),5.95(s,0.6H),4.98-4.86(m,2H),4.23-4.16(m,0.4H),4.03-3.91(m,2.6H),3.88(s,3H),2.96-2.86(m,2H),2.07-1.63(m,4H),1.12-1.05(m,3H)。

Compound II-58-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -6-methylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-58-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.508min,C₂₇H₂₅ClF₂N₆O₄Calculated mass of S602.1, M/z found 603.1[ M + H [)]⁺。¹H NMR(400MHz,CD₃OD)δ7.89-7.87(m,1H),7.72-7.71(m,1H),7.26-7.24(m,2H),7.04(s,1H),6.14(s,1H),5.14-5.07(m,2H),4.32-4.21(m,1H),4.14-4.06(m,2H),3.05-2.94(m,2H),2.43(s,3H),2.07-1.71(m,4H),1.18-1.15(m,3H)。

Compound II-59-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-isopropylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-59-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.327min,C₂₉H₂₉ClF₂N₆O₄Calculated mass of S630.2, found value of M/z 631.1[ M + H]⁺。¹H NMR(400MHz,CD₃OD)δ8.44(s,1H),7.87(d,J＝3.6Hz,1H),7.71(d,J＝2.8Hz,1H),7.27-7.22(m,2H),6.12(s,1H),4.99-4.93(m,2H),4.21-4.13(m,1H),4.07(q,J＝7.2Hz,2H),3.26-3.19(m,1H),3.04-2.94(m,2H),2.00-1.76(m,4H),1.27(d,J＝7.2Hz,6H),1.15(t,J＝7.2Hz,3H)。

Compound II-60-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-ethylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-60-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝2.832min,C₂₈H₂₇ClF₂N₆O₄Calculated mass of S616.2, found M/z 616.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ8.33(s,1H),7.87(d,J＝3.2Hz,1H),7.71(d,J＝3.2Hz,1H),7.27-7.22(m,2H),6.12(s,1H),4.98-4.94(m,2H),4.22-4.13(m,1H),4.06(q,J＝7.2Hz,2H),3.04-2.95(m,2H),2.70(q,J＝7.2Hz,2H),2.04-1.73(m,4H),1.20(d,J＝7.6Hz,3H),1.15(t,J＝7.2Hz,3H)。

Compound II-61-B:

5-chloro-2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-61-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.564min,C₂₆H₂₂Cl₂F₂N₆O₄Calculated mass of S622.1, found M/z 623.1[ M + H [)]⁺。¹H NMR(400MHz,DMSO-d₆+ one drop D₂O)δ8.44(s,1H),7.95-7.87(m,2H),7.47-7.40(m,1H),7.22-7.14(m,1H),6.01(s,0.4H),5.93(s,0.6H),4.82-4.66(m,2H),4.21-4.10(m,0.4H),4.00-3.88(m,2.6H),2.98-2.88(m,2H),2.05-1.59(m,4H),1.08-1.05(m,3H)。

Compound II-62-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-fluoropyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-62-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.973min，C₂₆H₂₂ClF₃N₆O₄The calculated mass of S is 606.1, found M/z 606.9[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.60(s,0.7H),9.16(s,0.3H),8.40(s,1H),8.02-7.93(m,1.7H),7.91(d,J＝3.6Hz,0.3H),7.52-7.42(m,1H),7.25-7.20(m,1H),6.04(s,0.3H),5.94(s,0.7H),4.84-4.66(m,2H),4.21-4.11(m,0.3H),4.04-3.95(m,2H),3.94-3.85(m,0.7H),2.97-2.82(m,2H),2.06-1.68(m,3.3H),1.65-1.57(m,0.7H),1.13-1.03(m,3H)。

Compound II-63-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compound BB2-1 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝2.909min,C₂₇H₂₅ClF₂N₆O₄Calculated mass of S602.1, found M/z 603.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.59(s,0.6H),9.15(s,0.4H),8.35(d,J＝4.0Hz,1H),7.98-7.90(m,2H),7.50-7.43(m,1H),7.24-7.16(m,1H),6.04(s,0.3H),5.95(s,0.7H),4.88-4.76(m,2H),4.21-4.15(m,0.2H),4.02-3.88(m,2.8H),2.95-2.84(m,2H),2.16(s,3H),2.02-1.61(m,4H),1.11-1.04(m,3H)。

Compound II-64-B:

lithium 2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4-methyloxazole-5-carboxylate (single stereoisomer)

The title compound was synthesized as a lithium salt of a yellow solid from compound XI-64-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.019min,C₂₆H₂₃ClF₂N₅O₅Calculated mass of SLi 597.1, found M/z 592.0[ (M-Li)⁺)+2H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(s,0.7H),9.20(s,0.3H),7.99-7.91(m,2H),7.50-7.44(m,1H),7.24-7.17(m,1H),6.03(s,0.3H),5.94(s,0.7H),4.14-3.95(m,4.3H),3.85-3.77(m,0.7H),3.00-2.87(m,2H),2.19(s,3H),2.12-1.58(m,4H),1.11-1.04(m,3H)。

Compound II-65-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized from compounds BB23 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.255min,C₂₆H₂₃ClF₂N₆O₄Calculated mass of S588.1, found M/z 588.9[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ8.54-8.48(m,1H),7.87(s,1H),7.70(s,1H),7.28-7.19(m,2H),7.14-7.07(m,1H),6.13(s,1H),5.14-4.98(m,2.7H),4.12-4.03(m,2.3H),3.09-2.95(m,2H),2.09-1.70(m,4H),1.16(t,J＝2.8Hz,3H)。

Compound II-66-B:

3- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-5-yl) propionic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-66-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.832min,C₂₈H₂₇ClF₂N₆O₄Calculated mass of S616.2, found M/z 617.1[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ8.26(s,2H),7.87(d,J＝3.2Hz,1H),7.71(d,J＝3.2Hz,1H),7.25-7.22(m,2H),6.15-6.10(m,1H),4.97-4.90(m,1H),4.83-4.76(m,1H),4.29(s,0.5H),4.09-4.04(m,2.5H),3.03-2.93(m,2H),2.76(t,J＝7.6Hz,2H),2.58-2.53(m,2H),2.11-1.68(m,4H),1.15(t,J＝7.2Hz,3H)。

Compound II-67-B:

2- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-5-yl) -2-methylpropionic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-67-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝2.854min,C₂₉H₂₉ClF₂N₆O₄Calculated mass of S630.2, found value of M/z 631.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(br s,0.7H),9.23(s,0.3H),8.38(s,0.6H),8.37(s,1.4H),7.99-7.90(m,2H),7.50-7.43(m,1H),7.24-7.16(m,1H),6.03(s,0.3H),5.94(s,0.7H),4.92-4.77(m,2H),4.22-4.14(m,0.3H),4.02-3.87(m,2.7H),2.96-2.84(m,2H),2.09-1.61(m,4H),1.47(s,6H),1.11-1.04(m,3H)。

Compound II-68-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) 5-methyloxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-68-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.571min,C₂₆H₂₄ClF₂N₅O₅Calculated mass of S591.1, found M/z 592.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.92(m,2H),7.50-7.43(m,1H),7.24-7.19(m,1H),6.04(s,0.3H),5.94(s,0.7H),4.07-3.96(m,4.2H),3.84-3.78(m,0.8H),3.01-2.93(m,2H),2.46(s,3H),2.06-1.60(m,4H),1.10-1.04(m,3H)。

Compound II-69-B:

2- (2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-5-yl) acetic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-69-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.467min,C₂₇H₂₅ClF₂N₆O₄Calculated mass of S602.1, found M/z 603.2[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ8.28(s,2H),7.87(d,J＝3.2Hz,1H),7.71(d,J＝3.2Hz,1H),7.25-7.23(m,2H),6.12(s,1H),5.06-4.89(m,2H),4.34-4.23(m,0.5H),4.10-3.99(m,2.5H),3.47(s,2H),3.05-2.95(m,2H),2.12-1.38(m,4H),1.15(t,J＝6.8Hz,3H)。

Compound II-70-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-70-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.374min,C₂₅H₂₂ClF₂N₅O₅Calculated mass of S577.1, found M/z 578.1[ M + H ]]⁺。¹H NMR(400MHz,CD₃OD)δ7.88(s,2H),7.73(d,J＝3.2Hz,1H),7.25-7.22(m,2H),6.15-6.11(m,1H),4.29-4.17(m,2.5H),4.05(q,J＝7.2Hz,2H),3.93(br s,0.5H),3.16-3.06(m,2H),2.19-1.68(m,4H),1.14(t,J＝7.2Hz,3H)。

Compound II-71-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4, 6-dimethylpyrimidine-5-carboxylic acid (single stereoisomer)

The title compound was synthesized from compounds BB36 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.317min，C₂₈H₂₇ClF₂N₆O₄The calculated mass of S is 616.2, found M/z 617.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝2.0Hz,0.7H),9.28(s,0.3H),7.99-7.90(m,2H),7.51-7.42(m,1H),7.25-7.15(m,1H),6.03(s,0.3H),5.94(d,J＝2.0Hz,0.7H),5.03-4.86(m,2H),4.27-4.16(m,0.3H),4.04-3.89(m,2.7H),2.98-2.85(m,2H),2.40(d,J＝3.2Hz,6H),2.10-1.60(m,4H),1.11-1.04(m,3H)。

Compound II-72-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4-methoxypyrimidine-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-72-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.583min,C₂₇H₂₅ClF₂N₆O₅Calculated mass of S618.1, M/z found 619.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.31(br s,1H),8.64-8.63(m,1H),7.99-7.95(m,1.7H),7.92-7.91(m,0.3H),7.50-7.44(m,1H),7.24-7.16(m,1H),6.04(s,0.3H),5.95(s,0.7H),4.98-4.88(m,2H),4.26-4.20(m,0.4H),4.03-3.94(m,2.6H),3.92(s,3H),3.04-2.96(m,2H),2.14-1.65(m,4H),1.11-1.04(m,3H)。

Compound II-73-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4-methylpyrimidine-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-73-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.539min,C₂₇H₂₅ClF₂N₆O₄Calculated mass of S602.1, M/z found 602.9[ M + H]⁺。¹H NMR(400MHz,CD₃OD)δ8.81(s,1H),7.87(d,J＝3.2Hz,1H),7.71(d,J＝2.8Hz,1H),7.24(d,J＝6.4Hz,2H),6.16(s,0.4H),-6.11(s,0.6H),5.16-5.02(m,2H),4.40-4.30(m,0.4H),4.10-4.05(m,2.6H),3.09-3.00(m,2H),2.65(s,3H),2.10-1.70(m,4H),1.16(t,J＝7.2Hz,3H)。

Compound II-74-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidine-5-carboxylic acid (single stereoisomer)

The title compound was synthesized from compounds BB7 and FA12 by a similar procedure using method E.

LC-MS(ESI)：R_T＝3.448min,C₂₆H₂₃ClF₂N₆O₄Calculated mass of S588.1, found M/z 589.1[ M + H ]]⁺. Chiral HPLC (column: Chiralpak IF 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 50:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R-_T＝12.275min)。¹H NMR(400MHz,DMSO-d₆)δ12.68(br s,1H),9.61(s,0.7H),9.26(s,0.3H),8.80(s,0.6H),8.79(s,1.4H),7.98-7.90(m,2H),7.50-7.43(m,1H),7.24-7.16(m,1H),6.04(s,0.3H),5.95(s,0.7H),5.02-4.89(m,2H),4.27-4.20(m,0.3H),4.03-4.00(m,2.7H),3.09-2.99(m,2H),2.13-1.66(m,4H),1.11-1.04(m,3H)。

Compound II-75-X:

ethyl 6- (1- (1,3, 4-thiadiazol-2-yl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-75-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.387min，C₂₃H₂₁ClF₂N₆O₂S₂Calculated Mass of 550.1, M/z found 550.8[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.66(d,J＝3.6Hz,0.7H),9.26(s,0.3H),8.82(s,1H),8.01-7.92(m,2H),7.51-7.44(m,1H),7.25-7.17(m,1H),6.04(s,0.3H),5.95(d,J＝3.6Hz,0.7H),4.16-3.91(m,4.3H),3.88-3.84(m,0.7H),3.30-3.17(m,2H),2.28-1.65(m,4H),1.11-1.04(m,3H)。

Compound II-76-B:

lithium 5- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-2-carboxylate (single stereoisomer)

The title compound was synthesized as a lithium salt of a yellow solid from compound XI-76-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.003min,C₂₅H₂₁ClF₂N₅O₄S₂Calculated mass of Li 599.1, found M/z 591.9[ M-Li [ ]]^-。¹H NMR(400MHz,DMSO-d₆)δ9.61(d,J＝3.2Hz,0.7H),9.04(s,0.3H),8.00-7.99(m,1.7H),7.94-7.93(m,0.3H),7.50-7.43(m,1H),7.25-7.18(m,1H),6.89(s,1H),6.04(s,0.3H),5.94(d,J＝3.2Hz,0.7H),4.02-3.95(m,2.3H),3.80-3.72(m,0.7H),3.63-3.54(m,2H),2.93-2.79(m,2H),2.20-1.97(m,2H),1.90-1.86(m,0.3H),1.80-1.77(m,1H),1.64-1.61(m,0.7H),1.10-1.04(m,3H)。

Compound II-77-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4- (methoxymethyl) thiazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-77-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.479min，C₂₇H₂₆ClF₂N₅O₅S₂Calculated mass of 637.1, M/z found 638.0[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.7(br s,1H),9.64(d,J＝2.0Hz,0.8H),9.33(s,0.2H),8.00-7.91(m,2H),7.50-7.44(m,1H),7.25-7.17(m,1H),6.04(s,0.2H),5.95(d,J＝2.4Hz,0.8H),4.59(s,2H),4.18-4.06(m,2H),4.02-3.95(m,2H),3.92-3.86(m,1H),3.31-3.30(m,3H),3.21-3.12(m,2H),2.24-2.20(m,0.2H),2.06-1.67(m,3.8H),1.11-1.04(m,3H)。

Compound II-78-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-78-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝4.263min，C₂₅H₂₂ClF₂N₅O₄S₂Calculated mass of 593.1, M/z found 594.1[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.30(br s,1H),8.00-7.96(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.70(s,1H),7.47(dd,J＝17.6,9.6Hz,1H),7.25-7.16(m,1H),6.04(s,0.3H),5.95(s,0.7H),4.18-4.05(m,2.3H),4.02-3.96(m,2H),3.92-3.85(m,0.7H),3.21-3.12(m,2H),2.26-1.66(m,4H),1.11-1.04(m,3H)。

Compound II-79-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -4- (trifluoromethyl) thiazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-79-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝2.845min,C₂₆H₂₁ClF₅N₅O₄S₂Calculated Mass of 661.1, M/z found 662.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.65(s,0.7H),9.36(s,0.3H),8.00-7.92(m,2H),7.50-7.44(m,1H),7.25-7.16(m,1H),6.04(s,0.3H),5.95(s,0.7H),4.19-3.92(m,4.3H),3.88-3.83(m,0.7H),3.19-3.11(m,2H),2.25-1.82(m,3H),1.75-1.66(m,1H),1.10-1.04(m,3H)。

Compound II-80-B2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-80-S by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.473min，C₂₅H₂₂ClF₂N₅O₄S₂Calculated mass of 593.1, M/z found 594.0[ M + H [ ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.97(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.58-7.54(m,1H),7.51-7.44(m,1H),7.25-7.17(m,1H),6.04(s,0.3H),5.95(s,0.7H),4.12-3.95(m,4.2H),3.91-3.82(m,0.8H),3.14-3.04(m,2H),2.15-1.65(m,4H),1.11-1.04(m,3H)。

Compound II-81-B:

2- (4- (6- (4-bromo-2-chlorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-81-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.308min,C₂₆H₂₄BrClN₆O₄Calculated mass of S630.1, M/z found 631.1[ M + H]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.50(s,0.7H),9.06(s,0.3H),8.00-7.91(m,3H),7.72-7.71(m,1H),7.57-7.55(m,1H),7.29-7.24(m,1H),6.01(s,0.3H),5.92(s,0.7H),4.84-4.73(m,2H),4.16-4.09(m,0.3H),3.89-3.83(m,0.7H),3.54(s,3H),2.83-2.74(m,2H),1.98(s,3H),1.93-1.68(m,3.4H),1.57-1.55(m,0.6H)。

Compound II-82-B:

2- (4- (6- (2-bromo-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-82-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.333min,C₂₄H₂₀BrF₂N₅O₄S₂Calculated mass of 623.0, M/z found 623.9[ M + H ]]⁺。HNMR(400MHz,DMSO-d₆)δ9.68(s,0.7H),9.41(s,0.3H),8.00-7.96(m,1.7H),7.92(d,J＝3.2Hz,0.3H),7.77(s,1H),7.53-7.46(m,1H),7.25-7.21(m,0.7H),7.16-7.13(m,0.3H),6.01(s,0.3H),5.94(s,0.7H),4.17-4.06(m,2.3H),3.92-3.87(m,0.7H),3.54(s,2H),3.53(s,1H),3.24-3.18(m,2H),2.29-2.22(m,0.3H),2.08-197(m,1H),1.93-1.82(m,1.7H),1.76-1.67(m,1H)。

Compound II-83-B:

2- (4- (6- (2-bromo-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-83-B by a similar procedure using method C.

LC-MS(ESI)：R_T＝4.273min，C₂₄H₂₁BrFN₅O₄S₂Calculated mass of 605.0, M/z found 605.8[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.00-7.96(m,1.6H),7.92-7.89(m,0.4H),7.64(s,1H),7.45-7.39(m,1H),7.32-7.28(m,1H),7.25-7.14(m,1H),6.06(s,0.3H),5.98(s,0.7H),4.17-4.04(m,2H),3.92-3.86(m,1H),3.54(s,2H),3.52(s,1H),3.23-3.11(m,2H),2.28-2.09(m,1H),2.05-1.97(m,1H),1.95-1.85(m,1H),1.82-1.65(m,1H)。

Compound II-84-B:

2- (4- (6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) thiazole-5-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-84-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝2.958min,C₂₄H₂₁BrFN₅O₄S₂Calculated mass of 605.0, M/z found 606.0[ M + H ]]⁺. Chiral analysis (column: Chiralpak ID 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 214nm, R ℃; temperature: 30 ℃; chiral analysis of the chiral compound (chiral compound)_T＝11.972min)。¹H NMR(400MHz,DMSO-d₆)δ12.58(br s,1H),9.55(d,J＝3.6Hz,0.7H),9.34(s,0.3H),8.00-7.96(m,1.8H),7.92-7.91(m,0.2H),7.78(s,1H),7.59-7.56(m,1H),7.38-7.24(m,2H),5.99(s,0.2H),5.91(d,J＝3.2Hz,0.8H),4.17-4.07(m,2.3H),3.92-3.86(m,0.7H),3.55(s,2.5H),3.53(s,0.5H),3.24-3.16(m,2H),2.04-1.75(m,3H),1.69-1.65(m,1H)。

Compound II-85-A:

2- (3- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) pyrrolidin-1-yl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-85-M by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.139min,C₂₄H₂₀ClF₂N₅O₅Calculated mass 563.1 of S, found value of M/z 563.8[ M + H]⁺. Chiral analysis (column: Chiralpak IF 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH: TFA: 80:20:0.2 at 1 mL/min; column temperature: 30 ℃; wavelength: 254nm, R _T＝9.215min)。¹H NMR(400MHz,DMSO-d₆)δ7.98-7.94(m,3H),7.53-7.48(m,1H),7.25-7.22(m,1H),5.96(s,1H),4.76-4.69(m,0.1H),4.46-4.43(m,0.9H),3.99(q,J＝6.8Hz,2H),3.81-3.67(m,3H),3.55-3.49(m,1H),2.23-2.16(m,2H),1.07(t,J＝6.8Hz,3H)。

Compound II-86-B:

2- (3- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) azetidin-1-yl) oxazole-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-86-N by a similar procedure using method C.

LC-MS(ESI)：R_T＝3.019min,C₂₃H₁₈ClF₂N₅O₅Calculated mass of S549.1, M/z found 549.8[ M + H [ ]]⁺. Chiral HPLC (column: Chiralpak OD-H5 μm 4.6 x 250 mm; mobile phase: Hex: IPA: TFA: 70:30:0.2 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R-_T＝10.127min)。¹H NMR(400MHz,DMSO-d₆)δ8.04-8.00(m,3H),7.49-7.43(m,1H),7.31-7.27(m,1H),5.97(s,1H),4.65(br s,1H),4.34-4.22(m,4H),3.98(q,J＝7.2Hz,2H),1.08(t,J＝7.2Hz,3H)。

Compound II-87-A:

methyl 6- (1-benzoylazetidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

Intermediate II-87-X:

methyl 6- (1-benzoylazetidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (mixture of 2 stereoisomers)

To a solution of methyl 6- (azetidin-3-yl) -4- (2-chloro-4-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate FA19(150mg, 0.37mmol) in dichloromethane (10mL) at 0 ℃ under a nitrogen atmosphere was added triethylamine (57mg, 0.56mmol) and benzoyl chloride BB51(52mg, 0.37 mmol). 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% ammonium bicarbonate), mobile phase B: acetonitrile, UV: 214nm, flow rate: 20mL/min, gradient: 40% -70% (% B)) to give the title compound as a yellow solid (156mg, 62% yield). LC-MS (ESI): r _T＝3.383min，C₂₅H₂₀ClFN₄O₃Calculated mass of S510.1, M/z found 510.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T12.587min and 14.340 min).¹HNMR(400MHz,DMSO-d₆)δ9.69(d,J＝3.2Hz,1H),8.02-8.01(m,2H),7.68(t,J＝7.2Hz,2H),7.52-7.39(m,5H),7.25-7.14(m,1H),6.02(s,0.1H),5.95(d,J＝2.8Hz,0.9H),4.62-4.42(m,3H),4.39-4.19(m,2H),3.53(s,3H)。

A stereoisomeric mixture of II-87-X (156mg, 0.310mmol) was separated by chiral preparative HPLC (column: Chiralpak IE 5 μm 20 × 250 mm; mobile phase: Hex: EtOH 60:40 at 13 mL/min; temperature: 30 ℃; wavelength: 214nm) to provide compound II-87-a (38mg, 24% yield, 100% stereopurity) and II-87-B (41mg, 26% yield, 99.1% stereopurity) as yellow solids.

II-87-A：LC-MS(ESI)：R_T＝3.379min，C₂₅H₂₀ClFN₄O₃Calculated mass of S510.1, M/z found 510.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝12.433min)。¹H NMR(400MHz,DMSO-d₆)δ9.69(s,1H),8.03-8.01(m,2H),7.68(t,J＝7.2Hz,2H),7.54-7.45(m,3H),7.43-7.39(m,2H),7.25-7.13(m,1H),6.02(s,0.1H),5.94(t,J＝2.8Hz,0.9H),4.62-4.42(m,3H),4.39-4.19(m,2H),3.53(s,3H)。

II-87-B：LC-MS(ESI)：R_T＝3.379min，C₂₅H₂₀ClFN₄O₃Calculated mass of S510.1, M/z found 510.9[ M + H [ ]]⁺. Chiral analysis (column: Chiralpak IE 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝14.174min)。¹H NMR(400MHz,DMSO-d₆)δ9.69(s,1H),8.03-8.01(m,2H),7.69(t,J＝6.8Hz,2H),7.54-7.39(m,5H),7.25-7.14(m,1H),6.02(s,0.1H),5.94(t,J＝2.8Hz,0.9H),4.63-4.49(m,3H),4.44-4.19(m,2H),3.53(s,3H)。

Compound II-88-B:

methyl 4- (2-chloro-4-fluorophenyl) -6- (1- (5-methylisoxazole-4-carbonyl) azetidin-3-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

The title compound was synthesized from compound BB52 and FA19-1B by a similar procedure using method E.

LC-MS(ESI)：R_T＝1.959min，C₂₃H₁₉ClFN₅O₄Calculated mass of S515.1, found M/z 515.9[ M + H [)]⁺. Chiral analysis (column: Chiralpak IA 5 μm 4.6 x 250 mm; mobile phase: Hex: EtOH 60:40 at 1.0 mL/min; temperature: 30 ℃; wavelength: 230nm, R_T＝8.135min)。¹H NMR(400MHz,DMSO-d₆)9.71(d,J＝2.8Hz,1H),8.84(d,J＝10.8Hz,1H),8.01(s,2H),7.45-7.41(m,2H),7.24-7.16(m,1H),5.95(s,1H),4.67-4.48(m,3H),4.36-4.13(m,2H),3.54(s,3H),2.65(s,3H)。

Compound II-89-B

2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylisonicotinic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-87-S by a similar procedure using method C.

LC-MS (ESI): RT 2.895min, calculated mass 569.1 for C27H25ClFN5O4S, M/z found 569.9[ M + H ] +. 1H NMR (400MHz, CD3OD) δ 7.91(s,1H),7.88(d, J ═ 3.2Hz,1H),7.72(d, J ═ 3.2Hz,1H),7.42-7.39(m,1H),7.24-7.21(m,2H),7.07-7.03(m,1H),6.11(s,1H),4.38-4.31(m,2H),4.11(br s,1H),3.61(s,3H),3.15-3.06(m,2H),2.35(s,3H),2.13-1.98(m,3H),1.86-1.76(m, 1H).

Compound II-90-B:

1- (2- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidin-5-yl) piperidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound VIII-20-6B by a similar procedure using method C.

LC-MS (ESI): calculated mass 639.2 for C30H31ClFN7O4S, RT 3.663min, found 639.9[ M + H ] +. 1H NMR (400MHz, DMSO-d6) Δ 9.45(s,0.7H),9.04(s,0.3H),8.21(s,0.6H),8.20(s,1.4H),7.98-7.90(m,2H),7.44-7.40(m,1H),7.38-7.32(m,1H),7.24-7.17(m,1H),6.02(s,0.3H),5.93(s,0.7H),4.80-4.65(m,2H),4.15-4.09(m,0.3H),3.90-3.82(m,0.7H),3.54(s,2H),3.53(s,1H),3.40-3.36(m,2H),2.88-2.79(m, 69.79, 2H), 2.54 (s,2H), 1.64-1H, 1H), 1.6.6.4.7.7 (m, 1H).

Compound II-91-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5- (dimethylamino) pyrimidine-4-carboxylic acid (single stereoisomer)

The title compound was synthesized as a yellow solid from compound XI-88-4 by a similar procedure using method C.

LC-MS (ESI): calculated mass 617.1 for C27H26ClF2N7O4S, found M/z 618.1[ M + H ] +, RT 3.720 min. 1H NMR (400MHz, DMSO-d6) Δ 9.59(br s,0.7H),9.21(s,0.3H),8.54(s,0.7H),8.53(s,0.3H),7.99-7.90(m,2H),7.49-7.42(m,1H),7.24-7.15(m,1H),6.03(s,0.3H),5.94(s,0.7H),4.85-4.73(m,2H),4.21-4.14(m,0.3H),3.94-3.87(m,0.7H),3.55(s,2.1H),3.54(s,0.9H),2.96-2.85(m,2H),2.73(s,4.2H),2.72(s,1.8H), 1.07 (m, 61H).

Compound II-92-B:

5-amino-2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidine-4-carboxylic acid (single stereoisomer)

Intermediate XI-89-3:

5- (bis (2, 4-dimethoxybenzyl) amino) -2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidine-4-carboxylic acid (single stereoisomer)

Compound XI-89-3 was synthesized as a yellow solid from Compound XI-89-2 by a similar procedure using method C.

1H NMR(400MHz,CDCl3)δ8.55(s,0.5H),8.51(s,0.5H),8.13(s,0.5H),7.82(d,J＝2.8Hz,0.5H),7.79(d,J＝2.8Hz,0.5H),7.49(d,J＝2.8Hz,0.5H),7.45-7.43(m,1H),7.08-7.06(m,2H),7.01-6.98(m,2H),6.39-6.37(m,4H),6.19(s,0.5H),6.07(d,J＝2.8Hz,0.5H),5.08-4.94(m,2H),4.38-4.23(m,0.5H),4.16(s,4H),4.05-3.92(m,0.5H),3.78(s,6H),3.73(s,3H),3.72(s,3H),3.63(s,1.3H),3.61(s,1.7H),3.08-2.97(m,2H),2.15-2.01(m,2H),1.75-1.69(m,2H)。

Compound II-92-B:

5-amino-2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidine-4-carboxylic acid (single stereoisomer)

To a solution of 5- (bis (2, 4-dimethoxybenzyl) amino) -2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyrimidine-4-carboxylic acid XI-89-3(70mg, 90% purity, 0.071mmol) in dichloromethane (1mL) was added trifluoroacetic acid (1mL) at room temperature. The mixture was stirred at room temperature for 2 hours, and then water (20mL) was added. The resulting mixture was extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with saturated sodium bicarbonate solution until pH about 6, and then washed with brine (20mL), dried over Na2SO4 (solid) and filtered. The filtrate was concentrated and purified by C18 (acetonitrile: water ═ 40% to 80%) to provide the title compound as a yellow solid (13mg, 97.4% purity, 30% yield). LC-MS (ESI): calculated mass 589.1 for RT 3.377min, C25H22ClF2N7O4S, found M/z 590.1[ M + H ] +. 1H NMR (400MHz, DMSO-d6) Δ 9.57(s,0.6H),9.06(s,0.4H),8.32(s,0.4H),8.31(s,0.6H),7.99-7.95(m,2H),7.49-7.42(m,1H),7.24-7.15(m,1H),6.03(s,0.4H),5.94(s,0.6H),4.78-4.64(m,2H),4.15-4.08(m,0.3H),3.87-3.82(m,0.7H),3.54(s,1.8H),3.53(s,1.2H),2.87-2.73(m,2H),1.99-1.57(m, 4H).

Compound II-93-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5- (dimethylamino) isonicotinic acid (single stereoisomer)

Intermediate XI-90-4:

methyl 6- (1- (5-amino-4- (methoxycarbonyl) pyridin-2-yl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

To a solution of methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (4- (methoxycarbonyl) -5-nitropyridin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate XI-90-3(120mg, 95% purity, 0.18mmol) in ethanol (5mL) and water (2mL) was added ammonium chloride (25mg, 0.467mmol) and iron powder (52mg, 0.931 mmol). After stirring at 80 ℃ for 1 hour, the mixture was cooled to room temperature, poured into water (20mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were concentrated and purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1 to 1:1) to give the title compound (100mg, obtained from¹Purity of H NMR 90%, 83% yield). LC-MS (ESI): r_T＝1.73min,C₂₇H₂₅ClF₂N₆O₄Calculated mass of S602.1, M/z found 603.1[ M + H [) ]+。¹H NMR(400MHz,CDCl₃)δ8.24(br s,0.7H),7.98(s,0.3H),7.97(s,0.7H),7.82-7.80(m,0.3H),7.79-7.76(m,0.7H),7.49-7.46(m,0.3H),7.44-7.42(m,0.7H),7.40-7.39(m,0.3H),7.15-6.99(m,3H),6.20(s,0.7H),6.07(d,J＝2.8Hz,0.3H),5.14-5.04(m,2H),4.43-4.34(m,0.3H),4.23-4.10(m,2.7H),3.92(s,3H),3.63(s,0.9H),3.61(s,2.1H),2.91-2.79(m,2H),2.37-1.73(m,4H)。

Intermediate XI-90-5:

methyl 4- (2-chloro-3, 4-difluorophenyl) -6- (1- (5- (dimethylamino) -4- (methoxycarbonyl) pyridin-2-yl) piperidin-4-yl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (single stereoisomer)

To a solution of methyl 6- (1- (5-amino-4- (methoxycarbonyl) pyridin-2-yl) piperidin-4-yl) -4- (2-chloro-3, 4-difluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate XI-90-4(100mg, 90% purity, 0.149mmol) in methanol (4mL) at 0 deg.C was added 37% aqueous formaldehyde (30mg, 0.37mmol) and acetic acid (40mg, 0.666 mmol). After stirring at room temperature for 10 min, sodium cyanoborohydride (20mg, 0.318mmol) was added. After stirring at room temperature for 2 hours, the mixture was quenched with aqueous ammonium chloride (5mL) and extracted twice with ethyl acetate (30 mL). The combined organic layers were concentrated and purified by C18 column (acetonitrile: water 70% to 80%) to give the title compound (55mg, from¹Purity by H NMR 95%, 55% yield). LC-MS (ESI): r_T＝1.83min,C₂₉H₂₉ClF₂N₆O₄Calculated mass of S630.2, M/z found 631.2[ M + H [ ]]⁺。¹H NMR(400MHz,CDCl₃)δ8.20(s,0.6H),8.09(s,0.4H),8.08(s,0.6H),7.82(d,J＝2.8Hz,0.4H),7.78(d,J＝3.2Hz,0.6H),7.48(d,J＝3.2Hz,0.4H),7.44(d,J＝2.8Hz,0.6H),7.40(d,J＝2.4Hz,0.4H),7.12-7.00(m,2H),6.92-6.91(m,1H),6.20(s,0.6H),6.07(d,J＝2.8Hz,0.4H),4.42-4.20(m,2.6H),4.02-3.98(m,0.4H),3.94(s,3H),3.63(s,1.3H),3.61(s,1.7H),3.00-2.88(m,2H),2.79(s,3.3H),2.78(s,2.7H),2.30-2.19(m,0.4H),2.11-1.72(m,3.6H)。

Compound II-93-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5- (dimethylamino) isonicotinic acid (single stereoisomer)

Compound II-93-B was synthesized as a yellow solid from Compound XI-90-5 by a similar procedure using method C.

LC-MS(ESI)：R_T＝4.043min,C₂₈H₂₇ClF₂N₆O₄Calculated mass of S616.1, found M/z 617.2[ M + H ]]⁺。¹H NMR(400MHz,DMSO-d₆)δ9.63(d,J＝2.8Hz,0.7H),9.19(s,0.3H),8.61(s,1H),8.00-7.91(m,2H),7.50-7.43(m,1H),7.23-7.15(m,2H),6.03(s,0.3H),5.94(d,J＝2.0Hz,0.7H),4.56-4.43(m,2H),4.20-4.12(m,0.3H),3.93-3.86(m,0.7H),3.55(s,2.1H),3.54(s,0.9H),3.00-2.83(m,8H),2.27-1.63(m,4H)。

Compound II-94-B:

2- (4- (6- (3, 4-difluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylic acid (single stereoisomer)

Compound II-94-B was synthesized as a yellow solid from Compound XI-91-1 by a similar procedure using method C.

LC-MS (ESI): calculated mass 568.2 for C27H26ClF2N6O4S, found M/z 568.9[ M + H ] +, RT 3.971 min. 1H NMR (400MHz, DMSO-d6) δ 9.53(s,0.8H),9.04(s,0.2H),8.01(s,1H),7.97-7.93(m,1.8H),7.88(d, J ═ 3.2Hz,0.2H),7.27-7.17(m,1H),7.13-7.10(m,0.8H),7.00-6.96(m,0.2H),5.83(s,0.2H),5.70(d, J ═ 3.2Hz,0.8H),4.87-4.73(m,2H),4.19-4.12(m,0.2H),3.89-3.83(m,0.8H),3.55(s,0.8H),3.54(s, 2.88H), 2.74(m,2H), 3.54 (m,2H), 3.44, 1.44H), 1.54(m, 1.7H), 1.2H), 7.7 (m, 1.2H), 3.2H).

Compound II-95-B:

2- (4- (6- (3, 4-difluoro-2-methylphenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methoxypyrimidine-4-carboxylic acid (single stereoisomer)

Compound II-95-B was synthesized as a yellow solid from Compound XI-92-1 by a similar procedure using method C.

LC-MS (ESI): RT 4.210min, calculated mass 584.2 for C27H26F2N6O5S, M/z found 585.2[ M + H ] +. 1H NMR (400MHz, CD3OD) δ 8.26(s,1H),7.87(d, J ═ 3.2Hz,1H),7.71(d, J ═ 3.2Hz,1H),7.12-7.09(m,1H),7.06-6.99(m,1H),5.88(s,1H),4.88-4.80(m,2H),4.18-4.07(m,1H),3.86(s,3H),3.62(s,3H),3.02-2.91(m,2H),2.51(d, J ═ 2.4Hz,3H),2.01-1.85(m,3H),1.77-1.73(m, 1H).

Compound II-96-B:

2- (4- (6- (2-chloro-3, 4-difluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-ethoxypyrimidine-4-carboxylic acid (single stereoisomer)

Compound II-96-B was synthesized as a yellow solid from Compound XI-93-3 by a similar procedure using method C.

LC-MS (ESI): calculated mass 632.1 for RT 3.626min, C28H27ClF2N6O5S, found M/z 632.9[ M + H ] +. 1H NMR (400MHz, CD3OD) δ 7.43(s,1H),7.78(d, J ═ 2.8Hz,1H),7.62(d, J ═ 3.2Hz,1H),7.20-7.10(m,2H),6.03(s,1H),4.73-4.63(m,2H),4.01-3.94(m,5H),2.94-2.78(m,2H),1.95-1.61(m,4H),1.27(t, J ═ 6.8Hz,3H),1.05(t, J ═ 7.2Hz, 3H).

Compound II-97-B:

2- (4- (6- (2-bromo-3-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5- (dimethylamino) pyrimidine-4-carboxylic acid (single stereoisomer)

Compound II-97-B was synthesized as a yellow solid from Compound XI-94-1 by a similar procedure using method C.

LC-MS (ESI): calculated mass 657.1 for RT 3.670min, C28H29BrFN7O4S, found M/z 658.2[ M + H ] +. 1H NMR (400MHz, CD3OD) δ 8.85(s,1H),7.88(d, J ═ 2.8Hz,1H),7.72(d, J ═ 3.2Hz,1H),7.39-7.33(m,1H),7.25-7.24(m,1H),7.16-7.12(m,1H),6.19(s,1H),5.18-5.07(m,2H),4.33(br s,1H),4.08(q, J ═ 7.2Hz,2H),3.34-3.32(m,6H),3.12-2.96(m,2H),2.09-1.70(m,4H),1.15(t, J ═ 7.2Hz, 3H).

Compound II-98-B:

2- (4- (6- (2-bromo-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylic acid (single stereoisomer)

Compound II-98-B was synthesized as a yellow solid from Compound XI-95S by a similar procedure using method C.

LC-MS (ESI): RT 4.078min, calculated mass 614.1 for C26H24BrFN6O4S, M/z found 614.8[ M + H ] +. 1H NMR (400MHz, DMSO-d6) Δ 9.49(s,0.6H),9.07(s,0.4H),8.12(s,1H),8.00-7.85(m,2H),7.47-7.35(m,1H),7.28-7.13(m,2H),6.06(s,0.3H),5.98(s,0.7H),4.91-4.68(m,2H),4.20-4.12(m,0.3H),3.94-3.82(m,0.7H),3.54(s,2.1H),3.52(s,0.9H),2.94-2.68(m,2H),1.99(s,3H),1.91-1.71(m,3.5H),1.62-1.54(m, 0.5H).

Compound II-99-B:

2- (4- (6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5-methylpyrimidine-4-carboxylic acid (single stereoisomer)

Compound II-99-B was synthesized as a yellow solid from compound XI-96-1 by a similar procedure using method C.

LC-MS (ESI): RT 3.439min, calculated mass 614.1 for C26H24BrFN6O4S, M/z found 614.9[ M + H ] +. 1H NMR (400MHz, CD3OD) δ 8.16(s,1H),7.86(d, J ═ 3.2Hz,1H),7.70(t, J ═ 2.8Hz,1H),7.42-7.38(m,2H),7.10(td, J ═ 8.4Hz,2.8Hz,1H),6.08(s,1H),5.02-4.95(m,2H),4.23-4.02(m,1H),3.61(s,3H),3.01-2.91(m,2H),2.19(s,3H),1.93-1.79(m,3H),1.75-1.65(m, 1H).

Compound II-100-B:

2- (4- (6- (2-bromo-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) -5- (dimethylamino) pyrimidine-4-carboxylic acid (single stereoisomer)

Compound II-100-B was synthesized as a yellow solid from Compound XI-97-1 by a similar procedure using method C.

LC-MS (ESI): calculated mass 657.1 for C28H29BrFN7O4S, M/z found 657.9[ M + H ] +, RT 3.638 min. 1H NMR (400MHz, CDCl3) δ 8.63(s,0.4H),8.61(s,0.6H),8.07(s,0.4H),7.81(d, J ═ 2.8Hz,0.6H),7.76(d, J ═ 3.2Hz,0.4H),7.47(d, J ═ 3.2Hz,0.6H),7.43(d, J ═ 3.2Hz,0.4H),7.40(s,0.6H),7.33 to 7.28(m,2H),7.04 to 6.95(m,1H),6.20(s,0.4H),6.07(d, J ═ 2.4Hz,0.6H),5.15 to 4.99(m,2H),4.39 to 4.33(m, 3.01H), 4.07 (d, J ═ 2.4H), 5.15 to 4.99(m,2H),4.39 to 4.33(m, 3H), 11.01 (m,2H), 3.19 (m,2H), 3.05 to 2H),1.80 (m, 1.6H), 3.75 to 3.6H), 1.6H), 1.6H, 1.9 (m, 1.80 (m, 1.75H).

Compound II-101-B：

3- (6- (4- (6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) piperidin-1-yl) pyridin-3-yl) propionic acid (single stereoisomer)

Compound II-101-B was synthesized as a yellow solid from compound VIII-23-B by a similar procedure using method D.

LC-MS (ESI): calculated mass 583.1 for C28H27ClFN5O4S, M/z found 583.9[ M + H ] +, RT 3.252 min. 1H NMR (400MHz, CD3OD) δ 7.96(s,1H),7.87(d, J ═ 3.2Hz,1H),7.72(d, J ═ 3.2Hz,1H),7.56-7.54(m,1H),7.42-7.38(m,1H),7.25-7.22(m,1H),7.07-7.03(m,1H),6.92-6.90(m,1H),6.10(br s,1H),4.43-3.96(m,3H),3.60(s,3H),3.03-2.93(m,2H),2.82(t, J ═ 7.2Hz,2H),2.57(t, J ═ 7.6Hz,2H),2.18-1.68(m, 4H).

Example 2:antiviral assays in HepG2.2.15 cells

1. Materials and apparatus

1.1. Cell lines

HepG2.2.15 (this HepG2.2.15 cell line can be generated by transfection of a HepG2 cell line, such as Sells, Chen and Acs 1987(Proc. Natl. Acad. Sci. USA [ Proc. Natl. Acad. Sci.USA. ]]84:1005-1009), and the HepG2 cell line can be obtained fromIn accession number HB-8065^TMObtained as follows).

Reagent

DMEM/F12(INVITROGEN-11330032)

FBS(GIBCO-10099-141)

Dimethyl sulfoxide (DMSO) (SIGMA-D2650)

Penicillin-streptomycin solution (HYCLONE-SV30010)

NEAA(INVITROGEN-1114050)

L-glutamine (INVITROGEN-25030081)

Geneticin selective antibiotic (G418, 500mg/ml) (INVITROGEN-10131027)

Trypsin digestive juice (INVITROGEN-25300062)

CCK8(BIOLOTE-35004)

QIAamp 96DNA Blood Kit(12)(QIAGEN-51162)

FastStart Universal Probe Mast Mix(ROCHE-04914058001)

1.2. Consumable material

96-well cell culture plate (COSTAR-3599)

Micro Amp Optical 96-well reaction plate (APPLIED BIOSYSTEMS-4306737)

Micro Amp Optical 384-hole reaction plate (APPLIED BIOSYSTEMS)

1.3. Device

Plate reader (MOLECULAR DEVICES, SPECTRAMAX M2e)

Centrifuge (BECKMAN, ALLEGRA-X15R)

Real-time PCR system (APPLID BIOSYSTEMS, QUANTSTUDIO 6)

Real-time PCR system (APPLID BIOSYSTEMS, 7900HT)

2. Method of producing a composite material

Determination of HBV inhibitory Activity and cytotoxicity

Cells hepg2.2.15 cells were seeded into 96-well plates in 2% FBS 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 overnight at 37 ℃ under 5% CO 2. The following day, media containing compounds was added to the cells to treat the cells for 6 days and was supplemented with media once during the treatment. Each compound was diluted 3-fold using 8 dose points, with the highest concentrations of compound being 10uM and 100uM for HBV inhibitory activity and cytotoxicity assays, respectively.

After 6 days of compound treatment, 20. mu.l of CCK-8 reagent was added to each well of the cytotoxicity assay plate, and the plate was incubated at 37 ℃ with 5% CO₂Incubate for 2.5h, and measure absorbance at 450nm wavelength while reading absorbance at 630nm wavelength as a reference.

HBV DAN changes in cell culture medium induced by the compounds were measured by the q-PCR method. Briefly, HBV DNA in the medium was extracted using QIAamp 96DNA Blood Kit according to the manual and then quantified by q-PCR using the primers and probes in the following table.

Table 3:

2.2. data analysis

EC is calculated by GRAPHPAD PRISM software₅₀And CC₅₀The value is obtained. Data from this batch of experiments were considered to be qualified if the% CV of the DMSO control was below 15% and the reference compound showed the expected activity or cytotoxicity.

2.3. Results

See table 4.

Table 4: