阅读说明：本技术 环状磺酰胺化合物及其使用方法 (Cyclic sulfonamide compounds and methods of use thereof ) 是由 W.J.小特纳 L.李 S.N.海达尔 M.G.布赖什 R.莱 S.弗朗西斯 L.D.阿 于 2018-03-01 设计创作，主要内容包括：本发明部分提供环状磺酰胺化合物及其药物组合物,其可用作乙肝(HBV)核心蛋白的调节剂,以及提供了治疗乙肝(HBV)感染的方法。(The present invention provides, in part, cyclic sulfonamide compounds and pharmaceutical compositions thereof, which are useful as modulators of Hepatitis B (HBV) core protein, and methods of treating Hepatitis B (HBV) infection.)

1. A compound of formula I:

wherein:

w is 2;

R¹is phenyl or pyridyl, each of which is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

R²is hydrogen;

R³selected from:

wherein:

R⁴is hydrogen or C optionally substituted with 1,2 or 3 substituents independently selected from_1-6Alkyl groups: halogen, -OH, -CN, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, formyl, -C (O) OH, -C (O) O-C_1-6Alkyl, benzyloxy, C_1-4Alkoxyphenyl, pyrrolidinyl, morpholinyl, tetrahydrofuryl and triazolyl;

R⁵is hydrogen or C optionally substituted with a substituent selected from_1-6Alkyl groups: halogen, -OH, C_1-6Alkoxy, -NR^aR^bAnd R^aR^bN-C_1-4An alkyl group;

R⁶is hydrogen or C_1-6An alkyl group;

R³³independently at each occurrence is selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy radicalRadical-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein the phenyl and 5-6 membered monocyclic heteroaryl are optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

R³⁴selected from hydrogen, C_1-4Alkyl and hydroxy C_1-4An alkyl group;

R^aand R^bIndependently is hydrogen or C_1-6An alkyl group; or

R^aAnd R^bCan be reacted with R^aAnd R^bThe attached nitrogens together form:

R^cis hydrogen or C_1-6An alkyl group;

at each occurrence, q is 0, 1 or 2,

at each occurrence, t is 1 or 2;

r is 0, 1 or 2;

r2 is 0, 1,2 or 3;

with the following conditions:

when R is³R2 is 1,2 or 3 when it is thiophen-2-yl or furan-2-yl;

when R is³When it is pyrazol-4-yl, in at least one occurrence, R³³Is other than C_1-6An alkyl group; and is

When R is³When it is phenyl, R³⁵、R³⁶And R³⁷At least one of which is not halogen and C_1-6An alkoxy group.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is formula II:

3. the compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, 1,2, 4-triazinyl, 1,2, 3-triazinyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, and 1,2, 5-thiadiazolyl.

4. The compound of claim 1,2 or 3, or a pharmaceutically acceptable salt thereof, wherein r and r2 are 1.

5. A compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R⁶Is hydrogen.

6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof,wherein R is⁵Is hydrogen.

7. A compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R⁴Is methyl or methoxyethyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R⁴Is methyl.

9. A compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R³Is composed of

10. A compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R³Is composed of

11. A compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R³Is composed of

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein r is 1.

13. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R³Is composed of

14. A compound according to claim 13, wherein said compound is,or a pharmaceutically acceptable salt thereof, wherein R³Is composed of

15. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R³Is composed of

16. A compound according to any one of claims 9-15, wherein R³³Independently at each occurrence is selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, phenyl, pyridyl, and pyrimidinyl, wherein the benzyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, phenyl, pyridyl, and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

17. The compound of claim 16, R³³Independently at each occurrence is selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4Alkylsulfonylaminoimidazolyl.

18. A compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R³Is composed of

19. The compound according to any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R¹Is phenyl optionally substituted with 1,2 or 3 substituents independently selected from: halogen, cyano, methyl and trifluoromethyl.

20. The compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein R¹Is phenyl optionally substituted with 1,2 or 3 substituents independently selected from: F. cl, Br and CF₃。

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R¹Is 3-chloro-4-fluorophenyl.

22. A pharmaceutical composition comprising a compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. A method of treating Hepatitis B (HBV) infection in a patient, the method comprising: administering to a patient in need thereof an effective amount of a compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof.

24. A method of treating Hepatitis B (HBV) infection in a patient, the method comprising: administering to a patient in need thereof an effective amount of the pharmaceutical composition of claim 22.

Background

Hepatitis B (HBV) causes viral hepatitis, which may further lead to chronic liver disease and increases the risk of cirrhosis and liver cancer (hepatocellular carcinoma). Worldwide, approximately 20 million people are infected with HBV, approximately 3.6 million people are chronically infected, and each year HBV infection results in the death of over 50 million people. HBV can be transmitted through body fluids: maternal-infant transmission, sexual transmission and transmission through blood products. Children born to HBV positive mothers may also be infected unless the vaccine is injected at birth.

The hepatitis virion consists of an outer lipid membrane coated with a surface protein (HBsAg) that surrounds the viral core. The core consists of a protein shell (or capsid) of 120 core protein (Cp) dimers, which itself contains the loose-loop dna (rcdna) viral genome as well as viral and host proteins. In infected cells, the genome is found as covalently closed circular dna (cccdna) in the nucleus of the host cell. The cccDNA is a template for viral RNA and thus for viral proteins. In the cytoplasm, Cp aggregates around a complex of full-length viral RNA, the so-called pregenomic RNA (or pgRNA), and the viral polymerase (P). Upon assembly, P transcribes the pgRNA back into rcDNA within the capsid, thereby generating a DNA-filled viral core.

Currently, chronic HBV is treated primarily with nucleoside (acid) analogs (e.g., entecavir), which inhibit the virus while the patient remains treated, but do not eliminate the infection, even after many years of treatment. Once a patient begins to take a nucleotide analog, most patients must continue to take the drug or be at risk for the possibility of a fatal immune response from a virus relapse. In addition, nucleoside (acid) therapy may lead to the emergence of antiviral drug resistance.

The only approved alternative nucleotide analog for FDA is treatment with interferon alpha or pegylated interferon alpha. Unfortunately, the incidence and profile of adverse events with interferon alpha may lead to poor tolerability and many patients are unable to complete the treatment. In addition, only a small fraction of patients are considered suitable for interferon therapy, as only a small fraction of patients may have a sustained clinical response to a course of interferon therapy. Therefore, interferon-based therapies are used for only a small percentage of all diagnosed patients selected for treatment.

Thus, current HBV treatment ranges from palliative therapy to watchful waiting (watchful waiting). Nucleotide analogs inhibit virus production, treat symptoms, but retain the infection intact. Interferon alpha has severe side effects and is poorly tolerated in patients and is successful in only a small fraction of patients due to limited therapeutic strategies. There is clearly a continuing need for more effective treatments for HBV infection.

Disclosure of Invention

The present invention provides, in part, cyclic sulfonamide compounds and pharmaceutical compositions thereof, which are useful as modulators of HBV core protein, and methods of treating Hepatitis B (HBV) infection.

In one aspect, the invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein the variables are described in the detailed description.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect, the present invention provides a method of treating HBV infection in a subject in need thereof, comprising: administering to the subject an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of treating HBV infection in a subject in need thereof, comprising: administering to the subject a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Brief Description of Drawings

FIG. 1 is the crystal structure of HBV-CSU-016-ISO-I as described herein.

Detailed Description

Features and other details of the invention will now be described in more detail. Before the invention is further described, specific terms used in the specification, examples and appended claims are collected here. These definitions should be read on the basis of the remainder of the disclosure and as understood by those skilled in the art. Unless otherwise mentioned, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

Definition of

"treating" includes any effect that results in amelioration, e.g., alleviation, regulation, or elimination, of a condition, disease, disorder, or the like.

The term "alkenyl" as used herein refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, straight or branched chain groups of 2-6 or 3-4 carbon atoms, respectively, referred to herein as C_2-6Alkenyl and C_3-4An alkenyl group. Exemplary alkenyl groups include, but are not limited to, ethenylAllyl, butenyl, pentenyl, and the like.

The term "alkoxy" as used herein refers to a straight or branched chain alkyl group (alkyl-O-) with oxygen attached. Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1 to 6 or 2 to 6 carbon atoms, which are referred to herein as C, respectively_1-6Alkoxy and C_2-6An alkoxy group. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

The term "alkoxyalkyl" as used herein refers to an alkyl group substituted with an alkoxy group. Examples include, but are not limited to, CH₃CH₂OCH₂-、CH₃OCH₂CH₂-and CH₃OCH₂-。

The term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched chain hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C, respectively_1-6Alkyl radical, C_1-4Alkyl and C_1-3An alkyl group. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like.

The term "alkynyl" as used herein refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched chain groups of 2-6 or 3-6 carbon atoms, respectively, referred to herein as C_2-6Alkynyl and C_3-6Alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, and the like.

The term "carbonyl" as used herein refers to the group-C (O) -.

The term "cyano" as used herein refers to the group-CN.

The term "cycloalkyl" or "carbocyclyl" as used herein "Refers to a saturated or partially unsaturated hydrocarbon, e.g., containing 3-6 or 4-6 carbons, which are referred to herein as C, respectively_3-6Cycloalkyl or C_4-6A cycloalkyl group. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, or cyclopropyl.

The term "halo" or "halogen" as used herein refers to F, Cl, Br or I.

The term "haloalkyl" as used herein refers to an alkyl group substituted with one or more halogen atoms. Examples include, but are not limited to-CH₂F、-CHCl₂、-CF₃、-CH₂CF₃、-CF₂CH₃、CCl₂CF₃and-CF₂CF₃。

The term "haloalkoxy" as used herein refers to an alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, CF₃-O-、CF₃CH₂-O-and CF₃CF₂-O-。

The term "heteroaryl" or "heteroaromatic group" as used herein refers to a monocyclic aromatic 5-6 membered ring system or a bicyclic aromatic 8-12 membered ring system containing one or more heteroatoms (e.g., one to three heteroatoms, such as nitrogen, oxygen, and sulfur). The heteroaryl ring may be attached to the adjacent group through carbon or nitrogen, if possible. Examples of 5-6 membered monocyclic heteroaryls include, but are not limited to: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, 1,2, 4-triazinyl, 1,2, 3-triazinyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, and 1,2, 5-thiadiazolyl. Examples of 8-12 membered bicyclic heteroaryls include, but are not limited to: benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, benzo [ c ] thienyl, indolyl, isoindolyl, benzo [ d ] isoxazolyl, benzo [ c ] isoxazolyl, benzo [ d ] oxazolyl, benzo [ d ] isothiazolyl, benzo [ c ] isothiazolyl, benzo [ d ] thiazolyl, indazolyl, benzo [ d ] imidazolyl, and benzo [ d ] [1,2,3] triazolyl.

The term "heterocyclyl" or "heterocyclic group" is art-recognized and refers to a saturated or partially unsaturated 4-7 membered ring structure containing one or three heteroatoms, such as nitrogen, oxygen, and sulfur. The heterocyclic ring may be attached to the adjacent group through carbon or nitrogen, if possible. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, oxetanyl, azetidinyl, tetrahydrofuranyl or dihydrofuranyl, and the like.

As used herein, the term "hydroxy (hydroxyl and hydroxyyl) refers to the group-OH.

The term "hydroxyalkyl" as used herein refers to an alkyl group substituted with one or more hydroxyl groups. Examples include, but are not limited to, HOCH₂-、HOCH₂CH₂-and CH₃CH(OH)CH₂-。

The term "hydroxyalkoxy" as used herein refers to an alkoxy group substituted with one or more hydroxyl groups. Examples include, but are not limited to, HOCH₂-O-、HOCH₂CH₂-O-and CH₃CH(OH)CH₂-O-。

The term "R" as used herein^aR^bN-C_1-6Alkyl- "means substituted with R as defined herein^aR^bAlkyl of the N-group. Examples include, but are not limited to, NH₂CH₂-、NH(CH₃)CH₂-、N(CH₃)₂CH₂CH₂-and CH₃CH(NH₂)CH₂-。

The term "R" as used herein^aR^bN-C_1-6Alkoxy "means substituted with one or more R as defined herein^aR^bAlkoxy of the N-group. Examples include, but are not limited to, NH₂CH₂-、NH(CH₃)CH₂-O-、N(CH₃)₂CH₂CH₂-O-and CH₃CH(NH₂)CH₂-O-。

The term "oxo" as used herein refers to the group ═ O.

"pharmaceutically acceptable" includes molecular entities and compositions that, when appropriate, do not produce an adverse, allergic, or other untoward reaction when administered to an animal or human. For human administration, the formulations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA's office of Biologics standards.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds that provide supplemental, additional, or enhanced therapeutic functions.

The term "pharmaceutical composition" as used herein refers to a composition comprising at least one compound as disclosed herein and one or more pharmaceutically acceptable excipients.

An "individual", "patient" or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans. The compounds or pharmaceutical compositions of the present disclosure can be administered to a mammal, such as a human, but can also be administered to other mammals in need of veterinary treatment, such as domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammal treated in the methods of the present disclosure is desirably one in which treatment for HBV infection is desired. "modulation" includes antagonism (e.g., inhibition), agonism, partial antagonism and/or partial agonism.

As used herein, the term "therapeutically effective amount" or "effective amount" refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal (e.g., a mammal or a human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds or pharmaceutical compositions of the present invention are administered in a therapeutically effective amount to treat the disease. Alternatively, a therapeutically effective amount of a compound is that amount necessary to achieve the desired therapeutic and/or prophylactic effect.

The term "one or more pharmaceutically acceptable salts" as used herein refers to salts of acidic or basic groups in the compounds that may be present in the composition. The compounds included in the compositions of the present invention that are basic in nature are capable of forming a variety of salts with a variety of inorganic and organic acids. Acids which can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those which form non-toxic acid addition salts, that is, the salts are salts containing pharmaceutically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1' -methylene-bis- (2-hydroxy-3-naphthoate)). The compounds contained in the compositions of the present invention, which are acidic in nature, are capable of forming basic salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium and iron salts. The compounds comprising basic or acidic moieties included in the compositions of the present invention may also form pharmaceutically acceptable salts with various amino acids. The compounds of the present disclosure may contain both acidic and basic groups; for example, one amino group and one carboxylic acid group. In this case, the compounds may be present as acid addition salts, zwitterions or base salts.

The compounds of the present disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. When the term "stereoisomer" is used herein, it consists of all enantiomers or diastereomers. These compounds may be designated with the symbols "(+)", "(-) -," R "or" S ", depending on the configuration of the substituents around the chiral carbon atom, but those skilled in the art will understand that structures may implicitly represent chiral centers. The present invention includes various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated "(±)" in nomenclature, but those skilled in the art will understand that a structure may implicitly represent a chiral center.

The compounds of the present disclosure may contain one or more double bonds and, therefore, exist as geometric isomers due to the arrangement of substituents around the carbon-carbon double bond. SymbolRepresents a bond, which may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as either the "Z" or "E" configuration, where the terms "Z" and "E" are used in accordance with the IUPAC standard. Unless otherwise mentioned, structures depicting double bonds include the "E" and "Z" isomers. Substituents around a carbon-carbon double bond may alternatively be referred to as "cis" or "trans," where "cis" indicates that the substituent is on the same side of the double bond and "trans" indicates that the substituent is on the opposite side of the double bond.

The compounds of the present disclosure may contain carbocyclic or heterocyclic rings and, therefore, exist as geometric isomers due to the arrangement of substituents around the ring. The arrangement of substituents around a carbocyclic or heterocyclic ring is designated as either the "Z" or "E" configuration, where the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise mentioned, structures depicting carbocyclic or heterocyclic rings include the "Z" and "E" isomers. Substituents around a carbocyclic or heterocyclic ring may also be referred to as "cis" or "trans," where the term "cis" denotes that the substituent is on the same side of the ring plane and the term "trans" denotes that the substituent is on the opposite side of the ring plane. Mixtures of compounds in which the substituents are arranged on both the same side of the ring plane and opposite side of the ring plane are designated "cis/trans".

The individual enantiomers and diastereomers of the compounds of the invention can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by preparing racemic mixtures and then synthetically by resolution methods well known to those skilled in the art. These resolution methods are illustrated by the following: (1) the linking of enantiomeric mixtures with chiral auxiliary reagents, the separation of the resulting diastereomeric mixtures by recrystallization or chromatography and the liberation of optically pure products from the auxiliary reagents, (2) salt formation with optically active resolving agents, (3) direct separation of the optical enantiomeric mixtures on chiral liquid chromatography columns, or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral liquid chromatography or crystallization of the compounds in chiral solvents. Stereoselective syntheses, chemical or enzymatic reactions in which a single reactant forms an unequal mixture of stereoisomers during the formation of a new stereocenter or during the conversion of a pre-existing one, are well known in the art. Stereoselective synthesis includes both enantioselective and diastereoselective transformations and may involve the use of chiral auxiliary agents. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: weinheim, 2009.

The compounds disclosed herein may exist in solvate as well as non-solvate forms with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.), and it is contemplated that the invention includes both solvate and non-solvate forms. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form.

The invention also includes isotopically-labeled compounds of the present invention, which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. For example, the compounds of the present invention may have one or more H atoms replaced by deuterium.

Some isotopically-labelled public compounds (e.g. with³H and¹⁴c-labeled ones) are used in compound and/or substrate tissue distribution assays. The tritiated (i.e.,³H) and carbon-14 (i.e.,¹⁴C) isotopes are particularly preferred for their ease of preparation and detection. In addition, the heavy isotopes such as deuterium (i.e.,²H) substitution may provide some therapeutic benefit due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and thus may be preferred in some circumstances. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

The term "prodrug" refers to a compound that is converted in vivo to yield the disclosed compound or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. The transformation can occur at various locations (e.g., in the intestinal lumen or upon passage through the intestinal tract, blood or liver) by various mechanisms (e.g., by esterase, amidase, phosphatase, oxidative and/or reductive metabolism). Prodrugs are well known in the art (see, e.g., Rautio, kumplainen et al, Nature Reviews drug discovery 2008, 7, 255). For example, if a compound of the invention, or a pharmaceutically acceptable salt, hydrate, or solvate of the compound, comprises a carboxylic acid functional group, the prodrug may comprise an ester formed by replacing the hydrogen atom of the acid group with a group such as (C)_1-8) Alkyl, (C)_2-12) Alkylcarbonyloxymethyl, 1- (alkylcarbonyloxy) ethyl having 4 to 9 carbon atoms, 1-methyl-1- (alkylcarbonyloxy) -ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, alkyl-carbonyloxymethyl having 5 to 8 carbon atoms1-methyl-1- (alkoxycarbonyloxy) ethyl having an atom, N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactone (crotonolactonyl), gamma-butyrolactone-4-yl, di-N, N- (C)_1-2) Alkylamino radical (C)_2-3) Alkyl (e.g.. beta. -dimethylaminoethyl), carbamoyl- (C)_1-2) Alkyl, N-di (C)_1-2) Alkylcarbamoyl- (C)_1-2) Alkyl and piperidino-, pyrrolidino-or morpholino (C)_2-3) Alkyl (piperidine-, pyrolidino-or morpholino (C)_2-3)alkyl)。

I. Cyclic sulfonamide compounds

In one aspect, the invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹selected from phenyl, naphthyl and 5-6 membered monocyclic or 8-12 membered bicyclic heteroaryl having 1,2 or 3 heteroatoms each selected from O, N and S, wherein said phenyl, naphthyl and heteroaryl may be optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, wherein q is 0, 1 or 2, wherein t is 1 or 2;

R²is hydrogen or C_1-6An alkyl group;

R³selected from 5-6 membered monocyclic or 8-12 membered bicyclic heteroaryl having 1,2 or 3 heteroatoms selected from O, N and S; a phenyl group; c_1-6An alkyl group; and C_3-6Cycloalkyl radicals, hetero thereinAryl, phenyl, C_1-6Alkyl and C_3-6Cycloalkyl may be optionally substituted with 1 or 2 substituents independently selected from: halogen, -OH, -CN, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy, halo C_1-6Alkoxy, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, -C (O) O-C_1-6Alkyl radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, phenyl, pyridyl and pyrimidinyl, wherein the thienyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, phenyl, pyridyl and pyrimidinyl are optionally substituted with 1,2 or 3 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl, hydroxy C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4Alkylsulfonylamino, wherein q is 0, 1 or 2, wherein t is 1 or 2;

R⁴is hydrogen or C optionally substituted with 1,2 or 3 substituents independently selected from_1-6Alkyl groups: halogen, -OH, -CN, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy, halo C_1-6Alkoxy, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, formyl, -C (O) OH, -C (O) O-C_1-6Alkyl, benzyloxy, C_1-4Alkoxyphenyl, pyrrolidinyl, morpholinyl, tetrahydrofuryl and triazolyl, wherein q is 0, 1 or 2, wherein t is 1 or 2;

R⁵is hydrogen or C optionally substituted with a substituent selected from_1-6Alkyl groups: halogen, -OH, C_1-6Alkoxy, -NR^aR^bAnd R^aR^bN-C_1-4An alkyl group;

R⁶is hydrogen or C_1-6An alkyl group;

R^aand R^bIndependently is hydrogen or C_1-6An alkyl group; or

R^aAnd R^bCan be reacted with R^aAnd R^bThe attached nitrogens together form:

R^cis hydrogen or C_1-6An alkyl group; and is

w is 1 or 2.

In certain embodiments, R³Is a 5-6 membered monocyclic heteroaryl having 1,2 or 3 heteroatoms selected from O, N and S, optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, -C (O) O-C_1-6Alkyl radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, phenyl, pyridyl and pyrimidinyl, wherein the thienyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl, hydroxy C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is furyl, thienyl, pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, or 1,3, 4-thiadiazolyl, each of which is optionally substituted with 1 or 2 independentA substituent selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Alkyl or hydroxy C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl of alkyl, optionally substituted with C_1-4Alkyl triazolyl, phenyl, pyridyl and pyrimidinyl, wherein said phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Selected from:

wherein:

R³³selected from: hydrogen, halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl of alkyl, optionally substituted with C_1-4Alkyl triazolyl, phenyl, pyridyl and pyrimidinyl, wherein said phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group;

R^33ais hydrogen, halogen or C_1-4An alkyl group;

R³⁴selected from hydrogen and C_1-4An alkyl group; and is

R³⁵、R³⁶And³⁷independently selected from hydrogen, halogen, hydroxy, cyano, carboxy, carbamoyl, haloC_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy, carboxyl C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy radical, C_1-4Alkoxycarbonyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, and optionally substituted with C_1-4Imidazolyl of an alkyl group.

In certain embodiments, R³Is composed of

Wherein R is³⁵、R³⁶And³⁷independently selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, carbamoyl, halogenated C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy, carboxyl C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy radical, C_1-4Alkoxycarbonyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, and optionally substituted with C_1-4Imidazolyl of an alkyl group.

In certain embodiments, R³Is composed of

Wherein R is³³Selected from: hydrogen, halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Alkyl or hydroxy C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Comprises the following steps:

wherein R is³³Selected from: hydrogen, halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Alkyl or hydroxy C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Comprises the following steps:

wherein R is³³Selected from: hydrogen, halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Alkyl or hydroxy C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Comprises the following steps:

wherein: r³³Selected from: hydrogen, halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Comprises the following steps:

wherein: r³³Selected from: hydrogen, halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Comprises the following steps:

wherein: r³³Selected from hydrogen, halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments:

w is 2;

R¹is phenyl optionally substituted with 1 to 3 substituents independently selected from: halogen, cyano, C_1-4Alkyl and halo C_1-4An alkyl group;

R²is hydrogen;

R³is C_1-4Alkyl radical, C_3-6A cycloalkyl group, a,

Furyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, or 1,3, 4-thiadiazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, thienyl, thiazolyl, optionally substituted with 1,2 or 3 independently selected from C_1-4Alkyl and hydroxy C_1-4Pyrazolyl optionally substituted with C, as substituents of alkyl_1-4Imidazolyl of alkyl, optionally substituted with C_1-4Alkyl triazolyl, benzyl, phenyl, pyridyl and pyrimidinyl, wherein said phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group,

phenyl or pyridyl, each of which is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, hydroxy, cyano, carboxy, carbamoyl, halogeno C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy, carboxyl C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, 1-methyl pyrazolyl, C_1-4Alkoxycarbonyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, and optionally substituted with C_1-4An imidazolyl group for an alkyl group;

R⁴is hydrogen, C optionally substituted by_2-6Alkenyl radical, C_2-6Alkynyl or C_1-4Alkyl groups: hydroxy, cyano, C_1-4Alkoxy, haloC_1-4Alkoxy radical, C_1-4Alkylsulfonyl radical, R^aR^bN-, formyl, carboxy, carbamoyl, benzyloxy, C_1-4Alkoxyphenyl, pyrrolidinyl, morpholinyl, tetrahydrofuryl or triazolyl;

R⁵is hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, or R^aR^bN-C_1-4An alkyl group;

R⁶is hydrogen; and is

R^aAnd R^bIndependently is hydrogen or C_1-4An alkyl group.

In certain embodiments:

w is 2;

R¹is phenyl optionally substituted with 1 to 3 substituents independently selected from: halogen, cyano, C_1-4Alkyl and halo C_1-4An alkyl group;

R²is hydrogen;

R³is furyl, thienyl, or thiazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, thienyl, thiazolyl, optionally substituted with C_1-4Alkyl or hydroxy C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, benzyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4An alkylsulfonylamino group,

phenyl or pyridyl, each of which is optionally substituted with 1 to 3 substituents independently selected from: halogen, hydroxy, cyano, carboxy, carbamoyl, halogeno C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy, carboxyl C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy radical, C_1-4Alkoxycarbonyl, thienyl, thiaAzolyl radical, optionally substituted with C_1-4Pyrazolyl of alkyl, and optionally substituted with C_1-4An imidazolyl group for an alkyl group;

R⁴is hydrogen, C optionally substituted by_2-6Alkenyl radical, C_2-6Alkynyl or C_1-4Alkyl groups: hydroxy, cyano, C_1-4Alkoxy, halo C_1-4Alkoxy radical, C_1-4Alkylsulfonyl radical, R^aR^bN-, carboxy, carbamoyl, benzyloxy, formyl, C_1-4Alkoxyphenyl, pyrrolidinyl, morpholinyl, tetrahydrofuryl or triazolyl;

R⁵is hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, or R^aR^bN-C_1-4An alkyl group;

R⁶is hydrogen; and is

R^aAnd R^bIndependently is hydrogen or C_1-4An alkyl group.

In certain embodiments:

w is 2;

R¹is phenyl optionally substituted with 1 to 3 substituents independently selected from: halogen, cyano, C_1-4Alkyl and halo C_1-4An alkyl group;

R²is hydrogen;

R³is C_1-4Alkyl radical, C_3-6A cycloalkyl group,

furyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl or 1,3, 4-thiadiazolyl, each of which is optionally substituted with halogen, C_1-4An alkyl group or a phenyl group, or a substituted or unsubstituted alkyl group,

thiazolyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl, thienyl, thiazolyl, pyrazolyl, 1-methylpyrazolyl, pyridyl optionally substituted with halogen, and phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen and C_1-4An alkoxy group,

thienyl optionally substituted with 1 or 2 substituents independently selected from: halogen, C_1-4Alkyl radical, R^aR^bN-C_1-4Alkoxy, thienyl, pyrimidinyl, pyrazolyl, 1-methylpyrazolyl, benzyl, optionally substituted by halogen or halogeno C_1-4Pyridyl of alkyl, and phenyl optionally substituted with 1 or 2 substituents independently selected from: halogen, cyano, C_1-4Alkoxy, halo C_1-4Alkyl and C_1-4Alkylsulfonylamino, or

Phenyl optionally substituted with 1 to 3 substituents independently selected from: halogen, hydroxy, cyano, carboxy, carbamoyl, halogeno C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy, carboxyl C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, 1-methyl pyrazolyl and C_1-4An alkoxycarbonyl group;

R⁴is hydrogen, C optionally substituted by_2-6Alkenyl radical, C_2-6Alkynyl or C_1-4Alkyl groups: hydroxy, cyano, C_1-4Alkoxy, halo C_1-4Alkoxy radical, C_1-4Alkylsulfonyl radical, R^aR^bN-, carboxy, carbamoyl, benzyloxy, formyl, C_1-4Alkoxyphenyl, pyrrolidinyl, morpholinyl, tetrahydrofuryl or triazolyl;

R⁵is hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, or R^aR^bN-C_1-4An alkyl group;

R⁶is hydrogen; and is

R^aAnd R^bIndependently is hydrogen or C_1-4An alkyl group.

In certain embodiments, R³Is C_1-6Alkyl or C_3-6Cycloalkyl, wherein said C_1-6Alkyl or C_3-6Cycloalkyl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, -C (O) O-C_1-6Alkyl radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, phenyl, pyridyl and pyrimidinyl, wherein the thienyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl, hydroxy C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4Alkylsulfonylamino, wherein q is 0, 1 or 2, and wherein t is 1 or 2.

In certain embodiments, R³Is C_1-6Alkyl or C_3-6A cycloalkyl group.

In another aspect, the present invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹selected from phenyl, naphthyl and 5-6 membered monocyclic or 8-12 membered bicyclic heteroaryl having 1,2 or 3 heteroatoms each selected from O, N and S, wherein said phenyl, naphthyl and heteroaryl may be optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

R²is hydrogen or C optionally substituted with a substituent selected from_1-6Alkyl groups: halogen, -OH, C_1-6Alkoxy, -NR^aR^bAnd R^aR^bN-C_1-6An alkyl group;

R³selected from 5-6 membered monocyclic or 8-12 membered bicyclic heteroaryl having 1,2 or 3 heteroatoms selected from O, N and S; a phenyl group; c_1-6An alkyl group; and C_3-6Cycloalkyl, wherein heteroaryl, phenyl, C_1-6Alkyl and C_3-6Cycloalkyl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

R⁴is hydrogen or C optionally substituted with 1,2 or 3 substituents independently selected from_1-6Alkyl groups: halogen, -OH, -CN, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, formyl, -C (O) OH, -C (O) O-C_1-6Alkyl, benzyloxy, C_1-4Alkoxyphenyl, pyrrolidinyl, morpholinyl, tetrahydrofuryl and triazolyl;

R⁵is hydrogen or C optionally substituted with a substituent selected from_1-6Alkyl groups: halogen, -OH, C_1-6Alkoxy, -NR^aR^bAnd R^aR^bN-C_1-6An alkyl group;

R⁶is hydrogen, halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

R^aand R^bIndependently is hydrogen or C_1-6An alkyl group; or

R^aAnd R^bCan be reacted with R^aAnd R^bThe attached nitrogens together form:

R^cis hydrogen or C_1-6An alkyl group;

at each occurrence, q is 0, 1 or 2;

at each occurrence, t is 1 or 2; and is

w is 1 or 2;

with the following conditions:

when R is³In the case of thien-2-yl or furan-2-yl, the thien-2-yl or furan-2-yl group is substituted with at least one substituent;

when R is³When it is pyrazol-4-yl, said pyrazol-4-yl group is substituted with at least one group other than C_1-6A substituent of an alkyl group; and is

When R is³In the case of phenyl, the phenyl group is substituted by at least one element other than halogen and C_1-6A substituent of an alkoxy group.

In certain embodiments, the 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, 1,2, 4-triazinyl, 1,2, 3-triazinyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, and 1,2, 5-thiadiazolyl.

In certain embodiments, the 8-12 membered bicyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, benzo [ c ] thienyl, indolyl, isoindolyl, benzo [ d ] isoxazolyl, benzo [ c ] isoxazolyl, benzo [ d ] oxazolyl, benzo [ d ] isothiazolyl, benzo [ c ] isothiazolyl, benzo [ d ] thiazolyl, indazolyl, benzo [ d ] imidazolyl, and benzo [ d ] [1,2,3] triazolyl.

In certain embodiments, the 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, 1,2, 4-triazinyl, 1,2, 3-triazinyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, and 1,2, 5-thiadiazolyl; and is

The 8-12 membered bicyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, benzo [ c ] thienyl, indolyl, isoindolyl, benzo [ d ] isoxazolyl, benzo [ c ] isoxazolyl, benzo [ d ] oxazolyl, benzo [ d ] isothiazolyl, benzo [ c ] isothiazolyl, benzo [ d ] thiazolyl, indazolyl, benzo [ d ] imidazolyl, and benzo [ d ] [1,2,3] triazolyl.

In certain embodiments, the compound of formula I is a compound of formula II or III:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula I is a compound of formula II:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula I is a compound of formula III:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula I is a compound of formula IV or V:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula I is a compound of formula IV:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of formula I is a compound of formula V:

or a pharmaceutically acceptable salt thereof.

In certain embodiments, w is 2.

In certain embodiments, R¹Is a 5-6 membered monocyclic heteroaryl having 1,2 or 3 heteroatoms each selected from O, N and S, optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S: (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group.

In certain embodiments, R¹Is a 5-6 membered monocyclic heteroaryl having 1,2 or 3 heteroatoms each selected from O, N and S, optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

wherein the 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, 1,2, 4-triazinyl, 1,2, 3-triazinyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, and 1,2, 5-thiadiazolyl.

In certain embodiments, R¹Is an 8-12 membered bicyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S, optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group.

In certain embodiments, R¹Is an 8-12 membered bicyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S, optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

wherein the 8-12 membered bicyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, benzo [ c ] thienyl, indolyl, isoindolyl, benzo [ d ] isoxazolyl, benzo [ c ] isoxazolyl, benzo [ d ] oxazolyl, benzo [ d ] isothiazolyl, benzo [ c ] isothiazolyl, benzo [ d ] thiazolyl, indazolyl, benzo [ d ] imidazolyl, and benzo [ d ] [1,2,3] triazolyl.

In certain embodiments, R¹Is phenyl optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group.

In certain embodiments, R¹Is composed of

Wherein R is¹¹、R¹²And R¹³Independently selected from halogen, cyano, C_1-6Alkyl and C_1-6A haloalkyl group.

In certain embodiments, R¹Is composed of

Wherein R is¹¹、R¹²And R¹³Independently selected from F, Cl and Br.

In certain embodiments, R¹Is composed of

In certain embodiments, R¹Is pyridyl, optionally substituted with 1,2 or 3 substituents independently selected from: halogen, cyano, C_1-6Alkyl and C_1-6A haloalkyl group.

In certain embodiments, R²Is hydrogen or C_1-6An alkyl group.

In certain embodiments, R²Is hydrogen or methyl.

In certain embodiments, R²Is hydrogen.

In certain embodiments, R³Is a 5-6 membered monocyclic heteroaryl having 1,2 or 3 heteroatoms selected from O, N and S, optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and SWherein said phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group.

In certain embodiments, R³Is a 5-6 membered monocyclic heteroaryl having 1,2 or 3 heteroatoms selected from O, N and S, optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein the phenyl or 5-6 membered monocyclic heteroaryl isMonocyclic heteroaryl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

wherein the 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, 1,2, 4-triazinyl, 1,2, 3-triazinyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, and 1,2, 5-thiadiazolyl.

In certain embodiments, R³Is an 8-12 membered bicyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group.

In certain embodiments, R³Is an 8-12 membered bicyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and a 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

wherein the 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, 1,2, 4-triazinyl, 1,2, 3-triazinyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, and 1,2, 5-thiadiazolyl; and is

The 8-12 membered bicyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, benzo [ c ] thienyl, indolyl, isoindolyl, benzo [ d ] isoxazolyl, benzo [ c ] isoxazolyl, benzo [ d ] oxazolyl, benzo [ d ] isothiazolyl, benzo [ c ] isothiazolyl, benzo [ d ] thiazolyl, indazolyl, benzo [ d ] imidazolyl, and benzo [ d ] [1,2,3] triazolyl.

In certain embodiments, R³Is phenyl optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group.

In certain embodiments, R³Is phenyl optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radicalC_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

wherein the 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, 1,2, 4-triazinyl, 1,2, 3-triazinyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, and 1,2, 5-thiadiazolyl.

In certain embodiments, R³Is C optionally substituted with 1,2 or 3 substituents independently selected from_3-6Cycloalkyl groups: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group.

In certain embodiments, R³Is C optionally substituted with 1,2 or 3 substituents independently selected from_3-6Cycloalkyl groups: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

wherein the 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, 1,2, 4-triazinyl, 1,2, 3-triazinyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, and 1,2, 5-thiadiazolyl.

In certain embodiments, R³Is C optionally substituted with 1,2 or 3 substituents independently selected from_1-6Alkyl groups: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and aryl radicalsA 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein said phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group.

In certain embodiments, R³Is C optionally substituted with 1,2 or 3 substituents independently selected from_1-6Alkyl groups: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, whereinSaid phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

wherein the 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, 1,2, 4-triazinyl, 1,2, 3-triazinyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, and 1,2, 5-thiadiazolyl.

In certain embodiments, R³Selected from:

wherein:

R³³independently at each occurrence is selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

R³⁴independently selected from hydrogen and C_1-4An alkyl group;

r is 0, 1 or 2; and is

r2 is 0, 1,2 or 3;

with the following conditions:

when R is³R2 is 1,2 or 3 when it is thiophen-2-yl or furan-2-yl;

when R is³When it is pyrazol-4-yl, in at least one occurrence, R³³Is other than C_1-6An alkyl group; and is

When R is³When it is phenyl, R³⁵、R³⁶And R³⁷At least one of which is not halogen and C_1-6An alkoxy group.

In certain embodiments, R³Selected from:

wherein:

R³³independently at each occurrence is selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2, or 3 independent optionsA substituent selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

R³⁴independently selected from hydrogen and C_1-4An alkyl group;

r is 0, 1 or 2;

r2 is 0, 1,2 or 3; and is

The 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, 1,2, 4-triazinyl, 1,2, 3-triazinyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, and 1,2, 5-thiadiazolyl;

with the following conditions:

when R is³R2 is 1,2 or 3 when it is thiophen-2-yl or furan-2-yl;

when R is³When it is pyrazol-4-yl, in at least one occurrence, R³³Is other than C_1-6An alkyl group; and is

When R is³When it is phenyl, R³⁵、R³⁶And R³⁷At least one of which is not halogen and C_1-6An alkoxy group.

In certain embodiments, R³Selected from:

wherein:

R³³independently at each occurrence is selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

R³⁴independently selected from hydrogen and C_1-4An alkyl group;

r is 0, 1 or 2; and is

r2 is 0, 1,2 or 3;

with the following conditions:

when R is³R2 is 1,2 or 3 when it is thiophen-2-yl or furan-2-yl;

when R is³When it is pyrazol-4-yl, in at least one occurrence, R³³Is other than C_1-6An alkyl group; and is

When R is³When it is phenyl, R³⁵、R³⁶And R³⁷At least one of which is not halogen and C_1-6An alkoxy group.

In certain embodiments, R³Selected from:

wherein:

R³³independently at each occurrence is selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2, or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group;

R³⁴independently selected from hydrogen and C_1-4An alkyl group;

r is 0, 1 or 2;

r2 is 0, 1,2 or 3; and is

The 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms each selected from O, N and S is selected from: furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, 1,2, 4-triazinyl, 1,2, 3-triazinyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, and 1,2, 5-thiadiazolyl;

with the following conditions:

when R is³R2 is 1,2 or 3 when it is thiophen-2-yl or furan-2-yl;

when R is³When it is pyrazol-4-yl, in at least one occurrence, R³³Is other than C_1-6An alkyl group; and is

When R is³When it is phenyl, R³⁵、R³⁶And R³⁷At least one of which is not halogen and C_1-6An alkoxy group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Is composed ofWherein:

R³⁵、R³⁶and³⁷independently selected from: hydrogen, halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6Alkyl, phenyl, and 5-6 membered monocyclic heteroaryl having 1,2, or 3 heteroatoms selected from O, N and S, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1,2 or 3 substituents independently selected from: halogen, -OH, -CN, -NO₂Oxo, hydrazino, formyl, azido, silyl, siloxy, -S (O)_q-C_1-6Alkyl, -NR^aR^b、-NR^c-S(O)_t-C_1-6Alkyl, -S (O)_t-NR^aR^b、C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, halo C_1-6Alkyl, hydroxy C_1-6Alkyl radical, R^aR^bN-C_1-6Alkyl-, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy C_1-6Alkoxy-, R^aR^bN-C_1-6alkoxy-C_1-6Alkoxy radical C_1-6Alkyl, -C (O) NR^aR^b、-C(O)-C_1-6Alkyl, -C (O) OH, and-C (O) O-C_1-6An alkyl group.

In certain embodiments, R³Is composed ofWherein:

R³⁵、R³⁶and³⁷independently selected from hydrogen, hydroxy, cyano, carboxy, carbamoyl, haloC_1-4Alkyl, halo C_1-4Alkoxy, carboxyl C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy radical, C_1-4Alkoxycarbonyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, and optionally substituted with C_1-4Imidazolyl of an alkyl group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Is composed ofWherein:

R³³independently at each occurrence is selected from: halogenElement, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Is composed ofWherein:

R³³independently at each occurrence is selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Is composed ofWherein:

R³³independently at each occurrence is selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Is composed ofWherein:

R³³independently at each occurrence is selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Is composed ofWherein:

R³³selected from: hydrogen, halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Is composed ofWherein:

R³³selected from: hydrogen, halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed ofWherein:

R³³selected from: hydrogen, halogen, C_1-4Alkyl, halo C_1-4Alkyl, thienylThiazolyl, pyrazolyl, 1-methylpyrazolyl, pyridyl optionally substituted with halogen, and phenyl optionally substituted with 1 or 2 substituents independently selected from: halogen and C_1-4An alkoxy group.

In certain embodiments, R³Comprises the following steps:

in certain embodiments, R³Is composed ofWherein:

R³³selected from: hydrogen, halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Comprises the following steps:wherein:

R³³selected from: hydrogen, halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidyl groups of alkyl radicals, whereinSaid phenyl, pyridyl and pyrimidinyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Is composed of

In certain embodiments, R³Is composed ofWherein:

R³³selected from hydrogen, methyl and halogen.

In certain embodiments, R³Is composed of

In certain embodiments, R³Comprises the following steps:wherein:

R³³independently at each occurrence is selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Alkyl or hydroxy C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Is composed ofWherein:

R³³selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Alkyl or hydroxy C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed ofWherein:

R³³selected from: halogen, C_1-4Alkyl radical, R^aR^bN-C_1-4Alkoxy, thienyl, pyrimidinyl, pyrazolyl, 1-methylpyrazolyl, benzyl, optionally substituted by halogen or halogeno C_1-4Pyridyl of alkyl, and phenyl optionally substituted with 1 or 2 substituents independently selected from: halogen, cyano, C_1-4Alkoxy, halo C_1-4Alkyl and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Is composed ofWherein:

R³³selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Alkyl or hydroxy C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Comprises the following steps:wherein:

R³³selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Alkyl or hydroxy C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Is composed ofWherein:

R³³independently at each occurrence is selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed ofWherein:

R³³selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Is composed ofWherein:

R³³selected from halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³Is composed of

In certain embodiments, R³Is composed ofWherein:

R³³selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³³At each occurrence is selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, hydroxy C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, phenyl, pyridyl and pyrimidinyl, wherein the benzyl, thienyl, thiazolyl, pyrazolyl, imidyl(ii) oxazolyl, phenyl, pyridyl and pyrimidinyl optionally substituted with 1 or 2 substituents independently selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, R³³At each occurrence is selected from: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical, R^aR^bN-C_1-4Alkoxy, benzyl, thienyl, thiazolyl, optionally substituted with C_1-4Alkyl or hydroxy C_1-4Pyrazolyl of alkyl, optionally substituted with C_1-4Imidazolyl, phenyl, pyridyl and pyrimidinyl of alkyl, wherein the phenyl, pyridyl and pyrimidinyl are optionally substituted with 1 or 2 substituents independently selected from the group consisting of: halogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, and C_1-4An alkylsulfonylamino group.

In certain embodiments, in one instance R³³Is optionally substituted with C_1-4Alkyl pyrazolyl or imidazolyl.

In certain embodiments, R⁴Is hydrogen, C optionally substituted by_2-6Alkenyl radical, C_2-6Alkynyl or C_1-4Alkyl groups: hydroxy, cyano, C_1-4Alkoxy, halo C_1-4Alkoxy, methylsulfonyl, diethylamino, carboxyl, carbamoyl, benzyloxy, formyl, methoxyphenyl, pyrrolidinyl, morpholinyl, tetrahydrofuryl, or triazolyl.

In certain embodiments, R⁴Is hydrogen or C optionally substituted with a substituent selected from_1-6Alkyl groups: c_1-6Alkoxy, -NR^aR^b、C_2-6Alkenyl, -OH, -COOH and C_1-6A haloalkoxy group.

In certain embodiments, R⁴Is C optionally substituted with a substituent selected from_1-6Alkyl groups: c_1-6Alkoxy, -NR^aR^b、C_2-6Alkenyl, -OH, -COOH and C_1-6A haloalkoxy group.

In certain embodiments, R⁴is-CH₂CH₂OCH₃。

In certain embodiments, R⁴Is methyl.

In certain embodiments, R⁵Is hydrogen, C_1-4Alkyl radical, C_1-4Alkoxy, or R^aR^bN-C_1-4An alkyl group.

In certain embodiments, R⁵Is hydrogen, methyl, methoxyethyl or dimethylaminoethyl.

In certain embodiments, R⁵Is hydrogen or methyl.

In certain embodiments, R⁵Is hydrogen.

In certain embodiments, R⁶Is hydrogen or C_1-6An alkyl group;

in certain embodiments, R⁶Is hydrogen.

In certain embodiments, R²And R⁶Is hydrogen.

In certain embodiments, R²And R⁶Is hydrogen and w is 2.

In certain embodiments, R²、R⁵And R⁶Is hydrogen.

In certain embodiments, R²、R⁵And R⁶Is hydrogen and w is 2.

In certain embodiments, R²、R⁵And R⁶Is hydrogen and R⁴Is methyl.

In certain embodiments, R²、R⁵And R⁶Is hydrogen, R⁴Is methyl and w is 2.

In certain embodiments, R¹Is 3-chloro-4-fluorophenyl and R²And R⁶Each is hydrogen.

In certain embodiments, R¹Is 3-chloro-4-fluorophenyl, R²And R⁶Is hydrogen and w is 2.

In certain embodiments, R¹Is 3-chloro-4-fluorophenyl andR²、R⁵and R⁶Each is hydrogen.

In certain embodiments, R¹Is 3-chloro-4-fluorophenyl; r²、R⁵And R⁶Each is hydrogen; and w is 2.

In certain embodiments, R¹Is 3-chloro-4-fluorophenyl; r²、R⁵And R⁶Each is hydrogen; and R is⁴Is methyl.

In certain embodiments, R¹Is 3-chloro-4-fluorophenyl; r²、R⁵And R⁶Each is hydrogen, R⁴Is methyl and w is 2.

It is to be understood that all chemically allowed embodiment combinations described above, as well as elsewhere in this disclosure, are contemplated as further embodiments of the invention.

Pharmaceutical compositions and kits

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In particular, the present invention provides pharmaceutical compositions comprising a compound as disclosed herein formulated with one or more pharmaceutically acceptable carriers. These include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated, and the nature of the particular compound being used. For example, the disclosed compositions can be formulated as a unit dose, and/or the disclosed compositions can be formulated for oral administration or subcutaneous administration.

In another aspect, the present invention provides a pharmaceutical combination comprising a compound of table 2, or a pharmaceutically acceptable salt and/or stereoisomer thereof.

Exemplary pharmaceutical compositions of the invention may be used in the form of pharmaceutical preparations, e.g., in solid, semi-solid or liquid form, containing as active ingredient one or more compounds of the invention in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral application. For example, the active ingredient may be combined with generally non-toxic, pharmaceutically acceptable carriers for tablets, mini-tablets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active subject compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect in the method or disorder of the disease.

To prepare solid compositions, such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dibasic calcium phosphate or gums) and other pharmaceutically acceptable diluents (e.g., water) to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention or a non-toxic pharmaceutically acceptable salt thereof. When referring to these homogeneous preformulation mixtures, it is meant that the active ingredient is dispersed uniformly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or two pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate) and/or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and (10) a colorant. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose, and high molecular weight polyethylene glycols and the like.

Tablets may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrating agents (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface active agents or dispersing agents. Molded tablets may be prepared by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets and other solid dosage forms (such as dragees, capsules, pills, and granules) can optionally be scored or prepared with coatings and shells (such as enteric coatings and other coatings well known in the pharmaceutical formulating art).

Compositions for inhalation or insufflation include pharmaceutically acceptable solutions and suspensions in aqueous or organic solvents or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the host composition, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

In addition to the subject compositions, suspensions may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing the subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or salicylate, and which is solid at room temperature, but liquid at body temperature and therefore will melt and release the active agent in the body cavity.

Dosage forms for transdermal administration of the subject compositions include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be necessary.

In addition to the subject compositions, the ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

In addition to the subject compositions, powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures of these materials. Sprays can additionally contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons (such as butane or propane).

The compositions and compounds of the present invention may alternatively be administered by aerosol. This can be accomplished by preparing an aqueous aerosol, liposome formulation, or solid microparticle containing the compound. Anhydrous suspensions (e.g., fluorocarbon propellants) may be used. Sonic nebulizers may be used because they can minimize exposure of the agent to shear, which can cause degradation of the compounds contained in the host composition. Generally, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the subject composition with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary according to the needs of a particular subject composition, but typically include nonionic surfactants (Tweens, Pluronics or polyethylene glycols), non-toxic proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are typically made from isotonic solutions.

Pharmaceutical compositions of the invention suitable for parenteral administration include combinations of the subject compositions with one or more of the following: pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate), and cyclodextrins. Proper fluidity can be maintained, for example, by the use of a coating material (such as lecithin), by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

In another aspect, the invention provides an enteral pharmaceutical formulation comprising the disclosed compound and an enteric material and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, but primarily soluble in small intestinal fluids at a particular pH. The small intestine is the part of the gastrointestinal tract (digestive tract) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5, and the pH of the terminal ileum is about 7.5. Thus, the enteric material is insoluble, for example, up to a pH of about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include Cellulose Acetate Phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropylmethylcellulose succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymers of methacrylic acid and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylic acid, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethylmethacrylate-methyl methacrylate-chlorotrimethylammonium ethacrylate copolymers, copolymers of methyl methacrylate and methyl methacrylate, and mixtures thereof, Natural resins such as zein, shellac, and copal colophonium, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is known or can be readily determined in vitro. The above is a list of possible materials, but those skilled in the art, having the benefit of this disclosure, will recognize that the list is not comprehensive and that there are other enteric materials that meet the objectives of the present invention.

Advantageously, the invention also provides kits for use by, for example, a consumer in need of treatment for HBV infection. These kits include suitable dosage forms such as those described above and instructions describing methods of using these dosage forms to mediate, reduce or prevent HBV infection. The instructions may direct the consumer or medical personnel to administer the dosage form according to a mode of administration known to those skilled in the art. These kits can advantageously be packaged and sold in a single kit unit or in multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging unit dose form pharmaceuticals (tablets, capsules, etc.). Blister packs are generally constructed from a sheet of relatively hard material covered with a sheet of preferably transparent plastic material. During the packaging process, a groove is formed in the plastic foil. The recess has the size and shape of the tablet or capsule to be packaged. Next, a tablet or capsule is placed in the recess and a sheet of relatively hard material encloses the plastic sheet on the side of the sheet opposite to the direction in which the recess is formed. Thus, the tablet or capsule is sealed in the groove between the plastic sheet and the sheet. Preferably, the strength of the sheet is such that the tablet or capsule can be removed from the blister pack by: pressure is manually applied to the recesses to form openings in the sheet at the location of the recesses. The tablet or capsule can then be removed via the opening.

It may be desirable to provide memory aids on the kit, for example in the form of numbers appearing next to the tablet or capsule, where the numbers correspond to the number of days that the dosage regimen for a given tablet or capsule should be taken. Another example of such a memory aid is a calendar printed on the card, for example as follows "first week, monday, tuesday", etc. "second week, monday, tuesday", etc. Other variations of the memory aid will become apparent. A "daily dose" may be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, the daily dose of the first compound may consist of one tablet or capsule, while the daily dose of the second compound may consist of several tablets or capsules, or vice versa. The memory aid should reflect these.

Method III

In another aspect, there is provided a method of treating hepatitis b infection in a patient in need thereof, comprising administering to the subject or patient an effective amount of a disclosed compound, and/or administering a first disclosed compound and optionally and additionally another disclosed compound. In another embodiment, there is provided a method of treating hepatitis b infection in a patient in need thereof, comprising administering to the subject or patient a therapeutically effective amount of a disclosed pharmaceutical composition or a pharmaceutical composition comprising one disclosed compound or two or more disclosed compounds and a pharmaceutically acceptable excipient.

For use in accordance with this aspect, it is contemplated that the appropriate dosage will vary depending upon, for example, the particular compound employed, the mode of administration and the nature and severity of the infection to be treated, as well as the particular infection to be treated, and within the purview of the treating physician. Generally, the prescribed dosage for administration can range from about 0.1 to about 1000 μ g/kg body weight. In some cases, the compound may be administered at a dose of less than 400 μ g/kg body weight. In other cases, the administered dose may be less than 200 μ g/kg body weight. In still other instances, the dosage administered may be in the range of about 0.1 to about 100 μ g/kg body weight. The dose may conveniently be administered once daily or in divided doses up to, for example, four times daily or in sustained release form.

The disclosed compounds may be administered by any conventional route, specifically: enterally, topically, orally, nasally, e.g. in the form of tablets or capsules, by suppositories or parenterally, e.g. in the form of injectable solvents or suspensions, for intravenous, intramuscular, subcutaneous or intraperitoneal injection. Suitable formulations and pharmaceutical compositions will comprise those formulated in conventional manner using one or more physiologically acceptable carriers or excipients and any of those known and commercially available and currently employed in the clinical setting. Thus, the compounds may be formulated for oral, buccal, topical, parenteral, rectal or transdermal administration or in a form suitable for inhalation or insufflation (either orally or nasally).

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or dibasic calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silicon dioxide); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may be prepared in conventional manner with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl parabens or sorbic acid). The formulations may also contain buffer salts, flavoring agents, coloring agents and sweetening agents, as appropriate.

Formulations for oral administration may also be suitably formulated to provide controlled or sustained release of the active compound over an extended period of time. For buccal administration, the compositions may take the form of tablets or lozenges formulated in a conventional manner known to the skilled person.

The disclosed compounds may also be formulated for parenteral administration by injection, for example as a bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain additives such as suspending, stabilizing and/or dispersing agents. Alternatively, the compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds may also be formulated for rectal administration as a suppository or retention enema, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

Methods and compositions comprising or administering a second active agent are also contemplated herein. For example, in addition to being infected with HBV, a subject or patient may have complications associated with HBV infection, i.e., diseases and other adverse health conditions associated with, exacerbated by, or exacerbated by HBV infection. Combinations of the disclosed compounds with at least one other agent that has previously been shown to treat these HBV infection-related diseases are contemplated herein.

In some cases, the disclosed compounds can be administered as part of a combination therapy in combination with one or more antiviral drugs. Examples of such antiviral drugs include nucleoside analogues, interferon alpha and other assembly effectors, such as heteroaryl dihydropyrimidine (HAP), for example 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (pyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester (HAP-1). For example, provided herein are methods of treating a patient having a hepatitis b infection comprising administering to the patient a first amount of a disclosed compound and a second amount of an antiviral or other anti-HBV agent, e.g., a second amount of a second compound selected from: HBV capsid assembly promoters (e.g., GLS4, BAY 41-4109, AT-130, DVR-23 (e.g., as depicted below),

NVR 3-778, NVR1221 (shown by code); and N890 (depicted below):

other CpAMs, such as those disclosed in the following patent applications incorporated herein by reference: WO2014037480, WO2014184328, WO2013006394, WO2014089296, WO2014106019, WO2013102655, WO2014184350, WO2014184365, WO2014161888, WO2014131847, WO2014033176, WO2014033167 and WO 2014033170; nucleoside analogues that interfere with viral polymerase, such as entecavir (boldine), lamivudine (Epivir-HBV), telbivudine (Tyzeka, Sebivo), adefovir dipivoxil (greedily), Tenofovir (Viread), Tenofovir Alafenamide Fumarate (TAF), a prodrug of Tenofovir (e.g., AGX-1009), L-FMAU (clevudine), LB80380(Besifovir), and:

viral entry inhibitors, such as Myrcludex B and related lipopeptide derivatives; HBsAg secretion inhibitors such as REP 9 AC' and related nucleic acid-based amphiphilic polymers, HBF-0529(PBHBV-001), PBHBV-2-15 as depicted below:

and BM601 as depicted below:

interfering agents of nucleocapsid formation or integrity, such as NZ-4/W28F:

cccDNA formation inhibitor: such as BSBI-25, CCC-0346, CCC-0975 (as depicted below):

HBc targeting transbodies, such as those described in Wang Y et al, Transbody againt hepatites B virus core protein inhibitors hepatites B virus replication in vitro, int.immunopharmacol (2014), located at// dx.doi.org/10.1016/j.int.2015.01.028; antiviral core protein mutants (e.g., Cp183-V124W and related mutants such as those described in WO/2013/010069, WO2014/074906, each of which is incorporated herein by reference); HBx-interaction inhibitors, such as RNAi targeting HBV RNA, antisense and nucleic acid-based polymers, e.g., RNAi (e.g., ALN-HBV, ARC-520, TKM-HBV, ddRNAi), antisense gene (ISIS-HBV) or nucleic acid-based polymers: (REP 2139-Ca); immunostimulants, such as interferon alpha 2a (rosmarin), Intron a (interferon alpha 2b), pyroxin (polyethylene glycol alpha 2a), polyethylene glycol IFN 2b, IFN λ 1a and PEG IFN λ 1a, Wellferon, rosmarin, atrazine, lymphotoxin beta receptor agonists, such as CBE11 and BS 1; non-interferon immune enhancers, such as thymosin alpha-1 (Ridaxin) and interleukin-7 (CYT 107); TLR-7/9 agonists such as GS-9620, CYT003, Resiquimod (Resiquimod); cyclophilin inhibitors, such as NVP 018; OCB-030; SCY-635; (ii) Alisporivir; NIM811 and related cyclosporin analogs; vaccines, such as GS-4774, TG1050, core antigen vaccines; SMAC mimetics, such as birinapag and other IAP-antagonists; epigenetic modulators (Epigenetic modulators), such as KMT inhibitors (EZH1/2, G9a, SETD7, Suv39 inhibitors), PRMT inhibitors, HDAC inhibitors, SIRT agonists, HAT inhibitors, WD antagonists (e.g., oic-9429), PARP inhibitors, APE inhibitors, DNMT inhibitors, LSD1 inhibitors, JMJD HDM inhibitors, and bromodomain antagonists; kinase inhibitors, such as TKB1 antagonists, PLK1 inhibitors, SRPK inhibitors, CDK2 inhibitors, ATM & ATR kinase inhibitors; STING agonists; ribavirin; n-acetyl cysteine; NOV-205(BAM 205); nitazoxanide (Alinia), Tizoxanide; SB 9200 small molecule nucleic acid hybrid (SMNH); DV-601; arbidol; FXR agonists (e.g., GW 4064 and Fexaramin); antibodies, therapeutic proteins, gene therapy, and biologicals directed against viral components or interacting with host proteins.

In some embodiments, the disclosure provides a method of treating a hepatitis b infection in a patient in need thereof, comprising administering a first compound selected from any of the disclosed compounds, and one or more additional HBV agents each selected from an HBV capsid assembly promoter, an HBF viral polymerase interfering nucleoside, a viral entry inhibitor, an HBsAg secretion inhibitor, a disrupter of nucleocapsid formation, a cccDNA formation inhibitor, an antiviral core protein mutant, an HBc-directed transbody, an RNAi targeting HBV RNA, an immunostimulant, a TLR-7/9 agonist, a cyclophilin inhibitor, an HBV vaccine, an SMAC mimetic, an epigenetic modulator, a kinase inhibitor, and a STING agonist. In some embodiments, the disclosure provides a method of treating a hepatitis b infection in a patient in need thereof comprising administering an amount of the disclosed compound and administering another HBV capsid assembly promoter.

In some embodiments, the first dose and the second dose together comprise a pharmaceutically effective amount. The first dose, the second dose, or both may be the same as, greater than, or less than the effective amount of each compound administered as monotherapy. Therapeutically effective amounts of the disclosed compounds and antiviral drugs can be co-administered to the subject, i.e., administered to the subject in any given order and by the same or different routes of administration, either simultaneously or separately. In some instances, it may be advantageous to begin administration of the disclosed compounds for the first time, e.g., one or more days or weeks, before beginning administration of the antiviral drug. In addition, additional agents may be administered in combination with the combination therapies described above.

In another embodiment, the disclosed compounds can be conjugated to a detection moiety (e.g., a fluorescent group that can re-emit a certain frequency of light, e.g., upon binding to a virus and/or upon photon excitation) (e.g., covalently linked to a free carbon, nitrogen (e.g., an amino group), or oxygen (e.g., an active ester) of the disclosed compound, either directly or through a molecular linker). Contemplated fluorophores include488(Invitrogen) and BODIPY FL (Invitrogen), as well as fluorescein, rhodamine, cyanine, indocarbocyanine, anthraquinone, fluorescent protein, aminocoumarin, methoxycoumarin, hydroxycoumarin, Cy2, Cy3, and the like. Such disclosed compounds conjugated to a detection group are useful, for example, in methods of detecting HBV or a biological pathway of HBV infection, e.g., in vitro or in vivo methods; and/or methods of assessing the biological activity of the novel compounds.

Examples

The compounds described herein can be prepared in a variety of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that, unless otherwise mentioned, all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and post-treatment steps, may be selected as standard conditions for the reaction. It will be appreciated by those skilled in the art of organic synthesis that the functionality present in various parts of the molecule should be compatible with the reagents and reactions suggested. Substituents incompatible with the reaction conditions will be apparent to those skilled in the art and thus indicate alternative methods. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. At least some of the compounds identified herein as "intermediates" are considered to be compounds of the invention.

At least some of the compounds identified herein as "intermediates" are considered to be compounds of the invention.

Abbreviations:

DCM dichloromethane

EtOAC Ethyl acetate

MeOH methanol

DMSO dimethyl sulfoxide

NMO N-methylmorpholine N-oxide

LiHMDS lithium bis (trimethylsilyl) amide

p-TSA-p-toluenesulfonic acid

DMF N, N-dimethylformamide

THF tetrahydrofuran

TLC thin layer chromatography

LCMS liquid chromatography-mass spectrometry

HPLC high performance liquid chromatography

General procedure for the Synthesis of 2, 4-diketoesters:

to a stirred solution of the corresponding acetyl compound (1eq.) in anhydrous THF (10V) at-78 ℃ under Ar atmosphere was added LiHMDS (1M in THF, 1.3eq.) and stirred at the same temperature for 1 h. To this solution was added dimethyl oxalate (1.5eq.) in anhydrous THF (5V) dropwise at-78 ℃ and the resulting reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. Diluting the residue with water; the precipitated solid was collected by filtration, successively washed with ethyl acetate and ethyl ether and dried under reduced pressure to obtain the desired compound (note: the desired compound was isolated in enol form and used as such in the next step).

General procedure for the synthesis of cyclic sulfonamides:

method A (HCl (g)/MeOH, sealed tube):

to a stirred solution of 2, 4-diketo ester (1eq.) and sulfonamide (1eq.) in MeOH (10V) in a sealed tube at 0 deg.C with HCl gas (by sodium chloride + H)₂SO₄Generated) was purged for 2 h. The resulting reaction mixture was stirred at 80 ℃ for 24 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was cooled to 0 ℃, the precipitated solid was filtered, washed successively with water and cold methanol and dried in vacuo to give the cyclic sulfonamide.

Method B (4N HCl in MeOH, RB flask):

in a round bottom flask equipped with a reflux condenser, the 2, 4-diketo ester (1eq.) and sulfonamide (1eq.) were dissolved in 4N HCl in methanol (10V). The resulting reaction mixture was stirred at 60 ℃ for 16 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was cooled to 0 ℃, the precipitated solid was filtered, washed with water, then ether and dried in vacuo to give the cyclic sulfonamide.

General procedure for alkylation

Method a (alkylation using NaH/MeI):

to a stirred solution of cyclic sulfonamide (1eq.) in anhydrous DMF (8V) under Ar atmosphere at 0 ℃ NaH (60% w/w in mineral oil, 1.5eq.) was added and stirred at 0 ℃ for 45 min. To this solution, MeI (1.1eq.) was added slowly and the resulting reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice-cold water; the resulting solid was collected by filtration. The solid was washed with ether and dried under vacuum to give the desired N-alkylated compound after silica gel column chromatography.

Method B (alkylation using Mitsunobu reaction):

to a stirred solution of cyclic sulfonamide (1eq.) in anhydrous THF (4V) at 0 ℃ under Ar atmosphere was added TPP (2eq.) and methanol (10eq.) and stirred at 0 ℃ for 45 minutes. DEAD/DIAD (2eq.) was added slowly to the solution and the resulting reaction mixture (which turned dark brown in color) was heated at 60 ℃ for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated in vacuo and the resulting residue was dissolved in ether and stirred for 30 minutes. And filtered. The resulting solid was further stirred in methanol for 30 minutes, filtered and dried under vacuum to give the desired compound which was N-alkylated (note: some compounds were further purified using silica gel column chromatography).

General procedure for amidation:

method A (AlMe)₃Mediated amidation):

to a stirred solution of the corresponding aniline (3eq.) in DCM/toluene at 0 ℃ under Ar atmosphere, AlMe was added₃(2M in toluene, 3eq.) and the reaction mixture was stirred at 0 ℃ for 10 minutes and continued stirring at room temperature for 1 h. To this solution was added the corresponding ester compound (1eq.) at 0 ℃ under Ar atmosphere and the resulting reaction mixture was refluxed at 40 ℃ overnight. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to 0 ℃; quench slowly with 1N HCl solution and extract with DCM. The combined organic layers were collected, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude compound was purified by silica gel column chromatography, followed by trituration with ether to give the compound HBV-CSU _ Int (note: the reaction heated some compounds at 110 ℃ with toluene as solvent).

Method B (hydrolysis followed by acid-amine coupling using HATU):

to the corresponding ester compound (1eq.) at 10V CH at 0 deg.C₃CN：H₂To the solution in O (1:1) was added TEA (5eq.) and the resulting reaction mixture was stirred at the same temperature until a clear solution was observed (typically 4-6 h). The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure, and the resulting residue was acidified with 6N HCl and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the acid derivative, which was used in the next step after trituration with ether. To a stirred solution of the above acid compound (1eq.) in DCM/DMF (10V) was added DIPEA (2eq.), stirred for 15min at 0 ℃, then HATU (2eq.), stirred again for 15min, then the corresponding aniline (1.2eq.) was added. The reaction mixture was then stirred at room temperature overnight. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was taken up in ice-cold waterDiluted and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound. The crude compound was dissolved in methanol (10V), stirred for 15 minutes, filtered and dried under reduced pressure to give the desired compound.

Method C (hydrolysis followed by acid-amine coupling using edci. hcl):

to the corresponding ester compound (1eq.) at 10V CH at 0 deg.C₃CN：H₂To the solution in O (1:1) was added TEA (5eq.) and the resulting reaction mixture was stirred at the same temperature until a clear solution was observed (typically 4-6 h). The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure, and the resulting residue was acidified with 6N HCl and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the acid derivative, which was used in the next step after trituration with ether. To a stirred solution of the above acid compound (1eq.) in DMF (10-25V) at 0 ℃ edci.hcl (1.5eq.) and HOBt (1.5eq.) were added and stirred for 15 min; DIPEA (3eq.) and the corresponding aniline (1.2eq.) were then added successively. The reaction mixture was then stirred at room temperature overnight. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ice-cold water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound. The crude compound was purified using silica gel column chromatography to give the compound HBV-CSU _ Int.

General procedure for reduction:

to a stirred solution of the compound HBV-CSU _ Int (1eq.) in EtOH at 0 ℃ under Ar atmosphere was added NaBH₄(2eq.) and stirred at room temperature for 20 minutes. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated in vacuo, and the resulting residue was diluted with water and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and purified by silica gel column chromatography to give the desired compound. Note: regioselective alkylation and cis stereochemistry several representative compounds were confirmed by NOE experiments.

General methods for Suzuki coupling:

to a mixture of bromo compound (1eq.), boronic acid/boronic ester (1eq.) in 1, 4-dioxane was added 2M potassium phosphate solution, purged with Ar atmosphere for 15 minutes, then palladium tetratriphenylphosphine (0.06eq.) was added, and stirred at 90 ℃ overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water, then brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography/preparative HPLC to give the desired product.

General procedure for Stille coupling:

to a mixture of bromo compound (1eq.) in toluene/dioxane, stannane reagent (1eq.) was added and purged with an Ar atmosphere for 15 minutes, followed by tetratriphenylphosphine palladium (0.06 eq.). The resulting reaction mixture was then stirred at 90 ℃ overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography/preparative HPLC to give the desired product. (Note: the reaction has been carried out on some compounds in acetonitrile solvents, where the solubility of the bromo compound is an issue).

General procedure for Negishi coupling:

to an Ar purged mixture of bromo compound (1eq.) in 1, 4-dioxane was added PdCl₂(dppf). DCM (0.1eq.) and the reaction mixture were stirred for 10 min; then Me is added₂Zn (2eq.) and stirred at 90 ℃ for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched successively with methanol and water, and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product, which was purified by column chromatography/preparative HPLC to give the desired product as a solid.

The chiral separation method comprises the following steps:

method A

Column: YMC chiral Amylose-SA, 250mm x 20mm, 5 micron

Mobile phase:

a: n-Hexane + 0.1% DEA

B：DCM：MeOH(1:1)

Isocratic: 30-90% of B

Flow rate: 18mL/Min

Method B

Column: DIACEL CHIRALPACK-IA, 250mm x 20mm, 5 micron

Mobile phase:

a: n-Hexane + 0.1% DEA

B：DCM：MeOH(1:1)

Gradient: hold 50% B until 4min, then 100% B at 5min and Hold until 15min

Flow rate: 18mL/Min

Method C

Column: CHIRALPACK-IA, 250mm x 30mm, 5 micron

Mobile phase:

a: n-Hexane + 0.1% DEA

B：DCM：MeOH(1:1)

Isocratic: 30-90% of B

Flow rate: 30mL/Min

Chiral purity was confirmed by using the following method:

method A

Column: YMC chiral Amylose-SA, 250mm x 4.6mm, 5 micron

Mobile phase:

a: n-Hexane + 0.1% DEA

B：DCM：MeOH(1:1)

Isocratic: 30-90% of B

Flow rate: 1mL/Min

Method B

Column: YMC chiral ART Cellulose-SC, 250mm x 4.6mm, 5 micron

Mobile phase:

a: n-Hexane + 0.1% DEA

B：DCM：MeOH(1:1)

Isocratic: 30-90% of B

Flow rate: 1mL/Min

Method C

Column: CHIRALPACK-IA, 250mm x 4.6mm, 5 micron

Mobile phase:

a: n-Hexane + 0.1% DEA

B：DCM：MeOH(1:1)

Isocratic: 30-90% of B

Flow rate: 30mL/Min

The first eluting compound is labeled HBV-CSU-XXX-ISO-I, and the second eluting compound is labeled HBV-CSU-XXX-ISO-II.

Note that: the mobile phase has been modified according to solubility and preparative HPLC purification and other problems encountered during analysis. In rare cases, TFA and MeSO were used₃H and the like. For a few samples, isocratic gradient elution was used.

Scheme 1:

general synthetic scheme for 5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide derivatives with N-alkyl and aniline variations:

scheme 1:

synthesis of methyl 2, 4-dioxo-4- (thiophen-2-yl) butanoate (3):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 26g (77%, reaction scale 20g) as a yellow solid. TLC: 10% MeOH/DCM (R)_f：0.1)；¹H NMR(DMSO-d₆，400MHz)：δ7.68(d，J＝5.2Hz，1H)，7.61(d，J＝4.4Hz，1H)，7.10(t，J＝5.2Hz，1H)，6.34(s，1H)，3.69(s，3H)；C₉H₈O₄LCMS calculation of S: 212.01, respectively; and (3) observation value: 212.95(M +1)⁺。

Synthesis of 5- (thien-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (4):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 8g (62%, reaction scale 10g) as a yellow solid. TLC: 20% MeOH/DCM (R)_f：0.1)；¹H NMR(DMSO-d₆，400MHz)：δ11.50(br.s，1H)，8.06(d，J＝4.0Hz，1H)，7.93(d，J＝5.2Hz，1H)，7.23(t，J＝4.0Hz，1H)，6.99(s，1H)，3.87(s，3H)；C₉H₈N₂O₄S₂LCMS calculated of (d): 271.99, respectively; LCMS observations: 272.85(M +1)⁺。

Synthesis of 2-methyl-5- (thien-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (5):

the title compound was synthesized using general procedure a described above for alkylation to give 4g (77%, 5g reaction scale) as a yellow solid. TLC: 40% EtOAc/hexanes (R)_f：0.4)；¹H NMR(DMSO-d₆，400MHz)：δ8.23(d，J＝4.0Hz，1H)，8.10(d，J＝4.8Hz，1H)，7.32-7.30(m，2H)，3.94(s，3H)，3.50(s，3H)；C₁₀H₁₀N₂O₄S₂LCMS calculated of (d): 286.01, respectively; LCMS observations: 286.94(M +1)⁺。

2-Ethyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (5):

the title compound was synthesized using general procedure a described above for alkylation to give 0.2g (crude material) as a light yellow solid. TLC: 40% EtOAc/hexanes (R)_f：0.4)；¹H NMR(DMSO-d₆400 MHz): δ 7.93(d, J ═ 4.0Hz, 1H), 7.83(d, J ═ 4.8Hz, 1H), 7.21 to 7.19(m, 1H), 6.81(s, 1H), 4.32 to 4.25(m, 2H), 1.32(t, J ═ 6.8Hz, 3H), 3H are bound in the solvent peak; c₁₁H₁₂N₂O₄S₂LCMS calculated of (d): 300.02, respectively; LCMS observations: 300.90(M +1)⁺。

2-allyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (5):

the title compound was synthesized using general procedure a described above for alkylation to give 0.13g (45%, scale of reaction 0.25g)) as a yellow solid. TLC: 50% EtOAc/hexanes (R)_f：0.3)；¹H NMR(DMSO-d₆，400MHz)：δ8.26(dd，J＝3.9，1.3Hz，1H)，8.16-8.06(m，1H)，7.41(d，J＝1.2Hz，1H)，7.34-7.31(m，1H)，5.97-5.90(m，1H)，5.34-5.18(m，2H)，4.59-4.50(m，2H)，3.92(s，3H)；C₁₂H₁₂N₂O₄S₂LCMS calculated of (d): 312.02, respectively; LCMS observations: 312.95(M +1)⁺。

2-methyl-N-phenyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-006_ Int)

The title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (4-fluorophenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-007_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (3-chlorophenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-010_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (3, 4-difluorophenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-011_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

2-methyl-5- (thiophen-2-yl) -N- (3- (trifluoromethyl) phenyl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-012_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

2-methyl-5- (thiophen-2-yl) -N- (m-tolyl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-013_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (4-chlorophenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-014_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -N, 2-dimethyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-015_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (3-bromo-4-fluorophenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-016_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (3-bromophenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-017. Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (4-chloro-3-fluorophenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-018_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (4-cyanophenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-019_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (3-cyanophenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-020_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-023_ Int)

The title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2-ethyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-024_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

2-methyl-5- (thiophen-2-yl) -N- (3,4, 5-trifluorophenyl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-036_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

2-allyl-N- (3-chloro-4-fluorophenyl) -5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-040_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (3-cyano-4-fluorophenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-045_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (4-fluoro-3- (trifluoromethyl) phenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-046_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (3, 5-dichlorophenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-047_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (3, 5-dibromophenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-048_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

N- (3-bromo-4, 5-difluorophenyl) -2-methyl-5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-049_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 5 and the corresponding amine (see table 1 for analytical data).

cis-2-methyl-N-phenyl-5- (thiophen-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-006):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-006_ Int (see Table 2 for analytical data).

cis-N- (4-fluorophenyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-007):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-007_ Int (see Table 2 for analytical data).

cis-N- (3-chlorophenyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-010 and HBV-CSU-010-ISO-I):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-010_ Int (see Table 2 for analytical data).

cis-N- (3, 4-difluorophenyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-011):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-011_ Int (see Table 2 for analytical data).

Cis-2-methyl-5- (thiophen-2-yl) -N- (3- (trifluoromethyl) phenyl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-012):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-012_ Int (see Table 2 for analytical data).

Cis-2-methyl-5- (thiophen-2-yl) -N- (m-tolyl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-013):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-013_ Int (see Table 2 for analytical data).

cis-N- (4-chlorophenyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-014):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-014_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -N-2-dimethyl-5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-015):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-015_ Int (see Table 2 for analytical data).

cis-N- (3-bromo-4-fluorophenyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-016 and HBV-CSU-016-ISO-I):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-016_ Int (see Table 2 for analytical data).

cis-N- (3-bromophenyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-017 and HBV-CSU-017-ISO-I):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-017_ Int (see Table 2 for analytical data).

cis-N- (4-chloro-3-fluorophenyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-018):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-018_ Int (see Table 2 for analytical data).

cis-N- (4-cyanophenyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-019):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-019_ Int (see Table 2 for analytical data).

cis-N- (3-cyanophenyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-020 and HBV-CSU-020-ISO-I):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-020_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-ethyl-5- (thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-024):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-24_ Int (see Table 2 for analytical data).

Cis-2-methyl-5- (thiophen-2-yl) -N- (3,4, 5-trifluorophenyl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-036):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-36_ Int (see Table 2 for analytical data).

cis-2-allyl-N- (3-chloro-4-fluorophenyl) -5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-040):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-40_ Int (see Table 2 for analytical data).

cis-N- (3-cyano-4-fluorophenyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-045 and HBV-CSU-045-ISO-I):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-45_ Int (see Table 2 for analytical data).

cis-N- (4-fluoro-3- (trifluoromethyl) phenyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-046-ISO-I):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-46_ Int (see Table 2 for analytical data).

cis-N- (3, 5-dichlorophenyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-047-ISO-I):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-47_ Int (see Table 2 for analytical data).

cis-N- (3, 5-dibromophenyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-048-ISO-I):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-48_ Int (see Table 2 for analytical data).

cis-N- (3-bromo-4, 5-difluorophenyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-049-ISO-I):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-49_ Int (see Table 2 for analytical data).

Scheme 2:

general synthetic scheme for 5- (thien-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide derivatives with N-alkyl changes at C-6:

scheme 2

cis-N- (3-chloro-4-fluorophenyl) -2, 6-dimethyl-5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-023):

to a stirred solution of the compound HBV-CSU-023_ Int 1(0.15g, 0.372mmol) in acetonitrile (3mL) at 0 ℃ was added K₂CO₃(0.154g, 1.16mmol) and stirred at room temperature for 10 min. MeI (0.063g, 0.446mmol) was added to the solution. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude compound was purified by silica gel column chromatography to give the desired compound (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -6- (2- (dimethylamino) ethyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-043-ISO-I and ISO-II):

to a stirred solution of the compound HBV-CSU-023_ Int I (0.25g,0.621mmol) in acetonitrile (10mL) was added K₂CO₃(0.257g, 1.86mmol) and 2-chloro-N, N-dimethylethyl-1-amine hydrochloride (0.107g, 0.745mmol) and stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated in vacuo and the resulting crude compound was purified by chiral preparative HPLC to give the desired compound (25mg, 8.41%) as a white solid. TLC: 40% EtOAc/hexanes (R)_f: 0.1); (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -6- (2-methoxyethyl) -2-methyl-5- (thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-064):

to a stirred solution of the compound HBV-CSU-023_ Int 1(0.05g, 0.123mmol.) in acetonitrile (3mL) at 0 ℃ was added K₂CO₃(0.051g, 0.371mmol) and stirred at room temperature for 10 min. To this solution was added 1-bromo-2-methoxyethane (0.034g, 0.247 mmol). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude compound was purified by silica gel column chromatography to give the desired compound (see table 2 for analytical data).

Scheme 3:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2- (2-methoxyethyl) -5- (thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-25, HBV-CSU-025-ISO-I & II) and cis-N- (3-chloro-4-fluorophenyl) -6- (2-methoxyethyl) -5- (thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-044-ISO-I & II):

methyl 2- (2-methoxyethyl) -5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (7) and methyl 2- (2-methoxyethyl) -3- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-5-carboxylate 1, 1-dioxide (7A):

to a stirred solution of compound 3(5g, 23.58mmol) and compound 6(3.6g, 23.58mmol) in MeOH (40mL) in a sealed tube was added HCl gas (over sodium chloride + H) at 0 deg.C₂SO₄Generated) was purged for 2 h. The resulting reaction mixture was stirred at 80 ℃ for 24 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography using 15% EtOAc/hexanes to give a mixture of compound 7 and 7A (1g, 13%) as a white solid. TLC: 40% EtOAc/hexanes (R)_f：0.6)；C₉H₈N₂O₄S₂LCMS calculated of (d): 330.03, respectively; LCMS observations: 330.95(M +1)⁺。

N- (3-chloro-4-fluorophenyl) -2- (2-methoxyethyl) -5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-025_ Int) and N- (3-chloro-4-fluorophenyl) -2- (2-methoxyethyl) -3- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-5-carboxamide 1, 1-dioxide (HBV-CSU-044_ Int):

the title compound above has been isolated as an inseparable mixture of compounds following the general procedure described above for amidation (method a), by using the corresponding 7/7a and the corresponding amine. Desired product formation was confirmed by LCMS. C₁₇H₁₅ClFN₃O₄S₂LCMS calculated of (d): 443.02, respectively; LCMS observations: 444.04(M +1)⁺。

N- (2-methoxyethyl) sulfonamide (6):

to a stirred solution of sulfonamide (1g, 10.42mmol) in THF (5mL) was added 2-methoxyethyl-1-amine (0.78g, 10.41mmol) and the reaction mixture was stirred in a microwave at 100 ℃ for 30 min. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated in vacuo. The crude compound was purified by silica gel column chromatography to give compound 6(6.05g, 75.43%) as a colorless oil. TLC: 5% MeOH/DCM (R)_f：0.5)；¹H NMR(DMSO-d₆，400MHz)：δ6.48(br.s，3H)，3.40-3.32(m，2H)，3.23(s，3H)，3.02-2.99(m，2H)。

cis-N- (3-chloro-4-fluorophenyl) -2- (2-methoxyethyl) -5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-025, HBV-CSU-025-ISO-I and HBV-CSU-025-ISO-II):

the title compound was synthesized according to the general procedure described above for reduction by using an inseparable mixture of the corresponding HBV-CSU-025_ Int/HBV-CSU-044_ Int. Regioisomers were separated using preparative HPLC followed by chiral HPLC separation (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -6- (2-methoxyethyl) -5- (thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-044-ISO-I and HBV-CSU-044-ISO-II):

the title compound was synthesized according to the general procedure described above for reduction by using an inseparable mixture of HBV-CSU-025_ Int/HBV-CSU-044_ Int. Regioisomers were separated using preparative HPLC followed by chiral HPLC separation (see table 2 for analytical data).

Scheme 4:

general synthetic scheme for 5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide derivatives with N-alkyl changes at C-6:

2, 4-dioxo-4- (thiazol-2-yl) butanoic acid methyl ester (10):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 11g (66%, reaction scale 10g) as a yellow solid. TLC: 5% MeOH/DCM (R)_f：0.2)；¹H NMR(DMSO-d₆，400MHz)：δ7.92-7.82(m，2H)，6.72(s，1H)，3.68(s，3H)；C₈H₇NO₄LCMS calculation of S: 213.01, respectively; and (3) observation value: 213.97(M +1)⁺。

5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (11):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 4g (45%, reaction scale 7g) as a light yellow solid. TLC: 10% MeOH/DCM (R)_f：0.1)；¹H NMR(DMSO-d₆，400MHz,)δ11.13(br.s，1H)，7.99(d，J＝3.2Hz，1H)，7.93(d，J＝3.2Hz，1H)，6.96(s，1H)，3.80(s，3H)；C₈H₇N₃O₄S₂LCMS observation of (a): 273.85(M +1)⁺。

2-methyl-5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (12):

the title compound was synthesized using general procedure a for alkylation described above to give 1.3g (80%, scale of reaction 1.5g) as a yellow solid. TLC: 50% EtOAc/hexanes (R)_f：0.4)；¹H-NMR(DMSO-d₆，400MHz)：δ8.25(d，J＝2.8Hz，1H)，8.19(d，J＝2.8Hz，1H)，7.43(s，1H)，3.91(s，3H)，3.56(s，3H)；C₉H₉N₃O₄S₂LCMS observation of (a): 287.00, observed value: 287.90(M +1)⁺。

2- (2-methoxyethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (12):

the title compound was synthesized using general procedure C described above for alkylation to give 1.1g (45.3%, scale of reaction 2 g). C₁₁H₁₃N₃O₅S₂LCMS observation of (a): 331.03, observed value: 332(M +1)⁺。

Methyl 2- (2- (tert-butoxy) ethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (12):

the title compound was synthesized using general method B described above for alkylation to give 2.5g (61%, reaction scale 3 g).¹H NMR(DMSO-d₆，500MHz)：δ8.30(d，J＝2.9Hz，1H)，8.25(d，J＝2.9Hz，1H)，7.49(s，1H)，4.29(t，J＝4.9Hz，2H)，3.92(s，3H)，3.38(t，J＝4.9Hz，2H)，0.94(s，9H)。

5- (thiazol-2-yl) -2- (2- (trifluoromethoxy) ethyl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (12):

the title compound was synthesized using general procedure B described above for alkylation to give 0.7g (crude, 0.5g reaction scale). C₁₁H₁₀F₃N₃O₅S₂LCMS observation of (a): 385.00, observed value: 385.95(M +1)⁺。

2-allyl-5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (12):

the title compound was synthesized using general procedure a described above for alkylation to give 0.85g (74.56%, reaction scale 1 g/trans-esterification product was also observed, which was carried to the next step as a mixture); c₁₁H₁₁N₃O₄S₂LCMS observation of (a): 313.02, observed value: 313.6(M +1)⁺。

2- (prop-2-yn-1-yl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (12):

the title compound was synthesized using general method B described above for alkylation to give 0.75g (66.37%, scale of reaction 1 g); c₁₁H₉N₃O₄S₂LCMS observation of (a): 311.00, observed value: 311.95(M +1)⁺。

2- (3-methoxypropyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (12):

the title compound was prepared using the above for alkylGeneral procedure B synthesis to give 1.5g (59.28%, reaction scale 2 g); c₁₂H₁₅N₃O₅S₂LCMS observation of (a): 345.05, observed value: 346(M +1)⁺。

Methyl 2- ((tetrahydrofuran-2-yl) methyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (12):

the title compound was synthesized using general procedure B described above for alkylation to give 0.4g (61%, scale of reaction 0.5 g).¹H NMR(500MHz，DMSO-d₆)：δ8.31(d，J＝2.9Hz，1H)，8.25(d，J＝2.9Hz，1H)，7.48(s，1H)，4.32-4.27(m，1H)，4.24-4.14(m，1H)，3.99-3.93(m，1H)，3.93(s，3H)，3.61-3.54(m，1H)，3.47-3.41(m，1H)，1.96-1.85(m，1H)，1.78-1.58(m，2H)，1.51-1.42(m，1H)。

2- (2-Morpholinoethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (12):

the title compound was synthesized using general method B described above for alkylation to give 150mg (crude, reaction scale 1.5 g). C₁₄H₁₈N₄O₅S₂LCMS observation of (a): 386.07, observed value: 387.20(M +1)⁺。

Methyl 2- (3-methoxy-3-methylbutyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (12):

the title compound was synthesized using general method B described above for alkylation to give 1.5g (55%, scale of reaction 1.73 g).¹H NMR(400MHz，DMSO-d₆)：δ8.30(d，J＝3.0Hz，1H)，8.24(d，J＝3.0Hz，1H)，7.49(s，1H)，4.04-3.98(m，2H)，3.95(s，3H)，3.08(s，3H)，2.03-1.96(m，2H)，1.12(s，6H)。

2- (but-3-yn-1-yl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (12):

the title compound was synthesized using general method B described above for alkylation to give 310mg (26%, reaction scale 1 g).¹H-NMR(DMSO-d₆，400MHz)：δ8.32(d，J＝3.1Hz，1H)，8.25(d，J＝3.0Hz，1H)，7.56(s，1H)，4.21(t，J＝7.0Hz，2H)，3.96(s，3H)，3.00(t，J＝2.6Hz，1H)，2.65(td，J＝7.0，2.6Hz，2H)；C₁₂H₁₁N₃O₄S₂LCMS observation of (a): 325.02, observed value: 326.10(M +1)⁺。

2- (2- (benzyloxy) ethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (12):

the title compound was synthesized using general method B described above for alkylation to give 780mg (17.7%, reaction scale 2 g); c₁₇H₁₇N₃O₅S₂LCMS observation of (a): 407.06, observed value: 408.05(M +1)⁺。

2- (4-methoxybenzyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (12):

the title compound was synthesized using general method B for alkylation described above to give 900mg (24.32%, reaction scale 2 g).¹H-NMR(DMSO-d₆，400MHz)：δ8.32(d，J＝2.8Hz，1H)，8.24(d，J＝2.8Hz，1H)，7.49(s，1H)，7.19(d，J＝8.8Hz，1H)，6.91(d，J＝8.4Hz，1H)，5.16(s，2H)，3.85(s，3H)，3.72(s，3H)。

2- (2- (methylthio) ethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (12):

the title compound was synthesized using general method B described above for alkylation to give 1.5g (60%, reaction scale 2 g).¹H-NMR(DMSO-d₆，400MHz)：8.31(d，J＝3.1Hz，1H)，8.25(d，J＝2.9Hz，1H)，7.55(s，1H)，4.23(t，J＝7.0Hz，2H)，3.96(s，3H)，2.83(t，J＝7.0Hz，2H)，2.04(s，3H)；C₁₁H₁₃N₃O₄S₃LCMS observation of (a): 347.01, observed value: 347.10(M +1)⁺。

2- (2-ethoxyethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (12):

the title compound was synthesized using general method B described above for alkylation to give 1.3g (52%, reaction scale 2 g).¹H-NMR(DMSO-d₆，400MHz)：δ8.31(d，J＝3.1Hz，1H)，8.25(d，J＝3.1Hz，1H)，7.47(s，1H)，4.29(t，J＝5.0Hz，2H)，3.93(s，3H)，3.49(t，J＝5.0Hz，2H)，3.30(q，J＝7.4Hz，2H)，0.97(t，J＝7.0Hz，3H)；C₁₂H₁₅N₃O₅S₂LCMS observation of (a): 345.05, observed value: 346.10(M +1)⁺。

2- (2-Isopropoxyethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (12):

the title compound was synthesized using general method B described above for alkylation to give 1.3g (66%, scale of reaction 1.5 g).¹H-NMR(DMSO-d₆，400MHz)：δ8.31(d，J＝3.0Hz，1H)，8.25(d，J＝3.1Hz，1H)，7.49(s，1H)，4.29(t，J＝5.0Hz，2H)，3.93(s，3H)，3.46(t，J＝5.0Hz，2H)，3.43-3.35(m，1H)，0.92(d，J＝6.0Hz，6H)；C₁₃H₁₇N₃O₅S₂LCMS observation of (a): 359.06, observed value: 359.90(M +1)⁺。

N- (3-chloro-4-fluorophenyl) -2-methyl-5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-027_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 12 and the corresponding amine. The desired product formation was confirmed by LCMS and the crude intermediate was carried to the next step. C₁₄H₁₀ClFN₄O₃S₂LCMS observation of (a): 399.99, observed value: 400.90(M +1)⁺。

N- (3-chloro-4-fluorophenyl) -2- (2-methoxyethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-058_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

N- (3-bromo-4-fluorophenyl) -2- (2-methoxyethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-059_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

N- (3-bromo-4-fluorophenyl) -2-methyl-5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-060_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

2- (tert-butoxy) ethyl) -N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-071_ Int):

the title compound above has been synthesized following the general procedure for amidation described above (method C), using the corresponding 12 and the corresponding amine, analytical data see table 1).

N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -2- (2- (trifluoromethoxy) ethyl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-072_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2- (3-methoxypropyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-077_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2- ((tetrahydrofuran-2-yl) methyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-079_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2- (2-morpholinoethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-082_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method C) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2- (3-methoxy-3-methylbutyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-083_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2- (prop-2-yn-1-yl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-089_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

2- (but-3-yn-1-yl) -N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-090_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

2-allyl-N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-094_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

2- (2- (benzyloxy) ethyl) -N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-095_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2- (4-methoxybenzyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-108_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2- (2- (methylthio) ethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-109_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method C) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2- (2-ethoxyethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-142_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method C) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2- (2-isopropoxyethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-143_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method C) by using the corresponding 12 and the corresponding amine (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-027, HBV-CSU-027-ISO-I and HBV-CSU-027-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-027_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (2-methoxyethyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-058, HBV-CSU-058-ISO-I and HBV-CSU-058-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-058_ Int (see Table 2 for analytical data).

cis-N- (3-bromo-4-fluorophenyl) -2- (2-methoxyethyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-059, HBV-CSU-059-ISO-I and HBV-CSU-059-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-059_ Int (see Table 2 for analytical data).

cis-N- (3-bromo-4-fluorophenyl) -2-methyl-5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-060-ISO-I & HBV-CSU-060-ISO-II):

the title compound was synthesized following the general procedure described above for reduction, using the corresponding HBV-CSU-060_ Int. Chiral HPLC separation afforded the desired compound (see table 2 for analytical data).

Cis-2- (2- (tert-butoxy) ethyl) -N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-071, HBV-CSU-071-ISO-I and HBV-CSU-071-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-071_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -2- (2- (trifluoromethoxy) ethyl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-072, HBV-CSU-072-ISO-I and HBV-CSU-072-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-072_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (3-methoxypropyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-077-ISO-I and HBV-CSU-077-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-077_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- ((tetrahydrofuran-2-yl) methyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-079-rac-a and HBV-CSU-079-rac-B):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-079_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (2-morpholinoethyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-082):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-082_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (3-methoxy-3-methylbutyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine alkane-3-carboxamide 1, 1-dioxide (HBV-CSU-083, HBV-CSU-083-ISO-I and HBV-CSU-083-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-083_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (prop-2-yn-1-yl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-089-ISO-I and HBV-CSU-089-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-089_ Int (see Table 2 for analytical data).

Cis-2- (but-3-yn-1-yl) -N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-090, HBV-CSU-090-ISO-I, HBV-CSU-090-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-090_ Int (see Table 2 for analytical data).

cis-2-allyl-N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-094-ISO-I and HBV-CSU-094-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-094_ Int (see Table 2 for analytical data).

Cis-2- (2- (benzyloxy) ethyl) -N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-095, HBV-CSU-095-ISO-I and HBV-CSU-095-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-095_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (4-methoxybenzyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-108):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-108_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (2- (methylthio) ethyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-109, HBV-CSU-109-ISO-I and HBV-CSU-109-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-109_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (2-ethoxyethyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-142, HBV-CSU-142-ISO-I and HBV-CSU-142-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-142_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (2-isopropoxyethyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-143):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-143_ Int (see Table 2 for analytical data).

Scheme 5:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -5- (5-fluorothiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-029-ISO-I):

scheme 5

2- (5-bromothien-2-yl) -2-methyl-1, 3-dioxolane (14):

to a stirred solution of compound 13(5g, 24.39mmol) in toluene (50mL) was added p-TSA (0.413g, 2.43mmol) and ethane-1, 2-diol (6.04g, 97.56mmol) and the reaction refluxed for 24h using deanStark (deanStark) apparatus. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. The crude compound was purified by silica gel column chromatography to give the title compound 14(2.7g, 44.33%) as a white solid. TLC: 40% EtOAc/hexanes (R)_f：0.6)；¹H NMR(CDCl₃，400MHz)：δ6.92(d，J＝3.2Hz，1H)，6.80(d，J＝4.0Hz，1H)，4.08-3.95(m，4H)，7.78(s，3H)。

1- (5-fluorothien-2-yl) ethan-1-one (15):

to a stirred solution of compound 14(5g, 20mmol) in anhydrous THF (50mL) under Ar at-78 deg.C was added n-BuLi (2.5M, 13.04mL, 30mmol) dropwise and stirred at the same temperature for 45 min. To this solution, NFSI dissolved in anhydrous THF (10mL) (8.19g, 26mmol) was added slowly at-78 ℃. The resulting reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was saturated with NH₄The Cl solution was quenched and extracted with ether. The combined organic layers were washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. The crude compound was purified by silica gel column chromatography using 2% EtOAc/hexanes to give the fluoro-substituted compound (2.7 g). To the stirred solution above, a solution of fluoro-substituted compound (2.7g, 14.36mmol) in THF (20mL), 3N HCl (10mL) was added and stirred at rt for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound 15(2.2g, crude material) as a light brown oil. TLC: 10% EtOAc/hexanes (R)_f：0.4)；¹H NMR(DMSO-d₆，400MHz)：δ7.40(d，J＝4.0Hz，1H)，6.55(dd，J＝4.0，1.2Hz，1H)，2.51(s，3H)。

4- (5-Fluorothiophen-2-yl) -2, 4-dioxobutyric acid methyl ester (16):

to a stirred solution of compound 15(2.3g, 15.97mmol) in anhydrous THF (20mL) at-78 ℃ under Ar atmosphere was added LiHMDS (1M in THF, 20.76mL, 20.76mmol) and stirred at the same temperature for 1 h. To this solution was added dropwise a solution of compound 2(2.45g, 20.76mmol) in anhydrous THF (10mL) at-78 ℃. The resulting reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. Diluting the residue with water; the precipitated solid was collected by filtration, successively washed with ethyl acetate and diethyl ether and dried under reduced pressure to give compound 16(2.7g, 62.64%) as a yellow solid. (Note: 16 was isolated in the enol form and used as such in the next step). TLC: 10% MeOH in DCM (R)_f：0.1)；C₉H₇FO₄LCMS calculation of S: 230.0; and (3) observation value: 230.88(M +1)⁺。

5- (5-Fluorothiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (17):

to a stirred solution of compound 16(2.5g, 10.86mmol) and sulfonamide (1.25g, 10.86mmol) in MeOH (30mL) in a sealed tube at 0 deg.C with HCl gas (over sodium chloride + H)₂SO₄Generated) was purged for 2 h. The resulting reaction mixture was stirred at 80 ℃ for 24 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to 0 ℃ and filtered. The solid was washed with cold methanol and dried in vacuo to give compound 17(1.8g, 57.14%) C₉H₇FN₂O₄S₂LCMS calculated of (d): 289.98, respectively; LCMS observations: 290.94(M +1)⁺。

5- (5-Fluorothiophen-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (18):

to a stirred solution of compound 17(1.2g, 4.14mmol.) in DMF (10mL) at 0 deg.C was added K₂CO₃(1.8g, 12.41mmol) and stirred at room temperature for 10 min. To this solution, MeI (1.22g, 8.28mmol) was added. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. The crude compound was purified by silica gel column chromatography to give compound 18(0.4g, 32%) as a brown solid. TLC: 40% EtOAc/hexanes (R)_f：0.7)；¹H NMR(DMSO-d₆，400MHz)：δ8.13-8.11(m，1H)，7.33(s，1H)，7.05-7.04(m，1H)，3.94(s，3H)，3.49(s，3H)；C₁₀H₉FN₂O₄S₂LCMS calculated of (d): 304.00; LCMS observations: 304.85(M +1)⁺。

N- (3-chloro-4-fluorophenyl) -5- (5-fluorothiophen-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-029_ Int):

to a stirred solution of compound 18(0.287g, 1.97mmol) in DCM (10mL) at 0 deg.C under Ar was added AlMe₃(2M in toluene, 0.986mL, 1.97mmol) and the reaction mixture was stirred at 0 ℃ for 10 minutes and continued stirring at room temperature for 1 h. To this solution, aniline (0.2g, 0.657mmol) was added at 0 ℃ under an Ar atmosphere and the resulting reaction mixture was refluxed at 40 ℃ overnight. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was cooled to 0 ℃, quenched slowly with 1N HCl solution, and extracted with DCM. The combined organic layers were collected, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude compound was purified by silica gel column chromatography and then triturated with ether to give the compound HBV-CSU-029_ Int. (see Table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5-fluorothiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-029-ISO-I):

the title compound was synthesized according to the general procedure described above for reduction by using the corresponding HBV-CSU-029_ Int. Chiral HPLC separation afforded the desired compound (see table 2 for analytical data).

Scheme 6:

general synthetic scheme for 5- (phenyl/pyridyl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide derivatives with substituted phenyl/pyridyl, N-2 alkyl and aniline variations:

scheme 6

Synthesis of methyl 2, 4-dioxo-4- (pyridin-2-yl) butanoate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 3.2g (37.47%, reaction scale 5 g); c₁₀H₉NO₄LCMS calculated of (d): 207.05, respectively; and (3) observation value: 208.00(M +1)⁺。

Synthesis of methyl 4- (5-fluoropyridin-2-yl) -2, 4-dioxobutyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 2.5g (96.15%, scale of reaction 1.6 g); c₁₀H₈FNO₄LCMS calculated of (d): 225.04, respectively; and (3) observation value: 225.90(M +1)⁺。

Synthesis of methyl 2, 4-dioxo-4- (pyridin-3-yl) butanoate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 2g (23.52%, reaction scale 5 g); c₁₀H₉NO₄LCMS calculated of (d): 207.05, respectively; and (3) observation value: 207.95(M +1)⁺。

Synthesis of methyl 4- (4-fluorophenyl) -2, 4-dioxobutyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 13.84g (85.0%, reaction scale 10 g); c₁₁H₉FO₄LCMS calculated of (d): 224.05, respectively; and (3) observation value: 225.00(M +1)⁺。

Synthesis of methyl 2, 4-dioxo-4-phenylbutyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 17.24g (66%, reaction scale 15 g); c₁₁H₁₀O₄LCMS calculated of (d): 206.06, respectively; and (3) observation value: 207.10(M +1)⁺。

Synthesis of methyl 4- (4-methoxyphenyl) -2, 4-dioxobutyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 27g (crude, reaction scale 15 g); c₁₂H₁₂O₅LCMS calculated of (d): 236.07, respectively; and (3) observation value: 237.00(M +1)⁺。

Synthesis of methyl 4- (4-bromophenyl) -2, 4-dioxobutyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 33g (92.18%, reaction scale 25 g); c₁₁H₉BrO₄LCMS calculated of (d): 283.97, respectively; and (3) observation value: 286.95(M +2)⁺。

Synthesis of methyl 4- (3-methoxyphenyl) -2, 4-dioxobutyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 28.3g (crude, 25g reaction scale); c₁₂H₁₂O₅LCMS calculated of (d): 236.07, respectively; and (3) observation value: 236.95(M +1)⁺。

Synthesis of methyl 4- (2-methoxyphenyl) -2, 4-dioxobutyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 28g (70.93%, reaction scale 25 g); c₁₂H₁₂O₅LCMS calculated of (d): 236.07, respectively; and (3) observation value: 237.00(M +1)⁺。

Synthesis of methyl 2, 4-dioxo-4- (4- (trifluoromethyl) phenyl) butanoate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 34g (93.32%, reaction scale 25 g); c₁₂H₉F₃O₄LCMS calculated of (d): 274.05, respectively; and (3) observation value: 275.05(M +1)⁺。

Synthesis of methyl 4- (3, 4-difluorophenyl) -2, 4-dioxobutyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 30g (77.41%, reaction scale 25 g); c₁₁H₈F₂O₄LCMS calculated of (d): 242.04, respectively; and (3) observation value: 242.95(M +1)⁺。

Synthesis of methyl 4- (3-fluorophenyl) -2, 4-dioxobutyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 30g (73.65%, reaction scale 25 g); c₁₁H₉FO₄LCMS calculated of (d): 224.05, respectively; and (3) observation value: 225.00(M +1)⁺。

Synthesis of methyl 2, 4-dioxo-4- (4- (trifluoromethoxy) phenyl) butyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 70g (98.92%, reaction scale 50 g); c₁₂H₉F₃O₅LCMS calculated of (d): 290.04, respectively; and (3) observation value: 288.75(M-1)^-。

Synthesis of methyl 2, 4-dioxo-4- (3- (trifluoromethyl) phenyl) butanoate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 25g (68.60%, reaction scale 25 g).

Synthesis of methyl 4- (3-chlorophenyl) -2, 4-dioxobutyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 18g (96%, reaction scale 12 g); c₁₁H₉ClO₄LCMS calculated of (d): 240.02, respectively; and (3) observation value: 240.90(M +1)⁺。

Synthesis of methyl 2, 4-dioxo-4- (3- (trifluoromethoxy) phenyl) butyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 15g (crude, 10g reaction scale); c₁₂H₉F₃O₅LCMS calculated of (d): 290.04, respectively; and (3) observation value: 291.25(M +1)⁺。

Synthesis of methyl 4- (4- (difluoromethoxy) phenyl) -2, 4-dioxobutyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 12g (crude, 10g reaction scale); c₁₂H₁₀F₂O₅LCMS calculated of (d): 272.05, respectively; and (3) observation value: 272.95(M +1)⁺。

Synthesis of methyl 4- (3- (difluoromethoxy) phenyl) -2, 4-dioxobutyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 6.12g (81.92%, reaction scale 5 g); c₁₂H₁₀F₂O₅LCMS calculated of (d): 272.05, respectively; and (3) observation value: 272.85(M +1)⁺。

Synthesis of methyl 4- (4-chlorophenyl) -2, 4-dioxobutyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 32g (82.13%, 25g reaction scale); c₁₁H₉ClO₄LCMS calculated of (d): 240.02, respectively; and (3) observation value: 240.90(M +1)⁺。

Synthesis of methyl 4- (4-bromo-3-fluorophenyl) -2, 4-dioxobutyrate (20):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 8g (60.28%, scale of reaction 9.5 g); c₁₁H₈BrFO₄LCMS calculated of (d): 301.96, respectively; and (3) observation value: 303.85(M +2)⁺。

Synthesis of methyl 5- (pyridin-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using general procedure a above for the synthesis of cyclic sulfonamides to give 1g (19.68%, reaction scale 3 g); c₁₀H₉N₃O₄LCMS calculation of S: 267.03, respectively; LCMS observations: 268.15(M+1)⁺。

Synthesis of methyl 5- (5-fluoropyridin-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using general procedure a above for the synthesis of cyclic sulfonamides to give 2.5g (80.64%, scale of reaction 2.5 g); c₁₀H₈FN₃O₄LCMS calculation of S: 285.02, respectively; LCMS observations: 286.15(M +1)⁺。

Synthesis of methyl 5- (pyridin-3-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using general procedure a above for the synthesis of cyclic sulfonamides to give 3g (46.58% reaction scale 5 g); c₁₀H₉N₃O₄LCMS calculation of S: 267.03, respectively; LCMS observations: 267.95(M +1)⁺。

Synthesis of methyl 5- (4-fluorophenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using general procedure a above for the synthesis of cyclic sulfonamides to give 10.52g (64% reaction scale 13 g); c₁₁H₉FN₂O₄LCMS calculation of S: 284.03, respectively; LCMS observations: 285.15(M +1)⁺。

Synthesis of methyl 5-phenyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

use of the title CompoundGeneral procedure for the Synthesis of the above cyclic sulfonamides to give 15.2g (74%, reaction scale 16 g); c₁₁H₁₀N₂O₄LCMS calculation of S: 266.04, respectively; LCMS observations: 267.10(M +1)⁺。

Synthesis of methyl 5- (4-methoxyphenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using general procedure a above for the synthesis of cyclic sulfonamides to give 20g (59.1%, reaction scale 27 g); c₁₂H₁₂N₂O₅LCMS calculation of S: 296.05, respectively; LCMS observations: 296.95(M +1)⁺。

Synthesis of methyl 5- (4-bromophenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 33g (68.39%, 40g reaction scale); c₁₁H₉BrN₂O₄LCMS calculation of S: 343.95, respectively; LCMS observations: 346.95(M +2)⁺。

Synthesis of methyl 5- (3-methoxyphenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 18g (51%, reaction scale 28 g); c₁₂H₁₂N₂O₅LCMS calculation of S: 296.05, respectively; LCMS observations: 297.00(M +1)⁺。

Synthesis of methyl 5- (2-methoxyphenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using general procedure B above for the synthesis of the cyclic sulfonamides to give 24g (68.31%, scale 28 g; C)₁₂H₁₂N₂O₅LCMS calculation of S: 296.05, respectively; LCMS observations: 296.95(M +1)⁺。

Synthesis of methyl 5- (4- (trifluoromethyl) phenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 35g (71.79%, 40g reaction scale); c₁₂H₉F₃N₂O₄LCMS calculation of S: 334.02, respectively; LCMS observations: 334.95(M +1)⁺。

Synthesis of methyl 5- (3, 4-difluorophenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using general procedure B described above for the synthesis of cyclic sulfonamides to give 20g (53.43%, reaction scale 30 g); c₁₁H₈F₂N₂O₄LCMS calculation of S: 302.02, respectively; LCMS observations: 302.95(M +1)⁺。

Synthesis of methyl 5- (3-fluorophenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using general procedure B described above for the synthesis of cyclic sulfonamides to give 25g (66.03%, reaction scale 30 g); c₁₁H₉FN₂O₄LCMS calculation of S: 284.03, respectively; LCMS observations: 284.95(M +1)⁺。

Synthesis of methyl 5- (4- (trifluoromethoxy) phenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 48g (67.61%, reaction scale 60 g); c₁₂H₉F₃N₂O₅LCMS calculation of S: 350.02; LCMS observations: 350.95(M +1)⁺。

Synthesis of methyl 5- (3- (trifluoromethyl) phenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 10g (32.81%, reaction scale 25 g); c₁₂H₉F₃N₂O₄LCMS calculation of S: 334.02, respectively; LCMS observations: 335.05(M +1)⁺。

Synthesis of methyl 5- (3-chlorophenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 12g (53.3%, reaction scale 18 g); c₁₁H₉ClN₂O₄LCMS calculation of S: 300.00; LCMS observations: 300.90(M +1)⁺。

Synthesis of methyl 5- (3- (trifluoromethoxy) phenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 13g (crude, reaction scale 15 g); c₁₂H₉F₃N₂O₅LCMS calculation of S: 350.02; LCMS observations: 352(M +1)⁺。

Synthesis of methyl 5- (4- (difluoromethoxy) phenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 9g (crude, reaction scale 12 g); c₁₂H₁₀F₂N₂O₅LCMS calculation of S: 332.03, respectively; LCMS observations: 333(M +1)⁺。

Synthesis of methyl 5- (3- (difluoromethoxy) phenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 5.10g (69.76%, scale of reaction 6 g); c₁₂H₁₀F₂N₂O₅LCMS calculation of S: 332.03, respectively; LCMS observations: 333(M +1)⁺。

Synthesis of methyl 5- (4-chlorophenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 35g (87%, reaction scale 32 g); c₁₁H₉ClN₂O₄LCMS calculation of S: 300.00; LCMS observations: 300.95(M +1)⁺。

Synthesis of methyl 5- (4-bromo-3-fluorophenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (21):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 7.6g (79%, reaction scale 8 g); c₁₁H₈BrFN₂O₄LCMS calculation of S: 361.94, respectively; LCMS observations: 364.95(M +2)⁺。

Synthesis of methyl 2-methyl-5- (pyridin-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general procedure a described above for alkylation to give 0.8g (76.04%, scale of reaction 1 g); c₁₁H₁₁N₃O₄LCMS calculation of S: 281.05, respectively; LCMS observations: 282.20(M +1)⁺。

Synthesis of methyl 5- (5-fluoropyridin-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general method B described above for alkylation to give 1g (95.32%, reaction scale 1 g); c₁₁H₁₀FN₃O₄LCMS calculation of S: 299.04, respectively; LCMS observations: 299.95(M +1)⁺。

Synthesis of methyl 2-methyl-5- (pyridin-3-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title CompoundSynthesized using general procedure B described above for alkylation to give 1.6g (50.6%, reaction scale 3 g); c₁₁H₁₁N₃O₄LCMS calculation of S: 281.05, respectively; LCMS observations: 282.20(M +1)⁺。

Synthesis of methyl 5- (4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general method B described above for alkylation to give 0.5g (95%, scale of reaction 0.5 g); c₁₂H₁₁FN₂O₄LCMS calculation of S: 298.04, respectively; LCMS observations: 299.10(M +1)⁺。

Synthesis of methyl 5- (4-fluorophenyl) -2- (2-methoxyethyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general method B described above for alkylation to give 0.8g (crude, reaction scale 1 g); { notes: as a mixture of the desired product and the major trans-esterification by-products. The mixture is carried to the next reaction (ester hydrolysis) without any separation }. C₁₄H₁₅FN₂O₅LCMS calculation of S: 342.07, respectively; LCMS observations: 343.20(M +1)⁺。

Synthesis of methyl 2-methyl-5-phenyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general method B described above for alkylation to give 2.4g (46%, reaction scale 5 g); c₁₂H₁₂N₂O₄LCMS calculation of S: 280.05, respectively; LCMS observations: 281.15(M +1)⁺。

Synthesis of methyl 5- (4-methoxyphenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general method B described above for alkylation to give 5g (95.9%, reaction scale 5 g); c₁₃H₁₄N₂O₅LCMS calculation of S: 310.06, respectively; LCMS observations: 310.95(M +1)⁺。

Synthesis of methyl 5- (4-bromophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general procedure B described above for alkylation to give 28g (89.45%, reaction scale 30 g); c₁₂H₁₁BrN₂O₄LCMS calculation of S: 357.96, respectively; LCMS observations: 360.95(M +1)⁺。

Synthesis of methyl 5- (3-methoxyphenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general method B described above for alkylation to give 4.8g (92%, reaction scale 5 g); c₁₃H₁₄N₂O₅LCMS calculation of S: 310.06, respectively; LCMS observations: 310.90(M +1)⁺。

Synthesis of methyl 5- (2-methoxyphenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general method B described above for alkylation to18g (95.49%, reaction scale 18g) were obtained; c₁₃H₁₄N₂O₅LCMS calculation of S: 310.06, respectively; LCMS observations: 311.00(M +1)⁺。

Synthesis of methyl 2-methyl-5- (4- (trifluoromethyl) phenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general procedure B described above for alkylation to give 5g (99.9%, reaction scale 5 g); c₁₃H₁₁F₃N₂O₄LCMS calculation of S: 348.04, respectively; LCMS observations: 348.90(M +1)⁺。

Synthesis of methyl 5- (3, 4-difluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general procedure B described above for alkylation to give 4g (76.48%, reaction scale 5 g); c₁₂H₁₀F₂N₂O₄LCMS calculation of S: 316.03, respectively; LCMS observations: 317.00(M +1)⁺。

Synthesis of methyl 5- (3-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general procedure B described above for alkylation to give 7g (66.73%, reaction scale 10 g); c₁₂H₁₁FN₂O₄LCMS calculation of S: 298.04, respectively; LCMS observations: 299.00(M +1)⁺。

Synthesis of methyl 2-methyl-5- (4- (trifluoromethoxy) phenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general method B described above for alkylation to give 13.1g (84.08%, scale of reaction 15 g); c₁₃H₁₁F₃N₂O₄LCMS calculation of S: 364.03, respectively; LCMS observations: 364.90(M +1)⁺。

Synthesis of methyl 2-methyl-5- (3- (trifluoromethyl) phenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general procedure B described above for alkylation to give 7g (67.24%, reaction scale 10 g); c₁₃H₁₁F₃N₂O₄LCMS calculation of S: 348.04, respectively; LCMS observations: 349.15(M +1)⁺。

Synthesis of methyl 5- (3-chlorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general method B described above for alkylation to give 3.6g (69%, reaction scale 5 g); c₁₂H₁₁ClN₂O₄LCMS calculation of S: 314.01; LCMS observations: 314.95(M +1)⁺。

Synthesis of methyl 2-methyl-5- (3- (trifluoromethoxy) phenyl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general method B described above for alkylation to give 5g (96.15%, reaction scale 5 g); c₁₃H₁₁F₃N₂O₅LCMS calculation of S: 364.03, respectively; LCMS observations: 365.05(M +1)⁺。

Synthesis of methyl 5- (4- (difluoromethoxy) phenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general procedure B described above for alkylation to give 5g (95.96%, reaction scale 5 g); c₁₃H₁₂F₂N₂O₅LCMS calculation of S: 346.04, respectively; LCMS observations: 347.05(M +1)⁺。

Synthesis of methyl 5- (3- (difluoromethoxy) phenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general method B described above for alkylation to give 3g (96.77%, reaction scale 3 g); c₁₃H₁₂F₂N₂O₅LCMS calculation of S: 346.04, respectively; LCMS observations: 347.05(M +1)⁺。

Synthesis of methyl 5- (4-chlorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general method B described above for alkylation to give 9.0g (86%, reaction scale 10 g); c₁₂H₁₁ClN₂O₄LCMS calculation of S: 314.01; LCMS observations: 314.90(M +1)⁺。

Synthesis of methyl 5- (4-bromo-3-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (22):

the title compound was synthesized using general method B described above for alkylation to give 2.2g (70.7%, scale of reaction 3 g); c₁₂H₁₀BrFN₂O₄LCMS calculation of S: 375.95, respectively; LCMS observations: 378.95(M +2)⁺。

N- (3-chloro-4-fluorophenyl) -2-methyl-5- (pyridin-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-031_ Int)

The title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -5- (5-fluoropyridin-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-032_ Int)

The title compound above has been synthesized following the general procedure described above for amidation (method a) by using compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2-methyl-5- (pyridin-3-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-033_ Int)

The title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -5- (4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-112_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine. The crude intermediate was confirmed by LCMS and carried to the next step.

N- (3-chloro-4-fluorophenyl) -2-methyl-5-phenyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-113_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -5- (4-methoxyphenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-200_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

5- (4-bromophenyl) -N- (3-chloro-4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-202 — Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -5- (3-methoxyphenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-204_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -5- (4-fluorophenyl) -2- (2-methoxyethyl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-210_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine. The reaction was monitored by LCMS and the crude intermediate was carried to the next step.

N- (3-bromo-4-fluorophenyl) -5- (4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-211_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

5- (4-fluorophenyl) -2-methyl-N- (3,4, 5-trifluorophenyl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-212_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -5- (2-methoxyphenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-215_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (trifluoromethyl) phenyl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-217_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -5- (3, 4-difluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-230_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -5- (3-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-231_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine. The crude intermediate was confirmed by LCMS and carried to the next step.

N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (trifluoromethoxy) phenyl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-232_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2-methyl-5- (3- (trifluoromethyl) phenyl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-259_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -5- (3-chlorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-261_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2-methyl-5- (3- (trifluoromethoxy) phenyl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-262_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -5- (4- (difluoromethoxy) phenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-263_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -5- (3- (difluoromethoxy) phenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-264_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -5- (4-chlorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-265_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

5- (4-bromo-3-fluorophenyl) -N- (3-chloro-4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-283_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 22 and the corresponding amine (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (pyridin-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-031, HBV-CSU-031-ISO-I and HBV-CSU-031-ISO-II):

the title compound was synthesized according to the general procedure described above for reduction by using the corresponding HBV-CSU-031_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5-fluoropyridin-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-032, HBV-CSU-032-ISO-I and HBV-CSU-032-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-032_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (pyridin-3-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-033):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-033_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-112, HBV-CSU-112-ISO-I and HBV-CSU-112-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-112_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5-phenyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-113-ISO-I and HBV-CSU-113-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-113_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4-methoxyphenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-200):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-200_ Int (see Table 2 for analytical data).

Cis-5- (4-bromophenyl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-202):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-202_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (3-methoxyphenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-204):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-204_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4-fluorophenyl) -2- (2-methoxyethyl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-210, HBV-CSU-210-ISO-I and HBV-CSU-210-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-210_ Int (see Table 2 for analytical data).

cis-N- (3-bromo-4-fluorophenyl) -5- (4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-211, HBV-CSU-211-ISO-I and HBV-CSU-211-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-211_ Int (see Table 2 for analytical data).

Cis-5- (4-fluorophenyl) -2-methyl-N- (3,4, 5-trifluorophenyl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-212, HBV-CSU-212-ISO-I and HBV-CSU-212-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-212_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (2-methoxyphenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-215):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-215_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (trifluoromethyl) phenyl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-217, HBV-CSU-217-ISO-I and HBV-CSU-217-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-217_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (3, 4-difluorophenyl) -2-methyl-1, 2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-230, HBV-CSU-230-ISO-I and HBV-CSU-230-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-230_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (3-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-231, HBV-CSU-231-ISO-I and HBV-CSU-231-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-231_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (trifluoromethoxy) phenyl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-232):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-232_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (3- (trifluoromethyl) phenyl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-259, HBV-CSU-259-ISO-I and HBV-CSU-259-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-259_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (3-chlorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-261, HBV-CSU-261-ISO-I and HBV-CSU-261-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-261_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (3- (trifluoromethoxy) phenyl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-262, HBV-CSU-262-ISO-I and HBV-CSU-262-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-262_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4- (difluoromethoxy) phenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-263, HBV-CSU-263-ISO-I and HBV-CSU-263-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-263_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (3- (difluoromethoxy) phenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-264, HBV-CSU-264-ISO-I and HBV-CSU-264-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-264_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4-chlorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-265):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-265_ Int (see Table 2 for analytical data).

Cis-5- (4-bromo-3-fluorophenyl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-283):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-283_ Int (see Table 2 for analytical data).

Scheme 7:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2- (2-hydroxyethyl) -5- (thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-041):

scheme 7

N- (3-chloro-4-fluorophenyl) -2- (2-oxoethyl) -5- (thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-041_ Int):

to a stirred solution of HNB-CSU-40_ Int (0.2g, 0.47mmol) in DCM (10mL) at 0 deg.C was added NMO (0.169g, 1.41mmol) and stirred for 10 min. To the solution, OsO was added at 0 deg.C₄A solution in butanol (0.035g, 0.141mmol) was stirred at room temperature for 1 h. After completion, the reaction mixture was concentrated under reduced pressure. The crude residue obtained is dissolved in 10ml of THF H₂O (1:1) mixture, adding NaIO₄(0.278g, 1.41mmol) and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure and the resulting crude compound was purified by silica gel column chromatography using 15% EtOAc/hexanes to give the desired compound (0.1g, 49.75%) as an off-white solid. TLC of aldehyde: 40% EtOAc/hexanes (R)_f: 0.3); the reaction was monitored by TLC (DNP staining) and the crude intermediate was carried to the next step without any purification.

cis-N- (3-chloro-4-fluorophenyl) -2- (2-hydroxyethyl) -5- (thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-041):

the title compound was synthesized following the general procedure described above for reduction using HBV-CSU-041_ Int (see Table 2 for analytical data).

Scheme 8:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2, 5-dimethyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-050-ISO-I and HBV-CSU-050-ISO-II):

scheme 8

Synthesis of methyl 5-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (24):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 5.95g (84.03%, scale of reaction 5 g); c₆H₈N₂O₄LCMS calculation of S: 204.02, respectively; LCMS observations: 204.85(M +1)⁺。

Synthesis of methyl 2, 5-dimethyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (25):

the title compound was synthesized using general procedure a described above for alkylation to give 3.57g (83.6%, scale of reaction 4 g); c₇H₁₀N₂O₄LCMS calculation of S: 218.04, respectively; LCMS observations: 218.90(M +1)⁺。

Synthesis of N- (3-chloro-4-fluorophenyl) -2, 5-dimethyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-050_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 25 and the corresponding amine (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2, 5-dimethyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-050-ISO-I and HBV-CSU-050-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-050_ Int (see Table 2 for analytical data).

Scheme 9:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (1-methyl-1H-pyrazol-5-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-054, HBV-CSU-054-ISO-I and HBV-CSU-054-ISO-II):

scheme 9

Synthesis of N-methoxy-N, 1-dimethyl-1H-pyrazole-5-carboxamide (27):

to compound 26(12g, 95.23mmol) in CH at 0 deg.C under an inert atmosphere₂Cl₂(600mL) to a stirred solution was added N, O-dimethylhydroxylamine hydrochloride (10.26g, 104.76mmol), EDCI. HCl (19.2g, 100.00mmol), DMAP (12.8g, 104.91mmol) and N-methylmorpholine (12.8mL, 11.54mmol), then warmed to room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by flash column chromatography on silica gel using 10% EtOAc/hexanes to give compound 27(12g, 75%) as a brown liquid. TLC: 20% EtOAc/hexanes (R)_f：0.8)；¹H NMR(400MHz，CDCl₃)：δ7.48(d，J＝2.0Hz，1H)，6.77(d，J＝2.0Hz，1H)，4.13(s，3H)，3.66(s，3H)，3.36(s，3H)；C₇H₁₁N₃O₂LCMS calculated of (d): 169.09, respectively; and (3) observation value: 169.9(M +1) +.

Synthesis of 1- (1-methyl-1H-pyrazol-5-yl) ethan-1-one (28):

to a stirred solution of compound 27(6g, 35.50mmol) in dry ether (75mL) was added dropwise methylmagnesium bromide (23.6mL, 71.00mmol, 3M in ether) at-40 ℃ under an inert atmosphere for 15 minutes, then warmed to room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (50mL) and extracted with ether. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 28(5g, crude material) as a light brown liquid. TLC: 20% EtOAc/hexanes (R)_f：0.4)；¹H NMR(400MHz，CDCl₃)：δ7.46(d，J＝2.0Hz，1H)，6.83(d，J＝2.1Hz，1H)，4.16(s，3H)，2.52(s，3H)；C₆H₈N₂LCMS calculated for O: 124.06, respectively; and (3) observation value: 124.9(M +1)⁺。

Synthesis of methyl 4- (1-methyl-1H-pyrazol-5-yl) -2, 4-dioxobutyrate (29):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 7g (94% over 2 steps, reaction scale 5g) as a light yellow solid. TLC: 20% EtOAc/hexanes (R)_f：0.3)；¹H NMR(400MHz，DMSO-d₆)：δ13.33(br.s，1H)，7.59(d，J＝1.8Hz，1H)，7.38(br.s，1H)，6.93(s，1H)，4.13(s，3H)，3.85(s，3H)；C₉H₁₀N₂O₄LCMS calculated of (d): 210.06, respectively; and (3) observation value: 210.9(M)⁺。

Synthesis of methyl 5- (1-methyl-1H-pyrazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (30):

the title compound was synthesized using general procedure a described above for the synthesis of cyclic sulfonamides to give2g (44%, reaction scale 3.5g) as a pale yellow solid. TLC: 5% MeOH/CH₂Cl₂(R_f：0.2)；¹H NMR(400MHz，DMSO-d₆)：δ7.49(d，J＝2.0Hz，1H)，6.86(d，J＝2.0Hz，1H)，6.55(s，1H)，4.11(s，3H)，3.81(s，3H)。

Synthesis of methyl 2-methyl-5- (1-methyl-1H-pyrazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (31):

the title compound was synthesized using general procedure a for alkylation above to give 50mg (12%, reaction scale 400mg) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂(R_f：0.4)；¹H NMR(400MHz，DMSO-d₆)：δ7.64(d，J＝2.1Hz，1H)，7.33(d，J＝2.3Hz，1H)，7.17(s，1H)，4.16(s，3H)，3.94(s，3H)，3.53(s，3H)；C₁₀H₁₂N₄O₄LCMS calculation of S: 284.06, respectively; and (3) observation value: 285.1(M +1)⁺。

Synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (1-methyl-1H-pyrazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-054_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 31 and the corresponding amine (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (1-methyl-1H-pyrazol-5-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-054, HBV-CSU-054-ISO-I and HBV-CSU-054-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-054_ Int (see Table 2 for analytical data).

Scheme 10:

synthesis protocol for cis-N- (3-chloro-4-fluorophenyl) -5- (isoxazol-3-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-055, HBV-CSU-055-ISO-I and HBV-CSU-055-II):

scheme 10:

synthesis of N-methoxy-N-methylisoxazole-3-carboxamide (33):

to isoxazole-3-carboxylic acid 32(7g, 61.94mmol) in CH at 0 ℃ under an inert atmosphere₂Cl₂To a stirred solution in (200mL) was added N, O-dimethylhydroxylamine hydrochloride (6.64g, 68.14mmol), EDCI. HCl (13g, 68.14mmol), DMAP (7.6g, 61.94mmol) and N-methylmorpholine (9.5mL, 92.92mmol), then warmed to room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water and washed with CH₂Cl₂And (4) extracting. The combined organic extracts were washed with 2N HCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography on silica gel using 3% MeOH/CH₂Cl₂To give compound 33(6g, 63%) as a brown liquid. TLC: 5% MeOH/CH₂Cl₂(R_f：0.8)；¹H NMR(400MHz，DMSO-d₆)：δ9.08(d，J＝1.6Hz，1H)，6.86(d，J＝1.3Hz，1H)，3.68(s，3H)，3.31(s，3H)。

Synthesis of 1- (isoxazol-3-yl) ethan-1-one (34):

at-40 deg.CTo a stirred solution of compound 33(6g, 38.46mmol) in dry ether (100mL) was added dropwise methylmagnesium bromide (12.8mL, 38.46mmol, 3M in ether) under an inert atmosphere for 10min, then warmed to 0 ℃ and stirred for 2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution at 0 ℃ and stirred for 15 minutes, then extracted with ether. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 34(3g, 70%) as a light brown liquid. TLC: 20% EtOAc/hexanes (R)_f：0.8)；¹H NMR(400MHz，DMSO-d₆)：δ9.13(d，J＝1.8Hz，1H)，6.92(d，J＝1.8Hz，1H)，2.60(s，3H)。

Synthesis of methyl (E/Z) -4-hydroxy-4- (isoxazol-3-yl) -2-oxobut-3-enoate (35):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 2g (38, reaction scale 3g) as an off-white sticky solid. TLC: 5% MeOH/CH₂Cl₂(R_f：0.4)；¹H NMR(400MHz，DMSO-d₆)：δ9.19(d，J＝1.5Hz，1H)，7.08(s，1H)，5.24(br.s，2H)，3.85(s，3H)。

Synthesis of 5- (isoxazol-3-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (36):

the title compound was synthesized using general procedure a described above for the synthesis of cyclic sulfonamides to give 1.2g (crude, reaction scale 1g) as an off-white solid. TLC: 5% MeOH/CH ₂Cl₂(R_f: 0.4). The crude material was used as such for the next reaction without further characterization.

Synthesis of 5- (isoxazol-3-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (37):

the title compound was synthesized using general procedure a for alkylation above to give 350mg (26%, reaction scale 1.2g) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂(R_f：0.4)；¹H NMR(500MHz，DMSO-d₆)：δ9.26(s，1H)，7.27(s，1H)，7.21(s，1H)，3.94(s，3H)，3.60(s，3H)。

Synthesis of N- (3-chloro-4-fluorophenyl) -5- (isoxazol-3-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-055_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 37 and the corresponding amine (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (isoxazol-3-yl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-055, HBV-CSU-055-ISO-I and HBV-CSU-055-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-055_ Int (see Table 2 for analytical data).

Scheme 11:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -5- (isothiazol-3-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-056, HBV-CSU-056-ISO-I and HBV-CSU-056-ISO-II):

scheme 11:

synthesis of 3-methylisothiazole (39):

to but-3-yn-2-one 38(17g, 249.70mmol) in H at 0 deg.C₂To a stirred solution in O (100mL) was added hydroxylamine-O-sulfonic acid (29.1g, 257.23mmol) and stirred for 30 min. To this was added sodium bicarbonate (23.72g, 281.9mmol) portionwise at 0 ℃ for 20 minutes, followed by dropwise addition of sodium hydrosulfide dihydrate (26g, 282.2mmol) in H at 0 DEG C₂Solution in O (170mL) for 15min, then warmed to room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ether. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo at 20 ℃ to give compound 39(10g, 40%) as a colorless syrup. TLC: 15% EtOAc/hexanes (R)_f：0.5)；¹H-NMR(DMSO-d₆，400MHz)：δ8.96(d，J＝4.5Hz，1H)，7.20(d，J＝4.5Hz，1H)，2.45(s，3H)。

Synthesis of isothiazole-3-carboxylic acid (40):

to a stirred solution of compound 39(10g, 100.85mmol) in concentrated sulfuric acid (300mL) at 0 deg.C under an inert atmosphere was added chromium (VI) oxide (30.25g, 302.57mmol) in portions, which was then warmed to room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was slowly quenched with ice-cold water (3L) and extracted with ether (10 × 600 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude compound 40(3g, 23%) as a white solid. TLC: 20% EtOAc/hexanes (R)_f：0.1)。¹H-NMR(DMSO-d₆，400MHz)：δ10.95(br.s，1H)，9.16(d，J＝4.6Hz，1H)，7.80(d，J＝4.6Hz，1H)；C₄H₃NO₂LCMS calculation of S: 128.99, respectively; and (3) observation value: 130.4(M +1)⁺。

Synthesis of N-methoxy-N-methylisothiazole-3-carboxamide (41):

to compound 40(3g, 23.25mmol) in CH at 0 ℃ under an inert atmosphere₂Cl₂To a stirred solution in (60mL) were added EDCI. HCl (4.9g, 25.58mmol), DMAP (2.8g, 23.25mmol), N-methylmorpholine (7.65mL, 69.76mmol) and N, O-dimethylhydroxylamine hydrochloride (2.72g, 27.90mmol), then warmed to room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water and with CH₂Cl₂And (4) extracting. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by flash column chromatography on silica gel using 40-45% EtOAc/hexanes to give compound 41(2.5g, 63%) as a brown slurry. TLC: 40% EtOAc/hexanes (R)_f：0.5)；¹H NMR(400MHz，DMSO-d₆)：δ9.15(d，J＝4.8Hz，1H)，7.63(d，J＝4.4Hz，1H)，3.69(s，3H)，3.33(s，3H)；C₆H₇LCMS calculated for NOS: 141.02, respectively; and (3) observation value: 142.0(M +1)⁺.LC-MS：98.67％；172.9(M+1)⁺。

Synthesis of 1- (isothiazol-3-yl) ethan-1-one (42):

to a stirred solution of compound 41(2.5g, 14.53mmol) in dry ether (25mL) was added dropwise methylmagnesium bromide (58mL, 58.13mmol, 3M in ether) at-40 ℃ under an inert atmosphere for 20min, then warmed to 0 ℃ and stirred for 2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution at 0 ℃ and extracted with ether. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo at less than 20 ℃ to give crude compound 42(1.8g, 98%) as a yellow liquid. TLC: 30% EtOAc/hexanes (R)_f：0.8)；¹H NMR(500MHz，DMSO-d₆)：δ9.15(d，J＝4.5Hz，1H)，7.80(d，J＝4.5Hz，1H)，2.62(s，3H)；C₅H₅LCMS calculated for NOS: 127.01; and (3) observation value: 128.4(M +1)⁺。

Synthesis of methyl (E/Z) -4-hydroxy-4- (isothiazol-3-yl) -2-oxobut-3-enoic acid ester (43):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 1.5g (50%, scale of reaction 1.8g) as a yellow solid. TLC: 5% MeOH/CH₂Cl₂(R_f：0.4)；¹H NMR(400MHz，DMSO-d₆)：δ9.24(d，J＝4.6Hz，1H)，7.95(d，J＝4.4Hz，1H)，7.27-7.24(m，1H)，3.86(s，3H)；C₈H₇NO₄LCMS calculation of S: 213.01, respectively; and (3) observation value: 214.2(M +1)⁺。

Synthesis of methyl 5- (isothiazol-3-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (44):

the title compound was synthesized using general procedure a described above for the synthesis of cyclic sulfonamides to give 1.2g (63%, scale of reaction 1.5g) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂(R_f：0.1)；¹H NMR(400MHz，DMSO-d₆)：δ9.16(d，J＝4.6Hz，1H)，7.90(d，J＝4.6Hz，1H)，7.06(s，1H)，3.83(s，3H)；C₈H₇N₃O₄S₂LCMS calculated of (d): 272.99, respectively; LCMS observations: 271.9(M-1)^-。

Synthesis of methyl 5- (isothiazol-3-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (45):

use of the title CompoundGeneral procedure a above for alkylation was synthesized to give 450mg (61%, reaction scale 700mg) as an off-white solid. TLC: 40% EtOAc/hexanes (R)_f：0.6)；¹H NMR(400MHz，DMSO-d₆)：δ9.28(d，J＝4.8Hz，1H)，8.04(d，J＝4.8Hz，1H)，7.50(s，1H)，3.94(s，3H)，3.58(s，3H)。

Synthesis of N- (3-chloro-4-fluorophenyl) -5- (isothiazol-3-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-056_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 45 and the corresponding amine (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (isothiazol-3-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-056, HBV-CSU-056-ISO-I and HBV-CSU-056-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-055_ Int (see Table 2 for analytical data).

Scheme 12:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -5- (isothiazol-5-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-057, HBV-CSU-057-ISO-I and HBV-CSU-057-ISO-II):

scheme 12:

synthesis of N-methoxy-N-methylisothiazole-5-carboxamide (47):

isothiazole-5-carboxylic acid 46(1.75g, 13.56mmol) in CH at 0 ℃ under an inert atmosphere₂Cl₂To a stirred solution in (50mL) was added N, O-dimethylhydroxylamine (1.45g, 14.92mmol), EDCI. HCl (2.85g, 14.92mmol), DMAP (1.66g, 13.56mmol) and N-methylmorpholine (4.1mL, 40.69mmol), then warmed to room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water and washed with CH₂Cl₂And (4) extracting. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography on silica gel using 2% MeOH/CH₂Cl₂To give compound 47(1.2g, 52%) as a brown slurry. TLC: 5% MeOH/CH₂Cl₂(R_f：0.2)；¹H NMR(400MHz，DMSO-d₆)：δ8.64(d，J＝1.8Hz，1H)，7.96(d，J＝1.8Hz，1H)，3.82(s，3H)，3.33(s，3H)；C₆H₈N₂O₂LCMS calculation of S: 172.03, respectively; and (3) observation value: 173.1(M +1)⁺。

Synthesis of 1- (isothiazol-5-yl) ethan-1-one (48):

to a stirred solution of compound 47(1.2g, 6.97mmol) in dry ether (30mL) was added dropwise methylmagnesium bromide (6.97mL, 20.93mmol, 3M in ether) at-40 ℃ under an inert atmosphere for 10min, then warmed to 0 ℃ and stirred for 2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ether. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give compound 48(800mg, crude material) as a yellow liquid. TLC: 20% EtOAc/hexanes (R)_f：0.8)；¹H NMR(400MHz，DMSO-d₆)：δ8.75(d，J＝1.9Hz，1H)，8.04(d，J＝1.8Hz，1H)，2.64(s，3H)。

Synthesis of (E/Z) -4-hydroxy-4- (isothiazol-5-yl) -2-oxobut-3-enoic acid methyl ester (49):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 600mg (45%, reaction scale 800mg) as a yellow solid. TLC: 5% MeOH/CH₂Cl₂(R_f：0.4)；¹H NMR(400MHz，DMSO-d₆)：δ8.78(d，J＝1.9Hz，1H)，8.29(br.s，1H)，6.98(br.s，1H)，3.86(s，3H)。

Synthesis of methyl 5- (isothiazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (50):

the title compound was synthesized using general procedure a described above for the synthesis of the cyclic sulfonamides to give 300mg (36%, reaction scale 650mg) as a yellow solid. TLC: 10% MeOH/CH₂Cl₂(R_f：0.1)；¹H NMR(400MHz，DMSO-d₆)：δ8.59(d，J＝1.9Hz，1H)，7.93(d，J＝1.9Hz，1H)，6.73(br.s，1H)，6.60(s，1H)，3.80(s，3H)；C₁₃H₁₀N₄O₄S₂LCMS calculated of (d): 272.99, respectively; LCMS observations: 274.2(M +1)⁺。

Synthesis of methyl 5- (isothiazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (51):

the title compound was synthesized using general procedure a for alkylation above to give 85mg (32%, 250mg reaction scale) as an off-white solid. TLC: 30% EtOAc/hexanes (R)_f：0.48；¹H NMR(400MHz，DMSO-d₆)：δ8.80(d，J＝1.9Hz，1H)，8.37(d，J＝1.9Hz，1H)，7.37(s，1H)，3.96(s，3H)，3.58(s，3H)；C₁₃H₁₀N₄O₄S₂LCMS calculated of (d): 287.00, respectively; LCMS observations: 288.1(M +1)⁺。

Synthesis of N- (3-chloro-4-fluorophenyl) -5- (isothiazol-5-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-057_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 51 and the corresponding amine (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (isothiazol-5-yl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-057):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-057_ Int (see Table 2 for analytical data).

Scheme 13:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2- (2- (methylsulfonyl) ethyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-73, HBV-CSU-73-ISO-I and HBV-CSU-73-ISO-II):

scheme 13:

synthesis of N- (3-chloro-4-fluorophenyl) -2- (2- (methylsulfonyl) ethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-073_ Int):

to HBV-CSU-109_ Int (1g, 2.17mmol) in 1, 2-dichloroethane: CH (CH)₃CN：H₂To a stirred solution in O (1:1: 2, 20mL) was added sodium metaperiodate (1.3g, 6.07mmol) and ruthenium chloride (22.54mg, 0.10mmol) and stirred for 3 h. The reaction was monitored by TLC. After completion, the volatiles were removed in vacuo. The residue was diluted with water and extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography on silica gel using 1% MeOH/CH₂Cl₂. The resulting solid was washed with diethyl ether and dried in vacuo to give HBV-CSU-073_ Int (560mg, 53%) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂(R_f: 0.5) (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (2- (methylsulfonyl) ethyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-073:

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-073_ Int (see Table 2 for analytical data).

Scheme 14:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2- (2- (dimethylamino) ethyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-074) and cis-N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-096):

scheme 14:

cis-N- (3-chloro-4-fluorophenyl) -2- (2- (dimethylamino) ethyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-074):

to HBV-CSU-096(20mg, 0.051mmol.) in CH at 0 deg.C₃CN (0.5mL) in a stirred solution, K was added₂CO₃(14mg, 0.102mmol) and 2-chloro-N, NDimethylether-1-amine hydrochloride (7mg, 0.051 mmol). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice-cold water. The resulting solid was filtered and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. The crude compound was purified by silica gel column chromatography to give compound HBV-CSU-074 (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-096, HBV-CSU-096-ISO-I and HBV-CSU-096-ISO-II):

to a stirred solution of compound HBV-CSU-108(0.14g, 0.274mmol) in DCM (1mL) at 0 deg.C was added TFA (5mL) and stirred at room temperature for 30 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give the desired compound HBV-CSU-096(80mg, 76%) as an off-white solid. TLC: 40% EtOAc/hexanes (R)_f: 0.3) (see table 2 for analytical data).

Scheme 15:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2- (3-hydroxypropyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-078, HBV-CSU-078-ISO-I and HBV-CSU-078-ISO-II):

scheme 15:

to a stirred solution of compound HBV-CSU-077(50mg, 0.108mmol) in DCM (5mL) at-40 deg.C was added BBr₃(0.054g, 0.216mmol) and stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was taken up with saturated NaHCO₃The solution was quenched and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Novel compoundsPurification by silica gel column chromatography to give the desired compound HBV-CSU-078(0.042g, 88%) as a white solid. TLC: 40% EtOAc/hexanes (R)_f: 0.1) (see table 2 for analytical data).

Scheme 16:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2- (2- (methylsulfonyl) ethyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-092, HBV-CSU-092-ISO-I and HBV-CSU-092-ISO-II):

scheme 16:

2- (2- (1H-1,2, 3-triazol-4-yl) ethyl) -N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-092_ Int):

to HBV-CSU-090_ Int (300mg, 0.68mmol) in DMF at 10 deg.C: h₂To a stirred solution of a mixture of O (3: 1, 8mL) was added copper (II) sulfate pentahydrate (17mg, 0.068mmol) and L-ascorbic acid sodium salt (543mg, 2.73mmol) and azidotrimethylsilane (0.14mL, 1.02mmol), then warmed to room temperature and stirred for 36 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by flash column chromatography on silica gel with 1-2% MeOH/CH₂Cl₂To give HBV-CSU-092_ Int (80mg, 24%) as an off-white solid. TLC: 40% EtOAc/hexanes (R)_f: 0.3) (see table 1 for analytical data).

Cis-2- (2- (1H-1,2, 3-triazol-4-yl) ethyl) -N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-092, HBV-CSU-092-ISO-I, HBV-CSU-092-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-092_ Int (see Table 2 for analytical data).

Scheme 17:

cis-N- (3-chloro-4-fluorophenyl) -2- (cyanomethyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-ane-3-carboxamide 1, 1-dioxide (HBV-CSU-093)/cis-2- (3- ((3-chloro-4-fluorophenyl) carbamoyl) -1, 1-dioxo-5- (thiazol-2-yl) -1,2, 6-thiadiazine-N-2-yl) acetic acid (HBV-CSU-110) and cis-2- (3- ((3-chloro-4-fluorophenyl) carbamoyl) -1, 1-dioxo-5- (thiazol-2-yl) -1,2, 6-thiadiazine-2-yl) acetic acid (HBV-CSU-111):

methyl 2- (2- (tert-butoxy) -2-oxoethyl) -5- (thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (52):

the title compound was synthesized using general procedure B described above for alkylation to give 6g (84.74%, reaction scale 5 g); c₁₄H₁₇N₃O₆S₂LCMS calculated of (d): 387.06, respectively; LCMS observations: 332.15(M-55)⁺。

Synthesis of tert-butyl 2- (3- ((3-chloro-4-fluorophenyl) carbamoyl) -1, 1-dioxo-5- (thiazol-2-yl) -2H-1,2, 6-thiadiazin-2-yl) acetate (53):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 52 and the corresponding amine.¹H NMR suggests the desired alkylation (note: NMR indicates contamination by hydrazide by-product).

Tert-butyl 2- (3- ((3-chloro-4-fluorophenyl) carbamoyl) -1, 1-dioxo-5- (thiazol-2-yl) -1,2, 6-thiadiazinan-2-yl) acetate (54):

the title compound above has been synthesized following the general procedure described above for the reduction by using the corresponding compound 53. The crude material was used directly in the next step.

cis-N- (3-chloro-4-fluorophenyl) -2- (cyanomethyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-093, HBV-CSU-093-ISO-I and HBV-CSU-093-ISO-II):

to a stirred solution of HBV-CSU-111(50mg, 0.111mmol) in DCM (2mL) at 0 deg.C was added TFAA (0.046mL, 0.33mmol) and stirred at the same temperature for 20 min. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure; water was added and extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a solid which was triturated with ether to give the desired compound HBV-CSU-093(0.11g, 38.32%) as a white solid. TLC: 5% MeOH/DCM (R)_f: 0.2) (see table 2 for analytical data).

Cis-2- (3- ((3-chloro-4-fluorophenyl) carbamoyl) -1, 1-dioxo-5- (thiazol-2-yl) -1,2, 6-thiadiazin-an-2-yl) acetic acid (HBV-CSU-110):

to a stirred solution of compound 54(0.9g, 1.78mmol) in DCM (5mL) at 0 ℃ was added TFA (15mL) and stirred at rt for 6 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was washed with diethyl ether and purified by preparative HPLC to give the desired compound HBV-CSU-110(30mg, 23%) as a white solid. TLC: 40% EtOAc/hexanes (R)_f: 0.1) (see table 2 for analytical data).

Cis-2- (3- ((3-chloro-4-fluorophenyl) carbamoyl) -1, 1-dioxo-5- (thiazol-2-yl) -1,2, 6-thiadiazin-an-2-yl) acetic acid (HBV-CSU-111):

to a stirred solution of compound HBV-CSU-110(0.16g, 0.357mmol) in DMF (10mL) at 0 deg.C were added DIPEA (0.138g, 1.07mmol) and HATU (0.176g, 0.464mmol) and stirred for 15 min. Adding NH to the solution₄Cl (0.056g, 1.07 mmol). The reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ice-cold water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound. The crude compound was purified by silica gel column chromatography to give the desired compound HBV-CSU-111(0.1g, 63%) as a white solid. TLC: 10% MeOH/DCM (R)_f: 0.3) (see table 2 for analytical data).

Scheme 18:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2- (2-hydroxyethyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-097, HBV-CSU-097-ISO-I and HBV-CSU-097-ISO-II):

scheme 18:

to a stirred solution of HBV-CSU-058(0.25g, 0.558mmol) in DCM (10mL) at-40 deg.C was added BBr₃(0.104mL, 1.11mmol) and stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was taken up with saturated NaHCO₃The solution was quenched and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give the desired compound HBV-CSU-097(0.06g, 24.79%) as an off-white solid. TLC: 5% MeOH/DCM (R)_f: 0.2) (see table 2 for analytical data).

Scheme 19:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2- (3- (diethylamino) propyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-101)/cis-N- (3-chloro-4-fluorophenyl) -2- (3- (pyrrolidin-1-yl) propyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-102) and cis-N- (3-chloro-4-fluorophenyl) -2- (3-morpholinopropyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-103):

scheme 19:

2- (3-bromopropyl) -N- (3-chloro-4-fluorophenyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (55):

to a stirred solution of HBV-CSU-077(2g, 4.31mmol) in DCM (20mL) at-40 ℃ under Ar was added BBr dropwise₃(2.02mL, 21.59 mmol). The resulting reaction mixture was stirred at room temperature for 5 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was taken up with saturated NaHCO₃The solution was quenched and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude compound was purified by silica gel column chromatography using 2% MeOH in DCM to give compound 55(1.35g, 61.08%) as a brown oil. C₁₆H₁₇BrClFN₄O₃S₂LCMS calculated of (d): 509.16, respectively; and (3) observation value: 513.35(M +4)⁺。

cis-N- (3-chloro-4-fluorophenyl) -2- (3- (diethylamino) propyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-101-ISO-I and HBV-CSU-101-ISO-II):

to compound 55 (0) at 0 deg.C3g, 0.585mmol) in DMF (5mL) and K was added₂CO₃(0.161g, 1.17mmol) and diethylamine (0.042g, 0.585 mmol). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice-cold water. The resulting solid was filtered and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with water and brine; dried over anhydrous sodium sulfate and concentrated in vacuo. The crude compound was purified by preparative HPLC to give the compound HBV-CSU-101(0.26g, 75.80%) as a white solid. (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (3- (pyrrolidin-1-yl) propyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-102, HBV-CSU-102-ISO-I and HBV-CSU-102-ISO-II):

to a stirred solution of compound 55(0.5g, 0.976mmol.) in DMF (5mL) at 0 deg.C was added K₂CO₃(0.404g, 2.92mmol) and pyrrolidine (0.138g, 1.95 mmol). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice-cold water. The resulting solid was filtered and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude compound was purified by preparative HPLC to give the compound HBV-CSU-102 (cis isomer) (0.12g, 24.53%) as a white solid. TLC: 5% MeOH/DCM (R)_f: 0.1) (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (3-morpholinopropyl) -5- (thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-103):

to a stirred solution of compound 55(0.5g, 0.976mmol.) in DMF (5mL) at 0 deg.C was added K₂CO₃(0.404g, 2.92mmol) and morpholine (0.169g, 1.95 mmol). The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with ice-cold water. The resulting solid was filtered and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude compound was purified by preparative HPLC to give the compound HBV-CSU-103(0.16g, 31.74%) as a white solid. TLC: 5% MeOH/DCM (R)_f: 0.1) (see table 2 for analytical data).

Scheme 20:

general synthetic scheme for 5- (thien-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide derivatives with 5-substituted thiophene and aniline variations:

scheme 20

Synthesis of methyl 4- (5-bromothien-2-yl) -2, 4-dioxobutyrate (56):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 115g (81%, reaction scale 100g) as a brown solid. TLC: 10% MeOH/DCM (R)_f：0.1)；¹H NMR(DMSO-d₆400 MHz): δ 8.12(d, J ═ 4.0Hz, 1H), 7.45(d, J ═ 4.0Hz, 1H), 7.03(br.s, 1H), 3.84(s, 3H); { notes: by passing¹The enol form was observed by H NMR and no peak of the enol was observed }. C₉H₇BrO₄LCMS calculation of S: 289.92, respectively; and (3) observation value: 290.95(M+1)⁺。

Synthesis of methyl 5- (5-bromothien-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (57):

the title compound was synthesized using general procedure B described above for the synthesis of cyclic sulfonamides to give 100g (72%, reaction scale 115g) as a brown solid. TLC: 20% MeOH/DCM (R)_f：0.1)；¹H NMR(DMSO-d₆，400MHz)：δ7.85(d，J＝4.0Hz，1H)，7.33(d，J＝4.0Hz，1H)，6.87(s 1H)，3.84(s，3H)；C₉H₇BrN₂O₄S₂LCMS calculated of (d): 349.90, respectively; LCMS observations: 352.90(M +2)⁺。

Synthesis of methyl 5- (5-bromothien-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (58):

the title compound was synthesized using general procedure a described above for alkylation to give 65g (62%, reaction scale 100g) as a brown solid. TLC: 40% EtOAc/hexanes (R)_f：0.4)；¹H NMR(DMSO-d₆，400MHz)：δ8.11(d，J＝4.0Hz，1H)，7.48(d，J＝4.0Hz，1H)，7.31(s 1H)，3.93(s，3H)，3.50(s，3H)；C₁₀H₉BrN₂O₄S₂LCMS calculated of (d): 363.92, respectively; LCMS observations: 366.90(M +2)⁺。

5- (5-bromothiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-0114-Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 58 and the corresponding amine (see table 1 for analytical data).

N- (3-bromo-4-fluorophenyl) -5- (5-bromothiophen-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-257_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 58 and the corresponding amine. The crude intermediate was confirmed by LCMS and carried to the next step.

5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-114, HBV-CSU-114-ISO-I and HBV-CSU-114-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-0114-Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5-methylthiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-115, HBV-CSU-115-ISO-I and HBV-CSU-115-ISO-II):

the title compound was synthesized following the general procedure described above for Negishi coupling, using HBV-CSU-114 and dimethylzinc (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5-phenylthiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-116-ISO-I and HBV-CSU-116-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-114 and the corresponding boronic acid (see table 2 for analytical data).

Cis- (5-benzylthiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-117, HBV-CSU-117-ISO-I and HBV-CSU-117-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-114 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5- (4-cyano-3-fluorophenyl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-156, HBV-CSU-156-ISO-I and HBV-CSU-156-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-114 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5- (4-bromo-3-fluorophenyl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-157):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-114 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (6- (trifluoromethyl) pyridin-3-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-158, HBV-CSU-158-ISO-I and HBV-CSU-158-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-114 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (pyridin-3-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-159, HBV-CSU-159-ISO-I and HBV-CSU-159-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-114 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (pyridin-2-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-160, HBV-CSU-160-ISO-I and HBV-CSU-160-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling, using HBV-CSU-114 and the corresponding stannane (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-161, HBV-CSU-161-ISO-I and HBV-CSU-161-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-114 and the corresponding boronic acid (see table 2 for analytical data).

cis-N-5- ([2,2' -bithiophene ] -5-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-162, HBV-CSU-162-ISO-I and HBV-CSU-162-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-114 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (4- (methylsulfonylamino) phenyl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-163, HBV-CSU-163-ISO-I and HBV-CSU-163-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-114 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5- (2- (dimethylamino) ethoxy) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-188):

in a sealed tube, dimethylaminoethanol (462mg, 5.188mmol) was dissolved in THF (10mL), sodium metal (114.8mg, 5.188mmol) was added at 0 ℃ and stirred at room temperature for 30 min. To the reaction mixture, HBV-CSU-114(500mg, 1.0374mmol) and CuBr (14.8mg, 0.1037mmol) were added and heated to 100 ℃ overnight. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give the desired pure compound (12mg, 2%) as a solid (analytical data see table 2).

cis-N- (3-bromo-4-fluorophenyl) -5- (5-bromothiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-257):

the title compound was synthesized following the general procedure described above for reduction using HBV-CSU-257-Int-1 (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-5-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-271, HBV-CSU-271-ISO-I and HBV-CSU-271-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-114 and the corresponding boronic acid (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (pyrimidin-5-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-272, HBV-CSU-272-ISO-I and HBV-CSU-272-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-114 and the corresponding boronic acid (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5- (1-ethyl-1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-291, HBV-CSU-291-ISO-I and HBV-CSU-291-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-114 and the corresponding boronic acid (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5- (1-isopropyl-1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-292, HBV-CSU-292-ISO-I and HBV-CSU-292-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-114 and the corresponding boronic acid (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-293, HBV-CSU-293-ISO-I and HBV-CSU-293-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-114 and the corresponding boronic acid (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5- (1, 5-dimethyl-1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-312, HBV-CSU-312-ISO-I and HBV-CSU-312-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-114 and the corresponding boronic acid (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5- (1, 3-dimethyl-1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-313, HBV-CSU-313-ISO-I and HBV-CSU-313-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-114 and the corresponding boronic acid (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1,3, 5-trimethyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-314-ISO-I and HBV-CSU-314-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-114 and the corresponding boronic acid (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1- (trifluoromethyl) -1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-321-ISO-I and HBV-CSU-321-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-114 and the corresponding boronic acid (see Table 2 for analytical data).

Scheme 21:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5-phenyl-1, 3, 4-thiadiazol-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-120, HBV-CSU-120-ISO-I and HBV-CSU-120-ISO-II):

scheme 21:

synthesis of ethyl 5-bromo-1, 3, 4-thiadiazole-2-carboxylate (60):

to a stirred solution of compound 59(21g, 121.38mmol) in ACN (400mL) was added CuBr₂(53.3g, 239.01mmol) and stirred at room temperature for 15 min. To this solution, tert-butyl nitrite (24.65g, 239.04mmol) was added dropwise over 20 minutes. The resulting reaction mixture was stirred at room temperature for 30 minutes and then heated at 60 ℃ for 30 minutes. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water, ethyl acetate and filtered through a celite bed. Separating the organic layer; washing with brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound 60(25g, 87.40%) as a yellow solid. TLC: 20% EtOAc/hexanes (R)_f：0.7)；¹H NMR(400MHz，DMSO-d₆)：δ4.45-4.40(m，2H)，1.34(t，J＝6.8Hz，3H)。

Synthesis of (5-bromo-1, 3, 4-thiadiazol-2-yl) methanol (61):

to a stirred solution of compound 60(25g, 105.96mmol) in MeOH (250mL) at 0 deg.C was added NaBH in portions₄(12g, 317.20mmol) and stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with acetic acid (5 mL); diluted with water and extracted with ethyl acetate. The combined organic layers were washed with saturated NaHCO₃Washing the solution; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 15% EtOAc/hexanes to give compound 61(15g, 73%) as a yellow solid. TLC: 40% EtOAc/hexanes (R)_f：0.3)；¹H NMR(400MHz，DMSO-d₆)：δ6.39(t，J＝6.0Hz，1H)，4.85-4.83(s，2H)；C₃H₃BrN₂LCMS calculation for OS: 193.91, respectively; and (3) observation value: 194.90(M +1)⁺。

Synthesis of (5-phenyl-1, 3, 4-thiadiazol-2-yl) methanol (62):

to a mixture of bromo compound 61(3g, 15.54mmol) and phenylboronic acid (2.27g, 18.65mmol) in toluene: to a mixture of EtOH (1:1, 160mL) in a mixture was added 2M Na₂CO₃The solution (4.92g, 46.41mmol) was purged with Ar for 30 min. To the solution, Pd (PPh) was added₃)₄(0.890g, 0.77mmol) and the reaction mixture was stirred at 100 ℃ for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a celite bed and the filtrate was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 15% EtOAc/hexanes to give compound 62 as a yellow solid. The same reaction was carried out on a 2x3g scale to give 11g of the desired compound. TLC: 50% EtOAc/hexanes (R)_f：0.5)；C₉H₈N₂LCMS calculation for OS: 192.04, respectively; and (3) observation value: 192.95(M +1)⁺。

Synthesis of 5-phenyl-1, 3, 4-thiadiazole-2-carbaldehyde (63):

to a stirred solution of compound 62(11g, 57.29mmol) in DCM (330mL) was added dess-martin periodinane (36.47g, 85.98 mmol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was purified by addition of saturated NaHCO₃Quenching the solution; saturated sodium thiosulfate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 5% EtOAc/hexanes to give compound 63(8g, 73.5%) as an off-white solid. TLC: 50% EtOAc/hexanes (R)_f：0.4)；¹H NMR(400MHz，DMSO-d₆)：δ10.18(s，1H)，8.12-8.10(m，1H)，7.67–7.55(m，4H)。

Synthesis of 1- (5-phenyl-1, 3, 4-thiadiazol-2-yl) ethan-1-ol (64):

to a stirred solution of compound 63(8g, 42.10mmol) in anhydrous THF (80mL) at 0 deg.C under an inert atmosphere was added dropwise methylmagnesium iodide (3M, 42mL, 126.70 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 20% EtOAc/hexanes to give compound 64(0.5g, 76.53%) as a white solid. TLC: 40% EtOAc/hexanes (R)_f：0.2)；¹H NMR(400MHz，DMSO-d₆)：δ7.97-7.95(m，2H)，7.56-7.54(m，3H)，6.41(d，J＝4.8Hz，1H)，5.15-5.12(m，1H)，1.50-1.40(m，3H)；C₁₀H₁₀N₂LCMS calculation for OS: 206.05, respectively; and (3) observation value: 206.90(M +1)⁺。

Synthesis of 1- (5-phenyl-1, 3, 4-thiadiazol-2-yl) ethan-1-one (65):

to a stirred solution of compound 64(7g, 33.98mmol) in DCM (70mL) was added dess-martin periodinane (27.37g, 64.56 mmol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was purified by addition of saturated NaHCO₃Quenching the solution; saturated sodium thiosulfate solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 5% EtOAc/hexanes to give compound 65(3.2g, 43.24%) as an off-white solid. TLC:20% EtOAc/hexanes (R)_f：0.4)；¹H NMR(400MHz，DMSO-d₆)：δ8.08-8.05(m，2H)，7.62-7.54(m，3H)，2.73(m，3H)；C₁₀H₈N₂LCMS calculation for OS: 204.04, respectively; and (3) observation value: 204.95(M +1)⁺。

Synthesis of methyl 2, 4-dioxo-4- (5-phenyl-1, 3, 4-thiadiazol-2-yl) butanoate (66):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 4.44g (crude, reaction scale 3.13g) as a light brown solid. TLC: 40% EtOAc/hexanes (R)_f：0.1)；C₁₃H₁₀N₂O₄LCMS calculation of S: 290.04, respectively; and (3) observation value: 290.95(M +1)⁺。

Synthesis of methyl 5- (5-phenyl-1, 3, 4-thiadiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (67):

the title compound was synthesized using general procedure B described above for the synthesis of the cyclic sulfonamides to give 1.2g (24.89%, 4g on a reaction scale) as a light brown solid.¹H NMR(DMSO-d₆，400MHz)：δ8.07-8.04(m，2H)，7.61-7.55(m，3H)，6.93(s，1H)，3.82(s，3H)；C₁₃H₁₀N₄O₄S₂LCMS calculated of (d): 350.01, respectively; LCMS observations: 351(M +1)⁺。

Synthesis of methyl 2-methyl-5- (5-phenyl-1, 3, 4-thiadiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (68):

the title compound was synthesized using general method B for alkylation described above to give 1g (96.15%, reaction scheme)The modulus was 1g) which was a pale yellow solid. TLC: 40% EtOAc/hexanes (R)_f：0.3)。

Synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5-phenyl-1, 3, 4-thiadiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-120_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using compound 68 and the corresponding amine (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5-phenyl-1, 3, 4-thiadiazol-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-120, HBV-CSU-120-ISO-I and HBV-CSU-120-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-120_ Int (see Table 2 for analytical data).

Scheme 22:

general synthetic scheme for 5- (thiazol-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide derivatives with 5-substituted thiazole variations:

scheme 22:

synthesis of 2- (2-methyl-1, 3-dioxolan-2-yl) thiazole (69):

to a stirred solution of 1- (thiazol-2-yl) ethan-1-one 9(13g, 102.36mmol) in toluene (250mL) at room temperature under an inert atmosphere was added ethane-1, 2-diol (5.71mL, 153.54mmol) and p-toluenesulfonic acid (1.16g, 6.14mmol), then heated to 120 ℃ using a dean-Stark apparatus and stirred for 24 h. The reaction was monitored by TLC. After completion, the volatiles were removed in vacuo to give the crude material. For crude material CH₂Cl₂Diluted (300mL) and with 10% NaHCO₃The solution (100mL) was washed. The organic extract was dried over anhydrous sodium sulfate and concentrated in vacuo to give compound 69(13g, 74%) as a yellow liquid. TLC: 10% EtOAc/hexanes (R)_f：0.5)；¹H NMR(DMSO-d₆，400MHz)：δ7.80(d，J＝3.1Hz，1H)，7.71(d，J＝3.2Hz，1H)，4.08-4.01(m，2H)，4.00-3.93(m，2H)，1.71(s，3H)；C₇H₉NO₂LCMS calculation of S: 171.04; and (3) observation value: 171.8(M +1)⁺。

Synthesis of 5-bromo-2- (2-methyl-1, 3-dioxolan-2-yl) thiazole (70):

to a stirred solution of compound 69(17g, 99.41mmol) in anhydrous THF (275mL) at-78 deg.C was added n-butyllithium (39.7mL, 99.4mmol) dropwise under an inert atmosphere for 15 minutes, followed by stirring for 1 h. A solution of carbon tetrabromide (33g, 99.4mmol) in anhydrous THF (75mL) was added dropwise thereto at-78 deg.C for 20 minutes, then warmed to 0 deg.C and stirred for 30 minutes. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (50mL) and extracted with EtOAc (3 × 500 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 3% EtOAc/hexanes to give compound 70(15g, 60%) as a brown liquid. TLC: 10% EtOAc/hexanes (R)_f：0.8)；¹H NMR(DMSO-d₆，400MHz)：δ7.88(s，1H)，4.07-4.01(m，2H)，4.00-3.93(m，2H)，1.68(s，3H)；C₇H₈BrNO₂LCMS calculation of S: 248.95, respectively; and (3) observation value: 249.8(M +1)⁺。

Synthesis of 1- (5-bromothiazol-2-yl) ethan-1-one (71):

to compound 70(15g, 60.24mmol) in CH at 0 deg.C₂Cl₂(150mL) and H₂To a stirred solution in the mixture of O (5mL) was added trifluoroacetic anhydride (150mL, 10V), then warmed to room temperature and stirred for 36 h. The reaction was monitored by TLC. After completion of the reaction, the volatiles were removed in vacuo. For crude material CH₂Cl₂(500mL) diluted and then with 10% NaHCO₃Aqueous (150mL) wash. The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude compound 71(10.5g, 85%) as a brown solid. TLC: 10% EtOAc/hexanes (R)_f：0.8)；¹H-NMR(DMSO-d₆，400MHz)：δ8.21(s，1H)，2.60(s，3H)；C₅H₄LCMS calculation for BrNOS: 204.92, respectively; and (3) observation value: 208.0(M +2)⁺。

Synthesis of methyl 4- (5-bromothiazol-2-yl) -2, 4-dioxobutyrate (72):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 7.5g (50%, scale of reaction 10.5g) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂(R_f：0.4)；¹H NMR(400MHz，DMSO-d₆)：δ8.27(s，1H)，7.00(br.s，1H)，3.84(s，3H)；C₈H₆BrNO₄LCMS calculation of S: 290.92, respectively; and (3) observation value: 294.0(M +2)⁺。

Synthesis of methyl 5- (5-bromothiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (73):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 4g (44%, reaction scale 7.5g) as a light brown solid. TLC: 10% MeOH/CH₂Cl₂(R_f：0.3)；¹H NMR(400MHz，DMSO-d₆)：δ8.02(s，1H)，6.77(s，1H)，3.79(s，3H)；C₈H₆BrN₃O₄S₂LCMS calculated of (d): 350.90, respectively; and (3) observation value: 349.8(M-1)⁺。

Synthesis of methyl 5- (5-bromothiazol-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (74):

the title compound was synthesized using the general procedure for alkylation described above (method a) to give 2g (48%, 4g on reaction scale) as an off-white solid. TLC: 30% EtOAc/hexanes (R)_f：0.8)；¹H NMR(500MHz，DMSO-d₆)：δ8.34(s，1H)，7.37(s，1H)，3.94(s，3H)，3.59(s，3H)。

Synthesis of 5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-122_ Int/HBV-CSU-435):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 74 and the corresponding amine (see table 1 for analytical data).

Cis-5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-122, HBV-CSU-122-ISO-I and HBV-CSU-122-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-222_ Int/HBV-CSU-435 (see Table 2 for analytical data).

Cis-5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-124, HBV-CSU-124-I and HBV-CSU-124-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-122 and the corresponding boronic acid (see table 2 for analytical data).

Cis-5- (5- (4-bromo-3-fluorophenyl) thiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-173, HBV-CSU-173-ISO-I and HBV-CSU-173-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-122 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (pyridin-3-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-175, HBV-CSU-175-ISO-I and HBV-CSU-175-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-122 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (pyridin-2-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-176, HBV-CSU-176-ISO-I and HBV-CSU-176-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling, using HBV-CSU-122 and the corresponding stannane (see Table 2 for analytical data).

Note: the stannane reagent was synthesized according to the following scheme:

to a stirred solution of 2-bromopyridine (1g, 6.32mmol) in anhydrous THF (10mL) at-78 deg.C was added n-butyllithium (4.2mL, 6.32mmol, 1.6M solution in hexanes) under an inert atmosphere, which was then stirred for 1 h. Tributyltin chloride (1.71mL, 6.32mmol) was added dropwise thereto at-78 ℃ for 10 minutes, then it was stirred at the same temperature for 2h, then warmed to room temperature and stirred for 2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride (30mL) and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude stannane compound (2g) as a yellow slurry. The crude material was carried to the next step without further purification. TLC: 10% EtOAc/hexanes (R)_f：0.5)。

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-177, HBV-CSU-177-ISO-I and HBV-CSU-177-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-122 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (thiophen-2-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-178, HBV-CSU-178-ISO-I and HBV-CSU-178-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-122 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (4- (methylsulfonylamino) phenyl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-179, HBV-CSU-179-ISO-I and HBV-CSU-179-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-122 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5- (4-fluorophenyl) thiazol-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-248, HBV-CSU-248-ISO-I and HBV-CSU-248-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-122 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5- (4-methoxyphenyl) thiazol-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-250, HBV-CSU-250-ISO-I and HBV-CSU-250-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-122 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5- (5-fluoropyridin-2-yl) thiazol-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-252, HBV-CSU-252-ISO-I and HBV-CSU-252-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling, using HBV-CSU-122 and the corresponding stannane (see Table 2 for analytical data).

Note: the stannane reagent was synthesized according to the following scheme:

to a stirred solution of 2-bromo-5-fluoropyridine (300mg, 1.71mmol) in anhydrous toluene (10mL) at-78 deg.C was added n-butyllithium (1.28mL, 2.05mmol, 1.6M solution in hexanes) under an inert atmosphere and stirred for 1 h. Tributyltin chloride (0.55mL, 2.05mmol) was added dropwise thereto at-78 deg.C for 5 minutes, then it was warmed to 0 deg.C and stirred for 1.5 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride (30mL) and extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with water (75mL), brine (75mL), then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude stannane compound (1g) as a colorless liquid. The crude material was carried to the next step without further purification. TLC: 5% EtOAc/hexanes (R)_f：0.8)

Cis-5- (5- (1H-pyrazol-4-yl) thiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-254, HBV-CSU-254-ISO-I and HBV-CSU-254-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-122 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-276, HBV-CSU-276-ISO-I and HBV-CSU-276-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-122 and the corresponding boronic acid (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-5-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-277, HBV-CSU-277-ISO-I and HBV-CSU-277-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-122 and the corresponding boronic acid (see Table 2 for analytical data).

Cis-5- ([5,5' -bithiazol ] -2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-278, HBV-CSU-278-ISO-I and HBV-CSU-278-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-122 and the corresponding boronic acid (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-3-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-280, HBV-CSU-280-ISO-I and HBV-CSU-280-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-122 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-5-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-281, HBV-CSU-281-ISO-I and HBV-CSU-281-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-122 and the corresponding boronic acid (see table 2 for analytical data).

Scheme 23:

synthesis of cis-5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-123, HBV-CSU-123-ISO-I and HBV-CSU-123-ISO-II):

scheme 23:

synthesis of 1- (5-methylthiazol-2-yl) ethan-1-one (76):

to a stirred solution of 5-methylthiazole 75(9g, 90.90mmol) in anhydrous THF (200mL) at-78 deg.C was added n-butyllithium (40mL, 99.99mmol) dropwise under an inert atmosphere for 30 minutes. N-methoxy-N-methylacetamide (11.24mL, 109.1mmol) was added dropwise thereto at-78 deg.C for 20 minutes, then warmed to 0 deg.C and stirred for 16 minutes. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 3% EtOAc/hexanes to give compound 76(12g, 94%) as a light yellow liquid. TLC: 10% EtOAc/hexanes (R)_f：0.5)；¹H NMR(DMSO-d₆，400MHz)：δ7.83(s，1H)，2.58(s，3H)，2.54(s，3H)。

Synthesis of methyl 4- (5-methylthiazol-2-yl) -2, 4-dioxobutyrate (77):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 14g (73%, reaction scale 12g) as a yellow solid. TLC: 5% MeOH/CH₂Cl₂(R_f：0.2)；¹H NMR(400MHz，DMSO-d₆)：δ7.86(br.s，1H)，6.99(br.s，1H)，3.82(s，3H)，2.56(s，3H)；C₉H₉NO₄LCMS calculation of S: 227.03, respectively; and (3) observation value: 228.1(M +1)⁺。

Synthesis of methyl 5- (5-methylthiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (78):

the title compound was synthesized using general procedure a above for the synthesis of cyclic sulfonamides to give 1.9g (38%, 4g on a reaction scale) as an off-white solid (1.9g, 38%). TLC: 10% MeOH/CH₂Cl₂(R_f：0.1)；¹H NMR(400MHz，DMSO-d₆)：δ7.66(s，1H)，6.85(s，1H)，6.07(br.s，1H)，3.79(s，3H)，2.50(s，3H)；C₉H₉N₃O₄S₂LCMS calculated of (d): 287.00, respectively; and (3) observation value: 288.1(M +1)⁺。

Synthesis of methyl 2-methyl-5- (5-methylthiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (79):

the title compound was synthesized using general procedure a described above for alkylation to give 250mg (48%, reaction scale 500mg) as an off-white solid. TLC: 40% EtOAc/hexanes (R)_f：0.4)；¹H NMR(400MHz，DMSO-d₆)：δ7.96(s，1H)，7.41(s，1H)，3.94(s，3H)，3.57(s，3H)，2.60(s，3H)；C₁₀H₁₁N₃O₄S₂LCMS calculated of (d): 301.02, respectively; and (3) observation value: 302.1(M +1)⁺。

Synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5-methylthiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-123_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding 79 and the corresponding amine (see table 1 for analytical data).

Cis-5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-123, HBV-CSU-123-ISO-I and HBV-CSU-123-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-123_ Int (see Table 2 for analytical data).

Scheme 24:

general synthetic scheme for 5- (thien-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide derivatives with 4-substituted thiophene and aniline variations:

scheme 24:

synthesis of methyl 4- (4-bromothien-2-yl) -2, 4-dioxobutyrate (81):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 30g (84.57%, reaction scale 25 g); c₉H₇BrO₄LCMS calculation of S: 289.92, respectively; and (3) observation value: 292.80(M +2)⁺。

Synthesis of methyl 5- (4-bromothien-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (82):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 15g (41.60%, reaction scale 30 g); c₉H₇BrN₂O₄S₂LCMS calculated of (d): 349.90, respectively; LCMS observations: 353.05(M +2)⁺。

Synthesis of methyl 5- (4-bromothien-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (83):

the title compound was synthesized using general procedure B described above for alkylation to give 9g (57.58%, reaction scale 5 g); c₁₀H₉BrN₂O₄S₂LCMS calculated of (d): 363.92, respectively; LCMS observations: 367.10(M +2)⁺。

5- (4-bromothiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-146_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 83 and the corresponding amine (see table 1 for analytical data).

N- (3-bromo-4-fluorophenyl) -5- (4-bromothiophen-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-258_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 90 and the corresponding amine. The crude intermediate was confirmed by LCMS and carried to the next step.

5- (4-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-146, HBV-CSU-146-ISO-I and HBV-CSU-146-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-146_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4-methylthiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-147, HBV-CSU-147-ISO-I and HBV-CSU-147-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and dimethylzinc (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4-phenylthiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-148-ISO-I and HBV-CSU-148-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

Cis- (4-benzylthiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-149-ISO-I and HBV-CSU-149-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4- (4-cyano-3-fluorophenyl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-164, HBV-CSU-164-ISO-I and HBV-CSU-164-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4- (4-bromo-3-fluorophenyl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-165):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (6- (trifluoromethyl) pyridin-3-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-166, HBV-CSU-166-ISO-I and HBV-CSU-166-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (pyridin-3-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-167-ISO-I and HBV-CSU-167-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (pyridin-2-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-168, HBV-CSU-168-ISO-I and HBV-CSU-168-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-169-ISO-I and HBV-CSU-169-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N-4- ([2,2' -bithiophene ] -5-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-170, HBV-CSU-170-ISO-I and HBV-CSU-170-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (4- (methylsulfonylamino) phenyl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-171):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4- (5-fluoropyridin-2-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-243, HBV-CSU-243-ISO-I and HBV-CSU-243-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-bromo-4-fluorophenyl) -5- (4-bromothiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-258):

the title compound was synthesized following the general procedure described above for reduction using HBV-CSU-258-Int-1 (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (1-methyl-1H-pyrazol-5-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-289, HBV-CSU-289-ISO-I and HBV-CSU-289-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (pyrimidin-5-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-290, HBV-CSU-290-ISO-I and HBV-CSU-290-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4- (1-ethyl-1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-294, HBV-CSU-294-ISO-I and HBV-CSU-294-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4- (1-isopropyl-1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-295, HBV-CSU-295-ISO-I and HBV-CSU-295-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-296, HBV-CSU-296-ISO-I and HBV-CSU-296-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4- (1, 5-dimethyl-1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-315, HBV-CSU-315-ISO-I and HBV-CSU-315-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4- (1, 3-dimethyl-1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-316, HBV-CSU-316-ISO-I and HBV-CSU-316-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (1,3, 5-trimethyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-317, HBV-CSU-317-ISO-I and HBV-CSU-317-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-146 and the corresponding boronic acid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (1- (trifluoromethyl) -1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-325-ISO-I and HBV-CSU-325-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling, using HBV-CSU-146 and the corresponding boronic acid (see Table 2 for analytical data).

Scheme 25:

synthesis of 5- (4-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-150):

scheme 25

Synthesis of 1- (4-bromothiazol-2-yl) ethan-1-one (85):

to a stirred solution of 2, 4-dibromothiazole 84(50g, 205.82mmol) in anhydrous THF (500mL) at-40 deg.CN-butyllithium (193mL, 308.74mmol) was added dropwise under an inert atmosphere for 30 minutes and stirred at the same temperature for 1 h. A solution of 1-morpholinoethan-1-one (32g, 248mmol) in dry THF (100mL) was added dropwise thereto at-40 deg.C for 20min and stirred for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 1-2% EtOAc/hexanes to give compound 85(14g, 33%) as an off-white solid. TLC: 10% EtOAc/hexanes (R)_f：0.8)；¹H NMR(DMSO-d₆，400MHz)：δ8.33(s，1H)，2.62(s，3H)；C₅H₄LCMS calculation for BrNOS: 204.92, respectively; LCMS observations: 208.0(M +2)⁺。

Synthesis of methyl 4- (4-bromothiazol-2-yl) -2, 4-dioxobutyrate (86):

to a stirred solution of 1- (4-bromothiazol-2-yl) ethan-1-one 85(10g, 48.53mmol) in anhydrous THF (200mL) at-78 deg.C was added potassium tert-butoxide (122mL, 121.94mmol, 1M solution in THF) dropwise under an inert atmosphere for 25 minutes and stirred at the same temperature for 1 h. Dimethyl oxalate (8.6g, 72.81mmol) was added dropwise thereto at-78 ℃ for 20 minutes; warm to room temperature and stir for 16 h. The reaction was monitored by TLC; after completion of the reaction, the pH of the reaction mixture was quenched with 1N aq. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude material. The crude material was purified by column chromatography on silica gel using 1.5-2% MeOH/CH₂Cl₂To give compound 86(2g, 14%) as a yellow solid. TLC: 70% EtOAc/hexanes (R)_f：0.4)；¹H-NMR(DMSO-d₆，400MHz)：δ8.33(s，1H)，2.62(s，3H)；C₈H₆BrNO₄LCMS calculation of S: 290.92, respectively; LCMS observations: 292.0(M +1)⁺。

Synthesis of methyl 5- (4-bromothiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (87):

the title compound was synthesized using general procedure a for cyclization described above to give 800mg (33%, reaction scale 2g) as a brown solid. TLC: 10% MeOH/DCM (R)_f：0.1)；¹H NMR(DMSO-d₆，400MHz)：δ7.99(s，1H)，6.78(s，1H)，3.80(s，3H)；C₈H₆BrN₃O₄S₂LCMS calculated of (d): 350.90, respectively; LCMS observations: 351.90(M +1)⁺。

Synthesis of methyl 5- (4-bromothiazol-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (88):

the title compound was synthesized using general procedure a for alkylation above to give 350mg (42%, reaction scale 800mg) as an off-white solid. TLC: 10% MeOH/DCM (R)_f：0.4)；¹H NMR(DMSO-d₆，400MHz)：δ8.40(s，1H)，7.35(s，1H)，3.96(s，3H)，3.61(s，3H)；C₉H₈BrN₃O₄S₂LCMS calculated of (d): 364.91, respectively; LCMS observations: 368.0(M +2)⁺。

Synthesis of 5- (4-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-150_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding 88 and the corresponding amine (see table 1 for analytical data).

Cis-5- (4-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-150):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-0150_ Int (see Table 2 for analytical data).

Scheme 26

Synthesis of cis-N- (3-chloro-4-fluorophenyl) -5- (4-hydroxyphenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-201) and N- (3-chloro-4-fluorophenyl) -5- (4- (3- (dimethylamino) propoxy) phenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-208, HBV-CSU-208-ISO-I and HBV-CSU-208-ISO-II):

scheme 26:

cis-N- (3-chloro-4-fluorophenyl) -5- (4-hydroxyphenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-201):

to a stirred solution of the compound HBV-CSU-200(50mg, 0.116mmol) in DCM (2mL) at-40 deg.C was added BBr₃(0.025mL, 0.233mmol) and stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was taken up with saturated NaHCO₃The solution was quenched and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give the desired compound HBV-CSU-201(20mg, 41.66%) as a white solid (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4- (3- (dimethylamino) propoxy) phenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-208, HBV-CSU-208-ISO-I and HBV-CSU-208-ISO-II):

the title compound was synthesized using general method B for alkylation above to give 150mg (35.62% reaction scale 350mg) as an off-white solid. TLC: 10% MeOH/DCM (R)_f: 0.2) (see table 2 for analytical data).

Scheme 27:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -5- (3-hydroxyphenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-205) and N- (3-chloro-4-fluorophenyl) -5- (3- (3- (dimethylamino) propoxy) phenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-209):

scheme 27:

cis-N- (3-chloro-4-fluorophenyl) -5- (3-hydroxyphenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-205):

to a stirred solution of the compound HBV-CSU-204(0.71g, 1.66mmol) in DCM (7mL) at-40 deg.C was added BBr₃(7mL) and stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was taken up with saturated NaHCO₃The solution was quenched and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give the desired compound HBV-CSU-205(0.6g, 89.15%) as a white solid. TLC: 50% EtOAc/hexanes (R)_f: 0.3) (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (3- (3- (dimethylamino) propoxy) phenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-209):

the title compound was synthesized using general method B described above for alkylation (see table 2 for analytical data).

Scheme 28:

synthesis of N- (3-chloro-4-fluorophenyl) -5- (4-cyanophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-213) and 5- (4-carbamoylphenyl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-214):

scheme 28:

5- (4-carbamoylphenyl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-213_ Int):

to a mixture of bromo compound (200mg, 0.423mmol) in DMF, tetrakistriphenylphosphine palladium (48.8mg, 0.0423mmol) was added and purged with Ar for 15 min. To this solution, ZnCN was added₂(99.52mg, 0.847mmol) and an additional 15 minutes of Ar purging. The resulting reaction mixture was then stirred at 80 ℃ overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to give HBV-CSU-213_ Int (100mg, 56.5%) as an orange liquid. TLC: 40% EtOAc/hexanes (R)_f: 0.3) (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4-cyanophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-213):

the title compound was synthesized following the general procedure described above for reduction using HBV-CSU-213_ Int (see Table 2 for analytical data).

Cis-5- (4-carbamoylphenyl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-214, HBV-CSU-214-ISO-I and HBV-CSU-214-ISO-II):

to a stirred solution of compound HBV-CSU-213(0.3g, 0.709mmol) in DMSO (15mL) at 0 deg.C was added K₂CO₃(0.196g, 1.42mmol) and H₂O₂(30% in water 0.241mL, 2.13mmol) and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was quenched with ice-cold water. The precipitated solid was collected by filtration; washed with water and dried under reduced pressure to give the desired compound HBV-CSU-214(0.1g, 32.15%) as a white solid. TLC: 5% MeOH/DCM (R)_f: 0.4) (see table 2 for analytical data).

Scheme 29:

synthesis of 2- (4- (5- ((3-chloro-4-fluorophenyl) carbamoyl) -6-methyl-1, 1-dioxo-1, 2, 6-thiadiazin-an-3-yl) phenoxy) acetic acid (HBV-CSU-216, HBV-CSU-216-ISO-I and HBV-CSU-216-ISO-II):

scheme 29:

tert-butyl 2- (4- (5- ((3-chloro-4-fluorophenyl) carbamoyl) -6-methyl-1, 1-dioxo-1, 2, 6-thiadiazin-an-3-yl) phenoxy) acetate (89):

the title compound was synthesized using general method B for alkylation described above to give 0.15g (23.68%, scale of reaction)0.5g)；¹H-NMR(DMSO-d₆，400MHz)：δ10.53(s，1H)，7.96-7.94(m，1H)，7.56-7.35(m，5H)，6.88(d，J＝8.8Hz，2H)，4.65(s，2H)，4.54-4.49(m，1H)，4.26-4.19(m，1H)，2.63(s，3H)，2.09-2.01(m，2H)，1.42(s，9H)。

Cis-2- (4- (5- ((3-chloro-4-fluorophenyl) carbamoyl) -6-methyl-1, 1-dioxo-1, 2, 6-thiadiazin-an-3-yl) phenoxy) acetic acid (HBV-CSU-216, HBV-CSU-216-ISO-I and HBV-CSU-216-ISO-II):

to a stirred solution of compound 89(50mg, 0.246mmol) in DCM (5mL) at 0 ℃ was added TFA (0.083mL, 0.739mmol) and stirred at rt for 2 h. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was concentrated and co-evaporated with DCM twice and the resulting residue triturated with ether to give the desired compound HBV-CSU-216(90mg, 78%) as an off-white solid. TLC: 40% EtOAc/hexanes (R)_f: 0.3) (see table 2 for analytical data).

Scheme 30:

synthesis of cis-4- (5- ((3-chloro-4-fluorophenyl) carbamoyl) -6-methyl-1, 1-dioxo-1, 2, 6-thiadiazine-an-3-yl) benzoic acid (HBV-CSU-218, HBV-CSU-218-ISO-I and HBV-CSU-218-ISO-II) and cis-4- (5- ((3-chloro-4-fluorophenyl) carbamoyl) -6-methyl-1, 1-dioxo-1, 2, 6-thiadiazine-an-3-yl) benzoic acid methyl ester (HBV-CSU-256):

scheme 30:

cis-4- (5- ((3-chloro-4-fluorophenyl) carbamoyl) -6-methyl-1, 1-dioxo-1, 2, 6-thiadiazine-an-3-yl) benzoic acid methyl ester (HBV-CSU-256):

in an autoclave under Ar atmosphereTo a mixture of compound HBV-CSU-202(0.5g, 1.04mmol) in MeOH: to a stirred solution of a mixture of ACN (4:1, 2.5mL) was added TEA (0.05mL, 0.312mmol) and dppf (0.058g, 0.104mmol) and purged with Ar for 30 min. To this solution, Pd (OAc) is added₂(0.023g, 0.104mmol) and again flushed with carbon monoxide. The resulting reaction mixture was heated in an autoclave at 100 ℃ under 150psi pressure for 6 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was diluted with water (100mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 10% EtOAc in hexanes to give the compound HBV-CSU-256(0.03g, 6.3%) as a white solid. TLC: 40% EtOAc/hexanes (R)_f: 0.3) (see table 2 for analytical data).

Cis-4- (5- ((3-chloro-4-fluorophenyl) carbamoyl) -6-methyl-1, 1-dioxo-1, 2, 6-thiadiazin-an-3-yl) benzoic acid (HBV-CSU-218, HBV-CSU-218-ISO-I and HBV-CSU-218-ISO-II):

to HBV-CSU-256(0.25g, 0.549mmol) in THF: h₂To a stirred solution of O (1:1, 10mL) in a mixture was added an aqueous solution of LiOH (0.23g, 5.49mmol) and stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After completion, the volatiles were removed in vacuo. The residue was acidified to pH-3 with 1N HCl and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired compound HBV-CSU-218(0.1g, 41.49%) as a white solid. TLC: 40% EtOAc/hexanes (R)_f: 0.1) (see table 2 for analytical data).

Scheme 31:

general synthetic scheme for 5- (thien-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide derivatives with 5-substituted thiophene changes (reverse Suzuki method):

scheme 31:

synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophen-2-yl) -1,2, 6-thiadiazine-ane-3-carboxamide 1, 1-dioxide (90):

to a mixture of the bromo compound HBV-CSU-114(2g, 4.143mmol) and bis (pinacolato) diboron (2.63g, 10.35mmol) in 1, 4-dioxane (20mL) was added potassium acetate (2.03g, 20.71mmol) and purged with Ar for 15 minutes. To the solution, PdCl was added₂(dppf).CH₂Cl₂(0.101g, 0.124mmol) and the reaction mixture was stirred at 90 ℃ overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite, evaporated to dryness to give the desired boronic ester as crude product 90(2.35g, crude material) and used as such in the next step without further purification. TLC: 40% EtOAc/hexanes (R)_f：0.2)；C₂₁H₂₆BClFN₃O₅S₂LCMS calculated of (d): 529.11, respectively; and (3) observation value: 447.95(M +1)⁺For boric acid.

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (trifluoromethyl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-219, HBV-CSU-219-ISO-I and HBV-CSU-219-II):

to compound 90(0.25g, 0.472mmol) and NaSO at 0 deg.C₂CF₃(0.221g, 1.417mmol) in MeOH: DCM: H₂To a stirred solution of O (1:1:0.8, 5.6mL) in a mixture was added CuCl (0.046g, 0.472mmol) and stirred for 10min. To this solution was slowly added TBHP (70% aq., 0.303mL, 2.36 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC. Upon completion, the reaction mixture was concentrated under reduced pressure and the resulting crude compound was purified by silica gel column chromatography using 15% EtOAc/hexanes to give the title compound HBV-CSU-219(0.08g, 36.03%) as an off-white solid. TLC: 40% EtOAc/hexanes (R)_f: 0.5); (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5- (5-fluoropyridin-2-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-242-ISO-I and HBV-CSU-242-ISO-II):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using compound 90 and the corresponding bromo compound (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-266, HBV-CSU-266-ISO-I and HBV-CSU-266-II):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using compound 90 and the corresponding bromo compound (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-5-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-267, HBV-CSU-267-ISO-I and HBV-CSU-267-II):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using compound 90 and the corresponding bromo compound (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (thiazol-5-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-268, HBV-CSU-268-ISO-I and HBV-CSU-268-II):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using compound 90 and the corresponding bromo compound (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-3-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-270, HBV-CSU-270-ISO-I and HBV-CSU-270-ISO-II):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using compound 90 and the corresponding bromo compound (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-1, 2, 4-triazol-3-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-322-ISO-I and HBV-CSU-322-ISO-II):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using compound 90 and the corresponding bromo compound (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-1, 2, 4-triazol-5-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-323-ISO-I and HBV-CSU-323-ISO-II):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using compound 90 and the corresponding bromo compound (see table 2 for analytical data).

Scheme 32:

synthesis of N- (3-chloro-4-fluorophenyl) -5- (3-chloro-4-hydroxyphenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-220) and N- (3-chloro-4-fluorophenyl) -5- (3, 5-dichloro-4-hydroxyphenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-260):

scheme 32:

cis-N- (3-chloro-4-fluorophenyl) -5- (3-chloro-4-hydroxyphenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-220):

to a stirred solution of compound HBV-CSU-201(200mg, 0.483mmol) in acetonitrile was added NCS (65mg, 0.483mmol) at 0 ℃ and stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated and the crude compound was purified by silica gel column chromatography to give the desired compound HBV-CSU-220(150mg, 69.4%) as a white solid (analytical data see table 2).

cis-N- (3-chloro-4-fluorophenyl) -5- (3, 5-dichloro-4-hydroxyphenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-260):

to a stirred solution of compound HBV-CSU-201(200mg, 0.483mmol) in acetonitrile at 0 deg.C was added NCS (77mg, 0.579mmol) and stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated and the crude compound was purified by silica gel column chromatography to give the desired compound HBV-CSU-260(80mg, 34.33%) as a white solid (analytical data see table 2).

Scheme 33:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -5- (4-cyano-3-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-221, HBV-CSU-221-ISO-I and HBV-CSU-221-ISO-II):

scheme 33:

n- (3-chloro-4-fluorophenyl) -5- (4-cyano-3-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-221 — Int):

to a mixture of bromo compound (0.5g, 1.02mmol) in DMF (5mL) was added tetrakistriphenylphosphine palladium (0.118g, 0.102mmol) and purged with Ar for 15 min. To this solution, ZnCN was added₂(0.239g, 2.04mmol) and an additional 15 minutes of Ar purging. The resulting reaction mixture was then stirred at 80 ℃ overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was dissolved in ethyl acetate, washed with water, brine, then dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to give HBV-CSU-221_ Int (0.3g, 67.41%) as an orange liquid. TLC: 40% EtOAc/hexanes (R)_f: 0.3) (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4-cyano-3-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-221, HBV-CSU-221-ISO-I and HBV-CSU-221-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-221_ Int (see Table 2 for analytical data).

Scheme 34:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -5-cyclopentyl-2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-222, HBV-CSU-222-ISO-I and HBV-CSU-222-ISO-II):

scheme 34:

synthesis of methyl 4-cyclopentyl-2, 4-dioxobutyrate (92):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 6g (97%, scale of reaction 3.5 g); c₁₀H₁₄O₄LCMS calculated of (d): 198.05, respectively; and (3) observation value: 198.95(M +1)⁺。

Synthesis of methyl 5-cyclopentyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (93):

the title compound was synthesized using the general procedure for the synthesis of the above cyclic sulfonamides to give 5g (64%, reaction scale 6 g); c₁₀H₁₄N₂O₄LCMS calculation of S: 258.07, respectively; LCMS observations: 259(M +1)⁺。

Synthesis of methyl 5-cyclopentyl-2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (94):

the title compound was synthesized using the general procedure for alkylation described above (method B) to give 4.5g (85%, reaction scale 5 g); c₁₁H₁₆N₂O₄LCMS calculation of S: 272.08, respectively; LCMS observations: 273(M +1)⁺。

Synthesis of N- (3-chloro-4-fluorophenyl) -5-cyclopentyl-2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-222_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding compound 94 and the corresponding amine (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5-cyclopentyl-2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-222, HBV-CSU-222-ISO-I and HBV-CSU-222-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-222_ Int (see Table 2 for analytical data).

Scheme 35:

scheme for the synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (2-methylthiazol-5-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-224, HBV-CSU-224-ISO-I and HBV-CSU-224-ISO-II):

scheme 35:

synthesis of ethyl 2-chloro-3-oxopropanoate (96):

2-chloroethane at 0 ℃ in Ar atmosphereA stirred solution of ethyl acetate 95(5g, 40.98mmol) and ethyl formate (3.33mL, 40.98mmol) in diisopropyl ether (50mL) was added portionwise potassium tert-butoxide (45mL, 45.08mmol, 1M in THF) for 20min, then warmed to room temperature and stirred for 24 h. The reaction was monitored by TLC. After completion of the reaction, the pH of the reaction mixture was adjusted to-6 using 6N HCl and extracted with ether. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to give compound 96(5.6g, 91%) as a viscous slurry. TLC: 40% EtOAc/hexanes (R)_f：0.7)；¹H-NMR(DMSO-d₆，400MHz)：δ11.75(br.s，1H)，4.14(q，J＝7.0Hz，2H)，4.05(s，1H)，1.21(t，J＝7.1Hz，3H)。

Synthesis of ethyl 2-methylthiazole-5-carboxylate (97):

to a stirred solution of compound 96(110g, 733.33mmol) in ethanol (1.2L) at room temperature under Ar atmosphere was added thioacetamide (54.99g, 733.33mmol) and anhydrous magnesium sulfate (55mg, 454.66mmol), then heated to 80 ℃ for 16 h. The reaction was monitored by TLC. After completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water and extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 10% EtOAc/hexanes to give compound 97(41g, 33%) as a viscous slurry. TLC: 20% EtOAc/hexanes (R)_f：0.3)；¹H NMR(400MHz，DMSO-d₆)：δ8.26(s，1H)，4.29(q，J＝7.2Hz，2H)，2.71(s，3H)，1.29(t，J＝7.1Hz，3H)；C₇H₉NO₂LCMS calculation of S: 171.04; and (3) observation value: 172.1(M +1)⁺。

Synthesis of 2-methylthiazole-5-carboxylic acid (98):

to compound 97(41g, 239.76 mmol) at room temperature) In a THF: h₂To a stirred solution in O (7: 1, 400mL) was added lithium hydroxide monohydrate (29.49g, 719.29mmol) and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water and acidified to pH-2 with 2N HCl and extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 98(14g, 41%) as an off-white solid. TLC: 20% EtOAc/hexanes (R)_f：0.1)；¹H NMR(DMSO-d₆，400MHz)：δ13.29(br.s，1H)，8.16(s，1H)，2.69(s，3H)；C₅H₅NO₂LCMS calculation of S: 143.00, respectively; and (3) observation value: 144.1(M +1)⁺。

Synthesis of N-methoxy-N, 2-dimethylthiazole-5-carboxamide (99):

to a solution of compound 98(19g, 132.86mmol) in DMF (300mL) was added edci.hcl (38.06g, 199.26mmol), HOBt (26.9g, 199.25mmol), N, O-dimethylhydroxylamine hydrochloride (15.3g, 158.54mmol) and diisopropylethylamine (69.48mL, 398.44mmol) at 0 ℃ under an inert atmosphere, then warmed to room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ice-cold water and extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by flash column chromatography on silica gel using 50% EtOAc/hexanes to give compound 99(13g, 53%) as a viscous slurry. TLC: 10% MeOH/CH₂Cl₂(R_f：0.7)；¹H NMR(500MHz，DMSO-d₆)：δ8.26(s，1H)，3.75(s，3H)，3.27(s，3H)，2.68(s，3H)；C₇H₁₀N₂O₂LCMS calculation of S: 186.05, respectively; and (3) observation value: 187.1(M +1)⁺。

Synthesis of 1- (2-methylthiazol-5-yl) ethan-1-one (100):

to a stirred solution of compound 99(13g, 69.89mmol) in dry ether (200mL) was added dropwise methylmagnesium bromide (69.8mL, 209.67mmol, 3M in ether) at-40 ℃ under an inert atmosphere for 25 minutes, then warmed to room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution at 0 ℃ and extracted with ether. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by flash column chromatography on silica gel using 20% EtOAc/hexanes to give compound 100(5.62g, 57%) as a yellow solid. TLC: 20% EtOAc/hexanes (R)_f：0.3)；¹H NMR(400MHz，DMSO-d₆)：δ8.45(s，1H)，2.71(s，3H)，2.54(s，3H)；C₆H₇LCMS calculated for NOS: 141.02, respectively; and (3) observation value: 142.0(M +1)⁺。

Synthesis of methyl 4- (2-methylthiazol-5-yl) -2, 4-dioxobutyrate (101):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 9.01g (99% reaction scale 5.62g) as an off-white sticky solid. TLC: 5% MeOH/CH₂Cl₂(R_f：0.4)；C₉H₉NO₄LCMS calculation of S: 227.03, respectively; and (3) observation value: 228.1(M +1)⁺。

Synthesis of methyl 5- (2-methylthiazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (102):

the title compound was synthesized using general procedure a described above for the synthesis of cyclic sulfonamides to give 1.2g (crude material, reaction scale 1.2g) as a light brown solid. TLC: 20% MeOH/CH₂Cl₂(R_f：0.2)；C₁₃H₁₀N₄O₄S₂LCMS calculated of (d): 287.00, respectively; LCMS observations: 288.1(M +1)⁺。

Synthesis of methyl 2-methyl-5- (2-methylthiazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (103):

the title compound was synthesized using general procedure a for alkylation described above to give 100mg (8% over 2 steps, reaction scale 1g) as a yellow solid. TLC: 40% EtOAc/hexanes (R)_f：0.3)；¹H NMR(400MHz，DMSO-d₆)：δ8.77(s，1H)，7.36(s，1H)，3.94(s，3H)，3.51(s，3H)，2.76(s，3H)；C₁₀H₁₁N₃O₄S₂LCMS calculated of (d): 301.02, respectively; and (3) observation value: 302.1(M +1)⁺。

Synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (2-methylthiazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-224_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding 103 and the corresponding amine (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (2-methylthiazol-5-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-224, HBV-CSU-224-ISO-I and HBV-CSU-224-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-224_ Int (see Table 2 for analytical data).

Scheme 36:

synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (2-methylthiazol-5-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-226):

scheme 36:

synthesis of 2- (trifluoromethyl) thiazole-5-carboxylic acid (105):

to ethyl 2- (trifluoromethyl) thiazole-5-carboxylate 104(1g, 4.44mmol) in CH at 0 deg.C₃CN：H₂To a stirred solution of O (1:1, 20mL) was added triethylamine (3.2mL, 22.22 mml); warm to room temperature and stir for 16 h. The reaction was monitored by TLC. After completion of the reaction, the volatiles were removed in vacuo and further dried by azeotropic distillation using toluene to give compound 105(900mg, crude) as a light yellow solid. TLC: 50% EtOAc/hexanes (R)_f：0.1)；¹H NMR(DMSO-d₆，400MHz)：δ10.66(br.s，1H)，8.18(s，1H)。

Synthesis of N-methoxy-N-methyl-2- (trifluoromethyl) thiazole-5-carboxamide (106):

to a stirred solution of compound 105(900mg, crude material) in DMF (15mL) at 0 ℃ under an inert atmosphere was added N, O-dimethylhydroxylamine hydrochloride (537mg, 5.47mmol), HATU (3.47g, 9.13mmol) and diisopropylethylamine (2.38mL, 13.66mmol), then warmed to room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water and washed with CH₂Cl₂And (4) extracting. The combined organic extracts were washed with 2N HCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 20% EtOAc/hexanes to give compound 106 (60)0mg, 60%, over 2 steps) as a brown liquid. TLC: 30% EtOAc/hexanes (R)_f：0.7)；¹H NMR(500MHz，DMSO-d₆)：δ8.67(s，1H)，3.83(s，3H)，3.34(s，3H)；C₇H₇F₃N₂O₂LCMS calculation of S: 240.02, respectively; and (3) observation value: 241.1(M +1)⁺。

Synthesis of 1- (2- (trifluoromethyl) thiazol-5-yl) ethan-1-one (107):

to a stirred solution of compound 106(1.05g, 4.37mmol) in dry ether (20mL) at-40 deg.C was added methyl magnesium bromide (3.7mL, 10.93mmol, 3M in ether) dropwise under an inert atmosphere for 10min and stirred at the same temperature for 3 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice-cold water at 0 ℃ and extracted with ether. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 107(450mg, crude material) as a light yellow solid. TLC: 30% EtOAc/hexanes (R)_f：0.9)；¹H NMR(400MHz，DMSO-d₆)：δ8.89(s，1H)，2.67(s，3H)。

Synthesis of methyl 2, 4-dioxo-4- (2- (trifluoromethyl) thiazol-5-yl) butanoate (108):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 400mg (36% over 2 steps, reaction scale 450mg) as an off-white solid. TLC: 2% MeOH/CH₂Cl₂(R_f：0.4)；¹H NMR(400MHz，DMSO-d₆)：δ9.13(br.s，1H)，7.07(br.s，1H)，3.86(s，3H)；C₉H₆F₃NO₄LCMS calculation of S: 281.00, respectively; and (3) observation value: 279.9(M +1)⁺。

Synthesis of methyl 5- (2- (trifluoromethyl) thiazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (109):

the title compound was synthesized using general procedure a described above for the synthesis of the cyclic sulfonamides to give 400mg (83%, reaction scale 400mg) as an off-white solid. TLC: 6% MeOH/CH₂Cl₂(R_f：0.1)；¹H NMR(400MHz，DMSO-d₆)：δ8.75(s，1H)，8.39(br.s，1H)，6.71(s，1H)，3.80(s，3H)。

Synthesis of methyl 2-methyl-5- (2- (trifluoromethyl) thiazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (110):

the title compound was synthesized using general procedure a for alkylation described above to give 340mg (83%, reaction scale 400mg) as an off-white solid. TLC: 5% MeOH/CH₂Cl₂(R_f：0.6)；¹H NMR(400MHz，DMSO-d₆)：δ9.19(s，1H)，7.49(s，1H)，3.97(s，3H)，3.58(s，3H)。

Synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (2- (trifluoromethyl) thiazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-226_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding 110 and the corresponding amine (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (2- (trifluoromethyl) thiazol-5-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-226):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-226_ Int (see Table 2 for analytical data).

Scheme 37:

synthesis of cis-3-chloro-4-fluorophenyl) -2-methyl-5- (2-phenylthiazol-5-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-235, HBV-CSU-235-ISO-I and HBV-CSU-235-ISO-II):

scheme 37:

synthesis of ethyl 2-phenylthiazole-5-carboxylate (111):

to a stirred solution of thiobenzamide (25g, 182.48mmol) in toluene (250mL) at room temperature under an inert atmosphere was added ethyl 2-chloro-3-oxopropanoate 96(41.15g, 274.34mmol), anhydrous magnesium sulfate (65.85g, 547.44mmol) and heated to 90 ℃ and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 10% EtOAc/hexanes to give compound 111(15g, 35%) as a light yellow solid. TLC: 20% EtOAc/hexanes (R)_f：0.8)；¹H NMR(400MHz，DMSO-d₆)：δ8.49(s，1H)，8.04-8.01(m，2H)，7.58-7.51(m，3H)，4.34(q，J＝7.2Hz，2H)，1.32(t，J＝7.1Hz，3H)；C₁₂H₁₁NO₂LCMS calculation of S: 233.05, respectively; LCMS observations: 234.1(M +1)⁺。

Synthesis of 2-phenylthiazole-5-carboxylic acid (112):

to compound 111(1g, 4.28mmol) in THF: h₂To a stirred solution in O (1:1, 20mL) was added lithium hydroxide monohydrate (515mg, 21.45mmol) and stirred for 6 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo and the aqueous layer pH was neutralized with 1N aqueous HCl. The precipitated solid was filtered and dried in vacuo to give compound 112(600mg, 68%) as a pale yellow solid. TLC: 30% EtOAc/hexanes (R)_f：0.1)；¹H NMR(DMSO-d₆，400MHz)：δ7.93(s，1H)，7.92-7.88(m，2H)，7.51-7.43(m，3H)；C₁₀H₇NO₂LCMS calculation of S: 205.02, respectively; LCMS observations: 206.1(M +1)⁺。

Synthesis of N-methoxy-N-methyl-2-phenylthiazole-5-carboxamide (113):

to a stirred solution of compound 112(10g, 48.72mmol) in DMF (150mL) at 0 ℃ under an inert atmosphere was added N, O-dimethylhydroxylamine hydrochloride (5.73g, 58.46mmol), EDCI.HCl (14g, 73.17mmol), HOBt (6.68g, 48.787mmol), N' -diisopropylethylamine (25.5mL, 146.73 mmol); warm to room temperature and stir for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with ice-cold water (500mL) and extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by flash column chromatography on silica gel using 20% EtOAc/hexanes to give compound 113(9.6g, 79%) as a light yellow liquid. TLC: 30% EtOAc/hexanes (R)_f：0.8)；¹H NMR(500MHz，DMSO-d₆)：δ8.50(s，1H)，8.07-7.99(m，2H)，7.57-7.53(m，3H)，3.82(s，3H)，3.32(s，3H)；C₁₂H₁₂N₂O₂LCMS calculation of S: 248.06, respectively; LCMS observations: 249.1(M +1)⁺。

Synthesis of 1- (2-phenylthiazol-5-yl) ethan-1-one (114):

to a stirred solution of compound 113(1g, 4.03mmol) in dry ether (10mL) at-40 ℃ was added dropwise methylmagnesium bromide (3.36mL, 10.08mmol, 3M solution in ether) under an inert atmosphere for 10 minutes; warm to room temperature and stir for 3 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (50mL) at 0 ℃ and extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by flash column chromatography on silica gel using 20% EtOAc/hexanes to give compound 114(600mg, 74%) as a light yellow liquid. TLC: 20% EtOAc/hexanes (R)_f：0.7)；¹H NMR(500MHz，DMSO-d₆)：δ8.70(s，1H)，8.04(dd，J＝7.8，1.4Hz，2H)，7.61-7.52(m，3H)，2.61(s，3H)；C₁₁H₉LCMS calculated for NOS: 203.04, respectively; LCMS observations: 204.1(M +1)⁺。

Synthesis of methyl 2, 4-dioxo-4- (2-phenylthiazol-5-yl) butanoate (115):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 6.6g (86%, scale of reaction 5.4g) as a yellow solid. TLC: 5% MeOH/DCM (R)_f：0.6)；¹H NMR(DMSO-d₆，400MHz)：δ.92(br.s，1H)，8.04-7.98(m，2H)，7.57-7.47(m，3H)，7.05(br.s，1H)，3.80(s，3H)；C₁₄H₁₁NO₄LCMS calculation of S: 289.04, respectively; LCMS observations: 290.1(M +1)⁺。

Synthesis of methyl 5- (2-phenylthiazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (116):

the title CompoundSynthesized using general procedure a described above for cyclization to give 3.2g (41%, reaction scale 6.5g) as a light yellow solid. TLC: 5% MeOH/DCM (R)_f：0.1)；¹H NMR(DMSO-d₆，400MHz)：δ8.66(s，1H)，8.03(dd，J＝6.4，2.9Hz，2H)，7.58-7.50(m，3H)，6.85(br.s，1H)，3.84(s，3H)；C₁₄H₁₁N₃O₄S₂LCMS calculated of (d): 349.02, respectively; LCMS observations: 350.1(M +1)⁺。

Synthesis of methyl 2-methyl-5- (2-phenylthiazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (117):

the title compound was synthesized using general procedure a for alkylation described above to give 1.6g (48% yield, 3.2g reaction scale) as an off-white solid. TLC: 30% EtOAc/hexanes (R)_f：0.8)；¹H NMR(DMSO-d₆，400MHz)：δ9.01(s，1H)，8.09(d，J＝6.7Hz，2H)，7.64-7.54(m，3H)，7.44(s，1H)，3.96(s，3H)，3.54(s，3H)；C₁₅H₁₃N₃O₄S₂LCMS calculated of (d): 363.03, respectively; LCMS observations: 364.1(M +1)⁺。

Synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (2-phenylthiazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-235_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding 117 and the corresponding amine (see table 1 for analytical data).

N- (3-chloro-4-fluorophenyl) -2-methyl-5- (2-phenylthiazol-5-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-235, HBV-CSU-235-ISO-I and HBV-CSU-235-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-235_ Int (see Table 2 for analytical data).

Scheme 38:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-246, HBV-CSU-246-ISO-I and HBV-CSU-246-ISO-II):

scheme 38:

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-202 and the corresponding boronic acid (see table 2 for analytical data).

Scheme 39:

synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-247, HBV-CSU-247-ISO-I, HBV-CSU-247-ISO-II):

scheme 39:

3- (5- ((3-chloro-4-fluorophenyl) carbamoyl) -6-methyl-1, 1-dioxo-1, 2, 6-thiadiazin-an-3-yl) phenyl trifluoromethanesulfonate (118):

to a stirred solution of compound HBV-CSU-205(0.4g, 0.968mmol) in DCM at 0 deg.C was added pyridine (0.153g, 1.93mmol) dropwise and stirred at the same temperature for 10 min. To this solution was added dropwise trifluoromethanesulfonic anhydride (0.327mL1.93mmol) at 0 ℃. The resulting reaction mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC and LCMS.After completion, the reaction mass was concentrated under reduced pressure. The residue was quenched with 10% dilute HCl and saturated NaHCO₃Washed with brine and dried in vacuo. The crude compound was purified by silica gel column chromatography to give the desired compound 118(0.17g, 32.25%) as a white solid. TLC: 40% EtOAc/hexanes (R)_f：0.4)

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-247, HBV-CSU-247-ISO-I, HBV-CSU-247-ISO-II):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using compound 118 and the corresponding boronic acid (see table 2 for analytical data).

Scheme 40:

synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (oxazol-5-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-269, HBV-CSU-269-ISO-I and HBV-CSU-269-II):

scheme 40:

synthesis of 5- (5-bromothien-2-yl) oxazole (120):

to a stirred solution of compound 119(10g, 52.36mmol) and TosMIC (11.24g, 57.59mmol) in MeOH (300mL) was added K₂CO₃(7.91g, 57.59mmol) and the reaction mixture was refluxed for 4 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo to give crude material. The crude material was purified by silica gel column chromatography using 12% EtOAc/hexanes to give the title compound 120(8.23g, 62.50%) as a light yellow solid. TLC: 20% EtOAc/hexanes (R)_f：0.3)；¹H NMR(DMSO-d₆，400MHz)：δ8.42(s，1H)，7.54(s，1H)，7.31-7.28(m，2H)；C₇H₄LCMS calculation for BrNOS: 228.92: and (3) observation value: 229.75(M +1)⁺。

Synthesis of 1- (5- (oxazol-5-yl) thiophen-2-yl) ethan-1-one (122):

to a stirred solution of bromo compound 120(7.6g, 33.18mmol) in toluene (150mL) was added tributyl (1-ethoxyvinyl) stannane (17.97g, 49.78mmol) and purged with Ar for 15 minutes. To the solution, Pd (PPh) was added₃)₂Cl₂(1.16g, 1.16mmol) and the reaction mixture was stirred at 100 ℃ overnight. The progress of the reaction was monitored by TLC. Upon completion, intermediate compound 121 was treated with 2M HCl (60mL) at reflux temperature for 3 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was concentrated in vacuo to give a crude material, which was purified by silica gel column chromatography using 15% EtOAc/hexanes to give the title compound 122(4.75g, 74.45%) as a light yellow solid. TLC: 30% EtOAc/hexanes (R)_f：0.2)¹H NMR(DMSO-d₆，400MHz)：δ8.52(s，1H)，7.97(d，J＝3.6HZ，1H)，7.78(s，1H)，7.59(d，J＝4.0HZ，1H)，2.56(s，3H)；C₉H₇NO₂LCMS calculation of S: 193.02: and (3) observation value: 194(M +1)⁺。

Synthesis of methyl 4- (5- (oxazol-5-yl) thiophen-2-yl) -2, 4-dioxobutyrate (123):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 5.5g (84%, scale of reaction 4.5g) as a yellow solid. 30% EtOAc/hexanes (R)_f：0.1)；C₁₂H₉NO₅LCMS calculation of S: 279.02; and (3) observation value: 280(M +1)⁺。

Synthesis of 5- (5- (oxazol-5-yl) thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (124):

the title compound was synthesized using general procedure B described above for the synthesis of the cyclic sulfonamides to give 4g (59.90%, scale of reaction 5.5g) as a brown solid. TLC: 5% MeOH/DCM (R)_f：0.1)；¹H NMR(DMSO-d₆，400MHz)：δ8.49(s，1H)，7.94(d，J＝4.0Hz，1H)，7.70(s，1H)，7.52(d，J＝4.0Hz，1H)，6.80(s，1H)，3.83(s，3H)；C₁₂H₉N₃O₅S₂LCMS calculated of (d): 339.00, respectively; LCMS observations: 340.05(M +1)⁺。

Synthesis of 2-methyl-5- (5- (oxazol-5-yl) thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylic acid methyl ester 1, 1-dioxide (125):

the title compound was synthesized using general procedure B described above for alkylation to give 2.3g (49.14%, scale of reaction 4.5g) as a light brown solid. TLC: 10% MeOH/DCM (R)_f：0.1)；¹H NMR(DMSO-d₆，400MHz)：δ8.57(s，1H)，8.31(d，J＝4.0Hz，1H)，7.85(s，1H)，7.67(d，J＝4.4Hz，1H)，7.36(s 1H)，3.94(s，3H)，3.51(s，3H)；C₁₃H₁₁N₃O₅S₂LCMS calculated of (d): 353.01, respectively; LCMS observations: 354.02(M +1)⁺。

Synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (oxazol-5-yl) thiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-269_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 125 and the corresponding amine (see table 1 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (oxazol-5-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-269, HBV-CSU-269-ISO-I and HBV-CSU-269-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-269_ Int (see Table 2 for analytical data).

Scheme 41:

synthesis of cis-5- (benzo [ d ] thiazol-6-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-273):

scheme 41:

synthesis of 6-bromobenzo [ d ] thiazole (127):

the title compound was prepared using Organic Letters, 9(18), 3623-; the method preparation reported in 2007.

Synthesis of 6-bromobenzo [ d ] thiazole (128):

to a mixture of bromo compound 127(7g, 32.17mmol) in toluene (70mL) was added tributyl (1-ethoxyvinyl) stannane (11.40g, 35.98mmol), purged with Ar for 15 minutes, then PdCl was added₂(PPh₃)₂(2.29g, 3.27mmol) and the resulting reaction mixture was then stirred at 90 ℃ overnight. The progress of the reaction was monitored by TLC. After completion, the reaction is reversedThe mixture was concentrated in vacuo and the resulting residue treated with 6N HCl at room temperature for 1 h. After completion, the reaction mixture was concentrated in vacuo and taken up with NaHCO₃The aqueous solution was neutralized and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 128(4g, 69%) as an off-white solid. TLC: 20% EtOAc/hexanes (R)_f：0.2)；¹H NMR(DMSO-d₆，400MHz)：δ9.18(s，1H)，8.62(s，1H)，8.20(d，J＝8.8Hz，1H)，8.12(d，J＝8.8Hz，1H)，2.72(s，3H)；C₉H₇LCMS calculated for NOS: 177.02, respectively; LCMS observations: 178(M +1)⁺。

Synthesis of methyl 4- (benzo [ d ] thiazol-6-yl) -2, 4-dioxobutyrate (129):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 5g of compound 129 (84%, scale of reaction 4g) as a brown solid. TLC: 40% EtOAc/hexanes (R)_f：0.2)。

Synthesis of methyl 5- (benzo [ d ] thiazol-6-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (130):

the title compound was synthesized using general procedure a described above for the cyclization to give 0.5g of compound 130 (10%, scale of reaction 4g) as a brown solid. TLC: 20% MeOH/DCM (R)_f：0.1)；¹H NMR(DMSO-d₆，400MHz)：δ9.51(s，1H)，8.83(s，1H)，8.16–8.06(m，2H)，6.88(s，1H)，3.84(s，3H)；C₁₂H₉N₃O₄S₂LCMS calculated of (d): 323.00, respectively; LCMS observations: 324(M +1)⁺。

Synthesis of methyl 5- (benzo [ d ] thiazol-6-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (131):

the title compound was synthesized using general procedure B described above for alkylation to give 0.4g of compound 131 (76% yield, 0.5g on reaction scale) as a brown solid. TLC: 40% EtOAc/hexanes (R)_f：0.3)；¹H NMR(CDCl3，400MHz)：δ9.20(s，1H)，8.75(s，1H)，8.25(d，J＝8.8Hz，1H)，8.16(d，J＝8.8Hz，1H)，7.25(s，1H)，4.04(s，3H)，3.72(s，3H)；C₁₃H₁₁N₃O₄S₂LCMS calculated of (d): 337.02, respectively; LCMS observations: 338(M +1)⁺。

Synthesis of 5- (benzo [ d ] thiazol-6-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-273_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding 131 and the corresponding amine (see table 1 for analytical data).

Synthesis of cis-5- (benzo [ d ] thiazol-6-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-273)

The title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-273_ Int (see Table 2 for analytical data).

Scheme 42:

general synthetic scheme for 5- (thien-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide derivatives with 4-substituted thiophenes

Scheme 42:

synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiophen-2-yl) -1,2, 6-thiadiazine-ane-3-carboxamide 1, 1-dioxide (132):

to a mixture of the bromo compound HBV-CSU-146(3g, 6.21mmol) and bis (pinacolato) diboron (3.95g, 15.53mmol) in 1, 4-dioxane (30mL) was added potassium acetate (3.04g, 31.05mmol) and purged with Ar for 15 minutes. To this solution, 1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane adduct (PdCl) was added₂(dppf)。CH₂Cl₂) (0.152g, 0.186mmol) and the reaction mixture was stirred at 90 ℃ overnight. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite, evaporated to dryness to give the desired boronic ester as crude product 132(2.35g, crude material) and used as such in the next step without further purification. TLC: 40% EtOAc/hexanes (R)_f：0.2)；C₂₁H₂₆BClFN₃O₅S₂LCMS calculated of (d): 529.11, respectively; and (3) observation value: 448.05(M +1)⁺For boric acid.

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-284, HBV-CSU-284-ISO-I and HBV-CSU-284-II):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using compound 132 and the corresponding bromo compound (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (1-methyl-1H-imidazol-5-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-285, HBV-CSU-285-ISO-I and HBV-CSU-285-ISO-II):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using compound 132 and the corresponding bromo compound (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (thiazol-5-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-286, HBV-CSU-286-ISO-I and HBV-CSU-286-II):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using compound 132 and the corresponding bromo compound (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (1-methyl-1H-pyrazol-3-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-288, HBV-CSU-288-ISO-I and HBV-CSU-288-II):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using compound 132 and the corresponding bromo compound (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (1-methyl-1H-1, 2, 4-triazol-3-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-326-ISO-I and HBV-CSU-326-II):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using compound 132 and the corresponding bromo compound (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (1-methyl-1H-1, 2, 4-triazol-5-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-327-ISO-I and HBV-CSU-327-II):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using compound 132 and the corresponding bromo compound (see table 2 for analytical data).

Scheme 43:

synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4-methyl-5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-300, HBV-CSU-300-ISO-I and HBV-CSU-300-ISO-I) and 5- (5-bromo-4-methylthiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-335):

scheme 43:

synthesis of 1- (5-bromo-4-methylthiophen-2-yl) ethan-1-one (134):

to a stirred solution of compound 133(10g, 56.49mmol) in DCM (100mL) at 0 deg.C was added AlCl₃(9.3g, 70.62mmol) and stirred for 10 min. Acetyl chloride (4.85g, 61.51mmol) was added to the solution at the same temperature and the resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0 ℃; quench by addition of ice cold water, using saturated NaHCO₃The solution was basified and then extracted with DCM. The combined organic layers were collected, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude compound. The crude compound was purified by silica gel column chromatography using 5% EtOAc/hexanes to give the title compound 134(12g, 97%) as a brown solid. TLC: 10% EtOAc/hexanes (R)_f：0.4)；C₇H₇LCMS calculation for BrOS: 217.94, respectively; and (3) observation value: 218.80(M)⁺。

Synthesis of methyl 4- (5-bromo-4-methylthiophen-2-yl) -2, 4-dioxobutyrate (135):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 15g (90.09%, reaction scale 12g) as a brown solid. TLC: 20% EtOAc/hexanes (R)_f: 0.1). The crude material was used as such for the next reaction without further characterization.

Synthesis of methyl 5- (5-bromo-4-methylthiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (136):

the title compound was synthesized using general procedure B described above for the synthesis of the cyclic sulfonamides to give 13g of compound 136 (72.22%, 15g on a reaction scale) as a yellow solid. TLC: 50% EtOAc/hexanes (R)_f：0.1)；C₁₀H₉BrN₂O₄S₂LCMS calculated of (d): 363.92, respectively; LCMS observations: 366.90(M +2)⁺。

Synthesis of methyl 5- (5-bromo-4-methylthiophen-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (137):

the title compound was prepared using the general procedure described above for alkylationB was synthesized to give 10g of compound 137 (75%, reaction scale 13g) as a yellow solid. TLC: 40% EtOAc/hexanes (R)_f：0.3)；C₁₁H₁₁BrlN₂O₄S₂Calculated LCMS of 377.93; LCMS observations: 381.25(M +2)⁺。

Synthesis of 5- (5-bromo-4-methylthiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-335_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 137 and the corresponding amine (see table 1 for analytical data).

Cis-5- (5-bromo-4-methylthiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-335):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-335_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4-methyl-5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-300, HBV-CSU-300-ISO-I and HBV-CSU-300-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-335 and the corresponding bromo compound (see table 2 for analytical data).

Scheme 44:

synthesis of N- (3-chloro-4-fluorophenyl) -5- (4-chloro-5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-302, HBV-CSU-302-ISO-I and HBV-CSU-302-ISO-II):

scheme 44:

synthesis of 2-bromo-3-chlorothiophene (139):

to compound 138(5g, 42.37mmol) in CCl at 0 deg.C₄(30mL), Br was added dropwise to the stirred solution₂(6.4g, 40.25 mmol). The resulting reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0 ℃; quenched by addition of aqueous sodium thiosulfate and 50% NaOH solution and extracted with DCM. The combined organic layers were collected, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound 139(6g, 71.94%) as a colorless liquid and used as such in the next step without further purification, TLC: hexane (R)_f：0.4)；¹H NMR(DMSO-d₆，400MHz)：δ7.75(d，J＝5.6Hz，1H)，7.11(d，J＝6.0Hz，1H)。

Synthesis of 1- (5-bromo-4-chlorothien-2-yl) ethan-1-one (140):

to a stirred solution of compound 139(6g, 30.45mmol) in DCM (300mL) at 0 deg.C was added AlCl₃(4.41g, 33.16mmol) and stirred for 10 min. Acetyl chloride (2.96g, 38.07mmol) was added to the solution at the same temperature. The resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0 ℃; quenching by adding ice cold water; saturated NaHCO₃Solution and extracted with DCM. The combined organic layers were collected, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material is chromatographed on silica gelPurification by chromatography using 10% EtOAc/hexanes to give the title compound 140(5.5g, 75.34%) as a brown solid. TLC: 5% EtOAc/hexanes (R)_f：0.3)¹H NMR(DMSO-d₆，400MHz)：δ8.06(s，1H)，2.52(s，3H)。C₆H₄LCMS calculation for BrClOS: 237.89, respectively; and (3) observation value: 240.85(M +2)⁺。

Synthesis of methyl 4- (5-bromo-4-chlorothien-2-yl) -2, 4-dioxobutyrate (141):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 10g of compound 141 (crude, reaction scale 5.5g) as a brown solid. TLC: 10% MeOH/DCM (R)_f: 0.1). The crude material was used as such for the next reaction without further characterization.

Synthesis of methyl 5- (5-bromo-4-chlorothien-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (142):

the title compound was synthesized using general procedure B described above for the synthesis of the cyclic sulfonamides to give 7g of compound 142 (58%, reaction scale 10g) as a yellow solid. TLC: 20% EtOAc/hexanes (R)_f：0.1)；¹H NMR(DMSO-d₆，400MHz)：δ7.96(s，1H)，6.72(s，1H)，3.81(s，3H)；C₉H₆BrClN₂O₄S₂LCMS calculated of (d): 383.86, respectively; LCMS observations: 386.90(M +2)⁺。

Synthesis of methyl 5- (5-bromo-4-chlorothien-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (143):

the title compound was synthesized using general procedure B described above for alkylationTo give 9g of compound 143 (crude, reaction scale 7g) as a yellow solid. TLC: 40% EtOAc/hexanes (R)_f：0.4)；¹H NMR(DMSO-d₆，400MHz)：δ8.41(s 1H)，7.37(s，1H)，3.94(s，3H)，3.53(s，3H)；C₁₀H₈BrClN₂O₄S₂LCMS calculated of (d): 397.88, respectively; LCMS observations: 401.25(M +2)⁺。

Synthesis of 5- (5-bromo-4-chlorothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-329_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using compound 143 and the corresponding amine (see table 1 for analytical data).

Cis-5- (5-bromo-4-chlorothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-329):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-329_ Int (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (4-chloro-5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-302, HBV-CSU-302-ISO-I and HBV-CSU-302-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-329 and the corresponding bromo compound (see table 2 for analytical data).

Scheme 45:

synthesis of cis-3-chloro-4-fluorophenyl) -2-methyl-5- (5-phenyl-1, 3, 4-thiadiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-304, HBV-CSU-304-ISO-I and HBV-CSU-304-ISO-II):

scheme 45:

synthesis of 1- (4-bromo-5-methylthiophen-2-yl) ethan-1-one (145):

to a stirred solution of compound 144(5g, 35.71mmol) and NaOAc (3.22g, 39.28mmol) in water (300mL) at 0 deg.C was added Br dropwise₂(5.7g, 35.71 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to 0 ℃; quenched by using aqueous sodium thiosulfate and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound 145(7.5g, 96.77%) as a brown solid which was used as such in the next step without further purification of TLC: 40% EtOAc/hexanes (R)_f：0.5)；¹H NMR(DMSO-d₆400 MHz): δ 7.88(s, 1H), 2.46(s, 3H), 2.38(s, 3H); LCMS calcd for C7H7 BrOS: 217.94, respectively; and (3) observation value: 218.95(M +1)⁺。

Synthesis of methyl 4- (4-bromo-5-methylthiophen-2-yl) -2, 4-dioxobutyrate (146):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 6g of compound 146 (57.30%, reaction scale 7.5g) as a brown solid. TLC: 40% EtOAc/hexanes (R)_f: 0.3). The crude material was used as such for the next reaction without further characterization.

Synthesis of methyl 5- (4-bromo-5-methylthiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (147):

the title compound was synthesized using general procedure B described above for the synthesis of the cyclic sulfonamides to give 8.9g of compound 147 (crude, 6g reaction scale) as a yellow solid. TLC: 40% EtOAc/hexanes (R)_f：0.2)；¹H NMR(DMSO-d₆，400MHz)：8.01(s，1H)，6.92(s，1H)，3.84(s，3H)，2.42(s，3H)；C₁₀H₉BrN₂O₄S₂LCMS calculated of (d): 363.92, respectively; LCMS observations: 366.95(M +2)⁺。

Synthesis of methyl 5- (4-bromo-5-methylthiophen-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (148):

the title compound was synthesized using general procedure B described above for alkylation to give 7g of compound 148 (79.54%, scale of reaction 8.5g) as a yellow solid. TLC: 40% EtOAc/hexanes (R)_f：0.3)；¹H NMR(DMSO-d₆，400MHz)：δ8.30(s，1H)，7.34(s，1H)，3.93(s，3H)，3.51(s，3H)，2.47(s，3H)；C₁₁H₁₁BrN₂O₄S₂LCMS calculated of (d): 377.93, respectively; LCMS observations: 380.95(M +2)⁺。

Synthesis of 5- (4-bromo-5-methylthiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-304_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 148 and the corresponding amine (see table 1 for analytical data).

Synthesis of 5- (4-bromo-5-methylthiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-304_ Int-I):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-304_ Int-I (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5-methyl-4- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-304, HBV-CSU-304-ISO-I and HBV-CSU-304-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-304_ Int-I and the corresponding bromo compound (see Table 2 for analytical data).

Scheme 46:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -5- (5-ethyl-4- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-305, HBV-CSU-305-ISO-I and HBV-CSU-305-ISO-II) and cis-5- (4-bromo-5-ethylthiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-334):

scheme 46

Synthesis of 1- (5-ethylthiophen-2-yl) ethan-1-one (150):

addition of compound 149(10g, 8) at room temperature9.13mmol) in acetic anhydride (9.27mL, 98.04mmol) H was added portionwise under inert atmosphere₃PO₄(0.464mL, 8.913 mmol). The reaction was stirred at 100 ℃ for 1 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was slowly poured onto ice to be cooled and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude compound 150(12g, crude material) as a brown liquid. TLC: 40% EtOAc/hexanes (R)_f：0.5)。¹H-NMR(DMSO-d₆，400MHz)：δ7.77(d，J＝4.6Hz，1H)，6.98(d，J＝3.6Hz，1H)，2.88-2.82(m，2H)，2.47(s，3H)，1.25(t，J＝7.2Hz，3H)；C₈H₁₀LCMS calculation for OS: 154.05, respectively; and (3) observation value: 155(M +1)⁺。

Synthesis of 1- (4-bromo-5-methylthiophen-2-yl) ethan-1-one (151):

to a stirred solution of compound 150(14g, 90.90mmol) and NaOAc (8.20g, 99.99mmol) in water (100mL) at 0 deg.C was added dropwise Br₂(4.69mL, 90.90 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to 0 ℃; quenched by using aqueous sodium thiosulfate and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound 151(24g, crude material) as a brown viscous solid and used as such in the next step without further purification of TLC: 40% EtOAc/hexanes (R)_f：0.6)；¹H-NMR(DMSO-d₆，400MHz)：δ7.90(s，1H)，2.81-2.73(m，5H)，1.21-1.15(m，3H)；C₈H₉LCMS calculation for BrOS: 231.96, respectively; and (3) observation value: 232.90(M +1)⁺。

Synthesis of methyl 4- (4-bromo-5-ethylthiophen-2-yl) -2, 4-dioxobutyrate (152):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 12g of compound 152 (crude, 24g reaction scale) as a pale yellow solid. TLC: 40% EtOAc/hexanes (R)_f: 0.2). The crude material was used as such for the next reaction without further characterization.

Synthesis of methyl 5- (4-bromo-5-ethylthiophen-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (153):

the title compound was synthesized using general procedure B described above for the synthesis of cyclic sulfonamides to give 12g of compound 153 (crude, reaction scale 12g) as a brown viscous solid. TLC: 40% EtOAc/hexanes (R)_f：0.2)；¹H NMR(DMSO-d₆，400MHz)：8.03(s，1H)，6.94(s，1H)，6.32(br.s，1H)，3.85(s，3H)，2.83-2.81(m，2H)，1.24(t，J＝7.2Hz，3H)；C₁₁H₁₁BrN₂O₄S₂LCMS calculated of (d): 377.93, respectively; LCMS observations: 380.90(M +2)⁺。

Synthesis of methyl 5- (4-bromo-5-ethylthiophen-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (154):

the title compound was synthesized using general method B for alkylation described above to give 7.6g of compound 154 (61.09%, reaction scale 12g) as a yellow solid. TLC: 40% EtOAc/hexanes (R)_f：0.4)；¹H NMR(DMSO-d₆，400MHz)：8.31(s，1H)，7.35(s，1H)，3.94(s，3H)，3.51(s，3H)，2.87-2.81(m，2H)，1.24(t，J＝7.2Hz，3H)，；C₁₂H₁₃BrN₂O₄S₂LCMS calculated of (d): 391.95, respectively; LCMS observations: 395(M +2)⁺。

Synthesis of 5- (4-bromo-5-ethylthiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-334_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using the corresponding 154 and the corresponding amine (see table 1 for analytical data).

Synthesis of 5- (4-bromo-5-ethylthiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-334):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-334_ Int-I (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -5- (5-ethyl-4- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -2-methyl-1, 2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-305, HBV-CSU-305-ISO-I and HBV-CSU-305-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-334 and the corresponding bromo compound (see table 2 for analytical data).

Scheme 47:

synthesis of 5- (5-chloro-4- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-306, HBV-CSU-306-ISO-I and HBV-CSU-306-ISO-II) and 5- (4-bromo-5-chlorothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-330):

scheme 47:

synthesis of 1- (4-bromo-5-chlorothien-2-yl) ethan-1-one (156):

to compound 155(20g, 124.51mmol) in CHCl at 0 deg.C₃To a stirred solution (300mL), AlCl was added₃(48.14g, 361.07mmol) and stirred at the same temperature for 10 min. To the solution, Br was added dropwise at 0 deg.C₂(7.06mL, 136.96 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to 0 ℃; quenched by using aqueous sodium thiosulfate and extracted with ethyl acetate. The combined organic layers were collected, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound 156(25g, crude material) as a yellow liquid and used as such in the next step without further purification. TLC: 40% EtOAc/hexanes (R)_f：0.6)；¹H NMR(DMSO-d₆，400MHz)：δ7.50(s，1H)，2.51(s，3H)。

Synthesis of methyl 4- (4-bromo-5-chlorothien-2-yl) -2, 4-dioxobutyrate (157):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 22g of compound 157 (crude, 32g reaction scale) as a brown liquid. TLC: 40% EtOAc/hexanes (R)_f: 0.3). The crude material was used as such for the next reaction without further characterization.

Synthesis of methyl 5- (4-bromo-5-chlorothien-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (158):

the title compound is preparedSynthesized using general procedure B described above for the synthesis of the cyclic sulfonamides to give 20g of compound 158 (crude, reaction scale 22g) as a light black solid. TLC: 40% EtOAc/hexanes (R)_f：0.2)；¹H NMR(DMSO-d₆，400MHz)：δ8.00(s，1H)，6.75(s，1H)，3.81(s，3H)。

Synthesis of methyl 5- (4-bromo-5-chlorothien-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (159):

the title compound was synthesized using general procedure B described above for alkylation to give 10g of compound 159 (96%, 10g reaction scale) as a yellow solid. TLC: 40% EtOAc/hexanes (R)_f：0.4)；¹H NMR(DMSO-d₆，400MHz)：δ8.46(s 1H)，7.39(s，1H)，3.94(s，3H)，3.53(s，3H)；C₁₀H₈BrClN₂O₄S₂LCMS calculated of (d): 397.88, respectively; LCMS observations: 400.90(M +2)⁺。

Synthesis of 5- (4-bromo-5-chlorothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-330_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using the corresponding 159 and the corresponding amine (see table 1 for analytical data).

Cis-5- (4-bromo-5-chlorothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-330):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-330_ Int-I (see Table 2 for analytical data).

Cis-5- (5-chloro-4- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-306, HBV-CSU-306-ISO-I and HBV-CSU-306-ISO-II):

the title compound was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-330 and the corresponding bromo compound (see table 2 for analytical data).

Scheme 48:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (4-methyl-4H-1, 2, 4-triazol-3-yl) thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-324, HBV-CSU-324-ISO-I and HBV-CSU-324-ISO-II):

scheme 48:

synthesis of methyl 5- (5- ((3-chloro-4-fluorophenyl) carbamoyl) -6-methyl-1, 1-dioxo-1, 2, 6-thiadiazin-an-3-yl) thiophene-2-carboxylate (160):

to a compound HBV-CSU-114(5g, 10.33mmol) in MeOH: to a stirred solution of a mixture of ACN (50mL:12.5mL) was added TEA (3.13g, 30.99mmol) and dppf (0.57g, 1.03mmol) and purged with Ar for 15 min. To which Pd (OAc) is added₂(0.231g, 1.03mmol) and again flushed with carbon monoxide, and the resulting reaction mixture heated in an autoclave at 100 ℃ for 6h at 150psi pressure. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The resulting residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporatedConcentrate to give crude material. The crude material was purified by silica gel column chromatography using 30% EtOAc/hexanes to give the title compound 160(2.5g, 51.02%) as a brown solid. TLC: 40% EtOAc/hexanes (R)_f：0.3)；¹H-NMR(DMSO-d₆，400MHz)：δ10.60(s，1H)，7.98-7.96(m，1H)，7.84-7.81(m，1H)，7.71(d，J＝4Hz，1H)，7.57-7.53(m，1H)，7.41(t，J＝9.2Hz，1H)，7.25(d，J＝4Hz，1H)，4.88-4.83(m，1H)，4.33-4.30(m，1H)，3.82(s，3H)，2.62(s，3H)，2.30-1.98(m，2H)。C₁₇H₁₇ClFN₃O₅S₂LCMS calculated of (d): 461.03, respectively; LCMS observations: 462.15(M +1)⁺。

Synthesis of 5- (5- ((3-chloro-4-fluorophenyl) carbamoyl) -6-methyl-1, 1-dioxo-1, 2, 6-thiadiazinan-3-yl) thiophene-2-carboxylic acid (161):

to a stirred solution of compound 160(1g, 2.10mmol) in THF (15mL) was added aq. lioh (0.22g, 5.26mmol, dissolved in 15mL of water). The resulting reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water and acidified to pH-2 with 2N HCl and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 161(0.6g, 61.8%) as a white solid. TLC: 50% EtOAc/hexanes (R)_f：0.1)；C₁₆H₁₅ClFN₃O₅S₂LCMS calculated of (d): 447.01, respectively; LCMS observations: 448.05(M +1)⁺。

Synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (4-methyl-5-thioxo-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (162):

conversion in inert atmosphereCompound 161(0.6g, 1.34mmol) and a stirred solution of 4-methylaminothiourea (N-methyhydrazinecarbothioamide) (0.155g, 1.47mmol) in DMF (15mL) were added EDCI.HCl (38.06g, 199.26mmol) and HOBt (26.9g, 199.25 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.71g of crude compound, which was used in the next step. The crude compound was dissolved in 5% NaOH solution and heated at 60 ℃ for 16 h. After completion, the reaction mixture was cooled to 0 ℃; acidified to pH-6 with 1N HCl and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude compound was purified by silica gel column chromatography using 50% EtOAc/hexanes to give compound 162(0.21g, 27%) as an off-white solid. TLC: 80% EtOAc/hexanes (R)_f：0.7)；

¹H-NMR(DMSO-d₆，400MHz)：δ13.98(s，1H)，10.62(s，1H)，7.99-7.97(m，1H)，7.85-7.83(m，1H)，7.64-7.54(m，2H)，7.41(t，J＝8.8Hz，1H)，7.30-7.29(m，1H)，4.90-4.85(m，1H)，4.35-4.32(m，1H)，3.67(s，3H)，2.63(s，3H)，2.33-1.99(m，2H)。C₁₈H₁₈ClFN₆O₃S₃LCMS calculated of (d): 516.03, respectively; LCMS observations: 517.05(M +1)⁺。

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (4-methyl-4H-1, 2, 4-triazol-3-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-324, HBV-CSU-324-ISO-I and HBV-CSU-324-ISO-II):

to a stirred solution of compound 162(0.2g, 0.387mmol) in DCM (2mL) at 0 deg.C was added H₂O₂(0.028g, 0.85mmol) and acetic acid (0.5 mL). The reaction mixture was stirred at rt for 3 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was basified to pH-10 with 2N NaOH and extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude compound was purified by silica gel column chromatography using 50% EtOAc/hexanes to give the compound HBV-CSU-324(0.11g, 59%) as a white solid. TLC: 80% EtOAc/hexanes (R)_f: 0.2); (see Table 2 for analytical data).

Scheme 49:

synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (4-methyl-4H-1, 2, 4-triazol-3-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-328, HBV-CSU-328-ISO-I and HBV-CSU-328-ISO-II):

scheme 49:

synthesis of methyl 5- (5- ((3-chloro-4-fluorophenyl) carbamoyl) -6-methyl-1, 1-dioxo-1, 2, 6-thiadiazin-an-3-yl) thiophene-3-carboxylate (163):

to a compound HBV-CSU-146(5g, 10.33mmol) in MeOH: to a stirred solution of a mixture of ACN (50mL:12.5mL) was added TEA (3.13g, 30.99mmol) and dppf (0.57g, 1.03mmol) and purged with Ar for 15 min. To which Pd (OAc) is added₂(0.231g, 1.03mmol) and again flushed with carbon monoxide, and the resulting reaction mixture heated in an autoclave at 100 ℃ for 6h at 150psi pressure. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The resulting residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 30% EtOAc/hexanes to give the title compound 163(3g, 63.8%) as a brown solid. TLC: 40% EtOAc/hexanes (R)_f：0.2)；¹H-NMR(DMSO-d₆，400MHz)：δ10.57(s，1H)，8.37(s，1H)，7.97-7.95(m，1H)，7.75-7.72(m，1H)，7.57-7.53(m，1H)，7.46(s，1H)，7.40(t，J＝8.8Hz，1H)，4.83-4.77(m，1H)，4.32-4.28(m，1H)，3.78(s，3H)，2.63(s，3H)，2.30-2.27(m，1H)，2.16-1.97(m，1H)；C₁₇H₁₇ClFN₃O₅S₂LCMS calculated of (d): 461.03, respectively; LCMS observations: 462(M +1)⁺。

Synthesis of 5- (5- ((3-chloro-4-fluorophenyl) carbamoyl) -6-methyl-1, 1-dioxo-1, 2, 6-thiadiazinan-3-yl) thiophene-3-carboxylic acid (164):

to a stirred solution of compound 163(1g, 2.16mmol) in THF (10mL) was added aq. lioh (0.18g, 5.4mmol, dissolved in 10mL water). The resulting reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water and acidified to pH-2 with 2N HCl and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 164(0.9g, 93.7%) as a white solid. TLC: 40% EtOAc/hexanes (R)_f：0.1)；C₁₆H₁₅ClFN₃O₅S₂LCMS calculated of (d): 447.01, respectively; LCMS observations: 448(M +1)⁺。

Synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (4-methyl-5-thioxo-4, 5-dihydro-1H-1, 2, 4-triazol-3-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (165):

to a stirred solution of compound 164(0.9g, 2.01mmol) and 4-methylaminothiourea (0.22g, 2.21mmol) in DMF (10mL) under an inert atmosphere were added EDCI.HCl (0.41g, 2.21mmol) and HOBt (0.28g, 2.21 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. Combined organic extractsDried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude compound, which was used for the next step. The crude compound was dissolved in 5% NaOH solution and heated at 60 ℃ for 16 h. After completion, the reaction mixture was cooled to 0 ℃; acidified to pH-6 with 1N HCl and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude compound was purified by silica gel column chromatography using 20% EtOAc/hexanes to give compound 165(0.2g, 18.18%) as an off-white solid. TLC: 70% EtOAc/hexanes (R)_f：0.7)；

C₁₈H₁₈ClFN₆O₃S₃LCMS calculated of (d): 516.03, respectively; LCMS observations: 517(M +1)⁺。

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (4- (4-methyl-4H-1, 2, 4-triazol-3-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-328, HBV-CSU-328-ISO-I and HBV-CSU-328-ISO-II):

to a stirred solution of compound 165(0.2g, 0.387mmol) in DCM (10mL) at 0 deg.C was added H₂O₂(0.029g, 0.85mmol) and acetic acid (0.5 mL). The reaction mixture was stirred at rt for 3 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was basified to pH-10 with 2N NaOH and extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude compound was purified by silica gel column chromatography using 50% EtOAc in hexanes to give the compound HBV-CSU-328(0.1g, 53.9%) as an off-white solid. TLC: 5% MeOH/DCM (R)_f: 0.1); (see Table 2 for analytical data).

Scheme 50:

synthesis of 5- (5- (1H-imidazol-4-yl) thiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-331-ISO-I and HBV-CSU-331-ISO-II):

scheme 50:

synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-trityl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (166):

the title compound above was synthesized following the general procedure described above for the Suzuki coupling by using HBV-CSU-114 and (1-trityl-1H-imidazol-4-yl) boronic acid to give compound 166(0.75g, 34.69%). TLC: 50% EtOAc/hexanes (R)_f: 0.3); after column purification a new spot was isolated and used as such for the next reaction without characterization.

Synthesis of cis-5- (5- (1H-imidazol-4-yl) thiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-331-ISO-I and HBV-CSU-331-ISO-II):

to a stirred solution of compound 166(0.6g, 0.842mmol) in MeOH (10mL) was added 1N HCl (10mL) and refluxed for 1 h. The reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water; basified with 10% NaHCO3 solution and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude compound was purified by silica gel column chromatography to give compound HBV-CSU-331(0.1g, 25.64%)

(see Table 2 for analytical data).

Scheme 51:

synthesis of cis-5- (5- (1H-imidazol-4-yl) thiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-333-ISO-I and HBV-CSU-333-ISO-II):

scheme 51:

synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-trityl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (167):

to the compound HBV-CSU-122(1g, 2.06mmol) and (1-trityl-1H-imidazol-4-yl) boronic acid (1.4g, 4.12mmol) in THF: h₂O (10mL:2mL) mixture, NaHCO was added₃(0.51g, 6.18mmol), purged with Ar for 15 minutes, then Pd (dppf) Cl was added₂(0.15g, 0.206mmol) and stirred at 100 ℃ for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with 1N HCl, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the title compound 167(0.75g, 54%) as an off-white solid. TLC: 30% EtOAc/hexanes (R)_f: 0.2); after column purification a new spot was isolated and used as such for the next reaction without characterization.

Synthesis of 5- (5- (1H-imidazol-4-yl) thiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-333-ISO-I and HBV-CSU-333-ISO-II):

to a stirred solution of compound 167(0.75g, 1.05mmol) in MeOH (5mL) at 0 ℃ was added 1N HCl (5 mL). The reaction mixture was stirred at 70 ℃ for 1 h. The reaction was monitored by TLC. After completion, the reaction mixture was diluted with water; with saturated NaHCO₃The solution was basified and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified by preparative HPLC to give the desired compound.

(see Table 2 for analytical data).

Scheme 52:

synthesis of cis-5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) 1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-336, HBV-CSU-336-ISO-I and HBV-CSU-336-ISO-II):

synthesis of 5- (5-bromothiazol-2-yl) -2- (methyl-d₃) -2H-1,2, 6-thiadiazine-3-carboxylic acid ethyl ester 1, 1-dioxide (169):

the title compound was synthesized using general procedure B described above for alkylation to give 4.82g of compound 169 (71%, scale of reaction 6.45g) as a brown solid. TLC: 50% EtOAc/hexanes (R)_f：0.6)；C₁₀H₇D₃BrN₃O₄S₂LCMS calculated of (d): 381.95, respectively; LCMS observations: 385(M +2)⁺。

Synthesis of 5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-336_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 169 and the corresponding amine (see table 1 for analytical data).

Synthesis of 5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) 1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-336, HBV-CSU-336-ISO-I and HBV-CSU-336-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-336_ Int (see Table 2 for analytical data).

Scheme 53:

synthesis of N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1- (methyl-d)₃) -1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-337-ISO-I and HBV-CSU-337-ISO-II) and N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1-methyl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-338-ISO-I and HBV-CSU-338-ISO-II):

scheme 53:

cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1- (methyl-d)₃) -1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-337-ISO-I and HBV-CSU-337-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling, using HBV-CSU-336 and the corresponding stannane (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1-methyl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-338-ISO-I and HBV-CSU-338-ISO-II)

The title compound was synthesized following the general procedure described above for Stille coupling, using HBV-CSU-336 and the corresponding stannane (see Table 2 for analytical data).

Scheme 54:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1- (methyl-d)₃) -1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3, 4,5-d₃-3-carboxamide 1, 1-dioxide and cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1-methyl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-e-3, 4,5-d₃-3-carboxamide 1, 1-dioxide (HBV-CSU-340-ISO-I and HBV-CSU-340-ISO-II):

scheme 54:

synthesis of 5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -1,2, 6-thiadiazine-3, 4,5-d₃-3-carboxamide 1, 1-dioxide (170):

to the compound HBV-CSU-336_ Int (1g, 2.07mmol) in THF: D at 0 ℃ under Ar atmosphere₂To a stirred solution of O (1:1, 10mL) in a mixture was added NaBD₄(0.173g, 4.14mmol) and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated in vacuo. The crude compound was purified by silica gel column chromatography using 5% MeOH/DCM to give compound 170(0.9g, 88.75%) as a yellow solid. TLC: 30% EtOAc/hexanes (R)_f：0.2)；¹H-NMR(DMSO-d₆，400MHz)：δ10.59(s，1H)，7.98-7.93(m，2H)，7.90(s，1H)，7.58-7.54(m，1H)，7.40(t，J＝8.8Hz，1H)，2.12(s，1H)。C₁₄H₇D₆BrClFN₄O₃S₂LCMS calculated of (d): 487.97, respectively; LCMS observations: 491.1(M +1)⁺。

cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1- (methyl-d)₃) -1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3, 4,5-d₃-3-carboxamide 1, 1-dioxide (HBV-CSU-339-ISO-I and HBV-CSU-339-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling by using compound 170 and the corresponding stannane (see table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1-methyl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-e-3, 4,5-d₃-3-carboxamide 1, 1-dioxide (HBV-CSU-340-ISO-I and HBV-CSU-340-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling by using compound 170 and the corresponding stannane (see table 2 for analytical data).

Scheme 55:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1- (methyl-d)₃) -1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3, 4,5-d₃-3-carboxamide 1, 1-dioxide (HBV-CSU-341-ISO-I and HBV-CSU-341-ISO-II):

scheme 55:

cis-5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3, 4,5-d₃-3-carboxamide 1, 1-dioxide (171):

to the compound HBV-CSU-122-amide (1.2g, 2.5mmol) in THF: D at 0 ℃ under Ar atmosphere₂To a stirred solution of O (1:1, 10mL) in a mixture was added NaBD₄(0.209g, 5mmol) and stirred at room temperature for 45 min. The progress of the reaction was monitored by TLC and LCMS. Go toAfter completion, the reaction mixture was concentrated in vacuo. The crude compound was purified by silica gel column chromatography using 100% EtOAc/hexanes to give compound 171(1.1g, 90.9%) as a light yellow solid. TLC: 40% EtOAc/hexanes (R)_f：0.5)；¹H-NMR(DMSO-d₆，400MHz)：δ10.58(s，1H)，7.97-7.94(m，2H)，7.89(s，1H)，7.57-7.54(m，1H)，7.40(t，J＝8.8Hz，1H)，2.63(s，3H)，2.12(s，1H)；C₁₄H₁₀D₃BrClFN₄O₃S₂LCMS calculated of (d): 484.95, respectively; LCMS observations: 488(M +2)⁺。

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1- (methyl-d)₃) -1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3, 4,5-d₃-3-carboxamide 1, 1-dioxide (HBV-CSU-341-ISO-I and HBV-CSU-341-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling by using compound 171 and the corresponding stannane (see table 2 for analytical data).

Scheme 56:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (1-methyl-1H-benzo [ d ] imidazol-5-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-360, HBV-CSU-360-ISO-I and HBV-CSU-360-ISO-II):

scheme 56:

synthesis of N-methoxy-N, 1-dimethyl-1H-benzo [ d ] imidazole-5-carboxamide (173):

to a stirred solution of acid compound 172(6.7g, 38.06mmol) and N, O-dimethylhydroxylamine (5.57g, 57.09mmol) in DCM (70mL) at 0 deg.C was addedDIPEA (13.53mL, 76.13mmol) was added and stirred for 15min, then HATU (21.69g, 57.09mmol) was added and stirred again for 15 min. The reaction mixture was then stirred at room temperature overnight. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ice-cold water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound. The crude compound was purified by silica gel column chromatography using 2% MeOH in DCM to give the title compound 173(8.1g, 98.78%) as a brown liquid. TLC: 5% MeOH/DCM (R)_f：0.3)。¹H C₁₁H₁₃N₃O₂LCMS calculated of (d): 219.10, respectively; LCMS observations: 219.95(M +1)⁺。

Synthesis of 1- (1-methyl-1H-benzo [ d ] imidazol-5-yl) ethan-1-one (174):

to a stirred solution of compound 173(8.1g, 36.95mmol) in anhydrous THF (80mL) at 0 deg.C was added dropwise methylmagnesium bromide (24.77mL, 73.97mmol, 3M in ether) under an inert atmosphere for 15 minutes, then warmed to room temperature and stirred for 3 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (50mL) and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography using 2% MeOH in DCM to give the title compound 174(5.65g, 87.59%) as an off-white solid. TLC: 5% MeOH/DCM (R)_f：0.4)；¹H NMR(400MHz，DMSO-d₆)：δ8.34-8.32(m，2H)，7.90(d，J＝8.4Hz，1H)，7.66(d，J＝8.8Hz，1H)，3.87(s，3H)，2.64(s，3H)；C₁₀H₁₀N₂LCMS calculated for O: 174.08, respectively; and (3) observation value: 175.10(M +1)⁺。

Synthesis of methyl 4- (1-methyl-1H-benzo [ d ] imidazol-5-yl) -2, 4-dioxobutyrate (175):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 3.8g of compound 175 (crude, reaction scale 5g) as a brown solid. TLC: 80% EtOAc/hexanes (R)_f：0.1)；C₁₃H₁₂N₂O₄LCMS calculated of (d): 260.08, respectively; and (3) observation value: 261(M +1)⁺。

Synthesis of methyl 5- (1-methyl-1H-benzo [ d ] imidazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (176):

the title compound was synthesized using general procedure B described above for the synthesis of the cyclic sulfonamides to give 2g of compound 176 (42.82%, scale of reaction 3.8g) as a yellow solid. TLC: 5% MeOH/DCM (R)_f：0.1；C₁₃H₁₂N₄O₄LCMS observation of S: 320.06(M +1)⁺Observed values: 320.95(M +1)⁺。

Synthesis of methyl 2-methyl-5- (1-methyl-1H-benzo [ d ] imidazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (177):

the title compound was synthesized using general method B described above for alkylation to give 1.3g of compound 177 (crude, reaction scale 1.8 g); TLC: 5% MeOH/DCM (R)_f：0.2)；C₁₄H₁₄N₄O₄LCMS calculation of S: 334.07, respectively; LCMS observations: 335(M +1)⁺。

Synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (1-methyl-1H-benzo [ d ] imidazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-360_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using compound 177 and the corresponding amine (see table 1 for analytical data).

Synthesis of cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (1-methyl-1H-benzo [ d ] imidazol-5-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-360, HBV-CSU-360-ISO-I and HBV-CSU-360-ISO-II):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-360_ Int (see Table 2 for analytical data).

Scheme 57:

synthesis of cis-5- (benzo [ d ] thiazol-5-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-361):

synthesis of N-methoxy-N-methylbenzo [ d ] thiazole-5-carboxamide (179):

to a stirred solution of compound 178(4g, 22.32mmol) in DCM (50mL) at 0 deg.C were added DIPEA (7.77mL, 44.64mmol) and HATU (12.72g, 33.48mmol) and stirred for 15 min. To this solution was added N, O-dimethylhydroxylamine hydrochloride (3.26g, 33.48 mmol). The reaction mixture was stirred at rt for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ice-cold water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound. The crude compound was purified by silica gel column chromatography using 50% EtOAc/hexanes to give the title compound 179(3.7g, 60.48%) as a white solid. TLC: 60% EtOAc/hexanes (R)_f：0.3)。C₁₀H₁₀N₂O₂LCMS calculation of S: 222.05, respectively; LCMS observations: 222.95(M +1)⁺。

Synthesis of 1- (benzo [ d ] thiazol-5-yl) ethan-1-one (180):

to a stirred solution of compound 179(3.7g, 16.6mmol) in anhydrous THF (40mL) at 0 deg.C was added dropwise methylmagnesium bromide (11.09mL, 33.3mmol, 3M in ether) under an inert atmosphere for 15 minutes, then warmed to room temperature and stirred for 2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound 180(2.4g, 81.35%) as a yellow solid. TLC: 30% EtOAc/hexanes (R)_f：0.4)。C₉H₇LCMS calculated for NOS: 177.02, respectively; and (3) observation value: 177.90(M +1)⁺。

Synthesis of methyl 4- (benzo [ d ] thiazol-5-yl) -2, 4-dioxobutyrate (181):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 3g of compound 181 (crude, reaction scale 2.3 g); TLC: 30% EtOAc/hexanes (R)_f：0.1)；C₁₂H₉NO₄LCMS calculation of S: 263.03, respectively; and (3) observation value: 263.95(M +1)⁺。

Synthesis of methyl 5- (benzo [ d ] thiazol-5-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (182):

the title compound was synthesized using general procedure B described above for the cyclization to give 0.5g of compound 182 (13.57%, scale of reaction 3g) as a yellow solid. TLC：10％MeOH/DCM(R_f：0.2)；¹H NMR(DMSO-d₆，400MHz)：δ9.49(s，1H)，8.62(s，1H)，8.28(d，J＝8.4Hz，1H)，8.06(d，J＝8.4Hz，1H)，6.94(s，1H)，3.86(s，3H)；C₁₂H₉N₃O₄S₂LCMS calculated of (d): 323.00, respectively; LCMS observations: 323.9(M +1)⁺。

Synthesis of methyl 5- (benzo [ d ] thiazol-5-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (183):

the title compound was synthesized using general procedure B described above for alkylation to give 0.3g of compound 183 (58%, scale of reaction 0.5g) as a yellow solid. TLC: 30% EtOAc/hexanes (R)_f：0.1)；C₁₃H₁₁N₃O₄S₂LCMS calculated of (d): 337.02, respectively; LCMS observations: 338(M +1)⁺。

Synthesis of 5- (benzo [ d ] thiazol-5-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-361_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 183 and the corresponding amine (see table 1 for analytical data).

Synthesis of cis-5- (benzo [ d ] thiazol-5-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-361):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-361_ Int (see Table 2 for analytical data).

Scheme 58:

synthesis of cis-5- (benzo [ d ] thiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-364):

scheme 58:

synthesis of 1- (benzo [ d ] thiazol-2-yl) ethan-1-one (185):

to a stirred solution of compound 184(10g, 74.07mmol) in anhydrous THF (100mL) at-78 deg.C was added n-butyllithium (32.5mL, 81.48mmol, 2.5M in hexanes) dropwise under an inert atmosphere for 15min, then stirred for 1 h. N, N-dimethylacetamide (6.44g, 74.07mmol) was added thereto at-78 ℃ and stirred for 1 h. Concentrated HCl (15mL) was then added at 0 ℃ and stirred for 2 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into water and extracted with EtOAc (3 × 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 4% EtOAc/hexanes to give compound 185(3.1g, 23.64%) as an off-white solid. TLC: 10% EtOAc/hexanes (R)_f：0.3)；¹H NMR(DMSO-d₆，400MHz)：δ8.26-8.23(m，2H)，7.69-7.61(m，2H)，2.76(s，3H)；C₉H₇LCMS calculated for NOS: 177.02, respectively; and (3) observation value: 178(M +1)⁺。

Synthesis of methyl 4- (benzo [ d ] thiazol-2-yl) -2, 4-dioxobutyrate (186):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 2.7g of compound 186 (crude, reaction scale 3 g); c₁₂H₉NO₄LCMS calculation of S:263.03, respectively; and (3) observation value: 264.1(M +1)⁺。

Synthesis of methyl 5- (benzo [ d ] thiazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (187):

the title compound was synthesized using general procedure B described above for the cyclization to give 0.53g of compound 187 (28.80%, scale of reaction 1.5g) as an off-white solid. 50% EtOAc/hexanes (R)_f：0.1)；C₁₂H₉N₃O₄S₂LCMS calculated of (d): 323.00, respectively; LCMS observations: 324(M +1)⁺。

Synthesis of methyl 5- (benzo [ d ] thiazol-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (188):

the title compound was synthesized using general procedure a described above for alkylation to give 0.37g of compound 188 (59%, scale of reaction 0.6g) as an off-white solid. TLC: 20% EtOAc/hexanes (R)_f：0.5)；C₁₃H₁₁N₃O₄S₂LCMS calculated of (d): 337.02, respectively; LCMS observations: 338.05(M +1)⁺。

Synthesis of 5- (benzo [ d ] thiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-364_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using compound 188 and the corresponding amine (see table 1 for analytical data).

Synthesis of cis-5- (benzo [ d ] thiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-364):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-364_ Int (see Table 2 for analytical data).

Scheme 59:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (1-methyl-1H-benzo [ d ] imidazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-368):

synthesis of N-methoxy-N-methyl-1H-benzo [ d ] imidazole-2-carboxamide (190):

to a stirred solution of compound 189(24g, 148mmol) in DCM (250mL) was added DIPEA (51.58mL, 296mmol) and HATU (84.39g, 222mmol) under an inert atmosphere. To the solution, N, O-dimethylhydroxylamine hydrochloride (21.66g, 222mmol) was added and stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography using 50% EtOAc/hexanes to give compound 190(15g, 49.40%) as a white solid. TLC: 5% MeOH/DCM (R)_f：0.5)；¹H NMR(400MHz，DMSO-d₆)：δ13.19(s，1H)，7.84(d，J＝8.4Hz，1H)，7.54(d，J＝7.6Hz，1H)，7.34-7.24(m，2H)，3.83(s，6H)；C₁₀H₁₁N₃O₂LCMS calculated of (d): 205.09, respectively; and (3) observation value: 206(M +1)⁺。

Synthesis of 1- (1H-benzo [ d ] imidazol-2-yl) ethan-1-one (191):

to a stirred solution of compound 190(15g, 73.13mmol) in anhydrous THF (200mL) was added dropwise methylmagnesium bromide (48.75mL, 146.3mmol, 3M in ether) under an inert atmosphere at 0 deg.C for 15 minutes. The reaction mixture was stirred at 0 ℃ for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 191(7g, 60%) as a yellow solid. TLC: 30% EtOAc/hexanes (R)_f：0.5)；¹H NMR(400MHz，DMSO-d₆)：δδ13.28(s，1H)，7.82-7.80(m，1H)，7.55-7.53(m，1H)，7.35-7.30(m，2H)，2.69(s，3H)；C₉H₈N₂LCMS calculated for O: 160.06, respectively; and (3) observation value: 160.95(M +1)⁺。

Synthesis of 1- (1-methyl-1H-benzo [ d ] imidazol-2-yl) ethan-1-one (192):

to a stirred solution of compound 191(5.5g, 34.37mmol) in 2N NaOH (165mL) at 0 ℃ was added dimethyl sulfate (5.63g, 44.68mmol) and the reaction stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was acidified with 1N HCl and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 192(4g, 66.88%) as an off-white solid. TLC: 20% EtOAc/hexanes (R)_f：0.7)；¹H NMR(400MHz，DMSO-d₆)：δ7.82(d，J＝8.4Hz，1H)，7.21(d，J＝8.4Hz，1H)，7.45(t，J＝8.0Hz，1H)，7.35(d，J＝7.6Hz，1H)，4.07(s，3H)，2.73(s，3H)；C₁₀H₁₀N₂LCMS calculated for O: 174.08, respectively; and (3) observation value: 174.90(M +1)⁺。

Synthesis of methyl 4- (1-methyl-1H-benzo [ d ] imidazol-2-yl) -2, 4-dioxobutyrate (193):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 3.3g (51%, scale of reaction 4 g); TLC: 5% MeOH/DCM (R)_f：0.1)；¹C₁₃H₁₂N₂O₄LCMS calculated of (d): 260.08, respectively; and (3) observation value: 260.8(M +1)⁺。

Synthesis of methyl 5- (1-methyl-1H-benzo [ d ] imidazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (194):

the title compound was synthesized using general procedure B described above for the cyclization to give 2.1g of compound 194 (52%, scale of reaction 3.3g) as an off-white solid. TLC: 10% MeOH/DCM (R)_f：0.1)；¹H NMR(400MHz，DMSO-d₆)：δ7.97(d，J＝7.6Hz，1H)，7.82-7.78(m，1H)，7.63-7.60(m，2H)，7.30-7.04(m，1H)，6.85(s，1H)，4.28(s，3H)，3.84(s，3H)；C₁₃H₁₂N₄O₄LCMS calculation of S: 320.06, respectively; LCMS observations: 320.95(M +1)⁺。

Synthesis of methyl 2-methyl-5- (1-methyl-1H-benzo [ d ] imidazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (195):

the title compound was synthesized using general method B for alkylation described above to give 1.1g of compound 195 (51%, scale of reaction 2.1g) as a yellow solid. TLC: 5% MeOH/DCM (R)_f：0.5)；NMR(400MHz，DMSO-d6)：δ7.85(d，J＝8.0Hz，1H)，7.76(d，J＝8.4Hz，1H)，7.73(s，1H)，7.49(t，J＝8.4Hz，1H)，7.38(t，J＝8.4Hz，1H)，4.21(s，3H)，3.97(s，3H)，3.60(s，3H)；C₁₄H₁₄N₄O₄LCMS calculation of S: 334.07, respectively; LCMS observations: 334.95(M +1)⁺。

Synthesis of N- (3-chloro-4-fluorophenyl) -2-methyl-5- (1-methyl-1H-benzo [ d ] imidazol-2-yl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-368_ Int):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 195 and the corresponding amine (see table 1 for analytical data).

Synthesis of cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (1-methyl-1H-benzo [ d ] imidazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-368):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-368_ Int (see Table 2 for analytical data).

Scheme 60:

synthesis of (3S,5R) -N- (3-bromo-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-369) and (3S,5R) -N- (3-bromo-4-fluorophenyl) -5- (5-bromothiazol-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-383):

synthesis of (3S,5R) -N- (3-bromo-4-fluorophenyl) -5- (5-bromothiazol-2-yl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-383):

the title compound above has been synthesized following the general procedure described above for amidation (method a, amide coupling) by using compound 196 and the corresponding amine (see table 1 for analytical data).

Synthesis of (3S,5R) -N- (3-bromo-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-369):

the title compound was synthesized following the general procedure described above for Stille coupling, using HBV-CSU-383 and the corresponding stannane (see Table 2 for analytical data).

Scheme 61:

synthesis of cis-5- (5-bromothiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) 1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-370, HBV-CSU-370-ISO-I and HBV-CSU-370-ISO-I):

scheme 61:

synthesis of methyl 5- (5-bromothien-2-yl) -2- (methyl-d 3) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (197):

the title compound was synthesized using general procedure B described above for alkylation to give 15g of compound 197 (71.53%, 20g on a reaction scale) as a brown solid. TLC: 10% MeOH/DCM (R)_f：0.6)；C₁₀H₆D₃BrN₂O₄S₂LCMS calculated of (d): 366.94, respectively; LCMS observations: 373(M +2)⁺。

Synthesis of 5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-37)0_Int):

The title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 197 and the corresponding amine (see table 1 for analytical data).

Synthesis of cis-5- (5-bromothiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) 1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-370, HBV-CSU-370-ISO-I and HBV-CSU-370-ISO-I):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-370_ Int (see Table 2 for analytical data).

Scheme 62:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1- (methyl-d)₃) -1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3, 4,5-d₃-3-carboxamide 1, 1-dioxide (HBV-CSU-371, HBV-CSU-371-ISO-I and HBV-CSU-371-ISO-I):

scheme 62:

cis-5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3, 4,5-d₃-3-carboxamide 1, 1-dioxide (HBV-CSU-371, HBV-CSU-371-ISO-I and HBV-CSU-371-ISO-I):

to the compound HBV-CSU-114-amide (3g, 6.25mmol) in THF: D at 0 ℃ under Ar atmosphere₂To a stirred solution of O (1:1, 30mL) in a mixture was added NaBD₄(0.523g, 12.5mmol) and stirred at room temperature 3And 0 minute. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated in vacuo. The crude compound was purified by silica gel column chromatography to give compound HBV-CSU-371(2g, 66.6%) as a white solid. TLC: 50% EtOAc/hexanes (R)_f：0.3)；

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3, 4,5-d₃-3-carboxamide 1, 1-dioxide (HBV-CSU-375, HBV-CSU-375-ISO-I and HBV-CSU-375-ISO-I):

the title compound was synthesized following the general procedure described above for Stille coupling, using HBV-CSU-371 and the corresponding stannane (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1- (methyl-d)₃) -1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3, 4,5-d₃-3-carboxamide 1, 1-dioxide (HBV-CSU-376, HBV-CSU-376-ISO-I and HBV-CSU-376-ISO-I):

the title compound was synthesized following the general procedure described above for Stille coupling, using HBV-CSU-371 and the corresponding stannane (see Table 2 for analytical data).

Scheme 63:

synthesis of cis-5- (5-bromothiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -1,2, 6-thiadiazine-3, 4,5-d₃-3-carboxamide 1, 1-dioxide (HBV-CSU-372, HBV-CSU-372-ISO-I and HBV-CSU-372-ISO-I), cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3, 4,5-d 3-3-carboxamide (HBV-CSU-377, HBV-CSU-377-ISO-I and HBV-CSU-377-ISO-I) and cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d-fluorophenyl)₃) -5- (5- (1- (methyl-d)₃) -1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thia-di3,4,5-d oxazinane₃3-carboxamide 1, 1-dioxide (HBV-CSU-378, HBV-CSU-378-ISO-I and HBV-CSU-378-ISO-I):

scheme 63:

synthesis of cis-5- (5-bromothiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -1,2, 6-thiadiazine-3, 4,5-d₃-3-carboxamide 1, 1-dioxide (HBV-CSU-372, HBV-CSU-372-ISO-I and HBV-CSU-372-ISO-I, E17107-097):

to the compound HBV-CSU-370_ Int (1.5g, 3.11mmol) in THF: D at 0 ℃ under Ar atmosphere₂To a stirred solution of O (1:1, 20mL) in a mixture was added NaBD₄(0.261g, 6.22mmol) and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated in vacuo. The crude compound was purified by silica gel column chromatography using 2% MeOH/DCM to give the compound HBV-CSU-372(1.2g, 78.94%) as an off-white solid. TLC: 30% EtOAc/hexanes (R)_f：0.5)。

cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazinane-3, 4,5-d 3-3-carboxamide (HBV-CSU-377, HBV-CSU-377-ISO-I and HBV-CSU-377-ISO-I):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-372 and the corresponding stannane (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1- (methyl-d)₃) -1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3, 4,5-d₃-3-carboxamide 1, 1-dioxide (HBV-CSU-378, HBV-CSU-378-ISO-I and HBV-CSU-378-ISO-I):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-372 and the corresponding stannane (see Table 2 for analytical data).

Scheme 64:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-373-ISO-I and HBV-CSU-373-ISO-I) and cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1- (methyl-d)₃) -1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-374-ISO-I and HBV-CSU-374-ISO-I):

scheme 64:

cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-373-ISO-I and HBV-CSU-373-ISO-I):

the title compound was synthesized following the general procedure described above for Stille coupling, using HBV-CSU-370 and the corresponding stannane (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1- (methyl-d)₃) -1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-374-ISO-I and HBV-CSU-374-ISO-I):

the title compound was synthesized following the general procedure described above for Stille coupling, using HBV-CSU-370 and the corresponding stannane (see Table 2 for analytical data).

Scheme 65:

synthesis of cis-5- (5-bromothiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -1,2, 6-thiadiazine-3, 4,5-d₃3-carboxamide 1, 1-dioxide (HBV-CSU-379, HBV-CSU-379-ISO-I and HBV-CSU-379-ISO-I):

scheme 65:

synthesis of 4-methylbenzenesulfonic acid methyl-d₃Ester (199):

the title compound was prepared using Journal of Organic Chemistry, 81(17), 7675-; 2016.

Synthesis of 4-bromo-1- (methyl-d)₃) -1H-pyrazole (200):

to a stirred solution of 4-bromo-1H-pyrazole (5g, 34.01mmol) in DMF (30mL) was added CS₂CO₃(33.24g, 102.05mmol) and stirred for 10 min. To the solution, compound 199(8.36g, 51.02mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the title compound 200(4g, 72.72%) as a white solid. TLC: 50% EtOAc/hexanes (R)_f：0.3)；C₄H₂D₃BrN₂LCMS calculated of (d): 162.98, respectively; LCMS observations: 165.95(M +2)⁺。

Synthesis of 1- (methyl-d)₃) -4- (tributylstannyl) -1H-pyrazole (201):

to a stirred solution of compound 200(1g, 6.09mmol) in diethyl ether (10mL) under Ar at-78 deg.C was added n-BuLi (2.5M, 2.68mL, 6.69mmol) dropwise and stirred at the same temperature for 30 min. To this solution, tributyltin chloride (1.18mL, 6.69mmol) was added slowly at-78 ℃ and then warmed to-60 ℃ and stirred for 1 h. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude stannane compound. The crude compound was purified by silica gel column chromatography to give the title compound 201(0.5g, 21.92%) as a yellow oil. TLC: 20% EtOAc/hexanes (R)_f：0.5)C₁₆H₂₉D₃N₂LCMS calculation of Sn: 375.18, respectively; LCMS observations: 376.1(M +1)⁺。

Synthesis of cis-N- (3-chloro-4-fluorophenyl) -2- (methyl-d₃) -5- (5- (1- (methyl-d)₃) -1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3, 4,5-d₃3-carboxamide 1, 1-dioxide (HBV-CSU-379, HBV-CSU-379-ISO-I and HBV-CSU-379-ISO-I):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-372 and compound 201 (see Table 2 for analytical data).

Scheme 66:

synthesis of (3S,5R) -5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-114-ISO-I; ATH method):

scheme 66:

to a solution of HBV-CSU-114 — Int (1eq.) and Noyori catalyst 3a (0.1eq.) in dichloromethane (0.2M) was added 5eq. formic acid { 85% w/w in water } followed by 2eq. The reaction mixture was stirred at rt for 16 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a crude material, which was purified using combiflash chromatography to give the desired product. Enantioselectivity was confirmed using chiral HPLC.

General scheme for the synthesis of Noyori catalyst:

will [ RuCl ]₂(. eta.6-P-cymene)]₂A mixture of (1eq.), (1S, 2S) - (+) -N-p-toluenesulfonyl-1, 2-diphenylethylenediamine (2eq.) and triethylamine (4eq.) in propanol (25V) was heated at 80 ℃ for 2 h. The solvent was evaporated and the solid material obtained after filtration was washed with water and dried in vacuo to give { Noyori (S, S) catalyst }, i.e., RuCl [ (1S, 2S) -p-TsNCH (C)₆H₅)NH₂](. eta.6-p-cymene) as an orange solid. The catalyst was recrystallized from methanol. Formation of the desired catalyst by¹H NMR and LCMS confirmed (see table 2 for analytical data).

Scheme 67:

synthesis of (3S,5R) -N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-266-ISO-I; acid splitting by the cinchonine method):

scheme 67:

synthesis of 5- (5-bromothien-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylic acid 1, 1-dioxide (219):

to compound 58(65g, 178.08mmol) in 700mL (10.8V) CH at 0 deg.C₃CN：H₂To a solution in O (1:1) TEA (124mL, 890.41mmol) was added and the resulting reaction mixture was stirred at the same temperature until a clear solution was observed (typically 4-6 h). The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was concentrated under reduced pressure, and the resulting residue was acidified with 6n hcl and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 219(57g, 91%) as a brown solid. TLC: 5% MeOH/DCM (R)_f：0.3)；¹H NMR(DMSO-d₆400 MHz): δ 11.0(br.s, 1H), 8.10(d, J ═ 4.0Hz, 1H), 7.45(d, J ═ 4.0Hz, 1H), 7.19(s, 1H), 3.51(s, 3H); HPLC purity: 98.85%, LCMS purity: 97.50 percent; c₉H₇BrN₂O₄S₂LCMS calculated of (d): 349.90, respectively; LCMS observations: 352.90(M +2)⁺。

Synthesis of 5- (5-bromothien-2-yl) -2-methyl-1, 2, 6-thiadiazinane-3-carboxylic acid 1, 1-dioxide (220):

to a mixture of compound 219(40g, 114.3mmol) in 500mL EtOH: to a stirred solution in THF (9:1), NaBH was added₄(8.6g, 228.6mmol) and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with diethyl ether. Collecting the combined organic layers; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 220 (cis-rac) (32g, 75%) as a light brown solid. TLC: 10% MeOH/DCM (Rf: 0.1);¹H NMR(DMSO-d₆，400MHz)：δ11.39(s，1H)，7.60(d，J＝9.2Hz，1H)，7.11(d，J＝4.0Hz，1H)，6.97(d, J ═ 4.0Hz, 1H), 4.76-4.70(m, 1H), 4.20(dd, J ═ 12.0, 2.8Hz, 1H), 2.60(s, 3H), 2.21-2.15(m, 1H), 1.98-1.89(m, 1H); HPLC purity: 99.23%, LCMS purity: 99.87 percent; c₉H₁₁BrN₂O₄S₂LCMS calculated of (d): 353.93, respectively; LCMS observations: 354.90(M +1)⁺。

Synthesis of (3S,5R) -5- (5-bromothien-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxylic acid 1, 1-dioxide (Compound 221) and (3R, 5S) -5- (5-bromothien-2-yl) -2-methyl-1, 2, 6-thiadiazine-3-carboxylic acid 1, 1-dioxide (Compound 222):

racemic compound 220(40.0g, 112.9mmol) was dissolved in 1.2L of IPA (. about.30V) then cinchonine (33.3g, 112.9mmol) was added and the reaction mixture was heated at 90 ℃ for 2h (a clear solution was observed). After 10-20min the solid precipitated out at the same temperature. The reaction mixture was then cooled to accelerate crystallization and kept at room temperature overnight. After crystallization, the mother liquor and crystals were analyzed by HPLC on a chiral amylose SA column (eluent; DCM: MeOH 50:50) and then extracted to determine the relative amounts of compound 221-salt and compound 222-salt. Analysis showed enantiomeric enrichment of both crystals. The two isomers (# 211-salt, 38g) and the mother liquor (# 222-salt, 43g) were then separated.

A suspension of 38g of compound 221-salt in 150mL of ethyl acetate was acidified to pH 1.0 with 4N aq. HCl at 0 ℃. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (3 × 50 mL). The combined organic layers were concentrated, dried over anhydrous sodium sulfate, filtered and concentrated to give 16g of compound 221 (chiral HPLC 95.5%).

Analytical data for compound 221:

¹H NMR(DMSO-d₆，400MHz)：δ13.41(s，1H)，7.59(d，J＝8.8Hz，1H)，7.10(d，J＝4.0Hz，1H)，6.97-6.96(m, 1H), 4.76-4.70(m, 1H), 4.22-4.19(m, 1H), 2.59(s, 3H), 2.19-2.15(m, 1H), 1.98-1.88(m, 1H); HPLC purity: 99.53 percent; HPLC chiral purity: 94.29 percent;

analytical data for compound 222:

¹H NMR(DMSO-d₆400 MHz): δ 13.02(s, 1H), 7.60(d, J ═ 8.8Hz, 1H), 7.11(d, J ═ 4.0Hz, 1H), 6.98-6.97(m, 1H), 4.77-4.72(m, 1H), 4.24-4.20(m, 1H), 2.61(s, 3H), 2.21-2.16(m, 1H), 1.99-1.90(m, 1H); HPLC purity: 94.55 percent; HPLC chiral purity: 87.87 percent;

synthesis of (3S,5R) -5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-114-ISO-I):

to a stirred solution of compound 221(14g, 39.6mmol) in DCM (14V, 200mL) at 0 ℃ was added DIPEA (21.0mL, 118.6mmol), stirred for 15min, then HATU (22.5g, 59.3mmol) was added, stirred again for 15min, then aniline compound (6.3g, 43.5mmol) was added. The reaction mixture was then stirred at room temperature overnight. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ice-cold water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound. The crude compound was purified using silica gel column chromatography to give HBV-CSU-114-ISO-I (15g, 79%) as a light brown solid. (see Table 2 for analytical data).

Synthesis of (3S,5R) -N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-266-ISO-I):

to a stirred solution of HBV-CSU-114-ISO-I (14g, 28.9mmol) in dioxane (11V, 150mL) was added 1-methyl-4- (tributylstannyl) -1H-imidazole (12.9g, 34.79mmol) and purged under Ar atmosphere for 10 min; adding Pd (PPh) into a sealed tube₃)₄(3.34g, 2.89 mmol); heat to 100 ℃ and stir for 4 h. The reaction was monitored by TLC; after completion of the reaction the volatiles were removed in vacuo to give the crude material. The resulting residue was dissolved in 10% MeOH in DCM (35V, 500mL) and washed with 20% aq. The organic layer was then dried over anhydrous sodium sulfate, filtered and concentrated to give a crude material which was purified by flash column chromatography on silica gel with 2% MeOH/CH₂Cl₂To give HBV-CSU-266-ISO-I (11.3g, 80.5%) as an off-white solid (see Table 2 for analytical data).

Scheme 68:

synthesis of (3S,5R) -N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-276-ISO-I; acid splitting by the cinchonine method):

scheme 68:

synthesis of 5- (5-bromothiazol-2-yl) -2-methyl-2H-1, 2, 6-thiadiazine-3-carboxylic acid 1, 1-dioxide (223):

to compound 74(230g, 606.8mmol) in CH at 0 deg.C₃CN:H₂To a stirred solution in O (1:1, 2300mL, 10V) was added triethylamine (423mL, 3034.3mmol), 15min, then held at room temperature for 3.5h (a change in color from light yellow to brown was observed after 2h, then the reaction mixture became clear after 1 h). The progress of the reaction was monitored by TLC (40% ethyl acetate in hexane). After completion, the reaction mixture was concentrated under reduced pressure; the resulting residue was diluted with water (2L) and extracted with ether (3 × 500mL) (confirmation of organic layer by LCMS)Some compound was shown, after concentration to give-8 g of desired compound with-60% LCMS purity). The aqueous layer was acidified to pH 2-4 with 400mL 2N HCl at 0 deg.C, and the precipitated solid was filtered, washed with water (200mL), and dried in vacuo to give compound 223(190g, 88.95%) as a pale yellow solid. TLC: 30% EtOAc/hexanes (R)_f：0.1)；¹H NMR(DMSO-d₆400 MHz): Δ 8.30(s, 1H), 7.21(s, 1H), 3.59(s, 3H) (NMR showed some trapped triethylamine); HPLC purity: 91.45 percent; LCMS purity: 91.38 percent; c₈H₆BrN₃O₄S₂LCMS calculated of (d): 350.90, respectively; LCMS observations: 353.90(M +2) +.

Synthesis of 5- (5-bromothiazol-2-yl) -2-methyl-1, 2, 6-thiadiazinane-3-carboxylic acid 1, 1-dioxide (224):

to a mixture of compound 223(190g, 539mmol) in 2L EtOH: to a stirred solution in THF (10.5V, 3:1) was added NaBH in portions₄(40.83g, 1079mmol) and the reaction mixture was stirred at room temperature for 3h (at NaBH)₄During the addition, the reaction mixture thickened). The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water (1L) and extracted with diethyl ether (2 × 200 mL). The organic layer was discarded and the aqueous layer was acidified to pH-4 with 200mL 4N HCl at 0 ℃, the precipitated solid was filtered, washed with water (200mL), dried in vacuo to give compound 224 (cis-rac) (170g, 88.47%) as an off-white solid. TLC: 15% MeOH/DCM (Rf: 0.2);¹H NMR(DMSO-d₆400 MHz): δ 13.4(br.s, 1H), 7.88(s, 1H), 7.82(d, J ═ 9.6Hz, 1H), 4.93-4.87(m, 1H), 4.32-4.28(m, 1H), 2.63(s, 3H), 2.37-2.32(m, 1H), 2.05-1.95(m, 1H); HPLC purity: 95.57%, LCMS purity: 92.44 percent; c₈H₁₀BrN₃O₄S₂LCMS calculated of (d): 354.93, respectively; LCMS observations: 355.95(M)⁺

Synthesis of 5- (5-bromothiazol-2-yl) -2-methyl-1, 2, 6-thiadiazinane-3-carboxylic acid 1, 1-dioxide (196):

racemic compound 224(190g, 533.39mmol) was dissolved in 5.7L of IPA (. about.30V), cinchonine (157.03g, 533.39mmol) was added to the suspension and the reaction mixture was heated at 90 ℃ for 2h (no large scale clear solution was observed due to the solid precipitating at the same temperature). The reaction mixture was then cooled without any stirring to accelerate crystallization and kept at room temperature overnight. The crystalline solid was collected by filtration and washed with IPA (3x500mL) to give 210g of compound 196-salt (the mother liquor contained 230g of compound 225-salt). Both the mother liquor and the crystals were analyzed by HPLC on a chiral amylose SA column (eluent; DCM: MeOH 50:50), and analytical samples were prepared by acidification and then extracted to determine the relative amounts of compound 196-salt and compound 225-salt. Analysis showed chiral purity of compound 196 to be 1.18% 98.81% and compound 225 to be 95.5% 4.6%.

After IPA wash the whole batch of compound 196-salt was dissolved in 800mL ethyl acetate and acidified to pH 2-4 with 4N aq. HCl (420mL) at 0 ℃. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (3 × 250 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give 78g of compound 196 (chiral purity 98.60%). Similarly, 72g of compound 225 (chiral purity 94.71%) were obtained.

Analytical data for compound 196:

¹H NMR(DMSO-d₆400 MHz): δ 13.41(s, 1H), 7.87(s, 1H), 7.80(d, J ═ 10.0Hz, 1H), 4.93-4.86(m, 1H), 4.30(dd, J ═ 12.4, 1.8Hz, 1H), 2.61(s, 3H), 2.36-2.32(m, 1H), 2.04-1.95(m, 1H); HPLC purity: 98.59 percent; HPLC chiral purity: 98.60 percent; LCMS purity: 98.60 percent; c₈H₁₀BrN₃O₄S₂LCMS calculated of (d): 354.93, respectively;LCMS observations: 357.90(M +2)⁺。

Analytical data for compound 225:

¹H NMR(DMSO-d₆400 MHz): 13.41(s, 1H), δ 7.88(1H), 7.82(d, J ═ 9.6Hz, 1H), 4.94-4.87(m, 1H), 4.29(dd, J ═ 12.4, 2.4Hz, 1H), 2.62(s, 3H), 2.37-2.33(m, 1H), 2.04-1.95(m, 1H); HPLC purity: 91.68%, HPLC chiral purity: 94.71 percent; LCMS purity: 96.66 percent; c₈H₁₀BrN₃O₄S₂LCMS calculated of (d): 354.93, respectively; LCMS observations: 357.6(M +2)⁺。

Synthesis of (3S,5R) -5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-122-ISO-I):

to a stirred solution of compound 196(160g, 449.4mmol) in DCM (18V, 2.9L) was added DIPEA (234.4mL, 1344.8mmol) at 0 ℃, stirred for 30min, then HATU (256.1g, 674.2mmol) was added portionwise, stirred again for 30min, then aniline compound (78.2g, 539.3mmol) was added. The reaction mixture was then stirred at room temperature overnight. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated, the resulting residue was stirred with ethyl acetate (500mL) for 30 minutes, and the resulting solid materials (tetramethylurea by-product and HOBT) were filtered and washed with 200mL of ethyl acetate. The filtrate was washed with water (2x200mL) then brine (2x200mL), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude compound (60% purity by LCMS). The crude material was stirred with DCM (5V, 800mL), the precipitated solid was filtered, washed with DCM (2V, 300mL) and dried to give 146g (67.4%) of HBV-CSU-122-ISO-I; TLC: 30% EtOAc/hexanes (R)_f: 0.5) (see table 2 for analytical data).

Synthesis of (3S,5R) -N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-276-ISO-I):

to a stirred solution of HBV-CSU-122-ISO-I (72.5g, 150.4mmol) in 1, 4-dioxane (730mL) was added 1-methyl-4- (tributylstannyl) -1H-imidazole (83.8g, 225.6mmol) and purged under Ar atmosphere for 30 min; addition of Pd (PPh)₃)₄(17.37g, 15.04 mmol); heated to 100 ℃ and stirred at the same temperature for 4 h. The reaction mixture was monitored by TLC. Upon completion, the reaction mixture was filtered through a pad of celite, washed with ethyl acetate (2x500mL), the combined filtrates were concentrated and the resulting solid residue was triturated with ether (2x500mL) and the ether layer was concentrated (confirmed by TLC that the ether layer showed stannane and some compounds). The solid residue was again stirred with-500 mL hexane (confirmation of hexane layer by TLC showing some stannane; the hexane layer was laminated with ether and used for concentration). The residue obtained after washing with ether/hexane is dissolved in 1l of ethyl acetate; wash with 30% aq. kf (5 × 500mL), then brine (500 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a crude material which was purified using silica gel flash column chromatography (2-4% MeOH/CH)₂Cl₂). { notes: a further batch (72.5g) was carried out on the same scale. Combined processing and purification afforded HBV-CSU-276-ISO-I (110g, 75.5%) as an off-white solid. TLC: 10% MeOH/CH₂Cl₂(R_f：0.2)；¹H NMR showed some stannane related impurities. To remove stannane impurities, 110g of HBV-CSU-276-ISO-I was stirred with ether (500mL) for 30 minutes, filtered, washed with ether (2X100mL) and dried to provide 108g (74.17%) of HBV-CSU-276-ISO-I (see Table 2 for analytical data).

HCl salt formation:

to HBV-CSU-276-ISO-I (62g) at 0 ℃ in 620mL dioxane: to a solution in MeOH (1:1) (clear solution was observed) was added 160mL of a 4M solution of HCl in MeOH (5eq.) and the reaction mixture was stirred at 0 deg.C for 1h (at 0 deg.C)After 5 minutes at 0 ℃ we did not observe precipitation of a solid). The precipitated solid was collected by filtration, washed with ether (3x100mL) then pentane (3x100mL), and stirred and dried to give 63g of HBV-CSU-276-ISO-I-HCl salt.¹H NMR showed 4.66% w/w methanol; (see Table 2 for analytical data).

Scheme 69:

synthesis of (3R,5R) -5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-114-trans-ISO-I) and (3R,5R) -N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-266-trans-ISO-I):

scheme 69:

synthesis of (3R,5R) -5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-114-trans-ISO-I):

to a stirred solution of the compound HBV-CSU-114-cis-ISO-I (3g, 6.20mmol) in 1, 4-dioxane (30mL) was added Na₂CO₃(3.28g, 31 mmol). The reaction mixture was stirred at 100 ℃ for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound. The crude compound was purified using silica gel column chromatography to give HBV-CSU-114-trans-ISO-I (0.05g, 2%) (see Table 2 for analytical data).

(3R,5R) -N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-266-trans-ISO-I):

the title compound was synthesized following the general procedure described above for Stille coupling by using HBV-CSU-114-trans-ISO-I and the corresponding stannane (see Table 2 for analytical data).

Scheme 70:

synthesis of (3S,5S) -5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-114-trans-ISO-II) and (3S,5S) -N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-266-trans-ISO-II):

scheme 70:

synthesis of (3S,5S) -5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-114-trans-ISO-II):

to a stirred solution of the compound HBV-CSU-114-cis-ISO-II (0.2g, 0.413mmol) in 1, 4-dioxane (10mL) was added Na₂CO₃(0.22g, 2.07 mmol). The reaction mixture was stirred at 100 ℃ for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude compound. The crude compound was purified using silica gel column chromatography to give HBV-CSU-114-trans-ISO-II (0.02g, 10%) (see Table 2 for analytical data).

(3S,5S) -N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-266-trans-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling by using HBV-CSU-114-trans-ISO-II and the corresponding stannane (see Table 2 for analytical data).

Scheme 71:

synthesis of (3R,5R) -5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-122-trans-ISO-I) and (3R,5R) -N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-276-trans-ISO-I):

scheme 71:

synthesis of (3R,5R) -5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-122-trans-ISO-I)

To a stirred solution of the compound HBV-CSU-122-ISO-I (0.2g, 0.413mmol) in 1, 4-dioxane (5mL) was added Na₂CO₃(0.218g, 2.066 mmol). The reaction mixture was stirred at 100 ℃ for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound. The crude compound was purified using silica gel column chromatography to give HBV-CSU-122-trans-ISO-I (0.02g, 10%) (see Table 2 for analytical data).

(3R,5R) -N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-276-trans-ISO-I):

the title compound was synthesized following the general procedure described above for Stille coupling by using HBV-CSU-122-trans-ISO-I and the corresponding stannane (see Table 2 for analytical data).

Scheme 72:

synthesis of (3S,5S) -5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-122-trans-ISO-II) and (3S,5S) -N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-276-trans-ISO-II):

scheme 72:

synthesis of (3S,5S) -5- (5-bromothiazol-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-122-trans-ISO-II):

to a stirred solution of the compound HBV-CSU-122-ISO-II (0.99g, 2.06mmol) in 1, 4-dioxane (10mL) was added Na₂CO₃(1.09g, 10.37 mmol). The reaction mixture was stirred at 100 ℃ for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound. The crude compound was purified using silica gel column chromatography to give HBV-CSU-122-trans-ISO-II (0.07g, 7%) (see Table 2 for analytical data).

(see Table 2 for analytical data).

(3S,5S) -N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-imidazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-276-trans-ISO-II):

the title compound was synthesized following the general procedure described above for Stille coupling by using HBV-CSU-122-trans-ISO-II and the corresponding stannane (see Table 2 for analytical data).

Scheme 73:

synthesis of trans-5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-114-trans { Rac }) and trans-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-161-trans { Rac }):

scheme 73:

synthesis of trans-5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-114-trans { Rac }):

to the compound CSU-114_ amide (10g, 20.87mmol) and { Noyori (S, S) catalyst }, i.e., RuCl [ (1S, 2S) -p-TsNCH (C), at 0 deg.C₆H₅)NH₂](. eta.6-P-cymene) (5.64mL, 2.08mmol) in DCM (100mL) was added DIPEA (7.2mL, 41.74mmol) and formic acid (4.8g, 104.35mmol) and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound. The crude compound was purified by silica gel column chromatography to give the desired compound HBV-CSU-114-trans (Rac) (2.6g, 26%) (analytical data see Table 2). Note: the cis isomer was also observed, which was separated by column chromatography. Stereochemistry at C-3 was not confirmed and was assigned based on the results for the fully reduced cis-product after 16 h.

Synthesis of trans-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-161-trans { Rac }):

the title compound above has been synthesized following the general procedure described above for Suzuki coupling by using HBV-CSU-114-trans (Rac) and 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (see table 2 for analytical data).

Scheme 74:

amide synthesis using 2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxylic acid 1, 1-dioxide:

synthesis of 2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxylic acid 1, 1-dioxide (226):

to bromo compound 220(500mg, 1.41mmol), boronic acid/boronate (293mg, 1.41mmol) in 5mL 1, 4-dioxane H₂To the mixture in O (1:1), DIPEA (0.7mL, 4.2mmol) was added, purged with Ar for 15 minutes, and then PdCl was added₂(PPh₃)₂(9mg, 0.0141mmol), and stirred at 80 ℃ overnight. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was dissolved in water and acidified with 2N HCl (2-4pH), the precipitated solid was filtered and dried to give compound 226(400mg, 79%) as a light yellow solid. C₁₃H₁₆N₄O₄S₂LCMS calculated of (d): 356.06, respectively; LCMS observations: 357.6(M +1)⁺。

Synthesis of cis-2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -N- (3,4, 5-trifluorophenyl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-411):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 226 and the corresponding amine (see table 2 for analytical data).

Synthesis of cis-N- (3, 4-difluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-413):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 226 and the corresponding amine (see table 2 for analytical data).

Synthesis of cis-N- (3-cyclopropyl-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-415):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 226 and the corresponding amine (see table 2 for analytical data).

Synthesis of cis-N- (3-cyano-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-416):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 226 and the corresponding amine (see table 2 for analytical data).

Synthesis of cis-2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -N- (pyridin-3-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-425):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 226 and the corresponding amine (see table 2 for analytical data).

Scheme 75:

synthesis of rac-5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2, 4-dimethyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide ((HBV-CSU-423) and rac-N- (3-chloro-4-fluorophenyl) -2, 4-dimethyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-343):

scheme 75:

synthesis of 1- (5-bromothien-2-yl) propan-1-one (227):

to AlCl at 0 deg.C₃(29.44g, 221mmol) in EDC (300mL), propionyl chloride (17.02g, 184mmol) was added and the reaction mixture was stirred at 0 ℃ for 20 min. To the solution, compound 231(30g, 184mmol) was added and further stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound 227(38.20g, 95%) as a brown solid; TLC: 20% EtOAc/hexanes (R)_f：0.4)；¹H NMR(400MHz，DMSO-d₆)：δ7.79(d，J＝4.4Hz，1H)，7.38(d，J＝4.0Hz，1H)，2.97-2.92(m，2H)，1.07(t，J＝7.2Hz，3H)；C₇H₇LCMS calculation for BrOS: 217.94, respectively; and (3) observation value: 220.80(M +2)⁺。

Synthesis of methyl 4- (5-bromothien-2-yl) -3-methyl-2, 4-dioxobutyrate (228):

the title compound was synthesized using the general procedure for the synthesis of the above 2, 4-diketoesters to give 12.5g of compound 228 (45%, reaction scale 20g) as an off-white solid. TLC: 30% EtOAc/hexanes (R)_f：0.3)；C₁₀H₉BrO₄LCMS calculation of S: 303.94, respectively; and (3) observation value: 304.95(M +1)⁺。

Synthesis of methyl 5- (5-bromothien-2-yl) -4-methyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (229):

the title compound was synthesized using general procedure B described above for the synthesis of the cyclic sulfonamides to give 1.7g of compound 229 (18%, 8g on a reaction scale) as an off-white solid. TLC: 5% MeOH/DCM (R)_f：0.3)；C₁₀H₉BrN₂O₄S₂LCMS calculated of (d): 363.92, respectively; LCMS observations: 366.95(M +2)⁺。

Synthesis of methyl 5- (5-bromothien-2-yl) -2, 4-dimethyl-2H-1, 2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (230):

the title compound was synthesized using general procedure a for alkylation described above to give 0.32g of compound 230 (62% reaction scale 1g) as an off-white solid. TLC: 30% EtOAc/hexanes (R)_f：0.2)；C₁₁H₁₁BrN₂O₄S₂LCMS calculated of (d): 377.93, respectively; LCMS observations: 380.8(M +2)⁺。

Synthesis of 5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2, 4-dimethyl-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-423-Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using compound 230 and the corresponding amine (see table 1 for analytical data).

Synthesis of rac-5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2, 4-dimethyl-1, 2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-423):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-423_ Int (see Table 2 for analytical data).

Note: NMR suggested three diastereomers.

Synthesis of rac-N- (3-chloro-4-fluorophenyl) -2, 4-dimethyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-343):

to HBV-CSU-423(250mg, 0.502mmol), the corresponding boronic acid/boronic ester (104mg, 0.502mmol) in 5mL 1, 4-dioxane H₂To the mixture in O (1:1), DIPEA (0.129g, 1.00mmol) was added, purged with Ar for 15 minutes, and then PdCl was added₂(PPh₃)₂(4mg, 0.005mmol) and stirred at 80 ℃ overnight. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude compound. The crude compound was purified by preparative HPLC to give the title compound. HBV-CSU-343(42mg, 17%). (see Table 2 for analytical data).

Note: NMR suggested three diastereomers.

Scheme 76:

synthesis of 5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-3, 4-dihydro-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-367) and cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -3, 4-dihydro-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-429):

cis-5- (5-bromothiophen-2-yl) -N- (3-chloro-4-fluorophenyl) -2-methyl-3, 4-dihydro-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-367):

to a stirred solution of the compound HBV-CSU-114-Int (1g, 2.08mmol) in DCM at 0 deg.C was added formic acid (0.48g, 10.44mmol), then DIPEA (0.538g, 4.17mmol), then Noyori catalyst (0.132g, 0.208 mmol). The reaction mixture was warmed to room temperature and the cloudy solution was stirred at the same temperature for 50 minutes (until a red clear solution was obtained). The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure (at 30 ℃). The crude compound was purified by silica gel column chromatography to give the title compound HBV-CSU-367 (see Table 2 for analytical data).

cis-N- (3-chloro-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -3, 4-dihydro-2H-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-429):

the title compound was synthesized following the general procedure described above for Stille coupling, using HBV-CSU-367 and the corresponding stannane (see Table 2 for analytical data).

Scheme 77:

synthesis of cis-2-allyl-5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-391), cis-2-allyl-N- (3-chloro-4-fluorophenyl) -5- (5- (1-methyl-1H-pyrazol-4-yl) thien-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-394), cis-2-allyl-N- (3-chloro-4-fluorophenyl) -5-, (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-395), cis-2-allyl-N- (3-chloro-4-fluorophenyl) -5- (5- (pyridin-2-yl) thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-396), cis-N- (3-chloro-4-fluorophenyl) -5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazinane-3-carboxamide 1, 1-dioxide (HBV-CSU-427) &

Synthesis of methyl 2-allyl-5- (5-bromothien-2-yl) -2H-1,2, 6-thiadiazine-3-carboxylate 1, 1-dioxide (232):

to a stirred solution of the compound HBV-CSU-114-Int (10g, 28.40mmol) in anhydrous DMF (100mL) under Ar at 0 ℃ was added NaH (60% w/w in mineral oil, 1.49g, 62.4mmol) and stirred at 0 ℃ for 30 min. To this solution was slowly added 3-iodoprop-1-ene (5.6g, 33.89mmol) and the resulting reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography using 10% EtOAC/hexanes to give the title compound 232(3.8g, 34.38%) as a colorless oil. TLC: 30% EtOAc/hexanes (R)_f：0.5)；C₁₂H₁₁BrN₂O₄S₂LCMS calculated of (d): 389.93, respectively; LCMS observations: 392.90(M +2)⁺。

Synthesis of 2-allyl-5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-391-Int):

the title compound above has been synthesized following the general procedure described above for amidation (method a) by using compound 232 and the corresponding amine (see table 1 for analytical data).

Synthesis of cis-2-allyl-5- (5-bromothien-2-yl) -N- (3-chloro-4-fluorophenyl) -2H-1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-391):

the title compound was synthesized following the general procedure described above for reduction by using the corresponding HBV-CSU-391_ Int (see Table 2 for analytical data).

Synthesis of cis-2-allyl-N- (3-chloro-4-fluorophenyl) -5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-394):

the title compound was synthesized following the general procedure described above for the Suzuki coupling using HBV-CSU-391 and the corresponding boronic acid (see table 2 for analytical data).

Synthesis of cis-2-allyl-N- (3-chloro-4-fluorophenyl) -5- (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-395):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-391 and the corresponding stannane (see Table 2 for analytical data).

Synthesis of cis-2-allyl-N- (3-chloro-4-fluorophenyl) -5- (5- (pyridin-2-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-396):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-391 and the corresponding stannane (see Table 2 for analytical data).

Synthesis of cis-N- (3-chloro-4-fluorophenyl) -5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-427):

the title compound was synthesized following the general procedure described above for the Suzuki coupling using HBV-CSU-391 and the corresponding boronic acid (see table 2 for analytical data).

Note: this compound is obtained as a by-product.

Synthesis of cis-N- (3-chloro-4-fluorophenyl) -5- (5- (1-methyl-1H-imidazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-428):

the title compound was synthesized following the general procedure described above for Stille coupling using HBV-CSU-391 and the corresponding stannane (see Table 2 for analytical data).

Note: this compound is obtained as a by-product.

Scheme 78:

amide synthesis using 2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -1,2, 6-thiadiazine-e-3-carboxylic acid 1, 1-dioxide:

synthesis of 2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxylic acid 1, 1-dioxide (233):

to bromo compound 224(500mg, 1.41mmol), boronic acid/boronic ester (321mg, 1.54 m)mol) in 4mL of 1, 4-dioxane H₂To the mixture in O (1:1), DIPEA (543mg, 4.21mmol) was added, and the mixture was purged with Ar for 15 minutes, followed by addition of PdCl₂(PPh₃)₂(10mg, 0.0140mmol), and stirred at 80 ℃ overnight. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was filtered through celite and evaporated to dryness. The residue was dissolved in water and acidified with 2N HCl (2-4pH), the precipitated solid was filtered and dried to give compound 233(400mg, 80%) as a light yellow solid. C₁₂H₁₅N₅O₄S₂LCMS calculated of (d): 357.06, respectively; LCMS observations: 358.05(M +1)⁺。

Synthesis of cis-N- (3-cyclopropyl-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-421):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 233 and the corresponding amine (see table 2 for analytical data).

Synthesis of cis-N- (3-cyano-4-fluorophenyl) -2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiazol-2-yl) -1,2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-422):

the title compound above has been synthesized following the general procedure described above for amidation (method B) by using compound 233 and the corresponding amine (see table 2 for analytical data).

Scheme 79:

amide synthesis using 5- (5-bromothiazol-2-yl) -2-methyl-1, 2, 6-thiadiazinane-3-carboxylic acid 1, 1-dioxide followed by C-C coupling:

scheme 79:

to a stirred solution of the above acid compound (1eq.) in DCM/DMF (10V) was added DIPEA (3eq.), stirred for 15min at 0 ℃, then HATU (1.5eq.), stirred again for 15min, then the corresponding aniline (1.2eq.) was added. The reaction mixture was then stirred at room temperature overnight. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with ice-cold water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound. The crude compound was dissolved in methanol (10V), stirred for 15 minutes, filtered and dried under reduced pressure to give the desired compound. C₁₄H₁₂BrF₃N₄O₃S₂LCMS calculated of (d): 483.95, respectively; LCMS observations: 485.95(M +2)⁺。

Synthesis of cis-2-methyl-5- (5- (1-methyl-1H-pyrazol-4-yl) thiazol-2-yl) -N- (3,4, 5-trifluorophenyl) -1,2, 6-thiadiazine-e-3-carboxamide 1, 1-dioxide (HBV-CSU-417):

to HBV-CSU-417 corresponding bromo compound (1eq), boronic acid/boronic ester (1.2eq) in 1, 4-dioxane H₂To a mixture of O (1:1), DIPEA (2eq) was added, and the mixture was purged with Ar for 15 minutes, followed by addition of PdCl₂(PPh₃)₂(0.005eq) and stirred at 80 ℃ overnight. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give the title compound HBV-CSU-417 (see Table 2 for analytical data).

Scheme 80:

synthesis of cis-N- (3-chloro-4-fluorophenyl) -5- (5- (1-methyl-1H-pyrazol-4-yl) thiophen-2-yl) -2-propyl-1, 2, 6-thiadiazine-3-carboxamide 1, 1-dioxide (HBV-CSU-424):

scheme 80:

to a stirred solution of compound HBV-CSU-394(0.035g, 0.068mmol) in ethanol (5mL) was added 10% Pd/C (10% w/w of substrate, 3mg) and the reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a pad of celite, the filtrate was evaporated under reduced pressure and the resulting residue was triturated with ether and n-pentane to give the title compound HBV-CSU-424 (analytical data see table 2).

Table 1: analysis data of HBV-CSU _ Int:

table 2: analytical data for the racemic and pure enantiomers of HBV-CSU: