Thienopyridone compound and use thereof, and antituberculosis drug

Abstract

Provided are a thienopyridone compound and a use thereof, and an antituberculosis drug. The thienopyridone compound has a structure of formula (I). The thienopyridone compound has a new core scaffold structure and excellent antituberculosis activity, and has a strong inhibitory effect on the growth of tuberculosis.

Description

Thiophene-pyridone compounds, their uses, and anti-tuberculosis drugs

[0001] Cross-referencing

[0002] This application is based on and claims priority to CN application number 202510100991.9, filed on January 22, 2025, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This invention relates to the field of anti-tuberculosis drug technology, and in particular to thienopyridone compounds, their uses, and anti-tuberculosis drugs. Background Technology

[0004] Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb). It is one of the most important infectious diseases that can cause death from a single pathogen. Clinically, the treatment for susceptible TB still involves the combined use of isoniazid, rifampin, pyrazinamide, and ethambutol. However, the emergence of multidrug-resistant, extensively drug-resistant, and completely drug-resistant Mycobacterium tuberculosis, HIV co-infection with Mycobacterium tuberculosis, and the recent COVID-19 pandemic have hindered the diagnosis and treatment of TB, exacerbating the burden of TB. Furthermore, in the past fifty years, only three new drugs—bedaquiline, delamani, and pregamani—have been approved for the treatment of drug-resistant TB. However, patients experience serious side effects such as nausea, hepatitis, arrhythmia, and central nervous system poisoning after taking these drugs. Therefore, there is an urgent need to develop new drugs with high activity for the treatment of TB. Summary of the Invention

[0005] This invention provides a class of thienopyridone compounds with excellent anti-tuberculosis activity.

[0006] Specifically, in one aspect, the present invention provides a thienopyridone compound of formula (I) or a stereoisomer thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable solvate thereof;

[0007] in:

[0008] -Ar1-(R1) n It is a C6-C10 aryl group or a 5-10 heteroaryl group with n R1 substitutions;

[0009] n is selected from 0, 1, 2, 3 or 4;

[0010] Each R1 is independently selected from the following groups: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C10 cycloalkyl, halogen, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)-, C1-C6 alkyl-S(O)2-, hydroxyl-substituted C1-C6 alkyl, mercapto-substituted C1-C6 alkyl, C1-C6 haloalkyl, nitro or cyano;

[0011] -Ar2-(R2) m It is a C6-C10 aryl group or a 5-10 heteroaryl group with m R2 substitutions;

[0012] m is selected from 0, 1, 2, 3 or 4;

[0013] Each R2 is independently selected from the following groups: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C10 cycloalkyl, halogen, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)-, C1-C6 alkyl-S(O)2-, hydroxyl-substituted C1-C6 alkyl, mercapto-substituted C1-C6 alkyl, C1-C6 haloalkyl, cyano or nitro;

[0014] R3 is selected from the following groups: H, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)-, C1-C6 alkyl-S(O)2-, C6-C10 aryl-C(O)-, C6-C10 aryl-S(O)-, C6-C10 aryl-S(O)2-.

[0015] In some implementations, -Ar1-(R1) n It is a phenyl group with n R1 substitutions, a 5-6 membered heteroaryl group, or a 9 membered heteroaryl group.

[0016] In some implementations, -Ar1-(R1) n It is a phenyl group with n R1 substitutions, a 5-6 membered heteroaryl group, or a 9 membered fused heteroaryl group.

[0017] In some implementations, -Ar1-(R1) n It is a phenyl, furanyl, thiophene, pyrrole, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiophene, or indoleyl group with n R1 substitutions.

[0018] In some implementations, -Ar1-(R1) n It is a phenyl, thiophene, pyrazolyl, benzothiophene, or pyridyl group with n R1 substitutions.

[0019] In some implementations, -Ar1-(R1) n Replaced by n R1s

[0020] In some implementations, -Ar1-(R1) n Replaced by n R1s

[0021] In some implementations, -Ar1-(R1) n Replaced by n R1s

[0022] In some implementations, n is selected from 0, 1, or 2.

[0023] In some embodiments, each R1 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 alkyl-C(O)-, hydroxy-substituted C1-C6 alkyl, C1-C6 haloalkyl, nitro or cyano.

[0024] In some embodiments, each R1 is independently selected from C1-C4 alkyl, halogen, C1-C3 alkoxy, C1-C3 alkyl-C(O)-, hydroxy-substituted C1-C3 alkyl, fluorine-substituted C1-C3 alkyl, nitro or cyano.

[0025] In some embodiments, each R1 is independently selected from C1-C4 alkyl, halogen, C1-C3 alkoxy, C1-C3 alkyl-C(O)-, hydroxy-substituted C1-C3 alkyl, or fluorine-substituted C1-C3 alkyl.

[0026] In some embodiments, each R1 is independently selected from methyl, tert-butyl, fluorine, chlorine, methoxy

[0027] In some implementations, -Ar1-(R1) n As a whole, selected from

[0028] In some implementations, -Ar1-(R1) n As a whole, selected from

[0029] In some implementations, -Ar2-(R2) m It is a phenyl group with m R2 substitutions or a 6-membered heteroaryl group.

[0030] In some implementations, -Ar2-(R2) m It is a phenyl or pyridyl group with m R2 substitutions.

[0031] In some implementations, -Ar2-(R2) m For m R2 replacements

[0032] In some implementations, -Ar2-(R2) m For m R2 replacements

[0033] In some implementations, m is selected from 0, 1, or 2.

[0034] In some implementations, m is 0 or 1.

[0035] In some embodiments, each R2 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, and nitro groups.

[0036] In some embodiments, each R2 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and nitro groups.

[0037] In some embodiments, each R2 is independently selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, and nitro groups.

[0038] In some implementations, each R2 is independently selected from methyl, fluorine, chlorine, bromine, methoxy, and nitro.

[0039] In some implementations, -Ar2-(R2) m As a whole, selected from

[0040] In some implementations, -Ar2-(R2) m As a whole, selected from

[0041] In some embodiments, R3 is selected from H, C1-C6 alkyl-C(O)-, and C6-C10 aryl-C(O)-.

[0042] In some embodiments, R3 is selected from H, C1-C6 alkyl-C(O)-, and benzoyl.

[0043] In some embodiments, R3 is selected from H, C1-C3 alkyl-C(O)-, and benzoyl.

[0044] In some implementations, R3 is selected from H,

[0045] In some implementations, R3 is selected from H,

[0046] In some implementations, R3 is H.

[0047] In some embodiments, the compound is selected from the compounds in Table 1.

[0048] In another aspect, the present invention provides a pharmaceutical composition comprising the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate.

[0049] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0050] In some embodiments, the pharmaceutical composition is an anti-tuberculosis drug.

[0051] In some embodiments, the pharmaceutical composition may further comprise additional pharmaceutical ingredients.

[0052] In some embodiments, the additional drug is an antimycobacterial agent or an antituberculosis agent.

[0053] In another aspect, the present invention provides sterile containers, drug kits, medicine boxes, or combinations of drugs, comprising:

[0054] A first active ingredient, comprising the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate; and,

[0055] The second active ingredient is a different drug from the first active ingredient.

[0056] In some embodiments, the first active ingredient and the second active ingredient exist in separate forms.

[0057] In some implementations, the first active ingredient and the second active ingredient are applied separately.

[0058] In some embodiments, the additional drug is an antimycobacterial agent or an antituberculosis agent.

[0059] In another aspect, the present invention provides the use of the aforementioned compounds or stereoisomers thereof, their prodrugs, their pharmaceutically acceptable salts, their pharmaceutically acceptable esters or their pharmaceutically acceptable solvates, or the aforementioned pharmaceutical compositions in the preparation of medicaments for treating and / or preventing mycobacterial infections or diseases caused by mycobacterial infections.

[0060] In addition, the present invention also provides the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester or its pharmaceutically acceptable solvate, or the aforementioned pharmaceutical composition, for the treatment and / or prevention of mycobacterial infection or diseases caused by mycobacterial infection.

[0061] The present invention also provides a method for treating and / or preventing mycobacterial infection or diseases caused by mycobacterial infection, comprising: administering to a subject in need an effective amount of the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate, or the aforementioned pharmaceutical composition. In some embodiments, the method further comprises: administering to a subject in need an effective amount of an additional drug, said additional drug as described above.

[0062] In some embodiments, the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester or its pharmaceutically acceptable solvate, or the aforementioned pharmaceutical composition is used as the first active ingredient, and the additional drug is used as the second active ingredient, and the first active ingredient and the second active ingredient are applied simultaneously or sequentially.

[0063] In some implementations, the mycobacterium is Mycobacterium tuberculosis.

[0064] In some embodiments, the mycobacterium is drug-resistant Mycobacterium tuberculosis.

[0065] In some embodiments, the drug-resistant Mycobacterium tuberculosis includes multidrug-resistant Mycobacterium tuberculosis and extensively drug-resistant Mycobacterium tuberculosis. In some embodiments, multidrug resistance means resistance to at least rifampin and isoniazid. In some embodiments, extensively drug-resistant means resistance to at least one injectable drug and resistance to one quinolone drug in addition to the aforementioned multidrug resistance.

[0066] In another aspect, the present invention provides the use of the aforementioned compounds or stereoisomers thereof, their prodrugs, their pharmaceutically acceptable salts, their pharmaceutically acceptable esters or their pharmaceutically acceptable solvates, or the aforementioned pharmaceutical compositions in the preparation of medicaments for the treatment and / or prevention of tuberculosis (TB).

[0067] In addition, the present invention also provides the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester or its pharmaceutically acceptable solvate, or the aforementioned pharmaceutical composition for the treatment and / or prevention of tuberculosis (TB).

[0068] The present invention also provides a method for treating and / or preventing tuberculosis (TB), comprising: administering to a subject in need an effective amount of the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate, or the aforementioned pharmaceutical composition. In some embodiments, the method further comprises: administering to a subject in need an effective amount of an additional drug, said additional drug as described above.

[0069] In some embodiments, the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester or its pharmaceutically acceptable solvate, or the aforementioned pharmaceutical composition is used as the first active ingredient, and the additional drug is used as the second active ingredient, and the first active ingredient and the second active ingredient are applied simultaneously or sequentially.

[0070] In another aspect, the present invention provides the use of the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester or its pharmaceutically acceptable solvate, or the aforementioned pharmaceutical composition in the preparation of a mycobacterial inhibitor, or in the preparation of an antimycobacterial medicament.

[0071] In addition, the present invention also provides the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester or its pharmaceutically acceptable solvate, or the aforementioned pharmaceutical composition, for inhibiting the growth or proliferation of mycobacteria.

[0072] The present invention also provides a method for inhibiting the growth or proliferation of mycobacteria, or a method for inhibiting the growth or proliferation of mycobacteria in vitro, comprising: contacting the mycobacteria with the aforementioned compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate, or the aforementioned pharmaceutical composition. In some embodiments, the method is for non-diagnostic or non-therapeutic purposes.

[0073] In some implementations, the mycobacterium is Mycobacterium tuberculosis.

[0074] In some embodiments, the mycobacterium is drug-resistant Mycobacterium tuberculosis.

[0075] In some embodiments, the drug-resistant Mycobacterium tuberculosis includes multidrug-resistant Mycobacterium tuberculosis and extensively drug-resistant Mycobacterium tuberculosis. In some embodiments, multidrug resistance means resistance to at least rifampin and isoniazid. In some embodiments, extensively drug-resistant means resistance to at least one injectable drug and resistance to one quinolone drug in addition to the aforementioned multidrug resistance.

[0076] In addition, the present invention also provides a thienopyridone compound having the structure of formula (I');

[0077] in:

[0078] -Ar1-(R1) n It is a C6-C10 aromatic ring or a 4-10 membered heteroarylene ring with n R1 substitutions, wherein n is selected from 0, 1, 2, 3 or 4, and each of the n R1s is independently selected from the following groups: C1-C6 alkyl, C1-C5 alkoxy, C3-C10 cycloalkyl, halogen, C1-C8 acyl, hydroxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, nitro or cyano;

[0079] -Ar2-(R2) n It is a C6-C10 aromatic ring or a 4-10-membered heteroaryl ring with n R2 substitutions, wherein n is selected from 0, 1, 2, 3 or 4, and each of the n R2s is independently selected from the following groups: C1-C6 alkyl, C1-C5 alkoxy, C3-C10 cycloalkyl, halogen or nitro;

[0080] R3 is selected from the following groups: H or C1-C8 acyl groups.

[0081] As a preferred option, -Ar1-(R1) n It is a phenyl, thiophene, pyrazolyl, benzothiophene, or pyridyl group with n R1 substitutions.

[0082] As a preferred option, -Ar1-(R1) n In this context, n is selected from 0, 1, or 2, and each of the n R1s is independently selected from C1-C4 alkyl, halogen, C1-C3 alkoxy, C1-C3 acyl, hydroxy-substituted C1-C3 alkyl, fluorine-substituted C1-C3 alkyl, nitro, or nitrile.

[0083] As a preferred option, -Ar2-(R2) n It is a phenyl or pyridyl group with n R2 substitutions.

[0084] As a preferred option, -Ar2-(R2) n In this context, n is selected from 0, 1, or 2, and each of the n R2 groups is independently selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, or nitro groups.

[0085] As a preferred option, R3 is selected from H, C1-C3 acyl or benzoyl.

[0086] Some representative thiophenopyridone compounds are:

[0087] 7-Hydroxy-3,6-diphenylthiopheno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-3-phenyl-6-(o-tolyl)thiopheno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-3-phenyl-6-(m-tolyl)thiopheno[3,2-b]pyridin-5(4H)-one, 6-(2-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 6-(3-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 6-(4-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 6-(2-chlorophenyl)-7-hydroxy-3- Phenylaceto[3,2-b]pyridin-5(4H)-one, 6-(3-chlorophenyl)-7-hydroxy-3-phenylthiophento[3,2-b]pyridin-5(4H)-one, 6-(4-chlorophenyl)-7-hydroxy-3-phenylthiophento[3,2-b]pyridin-5(4H)-one, 6-(3-bromophenyl)-7-hydroxy-3-phenylthiophento[3,2-b]pyridin-5(4H)-one, 7-hydroxy-6-(3-methoxyphenyl)-3-phenylthiophento[3,2-b]pyridin-5(4H)-one, 7-hydroxy-6-(3-nitrophenyl)-3-phenylthiophento[3,2-b]pyridin-5(4H)-one, 7-hydroxy-3-phenyl-6-(pyridin-4-yl)thiophento [3,2-b]pyridin-5(4H)-one, 6-(3-fluorophenyl)-7-hydroxy-3-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one, 6-(3-fluorophenyl)-7-hydroxy-3-(m-tolyl)thieno[3,2-b]pyridin-5(4H)-one, 6-(3-fluorophenyl)-7-hydroxy-3-(p-tolyl)thieno[3,2-b]pyridin-5(4H)-one, 3-(2-fluorophenyl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 3,6-bis(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 6-(3-fluorophenyl)-3-(4-) 3-(4-chlorophenyl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 6-(3-fluorophenyl)-7-hydroxy-3-(4-methoxyphenyl)thieno[3,2-b]pyridin-5(4H)-one, 6-(3-fluorophenyl)-7-hydroxy-3-(thieno-2-yl)thieno[3,2-b]pyridin-5(4H)-one, 3-(2,3-difluorophenyl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 3-(2,5-dichlorophenyl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 3-(2,5-dichlorophenyl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one,2-b]pyridin-5(4H)-one, 3-(4-fluoro-2-methylphenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one, 3-(benzothiophen-2-yl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one, 6-(3-fluorophenyl)-7-hydroxy-3-(pyridin-3-yl)thiopheno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-6-phenyl-3-(o-tolyl)thiopheno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-6-phenyl-3-(m-tolyl)thiopheno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-6- Phenyl-3-(p-Tolyl)thiophene[3,2-b]pyridin-5(4H)-one, 3-(2-fluorophenyl)-7-hydroxy-6-phenylthiophene[3,2-b]pyridin-5(4H)-one, 3-(3-fluorophenyl)-7-hydroxy-6-phenylthiophene[3,2-b]pyridin-5(4H)-one, 3-(4-fluorophenyl)-7-hydroxy-6-phenylthiophene[3,2-b]pyridin-5(4H)-one, 3-(2-chlorophenyl)-7-hydroxy-6-phenylthiophene[3,2-b]pyridin-5(4H)-one, 3-(3-chlorophenyl)-7-hydroxy-6-phenylthiophene[3,2-b]pyridin-5(4H)-one, 3-(4-chlorophenyl)-7-hydroxy-6-phenylthiophene[3,2-b]pyridin-5(4H)-one, 3-(4-chlorophenyl)-7-hydroxy 3-(4-acetylphenyl)-7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-3-(4-methoxyphenyl)-6-phenylthieno[3,2-b]pyridin-5(4H)-one, 3-(4-acetylphenyl)-7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-3-(4-(hydroxymethyl)phenyl)-6-phenylthieno[3,2-b]pyridin-5(4H)-one, 3-(4-(tert-butyl)phenyl)-7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-6-phenyl-3-(thieno-2-yl)thieno[3,2-b]pyridin-5(4H)-one, 3-(3 ,4-Difluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 3-(2,5-dichlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 3-(4-fluoro-2-methylphenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 3-(benzothiophen-2-yl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-6-phenyl-3-(pyridin-3-yl)thiopheno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one,One of the following: [2-b]pyridin-5(4H)-one, 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)-one, 5-oxo-3,6-diphenyl-4,5-dihydrothieno[3,2-b]pyridin-7-yl acetate, and 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-oxo-6-phenyl-4,5-dihydrothieno[3,2-b]pyridin-7-yl benzoate.

[0088] The thienopyridone compounds described in this invention exhibit strong inhibitory effects on the growth of Mycobacterium tuberculosis. The above are only some representative thienopyridone compounds; other thienopyridone compounds with the structure of formula (I) also possess excellent anti-tuberculosis activity.

[0089] Another object of the present invention is to provide the use of any of the above-described thienopyridone compounds in the preparation of medicaments for the treatment and / or prevention of TB (a disease caused by tuberculosis infection).

[0090] Another object of the present invention is to provide the use of any of the above-described thienopyridone compounds in the preparation of tuberculosis inhibitors or in the preparation of anti-tuberculosis medicaments.

[0091] The thienopyridone compounds of the present invention can be used to prepare medicaments for treating and / or preventing tuberculosis, to prepare tuberculosis inhibitors, and to prepare anti-tuberculosis medicaments, particularly for preparing medicaments for treating infectious diseases caused by tuberculosis, and provide the use of the thienopyridone compounds as medicaments for treating infectious diseases caused by tuberculosis.

[0092] An anti-tuberculosis drug comprising any of the foregoing thienopyridone compounds and their pharmaceutically acceptable salts.

[0093] Terminology Definition

[0094] Unless otherwise specified, the above groups and substituents have the general meaning in the field of medicinal chemistry.

[0095] In this invention, unless otherwise explicitly stated, the descriptive phrases “...each independently selected from” or “each…independently selected from” used throughout this document are interchangeable. They can mean either that the specific options expressed by the same or different symbols in different groups do not affect each other, or that the specific options expressed by the same or different symbols in the same group do not affect each other.

[0096] The substituents of the compounds of this invention are disclosed according to the type or scope of the functional groups. In particular, this invention includes every independent secondary combination of each member of these types and scopes of functional groups.

[0097] The term "C1-C6 alkyl" refers to any straight-chain or branched group containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-pentyl, n-hexyl, etc., preferably "C1-C4 alkyl", and more preferably "C1-C3 alkyl".

[0098] The term "C1-C4 alkyl" refers to any straight-chain or branched group containing 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc.

[0099] The term "C1-C3 alkyl" refers to any straight-chain or branched group containing 1-3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, etc.

[0100] The term “C1-C6 alkoxy” refers to any of the above “C1-C6 alkyl” connected to the rest of the molecule by an oxygen atom (-O-), preferably “C1-C4 alkoxy”, and more preferably “C1-C3 alkoxy”.

[0101] The term “C1-C6 alkylthio” refers to any of the above “C1-C6 alkyl” linked to the rest of the molecule by a sulfur atom (-S-), preferably “C1-C4 alkylthio”, and more preferably “C1-C3 alkylthio”.

[0102] The term "C1-C6 haloalkyl" refers to a group obtained by substituting one or more (e.g., 2 or 3) hydrogen atoms from any of the aforementioned "C1-C6 alkyl" groups with a halogen (preferably fluorine). Correspondingly, the term "fluorine-substituted C1-C6 alkyl" refers to a group obtained by substituting one or more (e.g., 2 or 3) hydrogen atoms from any of the aforementioned "C1-C6 alkyl" groups with fluorine, such as... Trifluoromethyl, etc.

[0103] The term "hydroxyl-substituted C1-C6 alkyl" refers to a group obtained by substituting one or more (e.g., two or three) hydrogen atoms from any of the above "C1-C6 alkyl" groups with a hydroxyl group, such as... Similarly, the term "thiol-substituted C1-C6 alkyl" refers to a group obtained by replacing one or more (e.g., 2 or 3) hydrogen atoms in any of the above "C1-C6 alkyl" with a thiol group.

[0104] The term "C3-C10 cycloalkyl" refers to a 3- to 10-membered all-carbon saturated monocyclic ring, preferably "C3-C6 cycloalkyl". Examples of C3-C6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0105] In this invention, a complex group such as "C1-C6 alkyl-C(O)-" indicates that -C(O)- is covalently linked to any of the aforementioned "C1-C6 alkyl" groups, examples of which include, but are not limited to, those described above. Please refer to the foregoing explanation for other similar complex groups.

[0106] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0107] The term "hydroxyl group" refers to -OH.

[0108] The term "cyano" refers to -CN.

[0109] The term "nitro" refers to -NO2.

[0110] The term "thiol" refers to -SH.

[0111] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group having a conjugated π-electron system, preferably a 6- to 10-membered (i.e., C6-C10 aryl) group, such as phenyl and naphthyl.

[0112] The term "heteroaryl" refers to an aromatic monocyclic group, bicyclic group (such as a fused heteroaryl, preferably a 9-membered fused heteroaryl), or tricyclic group or more cyclic group having at least one heteroatom (N, O, or S) in at least one ring, which is 5-, 6-, 7-, 8-, 9-, or 10-membered (preferably 5- or 6-membered). The heteroatom-containing ring optionally also has one, two, or three heteroatoms selected from N, O, or S. For a heteroaryl to be bicyclic, tricyclic, or polycyclic, each ring must constitute an aromatic system. The carbon or sulfur atoms on the ring may optionally be oxidized (i.e., forming C(=O), sulfoxide, or sulfone), thereby forming part of the heteroaryl group. Non-limiting examples of the heteroaryl group include, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, pyrroleyl, phenyl-pyrroleyl, furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thiophenyl, benzofuranyl, benzothiophenyl, benzimidazolyl, inzolyl, quinolinyl, isoquinolinyl, etc.

[0113] In this invention, terms like "-Ar1-(R1)" are used. n In the description of "n R1-substituted C6-C10 aryl or 5-10 heteroaryl", "n R1-substituted" is used to modify all the groups following it. That is, the description actually means -Ar1-(R1). n This refers to a C6-C10 aryl group with n R1 substitutions or a 5-10 heteroaryl group with n R1 substitutions. For other similar descriptions, please refer to this explanation for clarification.

[0114] As used herein, unless otherwise stated, the term "stereoisomer" refers to a compound with the same molecular structure as the compound of the present invention but a different spatial configuration. The compounds of the present invention may include one or more asymmetric centers and therefore may exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isolation of individual isomers or the selective synthesis of individual isomers is achieved by applying various methods well known to those skilled in the art. For example, isomers may be isolated from mixtures by methods known to those skilled in the art, including but not limited to: chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. Unless otherwise stated, all such isomers and mixtures thereof are included within the scope of the compounds disclosed herein. Unless otherwise stated, the structures described herein also imply all stereochemical forms encompassing that structure; i.e., the (R) and (S) configurations of each asymmetric center. Therefore, those skilled in the art will generally consider single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers and diastereomers, to be stable within the scope of this disclosure.

[0115] As used herein, unless otherwise stated, the term "prodrug" refers to a derivative of a compound that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide the compound of the present invention. A prodrug only becomes an active compound under biological conditions through this reaction, or its unconverted form itself possesses a certain activity. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, 5th edition).

[0116] As used herein, the term "pharmaceutically acceptable salt" means (i) a salt formed by an acidic functional group that may be present in the compounds provided by the present invention and a suitable inorganic or organic cation (base), including but not limited to, alkali metal salts such as sodium, potassium, lithium, etc.; alkaline earth metal salts such as calcium, magnesium, etc.; other metal salts such as aluminum, iron, zinc, copper, nickel, cobalt, etc.; inorganic base salts such as ammonium salts; organic base salts such as tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N′-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenylethylamine salts, piperazine salts, tetramethylamine salts, and tris(hydroxymethyl)aminomethane salts. (ii) Salts formed by basic functional groups and suitable inorganic or organic anions (acids) in the compounds provided by the present invention, including but not limited to: hydrohalates, such as hydrofluoric acid, hydrochloride, hydrobromide, hydroiodide, etc.; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkyl sulfonates, such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, etc.; aryl sulfonates, such as benzenesulfonates, p-benzenesulfonates, etc.; organic acid salts, such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, maleates, etc.; amino acid salts, such as glycinates, trimethylglycinates, arginines, ornithines, glutamates, aspartates, etc.

[0117] Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting an adequate amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.

[0118] As used herein, the terms "solvent" or "solvent compound" are used interchangeably and refer to a compound existing in combination with a solvent molecule. This combination may include a stoichiometric amount of a solvent, such as a monohydrate or dihydrate, or may include any amount of water; similarly, methanol or ethanol may form an "alcohol," which may be stoichiometric or non-stoichiometric. The term "solvent compound" as used herein refers to a solid form, i.e., a compound in solution of a solvent that, while solvated, is not a solvate compound as used herein.

[0119] As used herein, the term "pharmaceutically acceptable ester" means an ester formed by -COOH and a suitable alcohol that may be present in the compounds provided by the present invention, or an ester formed by -OH and a suitable acid that may be present in the compounds provided by the present invention.

[0120] Methods for preparing various pharmaceutical compositions containing a certain amount of active ingredient are known, or will be obvious to those skilled in the art according to the disclosure of the present invention. As described in REMINGTON'S PHARMACEUTICAL SCIENCES, Martin, EW, ed., Mack Publishing Company, 19th ed. (1995), the method for preparing the pharmaceutical composition includes incorporating appropriate pharmaceutical excipients, carriers, diluents (such as saline solution, glucose solution, etc.).

[0121] The pharmaceutical formulations of the present invention can be manufactured using known methods, including conventional mixing, dissolving, or lyophilizing methods. The compounds of the present invention can be formulated into pharmaceutical compositions and administered to patients via various routes suitable for a selected manner of administration, such as oral or parenteral (via intravenous, intramuscular, local, or subcutaneous routes).

[0122] Therefore, the compounds of the present invention, combined with pharmaceutically acceptable carriers (such as inert diluents or assimilated edible carriers), can be administered systemically, for example, orally. They can be encapsulated in hard or soft-shell gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of swallowable tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, discs, emulsions (such as microemulsions), powders, solutions, etc. Such compositions and formulations should contain at least 0.1% of the active compound. The proportion of such compositions and formulations can, of course, vary and can range from about 1% to about 99% of the weight of a given unit dosage form. In such therapeutically useful compositions, the amount of the active compound enables the attainment of an effective dose level.

[0123] Tablets, lozenges, pills, capsules, etc., may also contain: binders such as gum arabic, gum arabic, corn starch, or gelatin; excipients such as dicalcium hydrogen phosphate; disintegrants such as corn starch, potato starch, alginate monosaccharides, monosaccharide derivatives (such as meglumine); lubricants such as magnesium stearate; sweeteners such as sucrose, fructose, lactose, or aspartame; or flavorings such as peppermint, wintergreen oil, or cherry flavor; and solubilizers such as hydrophilic polymers such as propylene glycol, polyethylene glycol, caprylic / capric glycerides, and tocopheryl polyethylene glycol succinate. When the unit dosage form is a capsule, in addition to the materials of the types mentioned above, it may also contain a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may be present as coatings or otherwise alter the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, or sugar. Syrups or elixirs may contain active compounds, sucrose or fructose as sweeteners, methylparaben or propylparaben as preservatives, dyes, and flavorings (such as cherry or orange flavorings). Of course, any materials used to prepare any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the applied amount. Furthermore, active compounds may be incorporated into sustained-release formulations and devices.

[0124] The active compound can also be administered intravenously or intraperitoneally by infusion or injection. Aqueous solutions of the active compound or its salts can be prepared, optionally mixed with a non-toxic surfactant. Dispersants in glycerol, liquid polyethylene glycol, glycerol triacetate, mixtures thereof, and oils can also be prepared. Under normal storage and use conditions, these formulations contain preservatives to prevent microbial growth.

[0125] Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions, dispersants, or sterile powders containing an active ingredient (optionally encapsulated in liposomes) of an injectable or infusionable solution or dispersant suitable for sterility. In all cases, the final dosage form must be sterile, liquid, and stable under the conditions of production and storage. The liquid carrier may be a solvent or liquid dispersion medium, including, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides, and suitable mixtures thereof. Suitable flowability may be maintained, for example, by the formation of liposomes, by maintaining the desired particle size in the case of dispersants, or by the use of surfactants (such as polyoxyethylene stearate). Antimicrobial activity may be achieved by a variety of antibacterial and antifungal agents (such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.). In many cases, isotonic agents, such as sugars, buffers, or sodium chloride, are preferred. Prolonged absorption of injectable compositions can be achieved by using compositions of retardant absorbents (e.g., aluminum monostearate and gelatin).

[0126] A sterile injectable solution is prepared by combining the required amount of the active compound in a suitable solvent with the various other ingredients listed above, followed by filtration and sterilization. In the case of sterile powders used to prepare the sterile injectable solution, a preferred preparation method is vacuum drying and freeze-drying techniques, which produce a powder containing the active ingredient plus any other desired components present in the previously sterile filtered solution.

[0127] Useful solid carriers include pulverized solids (such as talc, clay, microcrystalline cellulose, silica, alumina, etc.). Useful liquid carriers include water, ethanol, or ethylene glycol or water-ethanol / ethylene glycol mixtures, wherein the compounds of the present invention may optionally be dissolved or dispersed therein at effective concentrations with the aid of non-toxic surfactants. Adjuvants (such as flavorings) and additional antimicrobial agents may be added to optimize the properties for a given application.

[0128] Thickeners (such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose or modified inorganic materials) can also be used with liquid carriers to form coatable pastes, gels, ointments, soaps, etc., which can be applied directly to the user's skin.

[0129] The pharmaceutical composition may also contain appropriate amounts of pH adjusters, such as sodium hydroxide, citric acid, etc.

[0130] The above-described formulations may exist in unit dosage forms, which are physically dispersed units containing a unit dose suitable for administration to humans and other mammals. Unit dosage forms may be capsules or tablets, or multiple capsules or tablets. Depending on the specific treatment involved, the amount of the active ingredient per unit dose may vary or be adjusted between approximately 0.1 and approximately 1000 mg or more.

[0131] The therapeutic dose of a compound or its active salt or derivative depends on the method of administration, the nature of the disease to be treated, and the patient’s age and condition, and ultimately on the decision of the physician or clinician present.

[0132] In addition, it includes the application of various new drug formulations such as emulsion liposomes, microspheres, nanospheres and self-emulsifying drug delivery systems (SEDDS), such as drugs prepared using particulate dispersion systems including polymeric micelles, nanoemulsions, submicroemuls, microcapsules, microspheres, liposomes and niosomes (also known as nonionic surfactant vesicles).

[0133] In this invention, "treatment" generally refers to achieving the desired pharmacological and / or physiological effect. This effect may be preventative based on the complete or partial prevention of the disease or its symptoms; and / or therapeutic based on the partial or complete stabilization or cure of the disease and / or side effects resulting from the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) prevention of disease or symptoms occurring in a patient who is susceptible to the disease or its symptoms but has not yet been diagnosed with the disease; (b) suppression of the symptoms of the disease, i.e., prevention of its progression; or (c) relief of the symptoms of the disease, i.e., causing the disease or its symptoms to regress.

[0134] In this invention, "subject" refers to a vertebrate. In some embodiments, vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In some embodiments, mammal refers to a human.

[0135] In this invention, "effective amount" refers to the amount that effectively achieves the desired therapeutic effect at the necessary dosage and time. The "therapeutic effective amount" of the substance / molecule of this invention may vary depending on factors such as an individual's disease state, age, sex, weight, and the ability of the substance / molecule to elicit the desired response in the individual. Therapeutic effective amount also encompasses the amount in which the beneficial therapeutic effect of the substance / molecule outweighs any toxic or harmful consequences. Beneficial effects

[0136] The present invention has the following advantages and effects:

[0137] (1) A class of thienopyridone compounds with a novel core structure and excellent anti-tuberculosis activity was provided.

[0138] (2) Providing the use of the thienopyridone compound as a medicine for treating infectious diseases caused by Mycobacterium tuberculosis, wherein the thienopyridone compound of the present invention has a strong inhibitory effect on the growth of Mycobacterium tuberculosis. Detailed Implementation

[0139] This document describes various specific embodiments, methods, and examples, including exemplary implementations and definitions used to understand the claimed invention. While the following detailed description sets forth specific preferred embodiments, those skilled in the art will understand that these embodiments are merely exemplary and that the invention can be practiced in other ways. For the purpose of determining infringement, the scope of this invention will encompass any one or more of the appended claims, including their equivalents, and elements or limitations equivalent to those stated.

[0140] Example 1

[0141] 7-Hydroxy-3,6-diphenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0142] Step 1: Synthesis of intermediate methyl 4-phenyl-3-(2-phenylacetamido)thiophene-2-carboxylate

[0143] Methyl 3-amino-4-phenylthiophene-2-carboxylate (2 mmol, 466 mg) was dissolved in anhydrous 1,4-dioxane. Phenylacetyl chloride (2.4 mmol, 317 μL) was slowly added dropwise at room temperature. After the addition was complete, the reaction mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete. The reaction was quenched by adding saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The solution was purified by silica gel column chromatography to give 640 mg of white solid, namely methyl 4-phenyl-3-(2-phenylacetamido)thiophene-2-carboxylate, with a yield of 91%.

[0144] Step 2: Synthesis of the target compound 7-hydroxy-3,6-diphenylthiopheno[3,2-b]pyridine-5(4H)-one

[0145] Methyl 4-phenyl-3-(2-phenylacetamido)thiophene-2-carboxylic acid (1.82 mmol, 640 mg) and potassium carbonate (9.14 mmol, 1.2 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, and then 1 mol / L hydrochloric acid was added until a solid precipitated. The solution was kept slightly neutral, the solid was filtered, and after drying, 336 mg of white solid, namely 7-hydroxy-3,6-diphenylthiopheno[3,2-b]pyridine-5(4H)-one, was obtained, with a yield of 58%.

[0146] 1 H NMR (500MHz, DMSO-d6) δ10.67(s,2H),7.94(s,1H),7.72(d,J=7.5Hz,2H),7.47(t,J=7.6Hz,2H),7.42–7.35(m,5H),7.33–7.28(m,1H).

[0147] Example 2

[0148] 7-Hydroxy-3-phenyl-6-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0149] Step 1: Synthesis of 2-(2-methylphenyl)acetyl chloride

[0150] 2-(2-methylphenyl)acetic acid (9.75 mmol, 1.46 g) was dissolved in anhydrous DCM, and SOCl2 (14.63 mmol, 1.06 mL) was slowly added dropwise. Then, 10 drops of DMF were added to the reaction solution. After the addition was complete, the mixture was transferred to 40 °C. The reaction was monitored by TLC until it was complete. The solvent was then evaporated to obtain 2-(2-methylphenyl)acetyl chloride, which could be used directly in step 2 without purification.

[0151] Step 2: Synthesis of intermediate methyl 4-phenyl-3-(2-(2-tolyl)acetamido)thiophene-2-carboxylic acid

[0152] Methyl 3-amino-4-phenylthiophene-2-carboxylate (5 mmol, 1.16 g) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(2-methylphenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete. The reaction was quenched by adding saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The mixture was purified by silica gel column chromatography to give 1.65 g of brown solid, namely methyl 4-phenyl-3-(2-(2-tolyl)acetamido)thiophene-2-carboxylate, with a yield of 90%.

[0153] Step 3: Synthesis of the target compound 7-hydroxy-3-phenyl-6-(o-tolyl)thieno[3,2-b]pyridine-5(4H)-one

[0154] Methyl 4-phenyl-3-(2-(2-tolyl)acetamido)thiophene-2-carboxylic acid (0.5 mmol, 183 mg) was placed in a 25 mL double-necked flask under N2 protection and LiHMDS (1 M THF solution, 1.25 mmol, 1.25 mL) was slowly added dropwise at -40 °C. After the addition was complete, the mixture was transferred to room temperature. After the reaction was monitored by TLC until complete, 1 mol / L hydrochloric acid was added to keep the solution slightly neutral. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The mixture was purified by silica gel column chromatography and dried to obtain 101 mg of white solid, namely 7-hydroxy-3-phenyl-6-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one, with a yield of 60%.

[0155] 1 H NMR(400MHz,DMSO-d6)δ10.76(s,2H),7.91(s,1H),7.77–7.68(m,2H),7.46–7.39(m,2 H),7.35(t,J=7.3Hz,1H),7.31–7.20(m,3H),7.17(dd,J=7.2,1.9Hz,1H),2.15(s,3H).

[0156] Example 3

[0157] 7-Hydroxy-3-phenyl-6-(m-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0158] Step 1: Synthesis of 2-(3-methylphenyl)acetyl chloride

[0159] 2-(3-methylphenyl)acetic acid (3.0 mmol, 450 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 326 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the reaction solution was transferred to 40 °C for reaction. After the reaction was complete as monitored by TLC, the solvent was evaporated to obtain 2-(3-methylphenyl)acetyl chloride, which could be used directly in step 2 without purification.

[0160] Step 2: Synthesis of intermediate methyl 3-(2-(3-methylphenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0161] Methyl 3-amino-4-phenylthiophene-2-carboxylate (2 mmol, 466 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-methylphenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete. The reaction was quenched with saturated sodium carbonate, and extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The solution was purified by silica gel column chromatography to give 727 mg of brown oily liquid, namely methyl 3-(2-(3-methylphenyl)acetamido)-4-phenylthiophene-2-carboxylate, with a yield of 99%.

[0162] Step 3: Synthesis of the target product 7-hydroxy-3-phenyl-6-(m-tolyl)thieno[3,2-b]pyridine-5(4H)-one

[0163] Methyl 3-(2-(3-methylphenyl)acetamido)-4-phenylthiophene-2-carboxylic acid (1.98 mmol, 720 mg) and potassium carbonate (10 mmol, 1.3 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid to keep the solution slightly neutral. The methanol was removed by rotary evaporation, and the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness, purified by silica gel column chromatography, and dried to obtain 326 mg of a pale yellow solid, namely 7-hydroxy-3-phenyl-6-(m-tolyl)thieno[3,2-b]pyridine-5(4H)-one, with a yield of 48%.

[0164] 1H NMR (400MHz, DMSO-d6) δ10.63(s,2H),7.93(s,1H),7.72(d,J=7.5Hz,2H),7.47(t,J=7. 5Hz,2H),7.38(t,J=7.3Hz,1H),7.29(t,J=7.5Hz,1H),7.20–7.08(m,3H),2.34(s,3H).

[0165] Example 4

[0166] 6-(2-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0167] Step 1: Synthesis of 2-(2-fluorophenyl)acetyl chloride

[0168] 2-(2-fluorophenyl)acetic acid (1.5 mmol, 231 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 326 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the solution was transferred to 40 °C. After the reaction was monitored by TLC, the DCM was evaporated to dryness to obtain 2-(2-fluorophenyl)acetyl chloride, which could be used directly in step 2 without purification.

[0169] Step 2: Synthesis of intermediate methyl 3-(2-(2-fluorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0170] Methyl 3-amino-4-phenylthiophene-2-carboxylate (2 mmol, 466 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(2-fluorophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. After the reaction was monitored by TLC until it was complete, saturated sodium carbonate was added to quench the reaction. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The mixture was purified by silica gel column chromatography to give 719 mg of yellowish-white solid, namely methyl 3-(2-(2-fluorophenyl)acetamido)-4-phenylthiophene-2-carboxylate, with a yield of 97%.

[0171] Step 3: Synthesis of the target product 6-(2-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0172] Methyl 3-(2-(2-fluorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid (1.94 mmol, 719 mg) and potassium carbonate (9.73 mmol, 1.3 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid, while maintaining a slightly neutral solution. The methanol was removed by rotary evaporation, and the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness, purified by silica gel column chromatography, and dried to obtain 411 mg of white solid, namely 6-(2-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one, with a yield of 62%.

[0173] 1 H NMR (500MHz, DMSO-d6) δ10.85(s,2H),7.96(s,1H),7.71(d,J=7.5Hz,2H),7.47(t,J= 7.5Hz,2H),7.43–7.36(t,J=7.4Hz,2H),7.34(t,J=7.4Hz,1H),7.23(t,J=8.3Hz,2H).

[0174] Example 5

[0175] 6-(3-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0176] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0177] 2-(3-fluorophenyl)acetic acid (3 mmol, 462 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 326 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the solution was transferred to 40 °C. After the reaction was monitored by TLC, the DCM was evaporated to dryness to obtain 2-(3-fluorophenyl)acetyl chloride, which could be used directly in step 2 without purification.

[0178] Step 2: Synthesis of intermediate methyl 3-(2-(3-fluorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0179] Methyl 3-amino-4-phenylthiophene-2-carboxylate (2 mmol, 466 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-fluorophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. After the reaction was monitored by TLC until it was complete, saturated sodium carbonate was added to quench the reaction. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The solution was purified by silica gel column chromatography to obtain 698 mg of reddish-brown oily liquid, namely methyl 3-(2-(3-fluorophenyl)acetamido)-4-phenylthiophene-2-carboxylate, with a yield of 94%.

[0180] Step 3: Synthesis of the target product 6-(3-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0181] Methyl 3-(2-(3-fluorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid (1.89 mmol, 695 mg) and potassium carbonate (9.45 mmol, 1.3 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated in the reaction solution. The solution was kept slightly neutral. The solid was filtered and dried to obtain 366 mg of white solid, namely 6-(3-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, with a yield of 59%.

[0182] 1 H NMR (400MHz, DMSO-d6) δ7.96 (s, 1H), 7.69 (d, J = 7.3Hz, 2H), 7.51–7.35 (m, 4H), 7.27–7.16 (m, 2H), 7.13 (td, J = 8.7, 2.6Hz, 1H).

[0183] Example 6

[0184] 6-(4-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0185] Step 1: Synthesis of intermediate methyl 4-phenyl-3-(2-(4-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0186] Methyl 3-amino-4-phenylthiophene-2-carboxylate (2 mmol, 466 mg) was dissolved in anhydrous 1,4-dioxane. 2-(4-fluorophenyl)acetyl chloride (2.6 mmol, 449 mg) was slowly added dropwise at room temperature. The mixture was then transferred to 90 °C. After the reaction was monitored by TLC until complete, saturated sodium carbonate was added to quench the reaction. The mixture was extracted three times with ethyl acetate and water. The organic phases were collected, dried by rotary evaporation, and purified by silica gel column chromatography to obtain 663 mg of a pale yellow solid, namely methyl 4-phenyl-3-(2-(4-fluorophenyl)acetamido)thiophene-2-carboxylate, with a yield of 89%.

[0187] Step 2: Synthesis of the target product 6-(4-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0188] Methyl 4-phenyl-3-(2-(4-fluorophenyl)acetamido)thiophene-2-carboxylic acid (0.8 mmol, 295 mg) and potassium carbonate (4.0 mmol, 552 mg) were dissolved in 4 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 4 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral. The solid was filtered and dried to obtain 139 mg of a white solid, namely 6-(4-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, with a yield of 51%.

[0189] 1 H NMR (400MHz, DMSO-d6) δ7.94 (s, 1H), 7.69 (d, J = 7.5Hz, 2H), 7.47 (t, J = 7.5Hz, 2H), 7.40 (dd, J = 8.2, 5.3Hz, 3H), 7.21 (t, J = 8.8Hz, 2H).

[0190] Example 7

[0191] 6-(2-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0192] Step 1: Synthesis of intermediate methyl 3-(2-(2-chlorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0193] Methyl 3-amino-4-phenylthiophene-2-carboxylate (2.0 mmol, 466 mg) was dissolved in anhydrous 1,4-dioxane. 2-(2-chlorophenyl)acetyl chloride (2.4 mmol, 453 mg) was slowly added dropwise at room temperature. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until complete, then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The mixture was purified by silica gel column chromatography to give 728 mg of white solid, namely methyl 3-(2-(2-chlorophenyl)acetamido)-4-phenylthiophene-2-carboxylate, with a yield of 94%.

[0194] Step 2: Synthesis of the target product 6-(2-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0195] Methyl 3-(2-(2-chlorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid (1.89 mmol, 728 mg) and potassium carbonate (9.45 mmol, 1.3 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid to keep the solution slightly neutral. Methanol was removed by rotary evaporation, and the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. After purification by silica gel column chromatography, 546 mg of a pale yellow solid, namely 6-(2-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one, was obtained, with a yield of 82%.

[0196] 1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),7.96(s,1H),7.72(d,J=7.3Hz,2H),7 .56–7.51(m,1H),7.50–7.43(m,2H),7.42–7.34(m,3H),7.34–7.26(m,1H).

[0197] Example 8

[0198] 6-(3-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0199] Step 1: Synthesis of 2-(3-chlorophenyl)acetyl chloride

[0200] 2-(3-chlorophenyl)acetic acid (3.0 mmol, 511 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 326 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the solution was transferred to 40 °C. After the reaction was monitored by TLC, the DCM was evaporated to dryness to obtain 2-(3-chlorophenyl)acetyl chloride, which could be used directly in step 2 without purification.

[0201] Step 2: Synthesis of intermediate methyl 3-(2-(3-chlorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0202] Methyl 3-amino-4-phenylthiophene-2-carboxylate (2 mmol, 466 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-chlorophenyl)acetyl chloride was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. After the reaction was monitored by TLC until it was complete, saturated sodium carbonate was added to quench the reaction. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The mixture was purified by silica gel column chromatography to give 700 mg of reddish-brown oily liquid, namely methyl 3-(2-(3-chlorophenyl)acetamido)-4-phenylthiophene-2-carboxylate, with a yield of 90%.

[0203] Step 3: Synthesis of the target product 6-(3-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0204] Methyl 3-(2-(3-chlorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid (1.79 mmol, 690 mg) and potassium carbonate (8.96 mmol, 1.2 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral, the solid was filtered, and dried to obtain 410 mg of a white solid, namely 6-(3-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, with a yield of 64%.

[0205] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,2H),7.95(s,1H),7.69(d,J=7.5Hz,2H),7.50–7.44(m,2H),7.43–7.32(m,5H).

[0206] Example 9

[0207] 6-(4-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0208] Step 1: Synthesis of intermediate methyl 3-(2-(4-chlorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0209] Methyl 3-amino-4-phenylthiophene-2-carboxylate (2 mmol, 466 mg) was dissolved in anhydrous 1,4-dioxane. 2-(4-chlorophenyl)acetyl chloride (2.6 mmol, 491 mg) was slowly added dropwise at room temperature. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until complete, then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The mixture was purified by silica gel column chromatography to give 600 mg of white solid, namely methyl 3-(2-(4-chlorophenyl)acetamido)-4-phenylthiophene-2-carboxylate, with a yield of 77%.

[0210] Step 2: Synthesis of the target product 6-(4-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0211] Methyl 3-(2-(4-chlorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid (0.8 mmol, 308 mg) and potassium carbonate (4 mmol, 552 mg) were dissolved in 4 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 4 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral and filtered to obtain 140 mg of a white solid, namely 6-(4-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one, with a yield of 49%.

[0212] 1 H NMR (400MHz, DMSO-d6) δ10.79(s,2H),7.94(s,1H),7.69(d,J=7.5Hz,2H),7.50–7.42(m,4H),7.40(d,J=8.2Hz,3H).

[0213] Example 10

[0214] 6-(3-bromophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0215] Step 1: Synthesis of 2-(3-bromophenyl)acetyl chloride

[0216] 2-(3-bromophenyl)acetic acid (3 mmol, 645 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 326 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the mixture was transferred to 40 °C. After the reaction was monitored by TLC until it was complete, the DCM was evaporated to dryness to obtain 2-(3-bromophenyl)acetyl chloride, which can be used directly in step 2 without purification.

[0217] Step 2: Synthesis of intermediate methyl 3-(2-(3-bromophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0218] Methyl 3-amino-4-phenylthiophene-2-carboxylate (2 mmol, 466 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-bromophenyl)acetyl chloride was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. After the reaction was monitored by TLC until it was complete, saturated sodium carbonate was added to quench the reaction. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The mixture was purified by silica gel column chromatography to give 828 mg of yellow solid, namely methyl 3-(2-(3-bromophenyl)acetamido)-4-phenylthiophene-2-carboxylate, with a yield of 96%.

[0219] Step 3: Synthesis of the target product 6-(3-bromophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0220] Methyl 3-(2-(3-bromophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid (1.92 mmol, 823 mg) and potassium carbonate (9.62 mmol, 1.3 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral, and after filtration, 417 mg of a white solid, namely 6-(3-bromophenyl)-7-hydroxy-3-phenylthiophene[3,2-b]pyridine-5(4H)-one, was obtained, with a yield of 82%.

[0221] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,2H),7.95(s,1H),7.68(d,J=7.5Hz,2H),7.56(t,J=1.8Hz,1H),7.52–7.43(m,3H),7.42–7.33(m,3H).

[0222] Example 11

[0223] 7-Hydroxy-6-(3-methoxyphenyl)-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0224] Step 1: Synthesis of 2-(3-methoxyphenyl)acetyl chloride

[0225] 2-(3-methoxyphenyl)acetic acid (3 mmol, 498 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 326 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the mixture was transferred to 40 °C. After the reaction was monitored by TLC until it was complete, the DCM was evaporated to dryness to obtain 2-(3-methoxyphenyl)acetyl chloride, which could be used directly in step 2 without purification.

[0226] Step 2: Synthesis of intermediate methyl 3-(2-(3-methoxyphenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0227] Methyl 3-amino-4-phenylthiophene-2-carboxylate (2 mmol, 466 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-methoxyphenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete. The reaction was quenched with saturated sodium carbonate, and the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The mixture was purified by silica gel column chromatography to give 590 mg of a yellow oil, namely methyl 3-(2-(3-methoxyphenyl)acetamido)-4-phenylthiophene-2-carboxylate, with a yield of 77%.

[0228] Step 3: Synthesis of the target product 7-hydroxy-6-(3-methoxyphenyl)-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0229] Methyl 3-(2-(3-methoxyphenyl)acetamido)-4-phenylthiophene-2-carboxylic acid (1.55 mmol, 590 mg) and potassium carbonate (7.75 mmol, 1.0 g) were dissolved in 8 mL DMSO. The reaction was carried out at 80 °C. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid to keep the solution slightly neutral. The methanol was removed by rotary evaporation, and the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The mixture was purified by silica gel column chromatography and dried to obtain 278 mg of a pale yellow solid, namely 7-hydroxy-6-(3-methoxyphenyl)-3-phenylthiophene[3,2-b]pyridine-5(4H)-one, with a yield of 51%.

[0230] 1 H NMR (400MHz, DMSO-d6) δ10.64(s,2H),7.93(s,1H),7.72(d,J=7.4Hz,2H),7.47(t,J=7. 4Hz,2H),7.39(t,J=7.3Hz,1H),7.31(t,J=7.8Hz,1H),6.98–6.83(m,3H),3.77(s,3H).

[0231] Example 12

[0232] 7-Hydroxy-6-(3-nitrophenyl)-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0233] Step 1: Synthesis of 2-(3-nitrophenyl)acetyl chloride

[0234] 2-(3-nitrophenyl)acetic acid (6 mmol, 1086 mg) was dissolved in anhydrous DCM, and SOCl2 (9.0 mmol, 653 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the mixture was transferred to 40 °C. After the reaction was monitored by TLC until it was complete, the DCM was evaporated to dryness to obtain 2-(3-nitrophenyl)acetyl chloride, which could be used directly in step 2 without purification.

[0235] Step 2: Synthesis of intermediate methyl 3-(2-(3-nitrophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0236] Methyl 3-amino-4-phenylthiophene-2-carboxylate (4 mmol, 928 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-nitrophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete. The mixture was then quenched with saturated sodium carbonate, extracted three times with ethyl acetate and water, and the organic layers were collected and evaporated to dryness. The mixture was purified by silica gel column chromatography to give 1.4 g of a pale yellow solid, namely methyl 3-(2-(3-nitrophenyl)acetamido)-4-phenylthiophene-2-carboxylate, with a yield of 93%.

[0237] Step 3: Synthesis of the target product 7-hydroxy-6-(3-nitrophenyl)-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0238] Methyl 3-(2-(3-nitrophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid (3.72 mmol, 1.4 g) and potassium carbonate (18.6 mmol, 2.6 g) were dissolved in 16 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 16 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral. After filtration, 1.2 g of a yellow solid, namely 7-hydroxy-6-(3-nitrophenyl)-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, was obtained, with a yield of 93%.

[0239] 1H NMR(400MHz,DMSO-d6)δ11.12(s,2H),8.36–8.27(m,1H),8.15(ddd,J=8.3,2.3,0.9Hz,1H), 7.97(s,1H),7.94–7.88(m,1H),7.72–7.62(m,3H),7.48(t,J=7.4Hz,2H),7.44–7.35(m,1H).

[0240] Example 13

[0241] 7-Hydroxy-3-phenyl-6-(pyridin-4-yl)thieno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0242] Step 1: Synthesis of intermediate methyl 4-phenyl-3-(2-(pyridin-4-yl)acetamido)thiophene-2-carboxylic acid

[0243] 2-(pyridin-4-yl)acetic acid (2.4 mmol, 329 mg) was dissolved in anhydrous DCM, and N,N-diisopropylethylamine (12 mmol, 1.5 g), methyl 3-amino-4-phenylthiophene-2-carboxylate (2 mmol, 466 mg), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.4 mmol, 912 mg) were added sequentially. The reaction was carried out at room temperature. After the reaction was completed by TLC, the solvent was evaporated and purified by silica gel column chromatography to give 161 mg of white solid, namely methyl 4-phenyl-3-(2-(pyridin-4-yl)acetamido)thiophene-2-carboxylate, in 23% yield.

[0244] Step 2: Synthesis of the target compound 7-hydroxy-3-phenyl-6-(pyridin-4-yl)thieno[3,2-b]pyridin-5(4H)-one

[0245] Methyl 4-phenyl-3-(2-(pyridin-4-yl)acetamido)thiophene-2-carboxylic acid (0.2 mmol, 70 mg) and potassium carbonate (1 mmol, 138 mg) were dissolved in 2 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 2 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral and filtered to obtain 34 mg of a light green solid, namely 7-hydroxy-3-phenyl-6-(pyridin-4-yl)thieno[3,2-b]pyridin-5(4H)-one, with a yield of 23%.

[0246] 1H NMR (400MHz, DMSO-d6) δ8.76–8.68(m,2H),8.48(d,J=6.4Hz,2H),8.01(s,1H),7.58(d,J=6.9Hz,2H),7.52–7.45(m,2H),7.45–7.38(m,1H).

[0247] Example 14

[0248] 6-(3-fluorophenyl)-7-hydroxy-3-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0249] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0250] 2-(3-fluorophenyl)acetic acid (3 mmol, 462 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 324.6 μL) was slowly added. Then, 4 drops of DMF were added. After the addition was complete, the mixture was transferred to 40 °C. The reaction was monitored by TLC until it was complete. The DCM was then evaporated to dryness to obtain 2-(3-fluorophenyl)acetyl chloride, which can be used directly in step 3 without purification.

[0251] Step 2: Synthesis of intermediate methyl 3-amino-4-(2-tolyl)thiophene-2-carboxylic acid

[0252] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), 2-tolylboronic acid (3 mmol, 405 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a 1,4-dioxane:methanol:water mixture (5 mL:2 mL:2 mL). Under N2 protection, the mixture was refluxed at 90 °C. After the reaction was complete as monitored by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 485 mg of colorless liquid, namely methyl 3-amino-4-(2-tolyl)thiophene-2-carboxylate, with a yield of 98%.

[0253] Step 3: Synthesis of methyl 3-(2-(3-fluorophenyl)acetamido)-4-(2-tolyl)thiophene-2-carboxylic acid

[0254] Methyl 3-amino-4-(2-tolyl)thiophene-2-carboxylate (1.96 mmol, 485 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-fluorophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. After the reaction was monitored by TLC until complete, the reaction was quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The mixture was purified by silica gel column chromatography to give 664 mg of brown oily liquid, namely methyl 3-(2-(3-fluorophenyl)acetamido)-4-(2-tolyl)thiophene-2-carboxylate, with a yield of 79%.

[0255] Step 4: Synthesis of the target product 6-(3-fluorophenyl)-7-hydroxy-3-(o-tolyl)thieno[3,2-b]pyridine-5(4H)-one

[0256] Methyl 3-(2-(3-fluorophenyl)acetamido)-4-(2-tolyl)thiophene-2-carboxylic acid (1.58 mmol, 664 mg) and K2CO3 (7.92 mmol, 1.1 g) were dissolved in 6 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral. After filtration, 209 mg of a brown solid, namely 6-(3-fluorophenyl)-7-hydroxy-3-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one, was obtained, with a yield of 37%.

[0257] 1 H NMR (400MHz, DMSO-d6) δ10.95 (s, 2H), 7.73 (s, 1H), 7.41 (td, J = 8.0, 6.3Hz, 1H), 7.35–7.28(m,2H),7.28–7.16(m,4H),7.11(td,J=8.7,2.7Hz,1H),2.14(s,3H).

[0258] Example 15

[0259] 6-(3-fluorophenyl)-7-hydroxy-3-(m-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0260] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0261] 2-(3-fluorophenyl)acetic acid (3 mmol, 462 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 324.6 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the solution was transferred to 40 °C. After the reaction was monitored by TLC until it was complete, the DCM was evaporated to dryness to obtain 2-(3-fluorophenyl)acetyl chloride, which can be used directly in step 3 without purification.

[0262] Step 2: Synthesis of intermediate methyl 3-amino-4-(m-Tolyl)thiophene-2-carboxylic acid

[0263] Methyl 3-amino-4-bromothiophene-2-carboxylic acid (2 mmol, 472 mg), 3-tolueneboronic acid (2.6 mmol, 353 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a toluene:methanol:water mixture (7.5 mL:5 mL:0.75 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The residue was purified by silica gel column chromatography to give 471 mg of a light blue oily liquid, namely methyl 3-amino-4-(m-toluyl)thiophene-2-carboxylic acid, with a yield of 95%.

[0264] Step 3: Synthesis of intermediate methyl 3-(2-(3-fluorophenyl)acetamido)-4-(m-tolyl)thiophene-2-carboxylic acid ester

[0265] Methyl 3-amino-4-(3-tolyl)thiophene-2-carboxylic acid (1.9 mmol, 471 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-fluorophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. After the reaction was monitored by TLC until complete, the reaction was quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The mixture was purified by silica gel column chromatography to give 722 mg of orange oily liquid, namely methyl 3-(2-(3-fluorophenyl)acetamido)-4-(m-tolyl)thiophene-2-carboxylic acid, with a yield of 99%.

[0266] Step 4: Synthesis of the target product 6-(3-fluorophenyl)-7-hydroxy-3-(m-tolyl)thiopheno[3,2-b]pyridine-5(4H)-one

[0267] Methyl 3-(2-(3-fluorophenyl)acetamido)-4-(m-tolyl)thiophene-2-carboxylic acid (1.88 mmol, 722 mg) and potassium carbonate (10 mmol, 1.38 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral and filtered to obtain 454 mg of a white solid, namely 6-(3-fluorophenyl)-7-hydroxy-3-(m-tolyl)thiophene[3,2-b]pyridin-5(4H)-one, with a yield of 68%.

[0268] 1 H NMR(400MHz,DMSO-d6)δ10.87(s,2H),7.90(s,1H),7.49–7.39(m,3H),7.35( t,J=7.5Hz,1H),7.26–7.17(m,3H),7.13(td,J=8.7,2.7Hz,1H),2.38(s,3H).

[0269] Example 16

[0270] 6-(3-fluorophenyl)-7-hydroxy-3-(p-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0271] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0272] 2-(3-fluorophenyl)acetic acid (3 mmol, 462 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 324.6 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the solution was transferred to 40 °C. After the reaction was monitored by TLC until it was complete, the DCM was evaporated to dryness to obtain 2-(3-fluorophenyl)acetyl chloride, which can be used directly in step 3 without purification.

[0273] Step 2: Synthesis of intermediate methyl 3-amino-4-(4-tolyl)thiophene-2-carboxylate

[0274] Methyl 3-amino-4-bromothiophene-2-carboxylic acid (2 mmol, 472 mg), 4-tolylboronic acid (3 mmol, 405 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a 1,4-dioxane:methanol:water mixture (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The residue was purified by silica gel column chromatography to give 484 mg of colorless liquid, namely methyl 3-amino-4-(4-tolyl)thiophene-2-carboxylic acid, with a yield of 98%.

[0275] Step 3: Synthesis of intermediate methyl 3-(2-(3-fluorophenyl)acetamido)-4-(4-tolyl)thiophene-2-carboxylic acid

[0276] Methyl 3-amino-4-(4-tolyl)thiophene-2-carboxylic acid (1.95 mmol, 484 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-fluorophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. After the reaction was monitored by TLC until complete, the reaction was quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness. The mixture was purified by silica gel column chromatography to give 520 mg of a powdery white solid, namely methyl 3-(2-(3-fluorophenyl)acetamido)-4-(4-tolyl)thiophene-2-carboxylic acid, with a yield of 69%.

[0277] Step 4: Synthesis of the target product 6-(3-fluorophenyl)-7-hydroxy-3-(p-tolyl)thieno[3,2-b]pyridine-5(4H)-one

[0278] Methyl 3-(2-(3-fluorophenyl)acetamido)-4-(4-tolyl)thiophene-2-carboxylic acid (1.35 mmol, 520 mg) and potassium carbonate (6.78 mmol, 936 mg) were dissolved in 8 mL of DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 309 mg of a white solid, namely 6-(3-fluorophenyl)-7-hydroxy-3-(p-tolyl)thieno[3,2-b]pyridin-5(4H)-one, with a yield of 64%.

[0279] 1 H NMR(400MHz,DMSO-d6)δ10.83(s,2H),7.89(s,1H),7.57(d,J=8.0Hz,2H),7.48–7 .39(m,1H),7.30–7.23(m,2H),7.23–7.17(m,2H),7.16–7.08(m,1H),2.36(s,3H).

[0280] Example 17

[0281] 3-(2-fluorophenyl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0282] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0283] 2-(3-fluorophenyl)acetic acid (1.5 mmol, 231 mg) was dissolved in anhydrous DCM, and SOCl2 (2.25 mmol, 163 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the mixture was transferred to 40 °C. After the reaction was monitored by TLC until it was complete, the DCM was evaporated to dryness to obtain 2-(3-fluorophenyl)acetyl chloride, which can be used directly in step 2 without purification.

[0284] Step 2: Synthesis of intermediate methyl 4-(2-fluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0285] Methyl 3-amino-4-bromothiophene-2-carboxylate (1 mmol, 236 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-fluorophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete. The reaction was then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 335 mg of orange-red solid, namely methyl 4-bromo-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylate, with a yield of 90%.

[0286] Step 3: Synthesis of intermediate methyl 4-(2-fluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0287] Methyl 4-bromo-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylate (1.5 mmol, 559 mg), o-fluorophenylboronic acid (2.25 mmol, 315 mg), potassium carbonate (6 mmol, 828 mg), and tetra(triphenylphosphine)palladium (0.15 mmol, 173 mg) were dissolved in a mixture of toluene:methanol:water (7.5 mL:5 mL:0.75 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 181 mg of a yellow oily liquid, namely methyl 4-(2-fluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylate, in 25% yield.

[0288] Step 4: Synthesis of the target product 3-(2-fluorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one

[0289] Methyl 4-(2-fluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid (0.45 mmol, 176 mg) and potassium carbonate (2.27 mmol, 313 mg) were dissolved in 3 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 3 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral and filtered to obtain 81 mg of a yellow solid, namely 3-(2-fluorophenyl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, with a yield of 50%.

[0290] 1 H NMR (400MHz, DMSO-d6) δ7.91(s,1H),7.55–7.44(m,2H),7.44–7.37(m,1H),7.34–7.26(m,2H),7.25–7.16(m,2H),7.16–7.08(m,1H).

[0291] Example 18

[0292] 3,6-Bis(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one was synthesized via the following route:

[0293] Step 1: Synthesis of intermediate methyl 4-(3-fluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0294] Methyl 4-bromo-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylate (0.9 mmol, 335 mg), m-fluorophenylboronic acid (1.35 mmol, 189 mg), potassium carbonate (3.6 mmol, 497 mg), and tetra(triphenylphosphine)palladium (0.09 mmol, 104 mg) were dissolved in a mixture of toluene:methanol:water (7.5 mL:5 mL:0.75 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 252 mg of a yellow oily liquid, namely methyl 4-(3-fluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylate, with a yield of 72%.

[0295] Step 2: Synthesis of the target product 3,6-bis(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one

[0296] Methyl 4-(3-fluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid (0.63 mmol, 247 mg) and potassium carbonate (3.18 mmol, 439 mg) were dissolved in 3 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 3 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral and filtered to give 94.6 mg of orange solid, namely 3,6-bis(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, with a yield of 42%.

[0297] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,2H),8.08(s,1H),7.65(d,J=9.9Hz,1H),7.58(d,J=7.6Hz ,1H),7.53–7.46(m,2H),7.43(dd,J=7.9,6.5Hz,1H),7.25–7.17(m,3H),7.16–7.10(m,1H).

[0298] Example 19

[0299] 6-(3-fluorophenyl)-3-(4-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0300] Step 1: Synthesis of intermediate methyl 4-(4-fluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0301] Methyl 4-bromo-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylate (2 mmol, 744 mg), p-fluorophenylboronic acid (3 mmol, 420 mg), potassium carbonate (8 mmol, 1.1 g), and tetra(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a toluene:methanol:water mixture (7.5 mL:5 mL:0.75 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 199 mg of a yellowish-white solid, namely methyl 4-(4-fluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylate, in 25% yield.

[0302] Step 2: Synthesis of the target product 6-(3-fluorophenyl)-3-(4-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one

[0303] Methyl 4-(4-fluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid (0.5 mmol, 194 mg) and potassium carbonate (2.5 mmol, 345 mg) were dissolved in 4 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 4 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral and filtered to obtain 115 mg of a yellow solid, namely 6-(3-fluorophenyl)-3-(4-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, with a yield of 64%.

[0304] 1 H NMR(400MHz,DMSO-d6)δ10.95(s,1H),7.95(s,1H),7.74(dd,J=8.0,5.8Hz,2H),7 .42(q,J=7.8Hz,1H),7.28(t,J=8.8Hz,2H),7.25–7.16(m,2H),7.16–7.07(m,1H).

[0305] Example 20

[0306] 3-(4-chlorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0307] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0308] 2-(3-fluorophenyl)acetic acid (3 mmol, 462 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 324.6 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the mixture was transferred to 40 °C. After the reaction was monitored by TLC until it was complete, the DCM was evaporated to dryness to obtain 2-(3-fluorophenyl)acetyl chloride, which can be used directly in the next step of the reaction without purification.

[0309] Step 2: Synthesis of intermediate methyl 3-amino-4-(4-chlorophenyl)thiophene-2-carboxylic acid

[0310] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), (4-chlorophenyl)boronic acid (2.5 mmol, 389 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC monitoring, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 470 mg of colorless liquid, namely methyl 3-amino-4-(4-chlorophenyl)thiophene-2-carboxylate, with a yield of 88%.

[0311] Step 3: Synthesis of intermediate methyl 4-(4-chlorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0312] Methyl 3-amino-4-(4-chlorophenyl)thiophene-2-carboxylate (1.76 mmol, 470 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-fluorophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete. The reaction was quenched with saturated sodium carbonate, and the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 536 mg of pink solid, namely methyl 4-(4-chlorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylate, with a yield of 75.6%.

[0313] Step 4: Synthesis of the target product 3-(4-chlorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one

[0314] Methyl 4-(4-chlorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid (1.31 mmol, 531 mg) and potassium carbonate (6.59 mmol, 910 mg) were dissolved in 6 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 224 mg of a white solid, namely 3-(4-chlorophenyl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, with a yield of 46%.

[0315] 1 H NMR(400MHz,DMSO-d6)δ10.94(s,2H),8.01(s,1H),7.75(d,J=8.2Hz,2H),7.60– 7.49(m,2H),7.43(td,J=8.0,6.3Hz,1H),7.25–7.17(m,2H),7.16–7.10(m,1H).

[0316] Example 21

[0317] 6-(3-fluorophenyl)-7-hydroxy-3-(4-methoxyphenyl)thiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0318] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0319] 2-(3-fluorophenyl)acetic acid (3 mmol, 462 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 324.6 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the solution was transferred to 40 °C. After the reaction was monitored by TLC until it was complete, the DCM was evaporated to dryness to obtain 2-(3-fluorophenyl)acetyl chloride, which can be used directly in step 3 without purification.

[0320] Step 2: Synthesis of intermediate methyl 3-amino-4-(4-methoxyphenyl)thiophene-2-carboxylic acid

[0321] Methyl 3-amino-4-bromothiophene-2-carboxylic acid (2 mmol, 472 mg), (4-methoxyphenyl)boronic acid (3 mmol, 457 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC monitoring, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 524 mg of white solid, namely methyl 3-amino-4-(4-methoxyphenyl)thiophene-2-carboxylic acid, with a yield of 99%.

[0322] Step 3: Synthesis of intermediate methyl 3-(2-(3-fluorophenyl)acetamido)-4-(4-methoxyphenyl)thiophene-2-carboxylic acid

[0323] Methyl 3-amino-4-(4-methoxyphenyl)thiophene-2-carboxylate (1.99 mmol, 524 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-fluorophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete. The reaction was quenched with saturated sodium carbonate, and the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 554 mg of white solid, namely methyl 3-(2-(3-fluorophenyl)acetamido)-4-(4-methoxyphenyl)thiophene-2-carboxylate, with a yield of 69%.

[0324] Step 4: Synthesis of the target product 6-(3-fluorophenyl)-7-hydroxy-3-(4-methoxyphenyl)thiopheno[3,2-b]pyridine-5(4H)-one

[0325] Methyl 3-(2-(3-fluorophenyl)acetamido)-4-(4-methoxyphenyl)thiophene-2-carboxylic acid (1.38 mmol, 554 mg) and potassium carbonate (6.94 mmol, 958 mg) were dissolved in 6 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral and filtered to obtain 420 mg of a white solid, namely 6-(3-fluorophenyl)-7-hydroxy-3-(4-methoxyphenyl)thiopheno[3,2-b]pyridine-5(4H)-one, with a yield of 83%.

[0326] 1 H NMR (400MHz, DMSO-d6) δ10.81(s,2H),7.85(s,1H),7.62(d,J=8.4Hz,2H),7.43(td,J= 8.0,6.4Hz,1H),7.26–7.16(m,2H),7.16–7.09(m,1H),7.06–6.98(m,2H),3.80(s,3H).

[0327] Example 22

[0328] 6-(3-fluorophenyl)-7-hydroxy-3-(thiophen-2-yl)thiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0329] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0330] 2-(3-fluorophenyl)acetic acid (3 mmol, 462 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 324.6 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the solution was transferred to 40 °C. After the reaction was monitored by TLC until it was complete, the DCM was evaporated to dryness to obtain 2-(3-fluorophenyl)acetyl chloride, which can be used directly in step 3 without purification.

[0331] Step 2: Synthesis of intermediate methyl 4'-amino-[2,3'-bisthiophene]-5'-carboxylic acid

[0332] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), thiophene-2-ylboronic acid (3 mmol, 384 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC monitoring, ethyl acetate and water were added and extracted three times. The organic layers were collected and purified by silica gel column chromatography to give 460 mg of a pale yellow solid, namely methyl 4'-amino-[2,3'-bisthiophene]-5'-carboxylate, with a yield of 96%.

[0333] Step 3: Synthesis of intermediate 4'-(2-(3-fluorophenyl)acetamido)-[2,3'-bisthiophene]-5'-carboxylic acid methyl ester

[0334] 4'-Amino-[2,3'-bisthiophene]-5'-carboxylic acid methyl ester (1.92 mmol, 460 mg) was dissolved in anhydrous 1,4-dioxane, and the above-mentioned 2-(3-fluorophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C, and the reaction was monitored by TLC until it was complete. The reaction was then quenched with saturated sodium carbonate, and extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 540 mg of white solid, namely 4'-(2-(3-fluorophenyl)acetamido)-[2,3'-bisthiophene]-5'-carboxylic acid methyl ester, with a yield of 75%.

[0335] Step 4: Synthesis of the target product 6-(3-fluorophenyl)-7-hydroxy-3-(thiophen-2-yl)thiopheno[3,2-b]pyridin-5(4H)-one

[0336] Methyl 4'-(2-(3-fluorophenyl)acetamido)-[2,3'-bisthiophene]-5'-carboxylic acid (1.43 mmol, 540 mg) and potassium carbonate (7.2 mmol, 993 mg) were dissolved in 6 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral and filtered to obtain 224 mg of white solid, namely 6-(3-fluorophenyl)-7-hydroxy-3-(thiophene-2-yl)thieno[3,2-b]pyridin-5(4H)-one, with a yield of 45%.

[0337] 1 H NMR (400MHz, DMSO-d6) δ8.06(s,1H),7.80(d,J=3.6,1H),7.57(dd,J=5.1,1.2Hz,1H),7.48–7.40(m,1H),7.27–7.18(m,2H),7.18–7.09(m,2H).

[0338] Example 23

[0339] 3-(2,3-difluorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0340] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0341] 2-(3-fluorophenyl)acetic acid (3 mmol, 462 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 324.6 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the reaction solution was transferred to 40 °C for reaction. After the reaction was complete as monitored by TLC, the DCM was evaporated to dryness to obtain 2-(3-fluorophenyl)acetyl chloride, which can be used directly in step 3 without purification.

[0342] Step 2: Synthesis of intermediate methyl 3-amino-4-(3,4-difluorophenyl)thiophene-2-carboxylate

[0343] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), (3,4-difluorophenyl)boronic acid (3 mmol, 473 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under nitrogen protection and refluxed at 90 °C. After the reaction was completed by TLC, ethyl acetate and water were added and extracted three times. The organic layers were collected and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 509 mg of white solid, namely methyl 3-amino-4-(3,4-difluorophenyl)thiophene-2-carboxylate, with a yield of 94%.

[0344] Step 3: Synthesis of intermediate methyl 4-(3,4-difluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0345] Methyl 3-amino-4-(3,4-difluorophenyl)thiophene-2-carboxylate (1.89 mmol, 509 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-fluorophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete. The reaction was quenched with saturated sodium carbonate, and the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 734 mg of white solid, namely methyl 4-(3,4-difluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylate, with a yield of 95%.

[0346] Step 4: Synthesis of the target product 3-(2,3-difluorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one

[0347] Methyl 4-(3,4-difluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid (1.81 mmol, 734 mg) and potassium carbonate (9.05 mmol, 1.25 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral and filtered to obtain 620 mg of white solid, namely 3-(2,3-difluorophenyl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, with a yield of 91%.

[0348] 1 H NMR (400MHz, DMSO-d6) δ8.07(s,1H),7.98–7.85(m,1H),7.58(s,1H),7.55–7.49(m,1H),7.48–7.39(m,1H),7.25–7.17(m,2H),7.17–7.10(m,1H).

[0349] Example 24

[0350] 3-(2,5-dichlorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0351] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0352] 2-(3-fluorophenyl)acetic acid (3 mmol, 462 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 324.6 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the solution was transferred to 40 °C. After the reaction was monitored by TLC until it was complete, the DCM was evaporated to dryness to obtain 2-(3-fluorophenyl)acetyl chloride, which can be used directly in step 3 without purification.

[0353] Step 2: Synthesis of intermediate methyl 3-amino-4-(2,5-dichlorophenyl)thiophene-2-carboxylate

[0354] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), (2,5-dichlorophenyl)boronic acid (2 mmol, 392 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC monitoring, ethyl acetate and water were added for extraction three times. The organic layers were collected and purified by silica gel column chromatography to give 506 mg of colorless and transparent liquid, namely methyl 3-amino-4-(2,5-dichlorophenyl)thiophene-2-carboxylate, with a yield of 83%.

[0355] Step 3: Synthesis of intermediate methyl 4-(2,5-dichlorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0356] Methyl 3-amino-4-(2,5-dichlorophenyl)thiophene-2-carboxylate (1.67 mmol, 506 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-fluorophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete. The reaction was quenched with saturated sodium carbonate, and the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 719 mg of yellow oily liquid, namely methyl 4-(2,5-dichlorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylate, with a yield of 98%.

[0357] Step 4: Synthesis of the target product 3-(2,5-dichlorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one

[0358] Methyl 4-(2,5-dichlorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid (1.64 mmol, 719 mg) and potassium carbonate (8.35 mmol, 1.1 g) were dissolved in 6 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral and filtered to give 278 mg of a white solid, namely 3-(2,5-dichlorophenyl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, with a yield of 41%.

[0359] 1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),10.81(s,1H),7.91(s,1H),7.62–7.57(m,1H), 7.54–7.49(m,2H),7.45–7.37(m,1H),7.24–7.16(m,2H),7.12(td,J=8.7,2.7Hz,1H).

[0360] Example 25

[0361] 3-(4-fluoro-2-methylphenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0362] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0363] 2-(3-fluorophenyl)acetic acid (3 mmol, 462 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 324.6 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the mixture was transferred to 40 °C. After the reaction was monitored by TLC until it was complete, the DCM was evaporated to dryness to obtain 2-(3-fluorophenyl)acetyl chloride, which can be used directly in the next step of the reaction without purification.

[0364] Step 2: Synthesis of intermediate methyl 3-amino-4-(4-fluoro-2-methylphenyl)thiophene-2-carboxylate

[0365] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), (4-fluoro-2-methylphenyl)boronic acid (3 mmol, 473 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC monitoring, ethyl acetate and water were added for extraction three times. The organic layers were collected and purified by silica gel column chromatography to give 533 mg of colorless liquid, namely methyl 3-amino-4-(4-fluoro-2-methylphenyl)thiophene-2-carboxylate, with a yield of 100%.

[0366] Step 3: Synthesis of intermediate methyl 4-(4-fluoro-2-methylphenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0367] Methyl 3-amino-4-(4-fluoro-2-methylphenyl)thiophene-2-carboxylate (2 mmol, 533 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-fluorophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete. The reaction was quenched with saturated sodium carbonate, and extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 763 mg of orange oily liquid, namely methyl 4-(4-fluoro-2-methylphenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylate, with a yield of 98%.

[0368] Step 4: Synthesis of the target product 3-(4-fluoro-2-methylphenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one

[0369] Methyl 4-(4-fluoro-2-methylphenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid (1.90 mmol, 763 mg) and potassium carbonate (9.50 mmol, 1.31 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral and filtered to obtain 393 mg of a pale yellow solid, namely 3-(4-fluoro-2-methylphenyl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, with a yield of 56%.

[0370] 1 H NMR (400MHz, DMSO-d6) δ7.73 (s, 1H), 7.41 (q, J = 7.9Hz, 1H), 7.28–7.14 (m, 4H), 7.14–7.03 (m, 2H), 2.13 (s, 3H).

[0371] Example 26

[0372] 3-(benzothiophene-2-yl)-6-(3-fluorophenyl)-7-hydroxythiophene[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0373] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0374] 2-(3-fluorophenyl)acetic acid (3 mmol, 462 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 324 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the solution was transferred to 40 °C. After the reaction was monitored by TLC until it was complete, the DCM was evaporated to dryness to obtain 2-(3-fluorophenyl)acetyl chloride, which can be used directly in step 3 without purification.

[0375] Step 2: Synthesis of intermediate methyl 3-amino-4-(benzothiophene-3-yl)thiophene-2-carboxylate

[0376] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), benzothiophene-3-ylboronic acid (2.5 mmol, 445 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC monitoring, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 560 mg of white solid, namely methyl 3-amino-4-(benzothiophene-3-yl)thiophene-2-carboxylate, with a yield of 96%.

[0377] Step 3: Synthesis of intermediate 4-(benzothiophene-3-yl)-3-(2-(3-fluorophenyl)acetamyl)thiophene-2-carboxylic acid methyl ester

[0378] Methyl 3-amino-4-(benzothiophen-3-yl)thiophen-2-carboxylate (1.93 mmol, 560 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-fluorophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete. The reaction was then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 697 mg of white solid, namely methyl 4-(benzothiophen-3-yl)-3-(2-(3-fluorophenyl)acetamyl)thiophen-2-carboxylate, with a yield of 84%.

[0379] Step 4: Synthesis of the target product 3-(benzothiophene-2-yl)-6-(3-fluorophenyl)-7-hydroxythiophene[3,2-b]pyridine-5(4H)-one

[0380] Methyl 4-(benzothiophene-3-yl)-3-(2-(3-fluorophenyl)acetamyl)thiophene-2-carboxylic acid (1.63 mmol, 697 mg) and potassium carbonate (8.19 mmol, 1.1 g) were dissolved in 6 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid until a solid precipitated. The solution was kept slightly neutral and filtered to obtain 470 mg of white solid, namely 3-(benzothiophene-2-yl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, with a yield of 73%.

[0381] 1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.88(s,1H),8.12–8.05(m,1H),8.01(s,1H),7.96(s ,1H),7.69–7.60(m,1H),7.48–7.38(m,3H),7.27–7.17(m,2H),7.12(td,J=8.7,2.7Hz,1H).

[0382] Example 27

[0383] 6-(3-fluorophenyl)-7-hydroxy-3-(pyridin-3-yl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0384] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0385] 2-(3-fluorophenyl)acetic acid (3 mmol, 462 mg) was dissolved in anhydrous DCM, and SOCl2 (4.5 mmol, 324.6 μL) was slowly added. Then, 4 drops of DMF were added to the reaction solution. After the addition was complete, the solution was transferred to 40 °C. After the reaction was monitored by TLC until it was complete, the DCM was evaporated to dryness to obtain 2-(3-fluorophenyl)acetyl chloride, which can be used directly in step 3 without purification.

[0386] Step 2: Synthesis of intermediate methyl 3-amino-4-(pyridin-3-yl)thiophene-2-carboxylate

[0387] Methyl 3-amino-4-bromothiophene-2-carboxylate (2.5 mmol, 590 mg), pyridin-3-ylboronic acid (3 mmol, 369 mg), potassium carbonate (10 mmol, 1.38 g), and tetrakis(triphenylphosphine)palladium (0.125 mmol, 144 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 590 mg of yellow solid, namely methyl 3-amino-4-(pyridin-3-yl)thiophene-2-carboxylate, in 100% yield.

[0388] Step 3: Synthesis of intermediate methyl 3-(2-(3-fluorophenyl)acetamido)-4-(pyridin-3-yl)thiophene-2-carboxylic acid

[0389] Methyl 3-amino-4-(pyridin-3-yl)thiophene-2-carboxylate (2.50 mmol, 590 mg) was dissolved in anhydrous 1,4-dioxane. The above-mentioned 2-(3-fluorophenyl)acetyl chloride solution was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete. The reaction was then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 802 mg of brown solid, namely methyl 3-(2-(3-fluorophenyl)acetamido)-4-(pyridin-3-yl)thiophene-2-carboxylate, with a yield of 86%.

[0390] Step 4: Synthesis of the target product 6-(3-fluorophenyl)-7-hydroxy-3-(pyridin-3-yl)thieno[3,2-b]pyridin-5(4H)-one. Methyl 3-(2-(3-fluorophenyl)acetamido)-4-(pyridin-3-yl)thieno-2-carboxylic acid ester (2.14 mmol, 797 mg) and potassium carbonate (10.73 mmol, 1.48 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, it was cooled to room temperature, 8 mL methanol was added, and then 1 mol / L hydrochloric acid was added until a solid precipitated. The solution was kept slightly neutral. Filtering yielded 499 mg of white solid, namely 6-(3-fluorophenyl)-7-hydroxy-3-(pyridin-3-yl)thieno[3,2-b]pyridin-5(4H)-one, with a yield of 70%.

[0391] 1 H NMR (400MHz, DMSO-d6) δ10.86 (s, 2H), 8.98 (s, 1H), 8.58 (dd, J = 4.8, 1.5Hz, 1H), 8.19 (d, J=7.8Hz,1H),8.12(s,1H),7.49(dd,J=7.8,4.8Hz,1H),7.44–7.35(m,4H),7.34–7.25(m 1H).

[0392] Example 28

[0393] 7-Hydroxy-6-phenyl-3-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0394] Step 1: Synthesis of intermediate methyl 3-amino-4-(2-tolyl)thiophene-2-carboxylate

[0395] Methyl 3-amino-4-bromothiophene-2-carboxylic acid (2 mmol, 472 mg), 2-tolylboronic acid (3 mmol, 405 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 487 mg of colorless liquid, namely methyl 3-amino-4-(2-tolyl)thiophene-2-carboxylic acid, with a yield of 98%.

[0396] Step 2: Synthesis of intermediate methyl 3-(2-phenylacetamido)-4-(2-tolyl)thiophene-2-carboxylic acid

[0397] Methyl 3-amino-4-(2-tolyl)thiophene-2-carboxylate (1.9 mmol, 487 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (2.57 mmol, 340 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C, and the reaction was monitored by TLC until it was complete. The reaction was then quenched with saturated sodium carbonate, extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 701 mg of a colorless oily liquid, namely methyl 3-(2-phenylacetamido)-4-(2-tolyl)thiophene-2-carboxylate, with a yield of 96%.

[0398] Step 3: Synthesis of the target product 7-hydroxy-6-phenyl-3-(o-tolyl)thieno[3,2-b]pyridine-5(4H)-one

[0399] Methyl 3-(2-phenylacetamido)-4-(2-tolyl)thiophene-2-carboxylic acid (1.92 mmol, 701 mg) and potassium carbonate (9.62 mmol, 1.32 g) were dissolved in 6 mL of DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 402 mg of a yellow solid, namely 7-hydroxy-6-phenyl-3-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one, with a yield of 62%.

[0400] 1 H NMR (400MHz, DMSO-d6) δ10.74(s,2H),7.70(s,1H),7.41–7.35(m,4H),7.33–7.30(m,2H),7.30–7.26(m,1H),7.26–7.20(m,2H),2.16(s,3H).

[0401] Example 29

[0402] 7-Hydroxy-6-phenyl-3-(m-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0403] Step 1: Synthesis of intermediate methyl 3-amino-4-(3-tolyl)thiophene-2-carboxylate

[0404] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), m-tolueneboronic acid (2.4 mmol, 326 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixture of toluene:methanol:water (7.5 mL:5 mL:0.75 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 523 mg of white solid, namely methyl 3-amino-4-(3-tolyl)thiophene-2-carboxylate, with a yield of 98%.

[0405] Step 2: Synthesis of intermediate methyl 3-(2-phenylacetamido)-4-(3-tolyl)thiophene-2-carboxylic acid

[0406] Methyl 3-amino-4-(3-tolyl)thiophene-2-carboxylate (1.97 mmol, 523 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (3 mmol, 396.7 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete, and then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 608 mg of a colorless oily liquid, namely methyl 3-(2-phenylacetamido)-4-(3-tolyl)thiophene-2-carboxylate, with a yield of 80%.

[0407] Step 3: Synthesis of the target product 7-hydroxy-6-phenyl-3-(m-tolyl)thieno[3,2-b]pyridine-5(4H)-one

[0408] Methyl 3-(2-phenylacetamido)-4-(3-tolyl)thiophene-2-carboxylic acid (1.56 mmol, 599 mg) and potassium carbonate (7.81 mmol, 1.07 g) were dissolved in 6 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 248 mg of a white solid, namely 7-hydroxy-6-phenyl-3-(m-tolyl)thieno[3,2-b]pyridine-5(4H)-one, with a yield of 47%.

[0409] 1H NMR (400MHz, DMSO-d6) δ10.81(s,2H),8.01(s,1H),7.59(d,J=7.4Hz,2H),7.54–7.46(m,5H),7.45–7.39(m,1H),7.35–7.29(m,1H),2.50(s,3H).

[0410] Example 30

[0411] 7-Hydroxy-6-phenyl-3-(p-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0412] Step 1: Synthesis of intermediate methyl 3-amino-4-(4-tolyl)thiophene-2-carboxylate

[0413] Methyl 3-amino-4-bromothiophene-2-carboxylic acid (2 mmol, 472 mg), 4-tolylboronic acid (2.5 mmol, 340 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain 488 mg of colorless liquid, namely methyl 3-amino-4-(4-tolyl)thiophene-2-carboxylic acid, with a yield of 98%.

[0414] Step 2: Synthesis of intermediate methyl 3-(2-phenylacetamido)-4-(4-tolyl)thiophene-2-carboxylic acid

[0415] 1.95 mmol (484 mg) of methyl 3-amino-4-(4-tolyl)thiophene-2-carboxylate was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (3 mmol, 396.7 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to a reaction vessel at 90 °C. The reaction was monitored by TLC until it was complete, and then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected and purified by silica gel column chromatography to give 621 mg of white solid, namely methyl 3-(2-phenylacetamido)-4-(4-tolyl)thiophene-2-carboxylate, in 86% yield.

[0416] Step 3: Synthesis of the target product 7-hydroxy-6-phenyl-3-(p-tolyl)thieno[3,2-b]pyridine-5(4H)-one

[0417] Methyl 3-(2-phenylacetamido)-4-(4-tolyl)thiophene-2-carboxylic acid (1.70 mmol, 621 mg) and potassium carbonate (8.5 mmol, 1.17 mg) were dissolved in 8 mL of DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 309 mg of a yellow solid, namely 7-hydroxy-6-phenyl-3-(p-tolyl)thieno[3,2-b]pyridin-5(4H)-one, with a yield of 54%.

[0418] 1 H NMR (400MHz, DMSO-d6) δ10.69(s,2H),7.87(s,1H),7.59(d,J=7.9Hz,2H),7.43 –7.35(m,4H),7.30(td,J=6.1,2.5Hz,1H),7.25(d,J=8.0Hz,2H),2.35(s,3H).

[0419] Example 31

[0420] 3-(2-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0421] Step 1: Synthesis of intermediate methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate

[0422] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), o-fluorophenylboronic acid (3 mmol, 417 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 499 mg of a pale yellow oily liquid, namely methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate, with a yield of 99%.

[0423] Step 2: Synthesis of intermediate methyl 4-(2-fluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0424] Methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (1.99 mmol, 499 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (2.6 mmol, 343 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete, and then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 728 mg of a pale yellow oily liquid, namely methyl 4-(2-fluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate, with a yield of 99%.

[0425] Step 3: Synthesis of the target product 3-(2-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0426] Methyl 4-(2-fluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid (1.97 mmol, 728 mg) and potassium carbonate (10 mmol, 1.38 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 461 mg of a white solid, namely 3-(2-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, with a yield of 69%.

[0427] 1 H NMR (400MHz, DMSO-d6) δ7.91(s,1H),7.57–7.50(m,1H),7.50–7.43(m,1H),7.42–7.34(m,4H),7.34–7.26(m,3H).

[0428] Example 32

[0429] 3-(3-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0430] Step 1: Synthesis of intermediate methyl 3-amino-4-(3-fluorophenyl)thiophene-2-carboxylate

[0431] Methyl 3-amino-4-bromothiophene-2-carboxylate (3 mmol, 708 mg), m-fluorophenylboronic acid (3.6 mmol, 503 mg), potassium carbonate (12 mmol, 1.65 g), and tetrakis(triphenylphosphine)palladium (0.15 mmol, 173 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (10 mL:4 mL:4 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 751 mg of white solid, namely methyl 3-amino-4-(3-fluorophenyl)thiophene-2-carboxylate, with a yield of 99%.

[0432] Step 2: Synthesis of intermediate methyl 4-(3-fluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0433] Methyl 3-amino-4-(m-fluorophenyl)thiophene-2-carboxylate (2.98 mmol, 751 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (3.58 mmol, 473 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete, and then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 998 mg of white solid, namely methyl 4-(3-fluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate, with a yield of 90%.

[0434] Step 3: Synthesis of the target product 3-(3-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0435] Methyl 4-(3-fluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid (2.66 mmol, 985 mg) and potassium carbonate (13.3 mmol, 1.84 g) were dissolved in 8 mL of DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 467 mg of a white solid, namely 3-(3-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, with a yield of 52%.

[0436] 1 H NMR (400MHz, DMSO-d6) δ10.73(s,1H),8.08(s,1H),7.70(d,J=10.5Hz,1H),7.62(d,J=7.8Hz ,1H),7.50(td,J=8.0,6.2Hz,1H),7.44–7.35(m,4H),7.35–7.28(m,1H),7.25–7.16(m,1H).

[0437] Example 33

[0438] 3-(4-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0439] Step 1: Synthesis of intermediate methyl 3-amino-4-(4-fluorophenyl)thiophene-2-carboxylate

[0440] Methyl 3-amino-4-bromothiophene-2-carboxylate (3 mmol, 708 mg), p-fluorophenylboronic acid (3.6 mmol, 640 mg), potassium carbonate (12 mmol, 1.65 g), and tetrakis(triphenylphosphine)palladium (0.15 mmol, 173 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (10 mL:4 mL:4 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 749 mg of white solid, namely methyl 3-amino-4-(4-fluorophenyl)thiophene-2-carboxylate, with a yield of 99%.

[0441] Step 2: Synthesis of intermediate methyl 4-(4-fluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate

[0442] Methyl 3-amino-4-(4-fluorophenyl)thiophene-2-carboxylate (2.98 mmol, 749 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (3.88 mmol, 512 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium carbonate, extracted three times with ethyl acetate and water, and the organic layers were collected and purified by silica gel column chromatography to give 1.07 g of white solid, namely methyl 4-(4-fluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate, in 98% yield.

[0443] Step 3: Synthesis of the target product 3-(4-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0444] Methyl 4-(4-fluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid (2.91 mmol, 1.07 g) and potassium carbonate (14.6 mmol, 2.01 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to give 651 mg of a white solid, namely 3-(4-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, with a yield of 66%.

[0445] 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H),7.94(s,1H),7.83–7.66(m,2H),7.43–7.35(m,4H),7.33–7.24(m,3H).

[0446] Example 34

[0447] 3-(2-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0448] Step 1: Synthesis of intermediate methyl 3-amino-4-(2-chlorophenyl)thiophene-2-carboxylic acid

[0449] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), (2-chlorophenyl)boronic acid (2.6 mmol, 407 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 520 mg of white solid, namely methyl 3-amino-4-(2-chlorophenyl)thiophene-2-carboxylate, with a yield of 97%.

[0450] Step 2: Synthesis of intermediate methyl 4-(2-chlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0451] Methyl 3-amino-4-(2-chlorophenyl)thiophene-2-carboxylate (1.94 mmol, 520 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (2.53 mmol, 391 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C for reaction. After the reaction was monitored by TLC until complete, saturated sodium carbonate was added to quench the reaction. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 707 mg of white solid, namely methyl 4-(2-chlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate, with a yield of 94%.

[0452] Step 3: Synthesis of the target product 3-(2-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0453] Methyl 4-(2-chlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid (1.81 mmol, 700 mg) and potassium carbonate (9.09 mmol, 1.2 g) were dissolved in 6 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 394 mg of a white solid, namely 3-(2-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, with a yield of 61%.

[0454] 1 H NMR (400MHz, DMSO-d6) δ7.81 (s, 1H), 7.56 (dt, J = 7.5, 1.2Hz, 1H), 7.48–7.40 (m, 3H), 7.40–7.33 (m, 4H), 7.31–7.26 (m, 1H).

[0455] Example 35

[0456] 3-(3-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0457] Step 1: Synthesis of intermediate methyl 3-amino-4-(3-chlorophenyl)thiophene-2-carboxylic acid

[0458] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), (3-chlorophenyl)boronic acid (2.6 mmol, 407 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 515 mg of white solid, namely methyl 3-amino-4-(3-chlorophenyl)thiophene-2-carboxylate, with a yield of 96%.

[0459] Step 2: Synthesis of intermediate methyl 4-(3-chlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0460] Methyl 3-amino-4-(3-chlorophenyl)thiophene-2-carboxylate (1.94 mmol, 520 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (2.53 mmol, 391 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete, and then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 641 mg of a colorless oily liquid, namely methyl 4-(3-chlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate, with a yield of 86%.

[0461] Step 3: Synthesis of the target product 3-(3-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0462] Methyl 4-(3-chlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid (1.66 mmol, 641 mg) and potassium carbonate (8.32 mmol, 1.1 g) were dissolved in 6 mL of DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 339 mg of a white solid, namely 3-(3-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, with a yield of 57%.

[0463] 1 H NMR (400MHz, DMSO-d6) δ8.06 (s, 1H), 7.82 (s, 1H), 7.72 (d, J = 7.5Hz, 1H), 7.48 (t, J=7.8Hz,1H),7.43(dt,J=6.8,1.3Hz,1H),7.41–7.35(m,4H),7.34–7.28(m,1H).

[0464] Example 36

[0465] 3-(4-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0466] Step 1: Synthesis of intermediate methyl 3-amino-4-(4-chlorophenyl)thiophene-2-carboxylate

[0467] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), (4-chlorophenyl)boronic acid (2.5 mmol, 389 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 530 mg of white solid, namely methyl 3-amino-4-(4-chlorophenyl)thiophene-2-carboxylate, with a yield of 99%.

[0468] Step 2: Synthesis of intermediate methyl 4-(4-chlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0469] Methyl 3-amino-4-(4-chlorophenyl)thiophene-2-carboxylate (1.76 mmol, 470 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (3 mmol, 396 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C for reaction. After the reaction was monitored by TLC until complete, saturated sodium carbonate was added to quench the reaction. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 770 mg of white solid, namely methyl 4-(4-chlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate, with a yield of 99%.

[0470] Step 3: Synthesis of the target product 3-(4-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0471] Methyl 4-(4-chlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid (1.99 mmol, 770 mg) and potassium carbonate (10 mmol, 1.4 g) were dissolved in 6 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 396 mg of a white solid, namely 3-(4-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, with a yield of 56%.

[0472] 1 H NMR (400MHz, DMSO-d6) δ10.76(s,2H),8.00(s,1H),7.79(d,J=8.3Hz,2H),7.54–7.48(m,2H),7.44–7.35(m,4H),7.34–7.28(m,1H).

[0473] Example 37

[0474] 7-Hydroxy-3-(4-methoxyphenyl)-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0475] Step 1: Synthesis of intermediate methyl 3-amino-4-(4-methoxyphenyl)thiophene-2-carboxylic acid

[0476] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), (4-methoxyphenyl)boronic acid (2.5 mmol, 400 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 513 mg of white solid, namely methyl 3-amino-4-(4-methoxyphenyl)thiophene-2-carboxylate, with a yield of 97%.

[0477] Step 2: Synthesis of intermediate methyl 4-(4-methoxyphenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0478] Methyl 3-amino-4-(4-methoxyphenyl)thiophene-2-carboxylate (1.95 mmol, 513 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (2.53 mmol, 335 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete, and then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 751 mg of brownish-white solid, namely methyl 4-(4-methoxyphenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate, with a yield of 98%.

[0479] Step 3: Synthesis of the target product 7-hydroxy-3-(4-methoxyphenyl)-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0480] Methyl 4-(4-methoxyphenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid (1.97 mmol, 751 mg) and potassium carbonate (9.85 mmol, 1.35 g) were dissolved in 6 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 345 mg of a white solid, namely 7-hydroxy-3-(4-methoxyphenyl)-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one, with a yield of 50%.

[0481] 1H NMR (400MHz, DMSO-d6) δ10.65(s,2H),7.83(s,1H),7.64(d,J=8.4Hz,2H),7.43–7.34(m,4H),7.33–7.26(m,1H),7.06–6.98(m,2H),3.80(s,3H).

[0482] Example 38

[0483] 3-(4-acetylphenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0484] Step 1: Synthesis of intermediate methyl 4-(4-acetylphenyl)-3-aminothiophene-2-carboxylic acid

[0485] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), 4-hydroxymethylphenylboronic acid (2.6 mmol, 395 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, filtered, washed with saturated brine, and dried to give 409 mg of a brown solid, namely methyl 4-(4-acetylphenyl)-3-aminothiophene-2-carboxylate, with a yield of 74%.

[0486] Step 2: Synthesis of intermediate methyl 4-(4-acetylphenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0487] 4-(4-acetylphenyl)-3-aminothiophene-2-carboxylic acid methyl ester (1.48 mmol, 409 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (1.93 mmol, 299 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C, and the reaction was monitored by TLC until complete. The reaction was then quenched with saturated sodium carbonate, extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 563 mg of white solid, namely 4-(4-acetylphenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid methyl ester, with a yield of 96%.

[0488] Step 3: Synthesis of the target product 3-(4-acetylphenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0489] Methyl 4-(4-acetylphenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid (1.43 mmol, 563 mg) and potassium carbonate (7.16 mmol, 988 mg) were dissolved in 3 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 3 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 278 mg of a yellow solid, namely 3-(4-acetylphenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one, with a yield of 53%.

[0490] 1 H NMR (400MHz, DMSO-d6) δ10.81(s,2H),8.13(s,1H),8.02(d,J=8.1Hz,2H),7.99–7.91(m,2H),7.44–7.36(m,4H),7.33–7.28(m,1H),2.62(s,3H).

[0491] Example 39

[0492] 7-Hydroxy-3-(4-(hydroxymethyl)phenyl)-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0493] Step 1: Synthesis of intermediate methyl 3-amino-4-(4-(hydroxymethyl)phenyl)thiophene-2-carboxylic acid

[0494] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), 4-hydroxymethylphenylboronic acid (2.6 mmol, 395 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 503 mg of yellow solid, namely methyl 3-amino-4-(4-(hydroxymethyl)phenyl)thiophene-2-carboxylate, with a yield of 95%.

[0495] Step 2: Synthesis of intermediate methyl 4-(4-(hydroxymethyl)phenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0496] Methyl 3-amino-4-(4-(hydroxymethyl)phenyl)thiophene-2-carboxylate (1.91 mmol, 503 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (2.48 mmol, 384 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete, and then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected. The organic layers were purified by silica gel column chromatography to give 274 mg of a yellow oily liquid, namely methyl 4-(4-(hydroxymethyl)phenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate, with a yield of 54%.

[0497] Step 3: Synthesis of the target product 7-hydroxy-3-(4-(hydroxymethyl)phenyl)-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0498] Methyl 4-(4-(hydroxymethyl)phenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid (1.03 mmol, 274 mg) and potassium carbonate (5.15 mmol, 710 mg) were dissolved in 3 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 3 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to give 71 mg of a white solid, namely 7-hydroxy-3-(4-(hydroxymethyl)phenyl)-6-phenylthieno[3,2-b]pyridin-5(4H)-one, with a yield of 19%.

[0499] 1 H NMR (400MHz, DMSO-d6) δ10.68(s,2H),7.91(s,1H),7.68(d,J=7.7Hz,2H),7.45–7.34(m,6H),7.33–7.26(m,1H),5.27(s,1H),4.55(s,2H).

[0500] Example 40

[0501] 3-(4-(tert-butyl)phenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0502] Step 1: Synthesis of intermediate methyl 3-amino-4-(4-(tert-butyl)phenyl)thiophene-2-carboxylate

[0503] Methyl 3-amino-4-bromothiophene-2-carboxylate (3 mmol, 708 mg), (4-(tert-butyl)phenyl)boronic acid (3.6 mmol, 640 mg), potassium carbonate (12 mmol, 1.65 g), and tetra(triphenylphosphine)palladium (0.15 mmol, 173 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 851 mg of white solid, namely methyl 3-amino-4-(4-(tert-butyl)phenyl)thiophene-2-carboxylate, with a yield of 98%.

[0504] Step 2: Synthesis of intermediate methyl 4-(4-(tert-butyl)phenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0505] Methyl 3-amino-4-(4-(tert-butyl)phenyl)thiophene-2-carboxylate (2.48 mmol, 719 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (3.5 mmol, 466 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C for reaction. After the reaction was monitored by TLC until complete, saturated sodium carbonate was added to quench the reaction. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 1.1 g of white solid, namely methyl 4-(4-(tert-butyl)phenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate, in 95% yield.

[0506] Step 3: Synthesis of the target product 3-(4-(tert-butyl)phenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0507] Methyl 4-(4-(tert-butyl)phenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid (2.82 mmol, 1.14 g) and potassium carbonate (14.1 mmol, 1.94 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 440 mg of a white solid, namely 3-(4-(tert-butyl)phenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, with a yield of 38%.

[0508] 1 H NMR (400MHz, DMSO-d6) δ7.88(s,1H),7.62(d,J=8.1Hz,2H),7.48(dd,J=8.7,2.2Hz,2H),7.43–7.35(m,4H),7.42–7.34(m,1H),1.33(s,9H).

[0509] Example 41

[0510] 7-Hydroxy-6-phenyl-3-(thiophen-2-yl)thiopheno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0511] Step 1: Synthesis of intermediate methyl 4'-amino-[2,3'-bisthiophene]-5'-carboxylic acid

[0512] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), thiophene-2-ylboronic acid (3 mmol, 384 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 323 mg of a light blue solid, namely methyl 4'-amino-[2,3'-bisthiophene]-5'-carboxylate, with a yield of 67%.

[0513] Step 2: Synthesis of intermediate 4'-(2-phenylacetamido)-[2,3'-bisthiophene]-5'-carboxylic acid methyl ester

[0514] 4'-Amino-[2,3'-bisthiophene]-5'-carboxylic acid methyl ester (1.35 mmol, 323 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (1.62 mmol, 250 μL) was slowly added dropwise. After the addition was complete, the reaction solution was transferred to 90 °C for further reaction. After the reaction was monitored by TLC until complete, saturated sodium carbonate was added to quench the reaction. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 466 mg of white solid, namely 4'-(2-phenylacetamido)-[2,3'-bisthiophene]-5'-carboxylic acid methyl ester, with a yield of 96%.

[0515] Step 3: Synthesis of the target product 7-hydroxy-6-phenyl-3-(thiophen-2-yl)thiopheno[3,2-b]pyridin-5(4H)-one

[0516] Methyl 4'-(2-phenylacetamido)-[2,3'-bisthiophene]-5'-carboxylic acid (1.33 mmol, 466 mg) and potassium carbonate (6.52 mmol, 900 mg) were dissolved in 4 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 4 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The solid was filtered to give 340 mg of a yellow solid, namely 7-hydroxy-6-phenyl-3-(thiophene-2-yl)thieno[3,2-b]pyridin-5(4H)-one, with a yield of 78%.

[0517] 1 H NMR (400MHz, DMSO-d6) δ10.66 (s, 1H), 8.05 (s, 1H), 7.84 (d, J = 3.6Hz, 1H), 7.57 (d,J=5.1Hz,1H),7.45–7.35(m,4H),7.35–7.28(m,1H),7.17(t,J=4.4Hz,1H).

[0518] Example 42

[0519] 3-(3,4-difluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one was synthesized via the following route:

[0520] Step 1: Synthesis of intermediate methyl 3-amino-4-(3,4-difluorophenyl)thiophene-2-carboxylate

[0521] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), (3,4-difluorophenyl)boronic acid (2.4 mmol, 379 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to give 537 mg of white solid, namely methyl 3-amino-4-(3,4-difluorophenyl)thiophene-2-carboxylate, with a yield of 99%.

[0522] Step 2: Synthesis of intermediate methyl 4-(3,4-difluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate

[0523] Methyl 3-amino-4-(3,4-difluorophenyl)thiophene-2-carboxylate (1.89 mmol, 509 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (3 mmol, 396.7 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C for reaction. The reaction was monitored by TLC until it was complete, then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 774 mg of white solid, namely methyl 4-(3,4-difluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate, with a yield of 96%.

[0524] Step 3: Synthesis of the target product 3-(3,4-difluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0525] Methyl 4-(3,4-difluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid (1.92 mmol, 774 mg) and potassium carbonate (10 mmol, 1.38 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 8 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 257 mg of a white solid, namely 3-(3,4-difluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one, with a yield of 36%.

[0526] 1 H NMR (400MHz, DMSO-d6) δ8.07(s,1H),7.96(t,J=10.1Hz,1H),7.63(d,J=8.1 Hz,1H),7.51(dt,J=11.0,8.6Hz,1H),7.45–7.34(m,4H),7.34–7.25(m,1H).

[0527] Example 43

[0528] 3-(2,5-dichlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0529] Step 1: Synthesis of intermediate methyl 3-amino-4-(2,5-dichlorophenyl)thiophene-2-carboxylate

[0530] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), (2,5-dichlorophenyl)boronic acid (2.5 mmol, 477 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 520 mg of blue liquid, namely methyl 3-amino-4-(2,5-dichlorophenyl)thiophene-2-carboxylate, with a yield of 86%.

[0531] Step 2: Synthesis of intermediate methyl 4-(2,5-dichlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0532] Methyl 3-amino-4-(2,5-dichlorophenyl)thiophene-2-carboxylate (1.67 mmol, 506 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (2.24 mmol, 296 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C for reaction. The reaction was monitored by TLC until complete, and then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 696 mg of a yellow oily liquid, namely methyl 4-(2,5-dichlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate, with a yield of 96%.

[0533] Step 3: Synthesis of the target product 3-(2,5-dichlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0534] Methyl 4-(2,5-dichlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid (1.66 mmol, 696 mg) and potassium carbonate (8.3 mmol, 1.14 g) were dissolved in 6 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 314 mg of a pale yellow solid, namely 3-(2,5-dichlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, with a yield of 48%.

[0535] 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),10.63(s,1H),7.88(s,1H),7.63–7.56(m,1H),7.54–7.48(m,2H),7.42–7.33(m,4H),7.32–7.25(m,1H).

[0536] Example 44

[0537] 3-(4-fluoro-2-methylphenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0538] Step 1: Synthesis of intermediate methyl 3-amino-4-(4-fluoro-2-methylphenyl)thiophene-2-carboxylate

[0539] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), (4-fluoro-2-methylphenyl)boronic acid (2.4 mmol, 369 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 511 mg of a light blue liquid, namely methyl 3-amino-4-(4-fluoro-2-methylphenyl)thiophene-2-carboxylate, with a yield of 96%.

[0540] Step 2: Synthesis of intermediate methyl 4-(4-fluoro-2-methylphenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0541] Methyl 3-amino-4-(4-fluoro-2-methylphenyl)thiophene-2-carboxylate (1.92 mmol, 511 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (2.5 mmol, 331 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C for reaction. After the reaction was monitored by TLC until complete, saturated sodium carbonate was added to quench the reaction. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to obtain 731 mg of colorless oily liquid, namely methyl 4-(4-fluoro-2-methylphenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate, with a yield of 99%.

[0542] Step 3: Synthesis of the target product 3-(4-fluoro-2-methylphenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one. Methyl 4-(4-fluoro-2-methylphenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid (1.90 mmol, 731 mg) and potassium carbonate (9.54 mmol, 1.31 g) were dissolved in 8 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, it was cooled to room temperature, 8 mL methanol was added, and then 1 mol / L hydrochloric acid was added until a solid precipitated. The solution was kept slightly neutral. The solid was filtered to obtain 300 mg of yellow solid, namely 3-(4-fluoro-2-methylphenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, with a yield of 45%.

[0543] 1 H NMR (400MHz, DMSO-d6) δ7.73 (s, 1H), 7.41 (q, J = 7.9Hz, 1H), 7.28–7.14 (m, 4H), 7.14–7.03 (m, 2H), 2.13 (s, 3H).

[0544] Example 45

[0545] 3-(benzothiophene-2-yl)-7-hydroxy-6-phenylthiophene[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0546] Step 1: Synthesis of intermediate methyl 3-amino-4-(benzothiophen-3-yl)thiophen-2-carboxylate

[0547] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), benzothiophene-3-ylboronic acid (2.4 mmol, 427 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 567 mg of white solid, namely methyl 3-amino-4-(benzothiophene-3-yl)thiophene-2-carboxylate, with a yield of 98%.

[0548] Step 2: Synthesis of intermediate methyl 4-(benzothiophene-3-yl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0549] Methyl 3-amino-4-(benzothiophen-3-yl)thiophen-2-carboxylate (1.96 mmol, 567 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (2.55 mmol, 337 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C for reaction. After the reaction was monitored by TLC until complete, saturated sodium carbonate was added to quench the reaction. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 782 mg of yellow oily liquid, namely methyl 4-(benzothiophen-3-yl)-3-(2-phenylacetamido)thiophen-2-carboxylate, with a yield of 98%.

[0550] Step 3: Synthesis of the target product 3-(benzothiophene-2-yl)-7-hydroxy-6-phenylthiophene[3,2-b]pyridine-5(4H)-one

[0551] Methyl 4-(benzothiophene-3-yl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid (1.92 mmol, 782 mg) and potassium carbonate (9.61 mmol, 1.32 g) were dissolved in 6 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 359 mg of a yellow solid, namely 3-(benzothiophene-2-yl)-7-hydroxy-6-phenylthiophene[3,2-b]pyridin-5(4H)-one, with a yield of 49%.

[0552] 1 H NMR (400MHz, DMSO-d6) δ10.76(s,2H),8.12–8.04(m,1H),7.98(d,J=8.5Hz,2H),7.71–7.61(m,1H),7.49–7.34(m,6H),7.33–7.26(m,1H).

[0553] Example 46

[0554] 7-Hydroxy-6-phenyl-3-(pyridin-3-yl)thieno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0555] Step 1: Synthesis of intermediate methyl 3-amino-4-(pyridin-3-yl)thiophene-2-carboxylate

[0556] Methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472 mg), pyridin-3-ylboronic acid (2.5 mmol, 307 mg), potassium carbonate (8 mmol, 1.1 g), and tetrakis(triphenylphosphine)palladium (0.1 mmol, 115 mg) were dissolved in a mixed solution of 1,4-dioxane:methanol:water (5 mL:2 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 460 mg of yellow solid, namely methyl 3-amino-4-(pyridin-3-yl)thiophene-2-carboxylate, with a yield of 98%.

[0557] Step 2: Synthesis of intermediate methyl 3-(2-phenylacetamido)-4-(pyridin-3-yl)thiophene-2-carboxylate

[0558] Methyl 3-amino-4-(pyridin-3-yl)thiophene-2-carboxylate (1.96 mmol, 460 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (2.55 mmol, 337 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until it was complete, and then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected three times. The organic layers were purified by silica gel column chromatography to give 485 mg of white solid, namely methyl 3-(2-phenylacetamido)-4-(pyridin-3-yl)thiophene-2-carboxylate, with a yield of 70%.

[0559] Step 3: Synthesis of the target product 7-hydroxy-6-phenyl-3-(pyridin-3-yl)thienro[3,2-b]pyridin-5(4H)-one

[0560] Methyl 3-(2-phenylacetamido)-4-(pyridin-3-yl)thiophene-2-carboxylic acid (1.37 mmol, 485 mg) and potassium carbonate (6.88 mmol, 950 mg) were dissolved in 4 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 4 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral. The mixture was filtered to obtain 230 mg of a white solid, namely 7-hydroxy-6-phenyl-3-(pyridin-3-yl)thieno[3,2-b]pyridin-5(4H)-one, with a yield of 52%.

[0561] 1 H NMR (400MHz, DMSO-d6) δ10.86(s,2H),8.98(s,1H),8.58(dd,J=4.8,1.5Hz,1H),8.19(d,J= 7.8Hz,1H),8.12(s,1H),7.49(dd,J=7.8,4.8Hz,1H),7.44–7.35(m,4H),7.43–7.34(m,1H).

[0562] Example 47

[0563] 7-Hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0564] Step 1: Intermediate methyl 3-amino-4-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxylate

[0565] Methyl 3-amino-4-bromothiophene-2-carboxylate (2.0 mmol, 472 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole (2.4 mmol, 499 mg), potassium carbonate (6.0 mmol, 828 mg), and bis(tert-butylphosphine)palladium (0.1 mmol, 51 mg) were dissolved in a mixture of 1,4-dioxane:water (5 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 299 mg of a pale yellow solid, namely methyl 3-amino-4-(1-methyl-1H-pyrazole-4-yl)thiophene-2-carboxylate, with a yield of 63%.

[0566] Step 2: Synthesis of intermediate methyl 4-(1-methyl-1H-pyrazole-4-yl)-3-(2-phenylacetamido)thiophene-2-carboxylate

[0567] 1.26 mmol (299 mg) of methyl 3-amino-4-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxylate was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (1.64 mmol, 217 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until complete, and then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected and purified by silica gel column chromatography to give 446 mg of white solid, namely methyl 4-(1-methyl-1H-pyrazol-4-yl)-3-(2-phenylacetamido)thiophene-2-carboxylate, with a yield of 99%.

[0568] Step 3: Synthesis of the target product 7-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one

[0569] 4-(1-methyl-1H-pyrazol-4-yl)-3-(2-phenylacetamido)thiophene-2-carboxylate (1.26 mmol, 446 mg) and potassium carbonate (6.28 mmol, 866 mg) were dissolved in 6 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated. The solution was kept slightly neutral and filtered to obtain 226 mg of a yellow solid, namely 7-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-6-phenylthieno[3,2-b]pyridin-5(4H)-one, with a yield of 56%.

[0570] 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.36(s,1H),7.94(s,1H),7.84(s,1H),7.44–7.35(m,4H),7.34–7.27(m,1H),3.89(s,3H).

[0571] Example 48

[0572] 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0573] Step 1: Synthesis of intermediate methyl 3-amino-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)thiophene-2-carboxylate

[0574] Methyl 3-amino-4-bromothiophene-2-carboxylate (2.0 mmol, 472 mg), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole (2.4 mmol, 585 mg), potassium carbonate (6.0 mmol, 828 mg), and bis(tert-butylphosphine)palladium (0.1 mmol, 51 mg) were dissolved in a mixture of 1,4-dioxane:water (5 mL:2 mL). The reaction was carried out under N2 protection at 90 °C. After the reaction was completed by TLC, the mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 523 mg of white solid, namely methyl 3-amino-4-(1-(difluoromethyl)-1H-pyrazole-4-yl)thiophene-2-carboxylate, in 96% yield.

[0575] Step 2: Synthesis of intermediate methyl 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-(2-phenylacetamido)thiophene-2-carboxylate

[0576] Methyl 3-amino-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)thiophene-2-carboxylate (1.91 mmol, 523 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (2.6 mmol, 343 μL) was slowly added dropwise. After the addition was complete, the mixture was transferred to 90 °C. The reaction was monitored by TLC until complete, and then quenched with saturated sodium carbonate. The mixture was extracted three times with ethyl acetate and water, and the organic layers were collected and purified by silica gel column chromatography to give 732 mg of white solid, namely methyl 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-(2-phenylacetamido)thiophene-2-carboxylate, in 98% yield.

[0577] Step 3: Synthesis of the target product 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one

[0578] 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-(2-phenylacetamido)thiophene-2-carboxylate (1.87 mmol, 732 mg) and potassium carbonate (9.36 mmol, 1.29 g) were dissolved in 6 mL DMSO and reacted at 80 °C. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, 6 mL of methanol was added, followed by 1 mol / L hydrochloric acid, until a solid precipitated and the solution was kept slightly neutral. The mixture was filtered to give 263 mg of a white solid, namely 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, with a yield of 39%.

[0579] 1H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.96(s,1H),8.38(s,1H),8.10(s,1H),7.88(t,J=59.3Hz,1H),7.46–7.36(m,4H),7.34–7.26(m,1H).

[0580] Example 49

[0581] 5-O-3,6-diphenyl-4,5-dihydrothiopheno[3,2-b]pyridin-7-yl acetate, which was synthesized via the following route:

[0582] 7-Hydroxy-3,6-diphenylthieno[3,2-b]pyridin-5(4H)-one (0.5 mmol, 160 mg) was dissolved in anhydrous 1,4-dioxane, and pyridine (0.6 mmol, 47 mg) was added. The mixture was stirred in an ice bath, and then acetyl chloride (0.75 mmol, 59 mg) was slowly added dropwise. The mixture was stirred continuously, and the reaction was monitored by TLC until it was complete. The reaction was then quenched with saturated sodium carbonate, extracted three times with ethyl acetate and water, and the organic layers were collected. The organic layers were purified by silica gel column chromatography to give 99 mg of white solid, namely 5-oxo-3,6-diphenyl-4,5-dihydrothieno[3,2-b]pyridin-7-yl acetate, with a yield of 55%.

[0583] 1 H NMR(400MHz,Chloroform-d)δ9.41(s,1H),7.47–7.40(m,3H),7.47–7.40(m,7H),7.40–7.32(m,1H),2.12(s,3H).

[0584] Example 50

[0585] 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-oxo-6-phenyl-4,5-dihydrothieno[3,2-b]pyridin-7-ylbenzoate was synthesized via the following route:

[0586] 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)-one (0.5 mmol, 130 mg) and pyridine (0.6 mmol, 48 μL) were dissolved in anhydrous 1,4-dioxane. Pyridine (0.6 mmol, 48 μL) was added, and the mixture was stirred in an ice bath. Benzoyl chloride (0.55 mmol, 75 μL) was then slowly added dropwise, and the mixture was stirred continuously. After the reaction was monitored by TLC until it was complete, saturated sodium carbonate was added to quench the reaction. The mixture was extracted three times with ethyl acetate and water. The organic layers were collected and purified by silica gel column chromatography to give 70 mg of white solid, namely 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-oxo-6-phenyl-4,5-dihydrothieno[3,2-b]pyridin-7-ylbenzoate, with a yield of 30%.

[0587] 1 H NMR(400MHz,Chloroform-d)δ8.34(s,1H),8.05–7.97(m,2H),7.88(s,1H),7.69–7.60(m,1H),7.5 5(s,1H),7.52–7.43(m,4H),7.34(t,J=7.5Hz,2H),7.29(d,J=7.3Hz,1H),6.75(t,J=60.1Hz,1H).

[0588] Bioactivity testing:

[0589] The minimum inhibitory concentration (MIC) of the thienopyridone compounds in Examples 1-50 against Mycobacterium tuberculosis (UAlRv strain, which is a Mycobacterium tuberculosis strain that can stably emit light autonomously without the addition of any substrate) was determined by the 2:5 dilution method.

[0590] 1. Liquid culture of UAlRv strain: 2 mL of primary luminescent bacteria (provided by Guangzhou National Laboratory; for specific construction methods, please refer to the literature "Engineering more stable, selectable marker-free autoluminescent mycobacteria by one step. PLoS One. 2015, 10(3):e0119341") frozen at -80℃ was inoculated into an Erlenmeyer flask containing 50 mL of 7H9 medium (containing 0.1% Tween 80) and cultured until the absorbance (OD) of the bacterial solution at 600 nm was reached. 600 It reaches between 0.8 and 1.0.

[0591] 2. Preparation of DMSO solutions of different concentrations of the test compounds: The thienopyridone compounds of Examples 1-50 were dissolved in DMSO to prepare a stock solution with a concentration of 10 mg / mL. The thienopyridone compounds were diluted accordingly according to actual needs.

[0592] 3. MIC Detection: A bacterial suspension with a luminescence value of (3000–5000) / 200 μL was used as the detection suspension. A two-fold dilution method was employed, adding 196 μL of the diluted bacterial suspension to a 96-well plate, followed by 4 μL of the test compound. The 96-well plate was then incubated at 37°C for approximately 1–2 hours. The RLUs of the blank control group were read using an Envision HTS (PerkinElmer) as the data for the first day of detection. The RLUs of the samples were then measured daily until the 5th day. MIC refers to the compound concentration at which 90% of the UAlRv strain's growth is inhibited. The results are shown in Table 1.

[0593] Table 1. MIC values ​​of compounds from Examples 1-50 against autoluminescent Mycobacterium tuberculosis UAlRv.

[0594] As can be seen from Table 1, the compounds of the present invention, such as the thienopyridone compounds of Examples 1-50, all exhibit excellent antibacterial activity against the growth of Mycobacterium tuberculosis (such as Mycobacterium tuberculosis UAlRv).

[0595] The above embodiments merely illustrate several implementation methods of the present invention, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention, and the present invention also intends to include these modifications and variations.

Claims

Thiophene-pyridone compounds or their stereoisomers, prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable esters, or pharmaceutically acceptable solvates of formula (I) are included. in: -Ar1-(R1) n It is a C6-C10 aryl group or a 5-10 heteroaryl group with n R1 substitutions; n is selected from 0, 1, 2, 3 or 4; Each R1 is independently selected from the following groups: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C10 cycloalkyl, halogen, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)-, C1-C6 alkyl-S(O)2-, hydroxyl-substituted C1-C6 alkyl, mercapto-substituted C1-C6 alkyl, C1-C6 haloalkyl, nitro or cyano; -Ar2-(R2) m It is a C6-C10 aryl group or a 5-10 heteroaryl group with m R2 substitutions; m is selected from 0, 1, 2, 3 or 4; Each R2 is independently selected from the following groups: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C10 cycloalkyl, halogen, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)-, C1-C6 alkyl-S(O)2-, hydroxyl-substituted C1-C6 alkyl, mercapto-substituted C1-C6 alkyl, C1-C6 haloalkyl, cyano or nitro; R3 is selected from the following groups: H, C1-C6 alkyl-C(O)-, C1-C6 alkyl-S(O)-, C1-C6 alkyl-S(O)2-, C6-C10 aryl-C(O)-, C6-C10 aryl-S(O)-, C6-C10 aryl-S(O)2-. The thienopyridone compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate according to claim 1, is characterized in that: -Ar1-(R1) n It can be a phenyl group with n R1 substitutions, a 5-6 membered heteroaryl group, or a 9 membered heteroaryl group; Preferably, -Ar1-(R1) n It can be a phenyl group with n R1 substitutions, a 5-6 membered heteroaryl group, or a 9 membered fused heteroaryl group; Preferably, -Ar1-(R1) n The following are phenyl, furanyl, thiophene, pyrrole, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyrazinyl, benzofuranyl, benzothiophene, or indoleyl groups with n R1 substitutions; Preferably, -Ar1-(R1) n It can be a phenyl, thiophene, pyrazolyl, benzothiophene, or pyridyl group with n R1 substitutions; Preferably, -Ar1-(R1) n Replaced by n R1s Preferably, -Ar1-(R1) n Replaced by n R1s Preferably, -Ar1-(R1) n Replaced by n R1s The thienopyridone compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate according to claim 1 or 2 is characterized in that: n is selected from 0, 1, or 2; Alternatively, each R1 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 alkyl-C(O)-, hydroxy-substituted C1-C6 alkyl, C1-C6 haloalkyl, nitro or cyano; Preferably, each R1 is independently selected from C1-C4 alkyl, halogen, C1-C3 alkoxy, C1-C3 alkyl-C(O)-, hydroxy-substituted C1-C3 alkyl, fluorine-substituted C1-C3 alkyl, nitro or cyano; Preferably, each R1 is independently selected from C1-C4 alkyl, halogen, C1-C3 alkoxy, C1-C3 alkyl-C(O)-, hydroxy-substituted C1-C3 alkyl, or fluorine-substituted C1-C3 alkyl; Preferably, each R1 is independently selected from methyl, tert-butyl, fluorine, chlorine, methoxy The thienopyridone compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate according to any one of claims 1-3 is characterized in that: -Ar1-(R1) n As a whole, selected from Preferably, -Ar1-(R1) n As a whole, selected from The thienopyridone compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate according to any one of claims 1-4 is characterized in that: -Ar2-(R2) m It is a phenyl group with m R2 substitutions or a 6-membered heteroaryl group; Preferably, -Ar2-(R2) m It consists of m R2-substituted phenyl or pyridyl groups; Preferably, -Ar2-(R2) m For m R2 replacements Preferably, -Ar2-(R2) m For m R2 replacements The thienopyridone compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate according to any one of claims 1-5 is characterized in that: m is selected from 0, 1 or 2, preferably 0 or 1; Alternatively, each R2 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, cyano, or nitro groups; Preferably, each R2 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, or nitro groups; Preferably, each R2 is independently selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, or nitro groups; Preferably, each R2 is independently selected from methyl, fluorine, chlorine, bromine, methoxy, and nitro. The thienopyridone compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate according to any one of claims 1-6 is characterized in that: -Ar2-(R2) m As a whole, selected from Preferably, -Ar2-(R2) m As a whole, selected from The thienopyridone compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate according to any one of claims 1-7 is characterized in that: R3 is selected from H, C1-C6 alkyl-C(O)-, and C6-C10 aryl-C(O)-; Preferably, R3 is selected from H, C1-C6 alkyl-C(O)-, and benzoyl; Preferably, R3 is selected from H, C1-C3 alkyl-C(O)-, and benzoyl; Preferably, R3 is selected from H, Preferably, R3 is selected from H, Preferably, R3 is H. The thienopyridone compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate according to any one of claims 1-8 is characterized in that: The thienopyridone compound is selected from: 7-Hydroxy-3,6-diphenylthiopheno[3,2-b]pyridine-5(4H)-one 7-Hydroxy-3-phenyl-6-(o-tolyl)thiopheno[3,2-b]pyridin-5(4H)-one 7-Hydroxy-3-phenyl-6-(m-tolyl)thiopheno[3,2-b]pyridin-5(4H)-one 6-(2-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one, 6-(3-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one, 6-(4-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 6-(2-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one 6-(3-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one 6-(4-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one 6-(3-bromophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one 7-Hydroxy-6-(3-methoxyphenyl)-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one 7-Hydroxy-6-(3-nitrophenyl)-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one 7-Hydroxy-3-phenyl-6-(pyridin-4-yl)thiopheno[3,2-b]pyridin-5(4H)-one 6-(3-Fluorophenyl)-7-hydroxy-3-(o-tolyl)thiopheno[3,2-b]pyridin-5(4H)-one 6-(3-fluorophenyl)-7-hydroxy-3-(m-tolyl)thiopheno[3,2-b]pyridin-5(4H)-one 6-(3-fluorophenyl)-7-hydroxy-3-(p-tolyl)thiopheno[3,2-b]pyridin-5(4H)-one 3-(2-fluorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one 3,6-Bis(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one, 6-(3-fluorophenyl)-3-(4-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one 3-(4-chlorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one 6-(3-fluorophenyl)-7-hydroxy-3-(4-methoxyphenyl)thiopheno[3,2-b]pyridine-5(4H)-one 6-(3-fluorophenyl)-7-hydroxy-3-(thiophen-2-yl)thiopheno[3,2-b]pyridin-5(4H)-one 3-(2,3-difluorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one, 3-(2,5-dichlorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one 3-(4-fluoro-2-methylphenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one 3-(benzothiophene-2-yl)-6-(3-fluorophenyl)-7-hydroxythiophene[3,2-b]pyridin-5(4H)-one 6-(3-fluorophenyl)-7-hydroxy-3-(pyridin-3-yl)thiopheno[3,2-b]pyridin-5(4H)-one 7-Hydroxy-6-phenyl-3-(o-tolyl)thiopheno[3,2-b]pyridin-5(4H)-one 7-Hydroxy-6-phenyl-3-(m-tolyl)thiopheno[3,2-b]pyridin-5(4H)-one 7-Hydroxy-6-phenyl-3-(p-tolyl)thiopheno[3,2-b]pyridin-5(4H)-one 3-(2-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one, 3-(3-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 3-(4-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 3-(2-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 3-(3-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 3-(4-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one, 7-Hydroxy-3-(4-methoxyphenyl)-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one 3-(4-acetylphenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one 7-Hydroxy-3-(4-(hydroxymethyl)phenyl)-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one 3-(4-(tert-butyl)phenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one, 7-Hydroxy-6-phenyl-3-(thiophen-2-yl)thiopheno[3,2-b]pyridin-5(4H)-one, 3-(3,4-difluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one, 3-(2,5-dichlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 3-(4-fluoro-2-methylphenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 3-(benzothiophene-2-yl)-7-hydroxy-6-phenylthiophene[3,2-b]pyridin-5(4H)-one, 7-Hydroxy-6-phenyl-3-(pyridin-3-yl)thiopheno[3,2-b]pyridin-5(4H)-one 7-Hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 5-O-3,6-diphenyl-4,5-dihydrothiopheno[3,2-b]pyridine-7-yl acetate, One of 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-oxo-6-phenyl-4,5-dihydrothiopheno[3,2-b]pyridine-7-ylbenzoate. A pharmaceutical composition comprising a thienopyridone compound or its stereoisomer as described in any one of claims 1-9, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent, and / or excipient. Preferably, the pharmaceutical composition is an anti-tuberculosis drug. The pharmaceutical composition according to claim 10, wherein, The pharmaceutical composition may also contain other pharmaceutical ingredients; Preferably, the additional drug is an antimycobacterial agent or an antituberculosis agent. Sterile containers, drug kits, medicine boxes, or combinations of drugs, comprising: The first active ingredient comprises the thienopyridone compound or its stereoisomer as described in any one of claims 1-9, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester, or its pharmaceutically acceptable solvate. and, The second active ingredient is a different drug from the first active ingredient; Preferably, the first active ingredient and the second active ingredient exist in separate forms; Preferably, the first active ingredient and the second active ingredient are applied separately; Preferably, the additional drug is an antimycobacterial agent or an antituberculosis agent. Use of the thienopyridone compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester or its pharmaceutically acceptable solvate, or the pharmaceutical composition of any one of claims 1-9 in the preparation of a medicament for treating and / or preventing mycobacterial infection or diseases caused by mycobacterial infection; Preferably, the mycobacterium is Mycobacterium tuberculosis; Preferably, the mycobacterium is drug-resistant Mycobacterium tuberculosis; Preferably, the drug-resistant Mycobacterium tuberculosis includes multidrug-resistant Mycobacterium tuberculosis and extensively drug-resistant Mycobacterium tuberculosis. Use of the thienopyridone compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester or its pharmaceutically acceptable solvate, or the pharmaceutical composition of any one of claims 1-9 in the preparation of a medicament for the treatment and / or prevention of tuberculosis (TB). Use of the thienopyridone compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt, its pharmaceutically acceptable ester or its pharmaceutically acceptable solvate, or the pharmaceutical composition of any one of claims 1-9 in the preparation of a mycobacterial inhibitor, or in the preparation of an antimycobacterial medicament; Preferably, the mycobacterium is Mycobacterium tuberculosis; Preferably, the mycobacterium is drug-resistant Mycobacterium tuberculosis; Preferably, the drug-resistant Mycobacterium tuberculosis includes multidrug-resistant Mycobacterium tuberculosis and extensively drug-resistant Mycobacterium tuberculosis.

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