Thienopyridone compound, application thereof and antituberculosis drug

Abstract

The invention relates to a thienopyridone compound, application thereof and an antituberculosis drug. The thienopyridone compound disclosed by the invention has a structure as shown in a formula (I), wherein-Ar1-(R1) n is a C6-C10 aromatic ring substituted by n R1 or a 4-10-membered heteroaromatic ring, n is selected from 0, 1, 2, 3 or 4, and n R1 is selected from C1-C6 alkyl, C1-C5 alkoxy, C3-C10 cycloalkyl, halogen, C1-C8 acyl, C1-C6 alkyl substituted by hydroxyl, C1-C6 alkyl substituted by halogen, nitro or cyano; -Ar2-(R2) n is a C6-C10 arylene ring substituted by n R2 or a 4-10-membered heteroaromatic ring, n is selected from 0, 1, 2, 3 or 4, and n R2 is respectively selected from C1-C6 alkyl, C1-C5 alkoxy, C3-C10 cycloalkyl, halogen or nitryl; and R3 is selected from the following groups: H or C1-C8 acyl groups. The thienopyridone compound has a novel mother nucleus structure and excellent anti-tubercle bacillus activity, and has a very strong inhibition effect on the growth of tubercle bacillus.

Description

Technical Field

[0001] 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

[0002] 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

[0003] One object of the present invention is to provide a class of thienopyridone compounds having anti-tuberculosis activity.

[0004] A thienopyridone compound having the structure of formula (I);

[0005]

[0006] Wherein: -Ar1-(R1) n It is a C6-C10 aromatic ring or a 4- to 10-membered heteroarylene ring with n R1-substituted groups, where n is selected from 0, 1, 2, 3, or 4, and each of the n R1 groups is independently selected from the following groups: C1-C6 alkyl, C1-C5 alkoxy, C3-C10 cycloalkyl, halogen, C1-C8 acyl, hydroxyl-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, nitro, or cyano; -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; R3 is selected from the following groups: H or C1-C8 acyl.

[0007] As a preferred option, -Ar1-(R1) n A phenyl, thiophene, pyrazolyl, benzothiophene, or pyridyl group with n R1 substitutions; -Ar1-(R1) nIn 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.

[0008] As a preferred option, -Ar2-(R2) n A phenyl or pyridyl group with n R2 substitutions; -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.

[0009] As a preferred option, R3 is selected from H, C1-C3 acyl or benzoyl.

[0010] Some representative thienopyridone compounds include: 7-hydroxy-3,6-diphenylthieno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-3-phenyl-6-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-3-phenyl-6-(m-tolyl)thieno[3,2-b]pyridin-5(4H)-one, 6-(2-fluorophenyl)-7-hydroxy-3-phenylthieno[3,2-b]pyridin-5(4H)-one, 6-(3-fluorophenyl)-7-hydroxy-3-phenylthieno[3,2-b]pyridin-5(4H)-one, 6-(4-fluorophenyl)-7-hydroxy-3-phenylthieno[3,2-b]pyridin-5(4H)-one, and 6-(4-fluorophenyl)-7-hydroxy-3-phenylthieno[3,2-b]pyridin-5(4H)-one. 6-(2-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 6-(3-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-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]pyridin-5(4H)-one, 7-hydroxy-6-(3-methoxyphenyl)-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-6-(3-nitrophenyl)-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one 7-Hydroxy-3-phenyl-6-(pyridin-4-yl)thieno[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 Pyridine-5(4H)-one, 6-(3-fluorophenyl)-3-(4-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one, 3-(4-chlorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-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]pyridine-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-hydroxythieno[3,2-b]pyridin-5(4H)-one, 3-(4-fluoro-2-methylphenyl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 3-(benzothiophene-2-yl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 6-(3-fluorophenyl)-7-hydroxy-3-(pyridin-3-yl)thieno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-6-phenyl-3-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-6-phenyl-3-( m-Tolyl)thieno[3,2-b]pyridin-5(4H)-one, 7-hydroxy-6-phenyl-3-(p-Tolyl)thieno[3,2-b]pyridin-5(4H)-one, 3-(2-fluorophenyl)-7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)-one, 3-(3-fluorophenyl)-7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)-one, 3-(4-fluorophenyl)-7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)-one, 3-(2-chlorophenyl)-7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)-one, 3-(3-chlorophenyl)-7-hydroxy- 6-Phenylaceto[3,2-b]pyridin-5(4H)-one, 3-(4-chlorophenyl)-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-(thiophen-2-yl)thiopheno[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,The following is an indication of: 2-b]pyridin-5(4H)-one, 7-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-6-phenylthiophene[3,2-b]pyridin-5(4H)-one, 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-7-hydroxy-6-phenylthiophene[3,2-b]pyridin-5(4H)-one, 5-oxo-3,6-diphenyl-4,5-dihydrothiophene[3,2-b]pyridin-7-yl acetate, and 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-oxo-6-phenyl-4,5-dihydrothiophene[3,2-b]pyridin-7-yl benzoate.

[0011] 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.

[0012] 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).

[0013] 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.

[0014] 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.

[0015] An anti-tuberculosis drug comprising any of the foregoing thienopyridone compounds and their pharmaceutically acceptable salts.

[0016] Compared with the prior art, the present invention has the following advantages and effects:

[0017] (1) A class of thienopyridone compounds with a novel core structure and excellent anti-tuberculosis activity was provided.

[0018] (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

[0019] Example 1

[0020] 7-Hydroxy-3,6-diphenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0021]

[0022] Step 1: Synthesis of intermediate methyl 4-phenyl-3-(2-phenylacetamido)thiophene-2-carboxylate

[0023] 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%.

[0024] Step 2: Synthesis of the target compound 7-hydroxy-3,6-diphenylthiopheno[3,2-b]pyridine-5(4H)-one

[0025] 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%.

[0026] 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).

[0027] Example 2

[0028] 7-Hydroxy-3-phenyl-6-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0029]

[0030] Step 1: Synthesis of 2-(2-methylphenyl)acetyl chloride

[0031] 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.

[0032] Step 2: Synthesis of intermediate methyl 4-phenyl-3-(2-(2-tolyl)acetamido)thiophene-2-carboxylic acid

[0033] 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%.

[0034] Step 3: Synthesis of the target compound 7-hydroxy-3-phenyl-6-(o-tolyl)thieno[3,2-b]pyridine-5(4H)-one

[0035] 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%.

[0036] 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).

[0037] Example 3

[0038] 7-Hydroxy-3-phenyl-6-(m-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0039]

[0040] Step 1: Synthesis of 2-(3-methylphenyl)acetyl chloride

[0041] 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.

[0042] Step 2: Synthesis of intermediate methyl 3-(2-(3-methylphenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0043] 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%.

[0044] Step 3: Synthesis of the target product 7-hydroxy-3-phenyl-6-(m-tolyl)thieno[3,2-b]pyridine-5(4H)-one

[0045] 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%.

[0046] 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).

[0047] Example 4

[0048] 6-(2-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0049]

[0050] Step 1: Synthesis of 2-(2-fluorophenyl)acetyl chloride

[0051] 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.

[0052] Step 2: Synthesis of intermediate methyl 3-(2-(2-fluorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0053] 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%.

[0054] Step 3: Synthesis of the target product 6-(2-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0055] 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%.

[0056] 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). Example 5

[0057] 6-(3-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0058]

[0059] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0060] 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.

[0061] Step 2: Synthesis of intermediate methyl 3-(2-(3-fluorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0062] 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%.

[0063] Step 3: Synthesis of the target product 6-(3-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0064] 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%.

[0065] 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).

[0066] Example 6

[0067] 6-(4-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0068]

[0069] Step 1: Synthesis of intermediate methyl 4-phenyl-3-(2-(4-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0070] 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%.

[0071] Step 2: Synthesis of the target product 6-(4-fluorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0072] 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%.

[0073] 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).

[0074] Example 7

[0075] 6-(2-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0076]

[0077] Step 1: Synthesis of intermediate methyl 3-(2-(2-chlorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0078] 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%.

[0079] Step 2: Synthesis of the target product 6-(2-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0080] 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%.

[0081] 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).

[0082] Example 8

[0083] 6-(3-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0084]

[0085] Step 1: Synthesis of 2-(3-chlorophenyl)acetyl chloride

[0086] 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.

[0087] Step 2: Synthesis of intermediate methyl 3-(2-(3-chlorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0088] 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%.

[0089] Step 3: Synthesis of the target product 6-(3-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0090] 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%.

[0091] 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).

[0092] Example 9

[0093] 6-(4-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0094]

[0095] Step 1: Synthesis of intermediate methyl 3-(2-(4-chlorophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0096] 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%.

[0097] Step 2: Synthesis of the target product 6-(4-chlorophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0098] 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%.

[0099] 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).

[0100] Example 10

[0101] 6-(3-bromophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0102]

[0103] Step 1: Synthesis of 2-(3-bromophenyl)acetyl chloride

[0104] 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.

[0105] Step 2: Synthesis of intermediate methyl 3-(2-(3-bromophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0106] 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%.

[0107] Step 3: Synthesis of the target product 6-(3-bromophenyl)-7-hydroxy-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0108] 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%.

[0109] 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).

[0110] Example 11

[0111] 7-Hydroxy-6-(3-methoxyphenyl)-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0112]

[0113] Step 1: Synthesis of 2-(3-methoxyphenyl)acetyl chloride

[0114] 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.

[0115] Step 2: Synthesis of intermediate methyl 3-(2-(3-methoxyphenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0116] 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%.

[0117] Step 3: Synthesis of the target product 7-hydroxy-6-(3-methoxyphenyl)-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0118] 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%.

[0119] 1H 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).

[0120] Example 12

[0121] 7-Hydroxy-6-(3-nitrophenyl)-3-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0122]

[0123] Step 1: Synthesis of 2-(3-nitrophenyl)acetyl chloride

[0124] 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.

[0125] Step 2: Synthesis of intermediate methyl 3-(2-(3-nitrophenyl)acetamido)-4-phenylthiophene-2-carboxylic acid

[0126] 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%.

[0127] Step 3: Synthesis of the target product 7-hydroxy-6-(3-nitrophenyl)-3-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0128] 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%.

[0129] 1 H 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).

[0130] Example 13

[0131] 7-Hydroxy-3-phenyl-6-(pyridin-4-yl)thieno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0132]

[0133] Step 1: Synthesis of intermediate methyl 4-phenyl-3-(2-(pyridin-4-yl)acetamido)thiophene-2-carboxylic acid

[0134] 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.

[0135] Step 2: Synthesis of the target compound 7-hydroxy-3-phenyl-6-(pyridin-4-yl)thieno[3,2-b]pyridin-5(4H)-one

[0136] 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%.

[0137] 1 H 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).

[0138] Example 14

[0139] 6-(3-fluorophenyl)-7-hydroxy-3-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0140]

[0141] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0142] 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.

[0143] Step 2: Synthesis of intermediate methyl 3-amino-4-(2-tolyl)thiophene-2-carboxylate

[0144] 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%.

[0145] Step 3: Synthesis of methyl 3-(2-(3-fluorophenyl)acetamido)-4-(2-tolyl)thiophene-2-carboxylic acid

[0146] 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%.

[0147] Step 4: Synthesis of the target product 6-(3-fluorophenyl)-7-hydroxy-3-(o-tolyl)thieno[3,2-b]pyridine-5(4H)-one. Methyl 3-(2-(3-fluorophenyl)acetamido)-4-(2-tolyl)thieno-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, it 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 brown solid, namely 6-(3-fluorophenyl)-7-hydroxy-3-(o-tolyl)thieno[3,2-b]pyridine-5(4H)-one, was obtained, with a yield of 37%.

[0148] 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).

[0149] Example 15

[0150] 6-(3-fluorophenyl)-7-hydroxy-3-(m-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0151]

[0152] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0153] 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.

[0154] Step 2: Synthesis of intermediate methyl 3-amino-4-(m-tolyl)thiophene-2-carboxylic acid

[0155] 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%.

[0156] Step 3: Synthesis of intermediate methyl 3-(2-(3-fluorophenyl)acetamido)-4-(m-tolyl)thiophene-2-carboxylic acid ester

[0157] 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%.

[0158] Step 4: Synthesis of the target product 6-(3-fluorophenyl)-7-hydroxy-3-(m-tolyl)thiopheno[3,2-b]pyridine-5(4H)-one

[0159] 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 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 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%.

[0160] 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).

[0161] Example 16

[0162] 6-(3-fluorophenyl)-7-hydroxy-3-(p-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0163]

[0164] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0165] 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.

[0166] Step 2: Synthesis of intermediate methyl 3-amino-4-(4-tolyl)thiophene-2-carboxylate

[0167] 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 solution 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%.

[0168] Step 3: Synthesis of intermediate methyl 3-(2-(3-fluorophenyl)acetamido)-4-(4-tolyl)thiophene-2-carboxylic acid

[0169] 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%.

[0170] Step 4: Synthesis of the target product 6-(3-fluorophenyl)-7-hydroxy-3-(p-tolyl)thieno[3,2-b]pyridine-5(4H)-one. Methyl 3-(2-(3-fluorophenyl)acetamido)-4-(4-tolyl)thieno-2-carboxylic acid (1.35 mmol, 520 mg) and potassium carbonate (6.78 mmol, 936 mg) were dissolved in 8 mL DMSO. The reaction was carried out at 80 °C. After the reaction was completed by TLC monitoring, it 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 to obtain 309 mg of white solid, namely 6-(3-fluorophenyl)-7-hydroxy-3-(p-tolyl)thieno[3,2-b]pyridine-5(4H)-one, with a yield of 64%.

[0171] 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).

[0172] Example 17

[0173] 3-(2-fluorophenyl)-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0174]

[0175] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0176] 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.

[0177] Step 2: Synthesis of intermediate methyl 4-(2-fluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0178] 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%.

[0179] Step 3: Synthesis of intermediate methyl 4-(2-fluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0180] 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.

[0181] Step 4: Synthesis of the target product 3-(2-fluorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one

[0182] 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%.

[0183] 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).

[0184] Example 18

[0185] 3,6-Bis(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one was synthesized via the following route:

[0186]

[0187] Step 1: Synthesis of intermediate methyl 4-(3-fluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0188] 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%.

[0189] Step 2: Synthesis of the target product 3,6-bis(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one

[0190] 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%.

[0191] 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).

[0192] Example 19

[0193] 6-(3-fluorophenyl)-3-(4-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0194]

[0195] Step 1: Synthesis of intermediate methyl 4-(4-fluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0196] 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.

[0197] Step 2: Synthesis of the target product 6-(3-fluorophenyl)-3-(4-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one

[0198] 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%.

[0199] 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).

[0200] Example 20

[0201] 3-(4-chlorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0202]

[0203] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0204] 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.

[0205] Step 2: Synthesis of intermediate methyl 3-amino-4-(4-chlorophenyl)thiophene-2-carboxylic acid

[0206] 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%.

[0207] Step 3: Synthesis of intermediate methyl 4-(4-chlorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0208] 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%.

[0209] Step 4: Synthesis of the target product 3-(4-chlorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one

[0210] 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%.

[0211] 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).

[0212] Example 21

[0213] 6-(3-fluorophenyl)-7-hydroxy-3-(4-methoxyphenyl)thiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0214]

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

[0216] 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.

[0217] Step 2: Synthesis of intermediate methyl 3-amino-4-(4-methoxyphenyl)thiophene-2-carboxylic acid

[0218] 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%.

[0219] Step 3: Synthesis of intermediate methyl 3-(2-(3-fluorophenyl)acetamido)-4-(4-methoxyphenyl)thiophene-2-carboxylic acid

[0220] 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%.

[0221] Step 4: Synthesis of the target product 6-(3-fluorophenyl)-7-hydroxy-3-(4-methoxyphenyl)thiopheno[3,2-b]pyridine-5(4H)-one

[0222] 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%.

[0223] 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).

[0224] Example 22

[0225] 6-(3-fluorophenyl)-7-hydroxy-3-(thiophen-2-yl)thiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0226]

[0227] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0228] 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.

[0229] Step 2: Synthesis of intermediate methyl 4'-amino-[2,3'-bisthiophene]-5'-carboxylic acid

[0230] 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%.

[0231] Step 3: Synthesis of intermediate 4'-(2-(3-fluorophenyl)acetamido)-[2,3'-bisthiophene]-5'-carboxylic acid methyl ester

[0232] 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%.

[0233] Step 4: Synthesis of the target product 6-(3-fluorophenyl)-7-hydroxy-3-(thiophen-2-yl)thiopheno[3,2-b]pyridin-5(4H)-one

[0234] 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%.

[0235] 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).

[0236] Example 23

[0237] 3-(2,3-difluorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0238]

[0239] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0240] 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.

[0241] Step 2: Synthesis of intermediate methyl 3-amino-4-(3,4-difluorophenyl)thiophene-2-carboxylate

[0242] 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%.

[0243] Step 3: Synthesis of intermediate methyl 4-(3,4-difluorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0244] 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%.

[0245] Step 4: Synthesis of the target product 3-(2,3-difluorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one

[0246] 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%.

[0247] 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).

[0248] Example 24

[0249] 3-(2,5-dichlorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0250]

[0251] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0252] 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.

[0253] Step 2: Synthesis of intermediate methyl 3-amino-4-(2,5-dichlorophenyl)thiophene-2-carboxylate

[0254] 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%.

[0255] Step 3: Synthesis of intermediate methyl 4-(2,5-dichlorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0256] 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 a yellow oily liquid, namely methyl 4-(2,5-dichlorophenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylate, with a yield of 98%.

[0257] Step 4: Synthesis of the target product 3-(2,5-dichlorophenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one

[0258] 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%.

[0259] 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). Example 25

[0260] 3-(4-fluoro-2-methylphenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0261]

[0262] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0263] 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.

[0264] Step 2: Synthesis of intermediate methyl 3-amino-4-(4-fluoro-2-methylphenyl)thiophene-2-carboxylate

[0265] 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%.

[0266] Step 3: Synthesis of intermediate methyl 4-(4-fluoro-2-methylphenyl)-3-(2-(3-fluorophenyl)acetamido)thiophene-2-carboxylic acid

[0267] 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%.

[0268] Step 4: Synthesis of the target product 3-(4-fluoro-2-methylphenyl)-6-(3-fluorophenyl)-7-hydroxythiopheno[3,2-b]pyridine-5(4H)-one

[0269] 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%.

[0270] 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).

[0271] Example 26

[0272] 3-(benzothiophene-2-yl)-6-(3-fluorophenyl)-7-hydroxythiophene[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0273]

[0274] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0275] 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.

[0276] Step 2: Synthesis of intermediate methyl 3-amino-4-(benzothiophene-3-yl)thiophene-2-carboxylate

[0277] 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%.

[0278] Step 3: Synthesis of intermediate 4-(benzothiophene-3-yl)-3-(2-(3-fluorophenyl)acetamyl)thiophene-2-carboxylic acid methyl ester

[0279] 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%.

[0280] Step 4: Synthesis of the target product 3-(benzothiophene-2-yl)-6-(3-fluorophenyl)-7-hydroxythiophene[3,2-b]pyridine-5(4H)-one

[0281] 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 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 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%.

[0282] 1 H 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).

[0283] Example 27

[0284] 6-(3-fluorophenyl)-7-hydroxy-3-(pyridin-3-yl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0285]

[0286] Step 1: Synthesis of 2-(3-fluorophenyl)acetyl chloride

[0287] 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.

[0288] Step 2: Synthesis of intermediate methyl 3-amino-4-(pyridin-3-yl)thiophene-2-carboxylate

[0289] 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.

[0290] Step 3: Synthesis of intermediate methyl 3-(2-(3-fluorophenyl)acetamido)-4-(pyridin-3-yl)thiophene-2-carboxylic acid

[0291] 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%.

[0292] 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%.

[0293] 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).

[0294] Example 28

[0295] 7-Hydroxy-6-phenyl-3-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0296]

[0297] Step 1: Synthesis of intermediate methyl 3-amino-4-(2-tolyl)thiophene-2-carboxylate

[0298] 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%.

[0299] Step 2: Synthesis of intermediate methyl 3-(2-phenylacetamido)-4-(2-tolyl)thiophene-2-carboxylic acid

[0300] 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%.

[0301] Step 3: Synthesis of the target product 7-hydroxy-6-phenyl-3-(o-tolyl)thieno[3,2-b]pyridine-5(4H)-one

[0302] 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%.

[0303] 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).

[0304] Example 29

[0305] 7-Hydroxy-6-phenyl-3-(m-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0306]

[0307] Step 1: Synthesis of intermediate methyl 3-amino-4-(3-tolyl)thiophene-2-carboxylate

[0308] 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%.

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

[0310] 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%.

[0311] Step 3: Synthesis of the target product 7-hydroxy-6-phenyl-3-(m-tolyl)thieno[3,2-b]pyridine-5(4H)-one

[0312] 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%.

[0313] 1 H 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).

[0314] Example 30

[0315] 7-Hydroxy-6-phenyl-3-(p-tolyl)thieno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0316]

[0317] Step 1: Synthesis of intermediate methyl 3-amino-4-(4-tolyl)thiophene-2-carboxylate

[0318] 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%.

[0319] Step 2: Synthesis of intermediate methyl 3-(2-phenylacetamido)-4-(4-tolyl)thiophene-2-carboxylic acid

[0320] 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.

[0321] Step 3: Synthesis of the target product 7-hydroxy-6-phenyl-3-(p-tolyl)thieno[3,2-b]pyridine-5(4H)-one

[0322] 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%.

[0323] 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).

[0324] Example 31

[0325] 3-(2-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0326]

[0327] Step 1: Synthesis of intermediate methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate

[0328] 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%.

[0329] Step 2: Synthesis of intermediate methyl 4-(2-fluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0330] 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%.

[0331] Step 3: Synthesis of the target product 3-(2-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0332] 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%.

[0333] 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).

[0334] Example 32

[0335] 3-(3-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0336]

[0337] Step 1: Synthesis of intermediate methyl 3-amino-4-(3-fluorophenyl)thiophene-2-carboxylate

[0338] 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%.

[0339] Step 2: Synthesis of intermediate methyl 4-(3-fluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0340] 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%.

[0341] Step 3: Synthesis of the target product 3-(3-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0342] 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%.

[0343] 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).

[0344] Example 33

[0345] 3-(4-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0346]

[0347] Step 1: Synthesis of intermediate methyl 3-amino-4-(4-fluorophenyl)thiophene-2-carboxylate

[0348] 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%.

[0349] Step 2: Synthesis of intermediate methyl 4-(4-fluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate

[0350] 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.

[0351] Step 3: Synthesis of the target product 3-(4-fluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0352] 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%.

[0353] 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).

[0354] Example 34

[0355] 3-(2-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0356]

[0357] Step 1: Synthesis of intermediate methyl 3-amino-4-(2-chlorophenyl)thiophene-2-carboxylic acid

[0358] 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%.

[0359] Step 2: Synthesis of intermediate methyl 4-(2-chlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0360] 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%.

[0361] Step 3: Synthesis of the target product 3-(2-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0362] 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%.

[0363] 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).

[0364] Example 35

[0365] 3-(3-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0366]

[0367] Step 1: Synthesis of intermediate methyl 3-amino-4-(3-chlorophenyl)thiophene-2-carboxylic acid

[0368] 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%.

[0369] Step 2: Synthesis of intermediate methyl 4-(3-chlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0370] 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%.

[0371] Step 3: Synthesis of the target product 3-(3-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0372] 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%.

[0373] 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).

[0374] Example 36

[0375] 3-(4-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0376]

[0377] Step 1: Synthesis of intermediate methyl 3-amino-4-(4-chlorophenyl)thiophene-2-carboxylic acid

[0378] 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%.

[0379] Step 2: Synthesis of intermediate methyl 4-(4-chlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0380] 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%.

[0381] Step 3: Synthesis of the target product 3-(4-chlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0382] 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%.

[0383] 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).

[0384] Example 37

[0385] 7-Hydroxy-3-(4-methoxyphenyl)-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0386]

[0387] Step 1: Synthesis of intermediate methyl 3-amino-4-(4-methoxyphenyl)thiophene-2-carboxylic acid

[0388] 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%.

[0389] Step 2: Synthesis of intermediate methyl 4-(4-methoxyphenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0390] 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%.

[0391] Step 3: Synthesis of the target product 7-hydroxy-3-(4-methoxyphenyl)-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0392] 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%.

[0393] 1 H 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).

[0394] Example 38

[0395] 3-(4-acetylphenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0396]

[0397] Step 1: Synthesis of intermediate methyl 4-(4-acetylphenyl)-3-aminothiophene-2-carboxylic acid

[0398] 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%.

[0399] Step 2: Synthesis of intermediate methyl 4-(4-acetylphenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0400] 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%.

[0401] Step 3: Synthesis of the target product 3-(4-acetylphenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0402] 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%.

[0403] 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).

[0404] Example 39

[0405] 7-Hydroxy-3-(4-(hydroxymethyl)phenyl)-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0406]

[0407] Step 1: Synthesis of intermediate methyl 3-amino-4-(4-(hydroxymethyl)phenyl)thiophene-2-carboxylic acid

[0408] 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%.

[0409] Step 2: Synthesis of intermediate methyl 4-(4-(hydroxymethyl)phenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0410] 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%.

[0411] Step 3: Synthesis of the target product 7-hydroxy-3-(4-(hydroxymethyl)phenyl)-6-phenylthieno[3,2-b]pyridine-5(4H)-one. 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. The reaction was carried out at 80 °C. After the reaction was completed by TLC monitoring, it was cooled to room temperature, 3 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 71 mg of white solid, namely 7-hydroxy-3-(4-(hydroxymethyl)phenyl)-6-phenylthieno[3,2-b]pyridine-5(4H)-one, with a yield of 19%.

[0412] 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).

[0413] Example 40

[0414] 3-(4-(tert-butyl)phenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0415]

[0416] Step 1: Synthesis of intermediate methyl 3-amino-4-(4-(tert-butyl)phenyl)thiophene-2-carboxylate

[0417] 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%.

[0418] Step 2: Synthesis of intermediate methyl 4-(4-(tert-butyl)phenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0419] 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.

[0420] Step 3: Synthesis of the target product 3-(4-(tert-butyl)phenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one. 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, 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 440 mg of white solid, namely 3-(4-(tert-butyl)phenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one, with a yield of 38%.

[0421] 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).

[0422] Example 41

[0423] 7-Hydroxy-6-phenyl-3-(thiophen-2-yl)thiopheno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0424]

[0425] Step 1: Synthesis of intermediate 4'-amino-[2,3'-bisthiophene]-5'-carboxylic acid methyl ester

[0426] 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%.

[0427] Step 2: Synthesis of intermediate 4'-(2-phenylacetamido)-[2,3'-bisthiophene]-5'-carboxylic acid methyl ester

[0428] 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%.

[0429] Step 3: Synthesis of the target product 7-hydroxy-6-phenyl-3-(thiophen-2-yl)thiopheno[3,2-b]pyridin-5(4H)-one

[0430] 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%.

[0431] 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).

[0432] Example 42

[0433] 3-(3,4-difluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one was synthesized via the following route:

[0434]

[0435] Step 1: Synthesis of intermediate methyl 3-amino-4-(3,4-difluorophenyl)thiophene-2-carboxylate

[0436] 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%.

[0437] Step 2: Synthesis of intermediate methyl 4-(3,4-difluorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylate

[0438] 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%.

[0439] Step 3: Synthesis of the target product 3-(3,4-difluorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0440] 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%.

[0441] 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).

[0442] Example 43

[0443] 3-(2,5-dichlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0444]

[0445] Step 1: Synthesis of intermediate methyl 3-amino-4-(2,5-dichlorophenyl)thiophene-2-carboxylate

[0446] 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%.

[0447] Step 2: Synthesis of intermediate methyl 4-(2,5-dichlorophenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0448] 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%.

[0449] Step 3: Synthesis of the target product 3-(2,5-dichlorophenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridine-5(4H)-one

[0450] 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%.

[0451] 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).

[0452] Example 44

[0453] 3-(4-fluoro-2-methylphenyl)-7-hydroxy-6-phenylthiopheno[3,2-b]pyridin-5(4H)-one, which was synthesized via the following route:

[0454]

[0455] Step 1: Synthesis of intermediate methyl 3-amino-4-(4-fluoro-2-methylphenyl)thiophene-2-carboxylate

[0456] 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%.

[0457] Step 2: Synthesis of intermediate methyl 4-(4-fluoro-2-methylphenyl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0458] 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%.

[0459] 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%.

[0460] 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).

[0461] Example 45

[0462] 3-(benzothiophene-2-yl)-7-hydroxy-6-phenylthiophene[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0463]

[0464] Step 1: Synthesis of intermediate methyl 3-amino-4-(benzothiophen-3-yl)thiophen-2-carboxylate

[0465] 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%.

[0466] Step 2: Synthesis of intermediate methyl 4-(benzothiophene-3-yl)-3-(2-phenylacetamido)thiophene-2-carboxylic acid

[0467] 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%.

[0468] Step 3: Synthesis of the target product 3-(benzothiophene-2-yl)-7-hydroxy-6-phenylthiophene[3,2-b]pyridine-5(4H)-one

[0469] 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%.

[0470] 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).

[0471] Example 46

[0472] 7-Hydroxy-6-phenyl-3-(pyridin-3-yl)thieno[3,2-b]pyridin-5(4H)-one, which is synthesized via the following route:

[0473]

[0474] Step 1: Synthesis of intermediate methyl 3-amino-4-(pyridin-3-yl)thiophene-2-carboxylate

[0475] 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%.

[0476] Step 2: Synthesis of intermediate methyl 3-(2-phenylacetamido)-4-(pyridin-3-yl)thiophene-2-carboxylate

[0477] 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%.

[0478] Step 3: Synthesis of the target product 7-hydroxy-6-phenyl-3-(pyridin-3-yl)thienro[3,2-b]pyridin-5(4H)-one

[0479] 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%.

[0480] 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).

[0481] Example 47

[0482] 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:

[0483]

[0484] Step 1: Intermediate methyl 3-amino-4-(1-methyl-1H-pyrazol-4-yl)thiophene-2-carboxylate

[0485] 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%.

[0486] Step 2: Synthesis of intermediate methyl 4-(1-methyl-1H-pyrazole-4-yl)-3-(2-phenylacetamido)thiophene-2-carboxylate

[0487] 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%.

[0488] 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

[0489] 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%.

[0490] 1H 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).

[0491] Example 48

[0492] 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:

[0493]

[0494] Step 1: Synthesis of intermediate methyl 3-amino-4-(1-(difluoromethyl)-1H-pyrazol-4-yl)thiophene-2-carboxylate

[0495] 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.

[0496] Step 2: Synthesis of intermediate methyl 4-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-(2-phenylacetamido)thiophene-2-carboxylate

[0497] 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.

[0498] 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

[0499] 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%.

[0500] 1 H 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).

[0501] Example 49

[0502] 5-O-3,6-diphenyl-4,5-dihydrothiopheno[3,2-b]pyridin-7-yl acetate, which was synthesized via the following route:

[0503]

[0504] 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%.

[0505] 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).

[0506] Example 50

[0507] 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:

[0508]

[0509] 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%.

[0510] 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).

[0511] Bioactivity testing:

[0512] The minimum inhibitory concentration (MIC) of the thienopyridone compounds in Examples 1-50 against autoluminescent tuberculosis (UAlRv strain) was determined by the 2:5 dilution method.

[0513] 1. Liquid culture of UAlRv strain: 2 mL of primary luminescent bacteria (provided by Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences) 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 culture at 600 nm was reached. 600 It reaches between 0.8 and 1.0.

[0514] 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.

[0515] 3. MIC Detection: Rifampicin (RIF) at 1 μg / mL was used as a positive control. A bacterial suspension with a luminescence value of (3000–5000) / 200 μL was used as the test suspension. A two-fold dilution method was used, adding 196 μL of the diluted bacterial suspension to a 96-well plate, followed by 4 μL of the test compound and RIF. 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 testing. The RLUs of the samples were then measured daily until day 5. MIC refers to the concentration of the compound at which 90% of the UAlRv strain's growth is inhibited.

[0516] Table 1. MIC values ​​of compounds from Examples 1-50 against autoluminescent Mycobacterium tuberculosis UAlRv.

[0517]

[0518]

[0519]

[0520]

[0521] The thienopyridone compounds of Examples 1-50 of this invention all exhibit good antibacterial activity against the growth of autoluminescent tuberculosis bacteria UAlRv. The results show that the MIC values ​​for Examples 1 and 49 are 0.0625-0.125 μg / mL, for Example 32 is 0.0312-0.0625 μg / mL, for Example 48 is 0.0078125-0.015625 μg / mL, and for Examples 4, 5, 18, 29, 39, and 43 are 0.125-0.25 μg / mL. This indicates that the thienopyridone compounds of these examples have a strong inhibitory effect on the growth of autoluminescent tuberculosis bacteria UAlRv, which is almost equivalent to or stronger than the positive control drug RIF.

[0522] 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

1. A thienopyridone compound, characterized in that: It has the structure of formula (Ⅰ); in: -Ar1-(R1) n It is a C6-C10 aromatic ring or a 4-10 membered heteroaryl ring with n R1 substitutions; wherein n is selected from 0, 1, 2, 3 or 4; 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, hydroxyl-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, nitro or cyano; -Ar2-(R2) n It is a C6-C10 aromatic ring or a 4- to 10-membered heteroaryl ring with n R2 substitutions; wherein n is selected from 0, 1, 2, 3 or 4; each of the n R2s is independently selected from the following groups: C1-C6 alkyl, C1-C5 alkoxy, C3-C10 cycloalkyl, halogen or nitro; R3 is selected from the following groups: H or C1 to C8 acyl groups.

2. The thienopyridone compound according to claim 1, characterized in that: -Ar1-(R1) n It is a phenyl, thiophene, pyrazolyl, benzothiophene, or pyridyl group with n R1 substitutions.

3. The thienopyridone compound according to claim 1 or 2, characterized in that: -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.

4. The thienopyridone compound according to claim 1, characterized in that: -Ar2-(R2) n It is a phenyl or pyridyl group with n R2 substitutions.

5. The thienopyridone compound according to claim 1 or 4, characterized in that: -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.

6. The thienopyridone compound according to claim 1, characterized in that: R3 is selected from H, C1-C3 acyl or benzoyl.

7. The thiophenopyridone compound according to claim 1, 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)thieno[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]pyridin-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]pyridin-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.

8. Use of a thienopyridone compound as described in any one of claims 1-7 in the preparation of a medicament for treating and / or preventing TB.

9. Use of a thienopyridone compound as described in any one of claims 1-7 in the preparation of a tuberculosis inhibitor or in the preparation of an anti-tuberculosis medicament.

10. An antituberculosis drug comprising the thienopyridone compound as described in any one of claims 1-7 and a pharmaceutically acceptable salt thereof.

Images