2-pyridone thiophene compound as well as preparation method and application thereof and antituberculous drug

Abstract

The invention relates to a 2-pyridone thiophene compound as well as a preparation method and application thereof and an antituberculosis drug. The 2-pyridone thiophene compound disclosed by the invention is a compound as shown in a formula (I), and in the imgabs0 #, R is one of phenyl, substituted phenyl and thienyl. The 2-pyridone thiophene compound has a novel mother nucleus structure and excellent activity of resisting mycobacterium tuberculosis (mycobacterium tuberculosis for short). According to the preparation method, 3-amino-4-bromothiophene-2-methyl formate is taken as a raw material, the compound is prepared through amidation reaction and ring closing reaction, and the reaction steps are simple. The 1, 2-pyridone thiophene compound can be used as a medicine for treating infectious diseases caused by tubercle bacillus, and has a very strong inhibition effect on the growth of tubercle bacillus.

Description

Technical Field

[0001] The present invention relates to the technical field of anti-tuberculosis drugs, in particular to a 2-pyridone thiophene compound, a preparation method and application thereof, and an anti-tuberculosis drug. Background Art

[0002] Tuberculosis (TB) is a chronic infectious disease caused by infection with Mycobacterium tuberculosis (Mtb for short) and is one of the most important infectious diseases that are fatal due to a single pathogen. Clinically, the treatment of sensitive TB is still the combined use of isoniazid, rifampicin, pyrazinamide and ethambutol. However, the emergence of multidrug-resistant, extensively drug-resistant and completely drug-resistant tuberculosis, HIV co-infection with tuberculosis and COVID-19 have hindered the diagnosis and treatment of TB and increased the burden of TB. In addition, in the past fifty years, only three new drugs, bedaquiline, delamanid and premanid, have been approved for the treatment of drug-resistant TB. However, patients will experience serious side effects such as nausea, hepatitis, arrhythmia and central nervous system poisoning after taking the medicine. Therefore, there is an urgent need to develop new drugs with strong activity for the treatment of TB. Summary of the invention

[0003] An object of the present invention is to provide a class of 2-pyridone thiophene compounds having anti-tuberculosis activity.

[0004] A 2-pyridone thiophene compound, which is a compound of formula (I);

[0005]

[0006] in:

[0007] R is one of phenyl, substituted phenyl and thienyl.

[0008] As a preferred embodiment, the substituted phenyl in R is a monosubstituted phenyl or a polysubstituted phenyl, and the substituent on the monosubstituted phenyl or the polysubstituted phenyl is one of methyl, ethyl, C3-C6 alkyl or cycloalkyl, fluorine, chlorine, bromine, methoxy, nitro, and nitrile.

[0009] Some representative 2-pyridone thiophene compounds include: 3-bromo-7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)-one, 3-bromo-7-hydroxy-6-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one, 3-bromo-7-hydroxy-6-(m-tolyl)thieno[3,2-b]pyridin-5(4H)-one, Pyridin-5(4H)-one (3-bromo-7-hydroxy-6-(m-tolyl)thieno[3,2-b]pyridin-5(4H)-one), 3-bromo-6-(2-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 3-bromo-6-(2-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 3-bromo-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one enyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one), 3-bromo-6-(4-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 3-bromo-6-(4-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 3-bromo-6-(2-chlorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, -b]pyridin-5(4H)-one), 3-bromo-6-(3-chlorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, and 3-bromo-7-hydroxy-6-(thiophen-2-yl)thieno[3,2-b]pyridin-5(4H)-one.

[0010] The 2-pyridone thiophene compounds of the present invention have a strong inhibitory effect on the growth of tuberculosis bacteria. The above are only some representative 2-pyridone thiophene compounds, and other 2-pyridone thiophene compounds such as formula (I) also have excellent anti-tuberculosis activity.

[0011] Another object of the present invention is to provide a method for preparing any of the above-mentioned 2-pyridone thiophene compounds.

[0012] A method for preparing any of the above-mentioned 2-pyridone thiophene compounds, using 3-amino-4-bromothiophene-2-carboxylic acid methyl ester as a raw material, and preparing the 2-pyridone thiophene compound through amidation reaction and ring-closure reaction.

[0013] As a preferred solution, the preparation method of the 2-pyridone thiophene compound includes the route of formula (II):

[0014]

[0015] The above-mentioned synthetic route has cheap and readily available raw materials, does not use highly toxic and highly polluting reagents, has simple reaction steps, is easy to operate, and can realize industrial production.

[0016] Another object of the present invention is to provide a use of any of the above-mentioned 2-pyridone thiophene compounds in the preparation of a drug for treating and / or preventing TB.

[0017] Another object of the present invention is to provide a use of any of the above-mentioned 2-pyridone thiophene compounds in the preparation of anti-tuberculosis drugs.

[0018] The 2-pyridone thiophene compound of the present invention can be used to prepare drugs for treating and / or preventing TB and anti-tuberculosis bacteria, in particular, for preparing drugs for treating infectious diseases caused by tuberculosis bacteria. The use of the 2-pyridone thiophene compound as a drug for treating infectious diseases caused by tuberculosis bacteria is provided.

[0019] An anti-tuberculosis drug comprising any one of the above-mentioned 2-pyridone thiophene compounds, or a pharmaceutically acceptable salt thereof.

[0020] Compared with the prior art, the present invention has the following advantages and effects:

[0021] (1) Provided is a class of 2-pyridone thiophene compounds having a new core structure and excellent anti-tuberculosis activity.

[0022] (2) A method for preparing the above-mentioned 2-pyridone thiophene compound is provided, which is prepared by using 3-amino-4-bromothiophene-2-carboxylic acid methyl ester as a raw material through an amidation reaction and a ring-closure reaction. The above-mentioned synthetic route has cheap and readily available raw materials, does not use highly toxic and highly polluting reagents, has simple reaction steps, and can be industrialized for production.

[0023] (3) Provide the use of the 2-pyridone thiophene compound as a drug for treating infectious diseases caused by tuberculosis. The 2-pyridone thiophene compound of the present invention has a strong inhibitory effect on the growth of tuberculosis. DETAILED DESCRIPTION

[0024] Example 1

[0025] This embodiment provides a 2-pyridone thiophene compound, specifically:

[0026] 3-Bromo-7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)one;

[0027] 3-bromo-7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)-one;

[0028] Its structural formula is as follows:

[0029]

[0030] The preparation method of 3-bromo-7-hydroxy-6-phenylthieno[3,2-b]pyridine-5(4H)one in this embodiment is as follows:

[0031] The compound 3-amino-4-bromothiophene-2-carboxylic acid methyl ester (1 mmol, 236 mg) was dissolved in anhydrous 1,4-dioxane, and phenylacetyl chloride (1.3 mmol, 200 mg) was slowly added dropwise at room temperature. After the addition was complete, the reaction solution was transferred to 90°C for reaction. After the reaction was completed as monitored by TLC, a saturated sodium carbonate solution was added to quench the reaction, and ethyl acetate and water were added for extraction 3 times. The organic layers were collected 3 times and dried to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-2:1 gradient elution) to obtain 300 mg of a white solid, namely 4-bromo-3-(2-phenylacetylamino)thiophene-2-carboxylic acid methyl ester, with a yield of 85%.

[0032] The compound 4-bromo-3-(2-phenylacetylamino)thiophene-2-carboxylic acid methyl ester (0.48mmol, 170mg) and potassium carbonate (2.4mmol, 331mg) were dissolved in 5mL DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 5mL methanol was added, and then 1mol / L hydrochloric acid was added until solid precipitated in the reaction solution, and the pH of the reaction solution was kept neutral. The solid was filtered, dried and weighed to obtain 89mg of a white solid, namely 3-bromo-7-hydroxy-6-phenylthieno[3,2-b]pyridine-5(4H)one, with a yield of 57.7%.

[0033] The characterization data of 3-bromo-7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)one are as follows:

[0034] 1 H NMR (500 MHz, DMSO-d 6 )δ11.03(s,2H),8.04(s,1H),7.38(t,J=7.5Hz,2H),7.34(d,J=7.5Hz,2H),7.29(t,J=7.3Hz,1H).

[0035] Example 2

[0036] This embodiment provides a 2-pyridone thiophene compound, specifically:

[0037] 3-Bromo-7-hydroxy-6-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one;

[0038] 3-bromo-7-hydroxy-6-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one

[0039] Its structural formula is as follows:

[0040]

[0041] The preparation method of 3-bromo-7-hydroxy-6-(o-tolyl)thieno[3,2-b]pyridine-5(4H)-one in this embodiment is:

[0042] The compound 2-(2-methylphenyl)acetic acid (3.0mmol, 450.5mg) was dissolved in anhydrous dichloromethane, thionyl chloride (4.5mmol, 326.4μL) was slowly added, and 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 dichloromethane in the reaction solution was dried to obtain 2-(2-methylphenyl)acetyl chloride, which was directly used in the next step without purification. The compound 3-amino-4-bromothiophene-2-carboxylic acid methyl ester (2 mmol, 472.1 mg) was dissolved in anhydrous 1,4-dioxane, and the above-mentioned acyl chloride solution was slowly added dropwise. After the addition was complete, the reaction solution was transferred to 90°C for reaction. After the reaction was completed as monitored by TLC, a saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added for extraction three times. The organic layers were collected three times and then spin-dried to obtain a crude product. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-5:1 gradient elution) to obtain 616 mg of a brown solid, namely 4-bromo-3-(2-(2-methylphenyl)acetylamino)thiophene-2-carboxylic acid methyl ester, with a yield of 83.6%.

[0043] The compound 4-bromo-3-(2-(2-methylphenyl)acetylamino)thiophene-2-carboxylic acid methyl ester (1.67mmol, 614mg) and potassium carbonate (8.36mmol, 1.15g) were dissolved in 8mL DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 8mL methanol was added, and then 1mol / L hydrochloric acid was added until solid precipitated in the reaction solution, and the pH of the reaction solution was kept neutral. The solid was filtered, dried and weighed to obtain 131mg of a white solid, namely 3-bromo-7-hydroxy-6-(o-tolyl)thieno[3,2-b]pyridine-5(4H)-one, with a yield of 23.3%.

[0044] The characterization data of 3-bromo-7-hydroxy-6-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one are as follows:

[0045] 1 H NMR (400 MHz, DMSO-d 6 )δ10.91(s,2H),8.05(s,1H),7.29–7.16(m,3H),7.09(dd,J=7.1,1.5Hz,1H),2.08(s,3H).

[0046] Example 3

[0047] This embodiment provides a 2-pyridone thiophene compound, specifically:

[0048] 3-Bromo-7-hydroxy-6-(m-tolyl)thieno[3,2-b]pyridin-5(4H)-one;

[0049] 3-bromo-7-hydroxy-6-(m-tolyl)thieno[3,2-b]pyridin-5(4H)-one

[0050] Its structural formula is as follows:

[0051]

[0052] The preparation method of 3-bromo-7-hydroxy-6-(m-tolyl)thieno[3,2-b]pyridine-5(4H)-one in this embodiment is:

[0053] The compound 2-(3-methylphenyl)acetic acid (3.0mmol, 450.5mg) was dissolved in anhydrous dichloromethane, thionyl chloride (4.5mmol, 326.4μL) was slowly added, and 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 dichloromethane in the reaction solution was dried to obtain 2-(3-methylphenyl)acetyl chloride, which was directly used in the next step without purification. The compound 3-amino-4-bromothiophene-2-carboxylic acid methyl ester (2 mmol, 472.1 mg) was dissolved in anhydrous 1,4-dioxane, and the above-mentioned acyl chloride solution was slowly added dropwise. After the addition was complete, the reaction solution was transferred to 90°C for reaction. After the reaction was completed as monitored by TLC, a saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added for extraction three times. The organic layers were collected three times and then spin-dried to obtain a crude product. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-2:1 gradient elution) to obtain 678 mg of a white solid, namely 4-bromo-3-(2-(3-methylphenyl)acetylamino)thiophene-2-carboxylic acid methyl ester, with a yield of 92.0%.

[0054] The compound 4-bromo-3-(2-(3-methylphenyl)acetylamino)thiophene-2-carboxylic acid methyl ester (1mmol, 368.2mg) and potassium carbonate (5mmol, 691.0mg) were dissolved in 4mL DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 4mL methanol was added, and then 1mol / L hydrochloric acid was added until solid precipitated in the reaction solution, and the pH of the reaction solution was kept neutral. The solid was filtered, dried and weighed to obtain 219mg of a white solid, namely 3-bromo-7-hydroxy-6-(m-tolyl)thieno[3,2-b]pyridine-5(4H)-one, with a yield of 59.4%.

[0055] The characterization data of 3-bromo-7-hydroxy-6-(m-tolyl)thieno[3,2-b]pyridin-5(4H)-one are as follows:

[0056] 1H NMR (400 MHz, DMSO-d 6 )δ11.06(s,2H),8.02(s,1H),7.27(t,J=7.5Hz,1H),7.18–7.08(m,3H),2.33(s,3H).

[0057] Example 4

[0058] This embodiment provides a 2-pyridone thiophene compound, specifically:

[0059] 3-Bromo-6-(2-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one;

[0060] 3-bromo-6-(2-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one;

[0061] Its structural formula is as follows:

[0062]

[0063] The preparation method of 3-bromo-6-(2-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one in this embodiment is:

[0064] The compound 2-(2-fluorophenyl)acetic acid (5.55mmol, 855.4mg) was dissolved in anhydrous DCM, thionyl chloride (8.33mmol, 605μL) was slowly added, and 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 dichloromethane in the reaction solution was dried to obtain 2-(2-fluorophenyl)acetyl chloride, which was directly used in the next reaction without purification. The compound 3-amino-4-bromothiophene-2-carboxylic acid methyl ester (3.7 mmol, 873.2 mg) was dissolved in anhydrous 1,4-dioxane, and the above-mentioned acyl chloride intermediate was slowly added dropwise at room temperature. After the addition was complete, the reaction solution was transferred to 90°C for reaction. After the reaction was completed as monitored by TLC, a saturated sodium carbonate solution was added to quench the reaction, and ethyl acetate and water were added for extraction 3 times. The organic layers were collected 3 times and then spin-dried to obtain a crude product. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-2:1 gradient elution) to obtain 1351 mg of a white solid, namely 4-bromo-3-(2-(2-fluorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester, with a yield of 98.1%.

[0065] Compound 4-bromo-3-(2-(2-fluorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester (3.63mmol, 1.3g) and potassium carbonate (6.82mmol, 941.2mg) were dissolved in 8mL DMSO and reacted at 80℃. After TLC monitoring, the reaction solution was cooled to room temperature, 8mL methanol was added, and then 1mol / L hydrochloric acid was added until solid precipitated in the reaction solution, and the pH of the reaction solution was kept neutral. The solid was filtered, dried and weighed to obtain 1.02g of white solid, namely 3-bromo-6-(2-fluorophenyl)-7-hydroxythieno[3,2-b]pyridine-5(4H)-one, with a yield of 83.2%. .

[0066] The characterization data of 3-bromo-6-(2-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one are as follows:

[0067] 1 H NMR (400 MHz, DMSO-d 6 )δ11.18(s,1H),8.08(s,1H),7.44–7.35(m,1H),7.32(td,J=7.4,1.9Hz,1H),7.27–7.17(m,2H).

[0068] Example 5

[0069] This embodiment provides a 2-pyridone thiophene compound, specifically:

[0070] 3-Bromo-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one;

[0071] 3-bromo-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one;

[0072] Its structural formula is as follows:

[0073]

[0074] The preparation method of 3-bromo-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one in this embodiment is as follows:

[0075] The compound 2-(3-fluorophenyl)acetic acid (3mmol, 462.4mg) was dissolved in anhydrous dichloromethane, thionyl chloride (4.5mmol, 326.4μL) was slowly added, and 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 dichloromethane in the reaction solution was dried to obtain 2-(3-fluorophenyl)acetyl chloride, which was directly used in the next step without purification. The compound 3-amino-4-bromothiophene-2-carboxylic acid methyl ester (2 mmol, 472.1 mg) was dissolved in anhydrous 1,4-dioxane, and the above compound was slowly added dropwise at room temperature. After the addition was complete, the reaction solution was transferred to 90°C for reaction. After the reaction was completed as monitored by TLC, a saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added for extraction three times. The organic layers were collected three times and then spin-dried to obtain a crude product. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-5:1 gradient elution) to obtain 732 mg of a brown solid, namely 4-bromo-3-(2-(3-fluorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester, with a yield of 98.2%.

[0076] The compound 4-bromo-3-(2-(3-fluorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester (1.96mmol, 732mg) and potassium carbonate (9.82mmol, 1.3g) were dissolved in 8mL DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 8mL methanol was added, and then 1mol / L hydrochloric acid was added until solid precipitated in the reaction solution, and the pH of the reaction solution was kept neutral. The solid was filtered, dried and weighed to obtain 359mg of a white solid, namely 3-bromo-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridine-5(4H)-one, with a yield of 53.7%.

[0077] The characterization data of 3-bromo-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one are as follows:

[0078] 1 H NMR (400 MHz, DMSO-d 6 )δ11.18(s,2H),8.08(s,1H),7.44–7.35(m,1H),7.32(td,J=7.4,1.9Hz,1H),7.27–7.17(m,2H).

[0079] Example 6

[0080] This embodiment provides a 2-pyridone thiophene compound, specifically:

[0081] 3-Bromo-6-(4-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one;

[0082] 3-bromo-6-(4-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one;

[0083] Its structural formula is as follows:

[0084]

[0085] The preparation method of 3-bromo-6-(4-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one in this embodiment is as follows:

[0086] The compound 3-amino-4-bromothiophene-2-carboxylic acid methyl ester (1.2 mmol, 283.2 mg) was dissolved in anhydrous 1,4-dioxane, and 2-(4-fluorophenyl)acetyl chloride (1.44 mmol, 247.7 mg) was slowly added dropwise at room temperature. After the addition was complete, the reaction solution was transferred to 90°C for reaction. After the reaction was completed as monitored by TLC, a saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added for extraction three times, and the organic layers were collected three times and then spin-dried to obtain a crude product. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:1-2:1 gradient elution) to obtain 313 mg of a light yellow solid, namely 4-bromo-3-(2-(4-fluorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester, with a yield of 84.3%.

[0087] The compound 4-bromo-3-(2-(4-fluorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester (0.83mmol, 308.0mg) and potassium carbonate (4.15mmol, 572.8mg) were dissolved in 4mL DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 4mL methanol was added, and then 1mol / L hydrochloric acid was added until solid precipitated in the reaction solution, and the pH of the reaction solution was kept neutral. The solid was filtered, dried and weighed to obtain 167mg of a light yellow solid, namely 3-bromo-6-(4-fluorophenyl)-7-hydroxythieno[3,2-b]pyridine-5(4H)-one, with a yield of 49.2%.

[0088] The characterization data of 3-bromo-6-(4-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one are as follows:

[0089] 1 H NMR (400 MHz, DMSO-d 6 )δ11.22(s,2H),8.05(s,1H),7.45–7.32(m,2H),7.21(t,J=8.8Hz,2H).

[0090] Example 7

[0091] This embodiment provides a 2-pyridone thiophene compound, specifically:

[0092] 3-Bromo-6-(2-chlorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one;

[0093] 3-bromo-6-(2-chlorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one;

[0094] Its structural formula is as follows:

[0095]

[0096] The preparation method of 3-bromo-6-(2-chlorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one in this embodiment is as follows:

[0097] The compound 3-amino-4-bromothiophene-2-carboxylic acid methyl ester (2.0 mmol, 472.1 mg) was dissolved in anhydrous 1,4-dioxane, and 2-(2-chlorophenyl)acetyl chloride (2.4 mmol, 453.7 mg) was slowly added dropwise at room temperature. After the addition was complete, the reaction solution was transferred to 90°C for reaction. After the reaction was completed as monitored by TLC, a saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added for extraction three times. The organic layers were collected three times and then dried to obtain a crude product. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-5:1 gradient elution) to obtain 690 mg of a white solid, namely 4-bromo-3-(2-(2-chlorophenyl)acetamido)thiophene-2-carboxylic acid methyl ester, with a yield of 88.7%.

[0098] The compound 4-bromo-3-(2-chlorophenyl)acetamido)thiophene-2-carboxylic acid methyl ester (1.76mmol, 684mg) and potassium carbonate (8.8mmol, 1.2g) were dissolved in 8mL DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 8mL methanol was added, and then 1mol / L hydrochloric acid was added until solid precipitated in the reaction solution, and the pH of the reaction solution was kept neutral. The solid was filtered, dried and weighed to obtain 320mg of a yellow solid, namely 3-bromo-6-(2-chlorophenyl)-7-hydroxythieno[3,2-b]pyridine-5(4H)-one, with a yield of 51.0%.

[0099] The characterization data of 3-bromo-6-(2-chlorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one are as follows:

[0100] 1H NMR (400 MHz, DMSO-d 6 )δ11.16(s,2H),8.07(s,1H),7.55–7.47(m,1H),7.42–

[0101] 7.33 (m, 2H), 7.32–7.25 (m, 1H).

[0102] Example 8

[0103] This embodiment provides a 2-pyridone thiophene compound, specifically:

[0104] 3-Bromo-6-(3-chlorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one;

[0105] 3-bromo-6-(3-chlorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one;

[0106] Its structural formula is as follows:

[0107]

[0108] The preparation method of 3-bromo-6-(3-chlorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one in this embodiment is as follows:

[0109] The compound 2-(3-chlorophenyl)acetic acid (3.0mmol, 511.77mg) was dissolved in anhydrous dichloromethane, thionyl chloride (4.5mmol, 326.4μL) was slowly added, and 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 dichloromethane in the reaction solution was dried to obtain 2-(3-chlorophenyl)acetyl chloride, which was directly used in the next step without purification. The compound 3-amino-4-bromothiophene-2-carboxylic acid methyl ester (2 mmol, 472.1 mg) was dissolved in anhydrous 1,4-dioxane, and the above-mentioned acyl chloride solution was slowly added dropwise. After the addition was complete, the reaction solution was transferred to 90°C for reaction. After the reaction was completed as monitored by TLC, a saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added for extraction three times. The organic layers were collected three times and then spin-dried to obtain a crude product. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1-1:1 gradient elution) to obtain 743 mg of a brown solid, namely 4-bromo-3-(2-(3-chlorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester, with a yield of 95.6%.

[0110] The compound 4-bromo-3-(2-(3-chlorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester (1.91mmol, 743mg) and potassium carbonate (9.56mmol, 1.3g) were dissolved in 8mL DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 8mL methanol was added, and then 1mol / L hydrochloric acid was added until solid precipitated in the reaction solution, and the pH of the reaction solution was kept neutral. The solid was filtered, dried and weighed to obtain 384mg of a white solid, namely 3-bromo-6-(3-chlorophenyl)-7-hydroxythieno[3,2-b]pyridine-5(4H)-one, with a yield of 56.3%.

[0111] The characterization data of 3-bromo-6-(3-chlorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one are as follows:

[0112] 1 H NMR (400 MHz, DMSO-d 6 )δ11.42(s,2H),8.07(s,1H),7.42–7.38(m,2H),7.34(tt,J=7.6,1.5Hz,2H).

[0113] Example 9

[0114] This embodiment provides a 2-pyridone thiophene compound, specifically:

[0115] 3-Bromo-7-hydroxy-6-(thiophene-2-yl)thieno[3,2-b]pyridin-5(4H)-one;

[0116] 3-bromo-7-hydroxy-6-(thiophen-2-yl)thieno[3,2-b]pyridin-5(4H)-one;

[0117] Its structural formula is as follows:

[0118]

[0119] The preparation method of 3-bromo-7-hydroxy-6-(thiophene 2-yl)thieno[3,2-b]pyridin-5(4H)-one in this embodiment is:

[0120] The compound 3-amino-4-bromothiophene-2-carboxylic acid methyl ester (1.5 mmol, 354.1 mg) was dissolved in anhydrous 1,4-dioxane, and 2-(thiophen-2-yl)acetyl chloride (1.8 mmol, 289.1 mg) was slowly added dropwise at room temperature. After the addition was complete, the reaction solution was transferred to 90°C for reaction. After the reaction was complete as monitored by TLC, a saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added for extraction three times. The organic layers were collected three times and then dried to obtain a crude product. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:1-2:1 gradient elution) to obtain 502 mg of a light yellow solid, namely 4-bromo-3-(2-(thiophen-2-yl)acetylamino)thiophene-2-carboxylic acid methyl ester, with a yield of 92.9%.

[0121] The compound 4-bromo-3-(2-(thiophen-2-yl)acetylamino)thiophene-2-carboxylic acid methyl ester (1.39mmol, 502mg) and potassium carbonate (6.95mmol, 959.1mg) were dissolved in 6mL DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 6mL methanol was added, and then 1mol / L hydrochloric acid was added until solid precipitated in the reaction solution, and the pH of the reaction solution was kept neutral. The solid was filtered, dried and weighed to obtain 250mg of a brown solid, namely 3-bromo-7-hydroxy-6-(thiophen-2-yl)thiophen[3,2-b]pyridine-5(4H)-one, with a yield of 72.8%.

[0122] The characterization data of 3-bromo-7-hydroxy-6-(thiophen-2-yl)thieno[3,2-b]pyridin-5(4H)-one are as follows:

[0123] 1 H NMR (400 MHz, DMSO-d 6 )δ11.69(s,1H),8.06(s,1H),7.98(d,J=2.9Hz,1H),7.46(d,J=5.0Hz,1H),7.18–7.06(m,1H).

[0124] Table 1 Structural formula of 2-pyridone thiophene compounds of Examples 1-9

[0125]

[0126]

[0127] The minimum inhibitory concentration (MIC) of the 2-pyridone thiophene compounds of Examples 1-9 against the self-luminous Mycobacterium tuberculosis (UAlRa strain) was determined by the half-dilution method.

[0128] 1. Liquid culture of UAlRa strain: Take 2 mL of primary luminescent bacteria (provided by Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences) frozen at -80°C and inoculate it into a conical flask containing 50 mL of 7H9 medium (containing 0.1% Tween80) and culture until the absorbance value of the bacterial solution at 600 nm (OD 600 ) reaches between 0.3 and 1.0.

[0129] 2. Prepare DMSO solutions of different concentrations of the test compounds: The 2-pyridone thiophene compounds of Examples 1-9 were dissolved in DMSO to prepare a mother solution with a concentration of 10 mg / mL. Each 2-pyridone thiophene compound was diluted accordingly according to actual needs. Table 2 shows the dosing conditions of each well.

[0130] 3.MIC detection: Take the positive drug rifampicin (RIF) 1μg / mL as the positive control. Take the bacterial solution with a luminescence value of (3000-5000) / 200μL as the detection bacterial solution, use the two-fold dilution method, add 196μL of the diluted bacterial solution to a 96-well plate, then add 4μL of the test compound and the positive drug rifampicin, then put the 96-well plate in a 37-degree incubator for about 1-2 hours, use the GloMax reader to read the RLUs of the blank control group as the data for the first day of detection, and then test the RLUs of the sample once a day until the fifth day. After the test, use GraphPad Prism5 to draw the curve and obtain the MIC of the test compound. The results are shown in Table 3 below.

[0131] Table 2 Distribution of drug addition in 96-well plate (drug concentration in μg / mL)

[0132] 7H9 7H9 7H9 7H9 7H9 7H9 7H9 7H9 7H9 7H9 7H9 7H9 7H9 2% DMSO 64 64 64 1 1 1 7H9 7H9 2% DMSO 32 32 32 0.5 0.5 0.5 7H9 7H9 2% DMSO 16 16 16 7H9 7H9 RIF 8 8 8 7H9 7H9 RIF 4 4 4 7H9 7H9 RIF 2 2 2 7H9 7H9 7H9 7H9 7H9 7H9 7H9 7H9 7H9 7H9 7H9 7H9 7H9

[0133] Table 3 Minimum inhibitory concentration MIC of the 2-pyridone thiophene compounds of Examples 1-9 against self-luminous tuberculosis bacteria H37Ra (in μg / mL)

[0134] Example compounds MIC (μg / mL) 1 0.5-1 2 0.5-1 3 0.5 4 0.5 5 0.5-1 6 2-4 7 1-2 8 0.5 9 4-8 Positive control RIF 0.25-0.5 Negative control DMSO /

[0135] In general, when detecting the antibacterial activity of new compounds against tuberculosis, the maximum inhibitory concentration used is 64 μg / mL, that is, in the field of anti-tuberculosis drugs, when the MIC value of a new compound against tuberculosis is less than 64 μg / mL, it indicates that the new compound has antibacterial activity against tuberculosis. Please refer to Table 3. The 2-pyridone thiophene compounds of Examples 1-9 of the present invention have good antibacterial activity against the growth of self-luminous tuberculosis bacteria. From the above results, it can be seen that the MIC values ​​of Examples 3, 4, and 8 are 0.5 μg / mL, and the MIC values ​​of Examples 1, 2, and 5 are between 0.5-1 μg / mL, indicating that the 2-pyridone thiophene compounds of the above-mentioned examples have a strong inhibitory effect on the growth of self-luminous tuberculosis bacteria.

[0136] The above-mentioned embodiments only express several implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the invention patent. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, and the present invention is also intended to include these modifications and modifications.

Claims

1. A 2-pyridone thiophene compound, characterized in that: is a compound of formula (I); in: R is one of phenyl, substituted phenyl and thienyl.

2. The 2-pyridone thiophene compound according to claim 1, characterized in that: The substituted phenyl in R is a monosubstituted phenyl or a polysubstituted phenyl, and the substituent on the monosubstituted phenyl or the polysubstituted phenyl is one of methyl, ethyl, C3-C6 alkyl or cycloalkyl, fluorine, chlorine, bromine, methoxy, nitro, and nitrile.

3. The 2-pyridone thiophene compound according to claim 1 or 2, characterized in that: The 2-pyridone thiophene compound is selected from: 3-Bromo-7-hydroxy-6-phenylthieno[3,2-b]pyridin-5(4H)one, 3-Bromo-7-hydroxy-6-(o-tolyl)thieno[3,2-b]pyridin-5(4H)-one, 3-Bromo-7-hydroxy-6-(m-tolyl)thieno[3,2-b]pyridin-5(4H)-one, 3-Bromo-6-(2-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 3-Bromo-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 3-Bromo-6-(4-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 3-Bromo-6-(2-chlorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, 3-Bromo-6-(3-chlorophenyl)-7-hydroxythieno[3,2-b]pyridin-5(4H)-one, One of the 3-bromo-7-hydroxy-6-(thiophene-2-yl)thieno[3,2-b]pyridin-5(4H)-ones.

4. A method for preparing a 2-pyridone thiophene compound according to any one of claims 1 to 3, characterized in that: The product is prepared from 3-amino-4-bromothiophene-2-carboxylic acid methyl ester via amidation and ring-closure reactions.

5. The method for preparing a 2-pyridone thiophene compound according to claim 4, characterized in that: The preparation method of the 2-pyridone thiophene compound includes the route of formula (II):

6. Use of the 2-pyridone thiophene compound according to any one of claims 1 to 3 in the preparation of a drug for treating and / or preventing TB.

7. Use of the 2-pyridone thiophene compound according to any one of claims 1 to 3 in the preparation of anti-tuberculosis drugs.

8. An anti-tuberculosis drug, characterized in that: The invention comprises the 2-pyridone thiophene compound as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

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