2-Pyridone thiophene compound, preparation method, use and anti-tuberculosis drug thereof

Abstract

The present invention relates to a 2-pyridone thiophene compound, its preparation method, use, and anti-tuberculosis drug. The 2-pyridone thiophene compound of the present invention is a compound of formula (I); wherein: R is one of phenyl, substituted phenyl, and thienyl. The 2-pyridone thiophene compound has a new core structure and excellent anti-Mycobacterium tuberculosis (abbreviated as tuberculosis) activity. The preparation method uses 3-amino-4-bromothiophene-2-methyl carboxylate as a raw material, and is prepared through an amidation reaction and a ring-closure reaction. The reaction steps are simple. The 2-pyridone thiophene compound is used as a drug for treating infectious diseases caused by tuberculosis bacteria, and has a strong inhibitory effect on the growth of tuberculosis bacteria.

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 thereof, a use thereof and an anti-tuberculosis drug. Background Art

[0002] Tuberculosis (TB) is a chronic infectious disease caused by infection with Mycobacterium tuberculosis (Mtb) and is one of the most important infectious diseases causing death due to a single pathogen. Clinically, the treatment of sensitive TB still relies on the combination 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 five decades, only three new drugs, bedaquiline, delamanid, and premanid, have been approved for the treatment of drug-resistant TB. However, patients experience serious side effects such as nausea, hepatitis, arrhythmias, and central nervous system poisoning after taking these drugs. Therefore, there is an urgent need to develop new, highly active drugs 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 group in R is a monosubstituted phenyl group or a polysubstituted phenyl group, and the substituent on the monosubstituted phenyl group or the polysubstituted phenyl group 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. Other 2-pyridone thiophene compounds such as those of 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 and 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 medicament 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 with a new core structure and excellent anti-tuberculosis activity.

[0022] (2) A method for preparing the aforementioned 2-pyridone thiophene compound is provided, wherein the compound is prepared using methyl 3-amino-4-bromothiophene-2-carboxylate as a raw material through an amidation reaction and a ring-closure reaction. The aforementioned synthetic route utilizes inexpensive and readily available raw materials, does not use highly toxic or highly polluting reagents, and has simple reaction steps, enabling industrial 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]pyridin-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 complete as monitored by TLC, the reaction was quenched by adding saturated sodium carbonate solution. Ethyl acetate and water were added and extracted three times. The organic layers were collected and dried to obtain a crude product. The product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1-2:1 gradient elution) to obtain 300 mg of 4-bromo-3-(2-phenylacetylamino)thiophene-2-carboxylic acid methyl ester as a white solid in an 85% yield.

[0032] The compound 4-bromo-3-(2-phenylacetylamino)thiophene-2-carboxylic acid methyl ester (0.48 mmol, 170 mg) and potassium carbonate (2.4 mmol, 331 mg) were dissolved in 5 mL of DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 5 mL of methanol was added, and then 1 mol / L hydrochloric acid was added until solid precipitated in the reaction solution and the pH of the reaction solution was kept slightly neutral. The solid was filtered, dried, and weighed to obtain 89 mg of a white solid, namely 3-bromo-7-hydroxy-6-phenylthieno[3,2-b]pyridin-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 (500MHz, DMSO-d6) 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]pyridin-5(4H)-one in this embodiment is as follows:

[0042] The compound 2-(2-methylphenyl)acetic acid (3.0 mmol, 450.5 mg) was dissolved in anhydrous dichloromethane, and thionyl chloride (4.5 mmol, 326.4 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 TLC monitoring, the dichloromethane in the reaction solution was dried to obtain 2-(2-methylphenyl)acetyl chloride, which was directly used in the next reaction without purification. The compound methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472.1 mg) was dissolved in anhydrous 1,4-dioxane, and the above-mentioned acid 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, saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added three times, and the organic layer was collected and 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 give 616 mg of methyl 4-bromo-3-(2-(2-methylphenyl)acetylamino)thiophene-2-carboxylate as a brown solid in a yield of 83.6%.

[0043] The compound 4-bromo-3-(2-(2-methylphenyl)acetylamino)thiophene-2-carboxylic acid methyl ester (1.67 mmol, 614 mg) and potassium carbonate (8.36 mmol, 1.15 g) were dissolved in 8 mL of DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 8 mL of methanol was added, and then 1 mol / L hydrochloric acid was added until solid precipitated in the reaction solution and the pH of the reaction solution was kept slightly neutral. The solid was filtered, dried, and weighed to obtain 131 mg of a white solid, namely 3-bromo-7-hydroxy-6-(o-tolyl)thieno[3,2-b]pyridin-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 (400MHz, DMSO-d6) 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]pyridin-5(4H)-one in this embodiment is as follows:

[0053] The compound 2-(3-methylphenyl)acetic acid (3.0 mmol, 450.5 mg) was dissolved in anhydrous dichloromethane, and thionyl chloride (4.5 mmol, 326.4 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 TLC monitoring, the dichloromethane in the reaction solution was dried to obtain 2-(3-methylphenyl)acetyl chloride, which was directly used in the next reaction without purification. The compound methyl 3-amino-4-bromothiophene-2-carboxylate (2 mmol, 472.1 mg) was dissolved in anhydrous 1,4-dioxane, and the above-mentioned acid 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, saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added three times for extraction. 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 = 20:1-2:1 gradient elution) to obtain 678 mg of methyl 4-bromo-3-(2-(3-methylphenyl)acetylamino)thiophene-2-carboxylate as a white solid in a yield of 92.0%.

[0054] The compound 4-bromo-3-(2-(3-methylphenyl)acetylamino)thiophene-2-carboxylic acid methyl ester (1 mmol, 368.2 mg) and potassium carbonate (5 mmol, 691.0 mg) were dissolved in 4 mL of DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 4 mL of methanol was added, and then 1 mol / L hydrochloric acid was added until solid precipitated in the reaction solution and the pH of the reaction solution was kept slightly neutral. The solid was filtered, dried, and weighed to obtain 219 mg of a white solid, namely 3-bromo-7-hydroxy-6-(m-tolyl)thieno[3,2-b]pyridin-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 (400MHz, DMSO-d6) 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 as follows:

[0064] The compound 2-(2-fluorophenyl)acetic acid (5.55 mmol, 855.4 mg) was dissolved in anhydrous DCM, and thionyl chloride (8.33 mmol, 605 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 TLC monitoring, 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 acid 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, saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added and extracted 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 = 20:1-2:1 gradient elution) to obtain 1351 mg of white solid, namely, 4-bromo-3-(2-(2-fluorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester, in a yield of 98.1%.

[0065] The compound 4-bromo-3-(2-(2-fluorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester (3.63 mmol, 1.3 g) and potassium carbonate (6.82 mmol, 941.2 mg) were dissolved in 8 mL of DMSO and reacted at 80°C. After completion of the reaction as monitored by TLC, the reaction solution was cooled to room temperature and 8 mL of methanol was added. Then, 1 mol / L hydrochloric acid was added until solid precipitated in the reaction solution, and the pH of the reaction solution remained slightly neutral. The solid was filtered, drained, and weighed to yield 1.02 g of a white solid, 3-bromo-6-(2-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-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 (400MHz, DMSO-d6) 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 (3 mmol, 462.4 mg) was dissolved in anhydrous dichloromethane, and thionyl chloride (4.5 mmol, 326.4 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 TLC monitoring, the dichloromethane in the reaction solution was dried to obtain 2-(3-fluorophenyl)acetyl chloride, which was directly used in the next reaction 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, saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added three times, and the organic layer was collected and 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 brown solid, namely, 4-bromo-3-(2-(3-fluorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester, in a yield of 98.2%.

[0076] The compound 4-bromo-3-(2-(3-fluorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester (1.96 mmol, 732 mg) and potassium carbonate (9.82 mmol, 1.3 g) were dissolved in 8 mL of DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 8 mL of methanol was added, and then 1 mol / L hydrochloric acid was added until solid precipitated in the reaction solution and the pH of the reaction solution was kept slightly neutral. The solid was filtered, dried, and weighed to obtain 359 mg of a white solid, namely 3-bromo-6-(3-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-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 (400MHz, DMSO-d6) 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, saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added three times, and the organic layers were collected and 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 light yellow solid, namely 4-bromo-3-(2-(4-fluorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester, in a yield of 84.3%.

[0087] The compound 4-bromo-3-(2-(4-fluorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester (0.83 mmol, 308.0 mg) and potassium carbonate (4.15 mmol, 572.8 mg) were dissolved in 4 mL of DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 4 mL of methanol was added, and then 1 mol / L hydrochloric acid was added until solid precipitated in the reaction solution and the pH of the reaction solution was kept slightly neutral. The solid was filtered, dried, and weighed to obtain 167 mg of a light yellow solid, namely 3-bromo-6-(4-fluorophenyl)-7-hydroxythieno[3,2-b]pyridin-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 (400MHz, DMSO-d6) 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 methyl 3-amino-4-bromothiophene-2-carboxylate (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, saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added three times for extraction. 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 methyl 4-bromo-3-(2-(2-chlorophenyl)acetamido)thiophene-2-carboxylate as a white solid in a yield of 88.7%.

[0098] The compound 4-bromo-3-(2-chlorophenyl)acetamido)thiophene-2-carboxylic acid methyl ester (1.76 mmol, 684 mg) and potassium carbonate (8.8 mmol, 1.2 g) were dissolved in 8 mL of DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 8 mL of methanol was added, and then 1 mol / L hydrochloric acid was added until solid precipitated in the reaction solution and the pH of the reaction solution was kept slightly neutral. The solid was filtered, dried, and weighed to obtain 320 mg of a yellow solid, namely 3-bromo-6-(2-chlorophenyl)-7-hydroxythieno[3,2-b]pyridin-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(400MHz,DMSO-d6)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 (3.0 mmol, 511.77 mg) was dissolved in anhydrous dichloromethane, and thionyl chloride (4.5 mmol, 326.4 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 TLC monitoring, the dichloromethane in the reaction solution was dried to obtain 2-(3-chlorophenyl)acetyl chloride, which was directly used in the next reaction 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 acid 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, saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added three times, and the organic layer was collected and 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 4-bromo-3-(2-(3-chlorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester as a brown solid in a yield of 95.6%.

[0110] The compound 4-bromo-3-(2-(3-chlorophenyl)acetylamino)thiophene-2-carboxylic acid methyl ester (1.91 mmol, 743 mg) and potassium carbonate (9.56 mmol, 1.3 g) were dissolved in 8 mL of DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 8 mL of methanol was added, and then 1 mol / L hydrochloric acid was added until solid precipitated in the reaction solution and the pH of the reaction solution was kept slightly neutral. The solid was filtered, dried, and weighed to obtain 384 mg of a white solid, namely 3-bromo-6-(3-chlorophenyl)-7-hydroxythieno[3,2-b]pyridin-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 (400MHz, DMSO-d6) 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-(thien-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 as follows:

[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 completed as monitored by TLC, saturated sodium carbonate solution was added to quench the reaction. Ethyl acetate and water were added three times, and the organic layers were collected and 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 4-bromo-3-(2-(thiophen-2-yl)acetylamino)thiophene-2-carboxylic acid methyl ester as a light yellow solid in a yield of 92.9%.

[0121] The compound 4-bromo-3-(2-(thiophen-2-yl)acetylamino)thiophene-2-carboxylic acid methyl ester (1.39 mmol, 502 mg) and potassium carbonate (6.95 mmol, 959.1 mg) were dissolved in 6 mL of DMSO and reacted at 80°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, 6 mL of methanol was added, and then 1 mol / L hydrochloric acid was added until solid precipitated in the reaction solution and the pH of the reaction solution was kept slightly neutral. The solid was filtered, dried, and weighed to obtain 250 mg of a brown solid, namely 3-bromo-7-hydroxy-6-(thiophen-2-yl)thiophen[3,2-b]pyridin-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 (400MHz, DMSO-d6) 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 self-luminous Mycobacterium tuberculosis (UAlRa strain) was determined by the half-fold dilution method.

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

[0129] 2. Preparation of DMSO solutions of different test compound concentrations: The 2-pyridone-thiophene compounds of Examples 1-9 were dissolved in DMSO to prepare a stock solution with a concentration of 10 mg / mL. Each 2-pyridone-thiophene compound was diluted accordingly as needed. Table 2 shows the dosage status of each well.

[0130] 3. MIC test: Use 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 test bacterial solution. Using 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, place the 96-well plate in a 37-degree incubator and incubate 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. Thereafter, test the RLUs of the sample once a day until the fifth day of detection. After the test is completed, 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 the self-luminous tuberculosis bacteria H37Ra (unit: 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] Generally, when testing the antibacterial activity of new compounds against tuberculosis bacteria, the maximum inhibitory concentration used is 64 μg / mL. That is to say, in the field of anti-tuberculosis drugs, when the MIC value of a new compound against tuberculosis bacteria is less than 64 μg / mL, it indicates that the new compound has antibacterial activity against tuberculosis bacteria. Please refer to Table 3. The 2-pyridone thiophene compounds of Examples 1-9 of the present invention all 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-described embodiments merely represent several implementations of the present invention. While the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that a person skilled in the art would be able to make numerous modifications and improvements without departing from the spirit of the present invention, and the present invention is intended to encompass such modifications and variations.

Claims

1. A 2-pyridone thiophene compound, 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-(thien-2-yl)thieno[3,2-b]pyridin-5(4H)-ones.

2. A method for preparing a 2-pyridone thiophene compound according to claim 1, characterized in that: It is prepared from methyl 3-amino-4-bromothiophene-2-carboxylate via amidation and ring-closure reactions.

3. The method for preparing a 2-pyridone thiophene compound according to claim 2, wherein: The preparation method of the 2-pyridone thiophene compound includes the route of formula (II): Wherein, the R group is determined according to the 2-pyridone thiophene compound according to claim 1.

4. Use of the 2-pyridone thiophene compound according to claim 1 in the preparation of a medicament for treating and / or preventing tuberculosis.

5. Use of the 2-pyridone thiophene compound according to claim 1 in the preparation of anti-tuberculosis drugs.

6. An anti-tuberculosis drug, characterized in that: The invention comprises the 2-pyridone thiophene compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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