Pyrrole derivatives, processes for their preparation and use thereof

Abstract

The present application relates to a kind of pyrrole derivatives and its preparation method and application.The compound has the structure shown in formula I, II.The present application also relates to the preparation method of the compound containing formula I, II structure and the composition of uric acid-lowering drug lead compound.The present application also provides the application of the above-mentioned compound in the preparation of uric acid-lowering drug lead compound.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis and pharmaceutical application technology. Specifically, this invention relates to a pyrrole derivative, its preparation method or a pharmaceutical combination containing the same, and its uses in medicine. Background Technology

[0002] Hyperuricemia (HUA) refers to a condition where, under normal purine dietary conditions, fasting serum uric acid levels are >420 μmol / L on two separate occasions, regardless of gender. Gout refers to crystal-related arthropathy caused by the deposition of monosodium urate (MSU) when serum uric acid concentration exceeds 6.8 mg / dL. It is directly related to hyperuricemia caused by purine metabolism disorders and specifically refers to acute characteristic arthritis and chronic tophi. According to the latest epidemiological survey results, the number of hyperuricemia patients in my country is as high as 188-296 million, with an overall incidence of gout of 1.1%, and the annual incidence continues to rise. Currently, there are two main types of small molecule drugs for lowering uric acid in the clinical treatment of gout: one is xanthine oxidase inhibitors that inhibit uric acid production, and the other is uric acid transporter 1 (URAT1) inhibitors that promote uric acid excretion. However, most existing xanthine oxidase inhibitors have adverse reactions such as liver damage, nephrotoxicity, bone marrow suppression, and allergic reactions. For example, nearly half of patients do not respond to allopurinol and it easily leads to gastrointestinal bleeding; febuxostat can cause severe liver damage and gastrointestinal discomfort, and increases the risk of sudden cardiac death; topipsestat has limited clinical experience in the treatment of gout and has not yet been marketed in China. In addition, uricosuric drugs targeting URAT1, such as benzbromarone and lesinurad, also have serious toxicity problems. Therefore, there is an urgent clinical need to develop a new generation of uric acid-lowering drugs with novel frameworks that are highly effective and low in toxicity. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention provides a pyrrole derivative and its preparation method, as well as the activity screening results and applications of the above-mentioned compound as a novel skeleton for uric acid-lowering drug lead compounds.

[0004] The technical solution of the present invention is as follows:

[0005] I. Pyrrole derivatives

[0006] The pyrrole derivatives of the present invention, or pharmaceutically acceptable salts thereof, have the structures shown in general formulas I and II as follows:

[0007]

[0008] Wherein, R1 is cyclopropyl or bromine; R2 is methylene, isopropyl, or tert-butyl; R3 is selected from C1-C5 alkyl or cycloalkyl, phenyl or substituted phenyl, aromatic heterocyclic or substituted aromatic heterocyclic; the substituent is selected from fluorine, chlorine, bromine, hydroxyl, amino, nitro, C1-C5 alkyl or cycloalkyl, and the aromatic heterocyclic is selected from naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, furanyl, or thiophene.

[0009] According to a preferred embodiment of the present invention, R3 is selected from phenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 5-chlorothiophene, 4-methoxyphenyl, 4-ethylphenyl, 3-nitrophenyl, 2-nitrophenyl, 3-bromophenyl, 4-(2-hydroxy-2-propyl)furanyl, ethyl, methyl, tert-butyl, cyclopropyl, and propyl.

[0010] According to a further preferred embodiment of the present invention, the pyrrole derivative is one of the following:

[0011] Table 1. Structural formulas of compounds 1-36

[0012]

[0013]

[0014] II. Preparation methods of pyrrole derivatives

[0015] The preparation method of the pyrrole derivatives of the present invention is one of the following methods:

[0016] (1) Synthesis of compounds 1-6:

[0017] First, under the catalysis of benzoyl peroxide (BPO), starting with I-0 (1-bromo-4-methylnaphthalene), N-bromosuccinimide (NBS) reacts in n-hexane to give intermediate I-1 (1-bromo-4-(bromomethyl)naphthalene). Subsequently, in an acetonitrile system, I-1 reacts with methyl 2-pyrrolecarboxylate under the catalysis of cesium carbonate to generate the key intermediate II-0 (1-((4-bromonaphthyl-1-yl)methyl)-1H 1-Pyrrole-2-carboxylic acid methyl ester; II-0 is hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to give II-2, namely 1-((4-bromonaphthyl-1-yl)methyl)-1H-pyrrole-2-carboxylic acid; in dichloromethane (DCM), II-2 reacts with different... The amino acid ester hydrochloride undergoes a condensation reaction to give 1a-3a; then, it is hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to give compounds 1-3; the synthesis of compounds 4-6 is consistent with the synthesis of compounds 1-3, except that II-0 reacts with cyclopropylboronic acid in toluene in the presence of tricyclohexylphosphine, potassium phosphate, and palladium acetate to generate intermediate II-1, namely methyl 1-((4-cyclopropylnaphth-1-yl)methyl)-1H-pyrrole-2-carboxylic acid; subsequently, II-1 is hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to give II-3, namely 1-((4-cyclopropylnaphth-1-yl)methyl)-1H-pyrrole-2-carboxylic acid; in DCM, II-3 undergoes a condensation reaction with different amino acid ester hydrochloride in the presence of HATU and DIPEA to give 4a-6a; then, it is hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to give compounds 4-6;

[0018] Route 1:

[0019]

[0020] Reagents and conditions: (i) NBS, BPO, n-hexane, 70℃; (ii) methyl 2-pyrrolecarboxylate, cesium carbonate, acetonitrile, 70℃; (iii) lithium hydroxide, tetrahydrofuran, methanol, water, room temperature; (iv) glycine methyl hydrochloride or DL-alanine methyl hydrochloride or methyl 2-aminoisobutyrate hydrochloride, HATU, DIPEA, DCM, 0℃ to room temperature; (v) lithium hydroxide, tetrahydrofuran, methanol, water, room temperature; (vi) tricyclohexylphosphine, cyclopropylboronic acid, palladium acetate, potassium phosphate, toluene, 100℃, nitrogen.

[0021] R2 is the same as the corresponding position in compounds 1-6 above;

[0022] (2) Synthesis of compounds 7-36:

[0023] The synthesis of intermediates II-2 and II-3 is consistent with that of Route 1 above. Subsequently, in the DCM, II-2 undergoes a condensation reaction with different sulfonamide groups under the combined action of 4-dimethylaminopyridine (DMAP) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) to give compound 7-21. The synthesis of compound 22-36 is consistent with that of compound 7-21 above, except that II-2 is replaced by II-3. In the DCM, II-3 undergoes a condensation reaction with different sulfonamide groups under the combined action of DMAP and EDCI to give compound 22-36.

[0024] Route 2:

[0025]

[0026] Reagents and conditions: (i) NBS, BPO, n-hexane, 70℃; (ii) methyl 2-pyrrolecarboxylate, cesium carbonate, acetonitrile, 70℃; (iii) lithium hydroxide, tetrahydrofuran, methanol, water, room temperature; (iv) sulfonamide, DMAP, EDCI, DCM, 0℃ to room temperature; (v) tricyclohexylphosphine, cyclopropylboronic acid, palladium acetate, potassium phosphate, toluene, 100℃, nitrogen.

[0027] R3 is the same as the corresponding position shown in compounds 7-36 above;

[0028] The room temperature mentioned in this invention refers to 20~30℃.

[0029] III. Applications of Pyrrole Derivatives

[0030] This invention discloses the screening results of pyrrole derivatives for lowering uric acid activity and their first application in the preparation of lead compounds for uric acid-lowering drugs. Experiments demonstrate that the pyrrole derivatives of this invention can be used as lead compounds for lowering uric acid drugs. Specifically, they can be used as uric acid-lowering compounds in the preparation of lead compounds for uric acid-lowering drugs. This invention also provides the application of the above compounds in the preparation of lead compounds for lowering uric acid drugs.

[0031] Uric acid-lowering activity of the target compound:

[0032] Thirty-six compounds were synthesized according to the above method (the structural formulas of the compounds are shown in Table 1), and their uric acid-lowering activity was screened. Their uric acid-lowering activity data are listed in Table 2, with Lesinurad and Benzbromarone as positive control drugs.

[0033] As shown in Table 2, 23 compounds exhibited significant uric acid-lowering activity, which was stronger than that of the positive control drugs Lesinurad and Benzbromarone. Among them, the representative compounds 2, 4, 23, 24, 25, 27, 32, and 33 showed a uric acid reduction rate of over 85% in animal in vivo activity tests, demonstrating excellent uric acid-lowering activity and can be further developed as lead compounds for uric acid-lowering.

[0034] Therefore, the pyrrole derivatives in this invention are a novel class of compounds with uric acid-lowering activity, which can be used as uric acid-lowering active molecules to prepare lead compounds for uric acid-lowering drugs.

[0035] A uric acid-lowering drug lead compound composition comprising a pyrrole derivative of the present invention and one or more pharmaceutically acceptable carriers or excipients. Detailed Implementation

[0036] The following examples are helpful in understanding the present invention, but should not limit the scope of the invention. In the following examples, all target compounds are numbered the same as in Table 1.

[0037] Synthetic routes for compounds 1-6:

[0038]

[0039] Reagents and conditions: (i) NBS, BPO, n-hexane, 70℃; (ii) methyl 2-pyrrolecarboxylate, cesium carbonate, acetonitrile, 70℃; (iii) lithium hydroxide, tetrahydrofuran, methanol, water, room temperature; (iv) glycine methyl hydrochloride or DL-alanine methyl hydrochloride or methyl 2-aminoisobutyrate hydrochloride, HATU, DIPEA, DCM, 0℃ to room temperature; (v) lithium hydroxide, tetrahydrofuran, methanol, water, room temperature; (vi) tricyclohexylphosphine, cyclopropylboronic acid, palladium acetate, potassium phosphate, toluene, 100℃, nitrogen.

[0040] Preparation of compound I-1

[0041] BPO (0.32 g, 1.36 mmol) and NBS (8.00 g, 67.87 mmol) were mixed in a 250 mL round-bottom flask, and 50 mL of n-hexane was added. Then, I-O (10.00 g, 45.24 mmol) was added dropwise to the reaction system, and the mixture was heated to 70 °C for 14 h. The reaction was monitored for completeness by thin-layer chromatography (TLC), and heating was stopped. After the reaction system cooled to room temperature, the filter cake was collected by vacuum filtration. The filter cake was placed in a 250 mL beaker, and 150 mL of saturated NaHCO3 aqueous solution was added. After stirring for 30 min, the mixture was filtered, and the filter cake was collected. This operation was repeated twice. The collected filter cake was placed in a 250 mL flask, and 50 mL of n-hexane was added. The mixture was heated to reflux for 1 h, and then heating was stopped. After the reaction solution cooled to room temperature, it was filtered and dried under vacuum to obtain a white powder with a yield of 62.3% and a melting point of 100–102 °C. ESI-MS: m / z 299.20 [M+H] + 301.18 [M+2+H] + C 11 H8Br2 [297.90].

[0042] Preparation of compound II-0

[0043] I-1 (3.00 g, 10.03 mmol) was added to a 250 mL round-bottom flask, followed by approximately 60 mL of acetonitrile to dissolve it. Cesium carbonate (6.54 g, 20.07 mmol) was then added to the flask, followed by methyl 2-pyrrolecarboxylate (1.51 g, 12.04 mmol) dissolved in 35 mL of acetonitrile, which was slowly added dropwise to the reaction system. After heating to 70 °C and reacting for 12 h, the reaction was monitored by TLC until complete, and then filtered to collect the filter cake. The filter cake was then placed in a 250 mL beaker, and 100 mL of water was added. After stirring for 15 min, the mixture was filtered again, and the filter cake was collected. This process was repeated twice. Finally, the filter cake was placed in a 100 mL flask, and 50 mL of ethanol was added. The mixture was heated to 80 °C, stirred until the solution was clear, cooled to room temperature, filtered, and dried under vacuum to obtain a pure white solid, II-0, with a yield of 83.4% and a melting point of 110–112 °C. ESI-MS: m / z 344.07 [M+H] + 346.16 [M+2+H] + C 17 H 14 BrNO2 [343.02].

[0044] Preparation of compound II-1

[0045] II-0 (2.00 g, 5.83 mmol), cyclopropylboronic acid (0.75 g, 8.75 mmol), tricyclohexylphosphine (0.70 g, 1.16 mmol), potassium phosphate (4.33 g, 20.41 mmol), and palladium acetate (0.28 g, 0.58 mmol) were added sequentially to a 250 mL flask. 50 mL of toluene and 2 mL of distilled water were added, and the mixture was heated to 100 °C under a N2 atmosphere. After 12 h, the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The solvent was removed by vacuum distillation. The residue was dissolved in 100 mL of ethyl acetate and then washed with saturated NaCl aqueous solution (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate for 30 min and then filtered. The filtrate was concentrated under reduced pressure and then separated by column chromatography (ethyl acetate (EA): petroleum ether (PE) = 1:5) to give a white solid II-1 in 81.7% yield, melting point: 98–100 °C. ESI-MS: m / z 306.32 [M+H] + C 20 H 19 NO2 [305.14].

[0046] Preparation of compound II-2

[0047] II-0 (2.00 g, 5.83 mmol) was dissolved in a mixture of 15 mL tetrahydrofuran and 15 mL methanol in a 100 mL flask. Lithium hydroxide (1.40 g, 58.31 mmol) was dissolved in a small amount of water and added dropwise to the above solution. The mixture was then stirred at room temperature for 6 h. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure. 10 mL of water was added to the residue, and the pH was adjusted to 2-3 by adding 1 mol / L dilute hydrochloric acid solution dropwise. The product was collected by filtration and recrystallized from ethanol to give a white solid in 77.8% yield, melting point: 170–172 °C. ESI-MS: m / z 330.28 [M+2-H] - C 16 H 12 BrNO2 [329.01].

[0048] Preparation of compound II-3

[0049] II-1 (1.50 g, 4.92 mmol) was dissolved in a mixture of 15 mL tetrahydrofuran and 15 mL methanol in a 100 mL flask. Lithium hydroxide (1.18 g, 49.18 mmol) was dissolved in a small amount of water and added dropwise to the above solution. The mixture was then stirred at room temperature for 6 h. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure. 10 mL of water was added to the residue, and the pH was adjusted to 2-3 by adding 1 M HCl solution dropwise. The product was collected by filtration and recrystallized from ethanol to give a white solid in 75.3% yield, melting point: 138–140 °C. ESI-MS: m / z 290.28 [MH] - C 19 H 17 NO2[291.13].

[0050] Preparation of compounds 1a-3a

[0051] II-2 (0.20 g, 0.60 mmol) was placed in a 25 mL flask, dissolved in 15 mL of DCM, and then HATU (0.34 g, 9.04 mmol) was added. The mixture was stirred in an ice bath for 30 min, and then DIPEA (0.23 g, 1.81 mmol) was added. After stirring for another 10 min, glycine methyl hydrochloride (0.10 g, 0.72 mmol), D / L-alanine methyl hydrochloride (0.11 g, 0.72 mmol), or 2-aminoisobutyrate methyl hydrochloride (0.12 g, 0.72 mmol) was added. The ice bath was removed, and the mixture was stirred at room temperature for 12 h before TLC analysis. After the reaction was complete, 50 mL of EA and 50 mL of water were added. The mixture was extracted and separated, and the organic phase was washed with saturated NaCl aqueous solution (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (EA:PE = 1:3) to obtain the product. Recrystallization from EA yielded the target compounds 1a-3a. Compound 1a was a white solid with a yield of 79.8%, melting point of 132–134 °C, and ESI-MS at m / z 403.11 [M+2+H]. + C 19 H 17 BrN₂O₃ [400.04]. Compound 2a, white solid, yield: 74.6%, melting point: 140–142 °C, ESI-MS: m / z 417.29 [M₂H₂O]. + . C 20 H 19BrN₂O₃ [414.06]. Compound 3a, white solid, yield: 78.0%, melting point: 150–152 °C, ESI-MS: m / z 431.03 [M₂H₂O]. + C 21 H 21 BrN2O3 [428.07].

[0052] Preparation of compounds 1-3

[0053] Compound 1a (0.14 g, 0.35 mmol) was placed in a 25 mL flask and dissolved in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Lithium hydroxide (0.08 g, 3.50 mmol) was dissolved in a small amount of water and added dropwise to the above solution. The mixture was then stirred at room temperature for 6 h. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure. 10 mL of water was added to the residue, and the pH was adjusted to 2-3 by adding 1 M HCl solution dropwise. The product was collected by filtration and recrystallized from ethanol to give compound 1. The preparation of compounds 2 and 3 was similar to the above steps.

[0054] Example 1. Preparation of Compound 1

[0055]

[0056] White solid, yield 82.2%, melting point: 178~180℃. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ8.36 (t, J = 6.0 Hz, 1H), 8.22 – 8.19 (m, 2H), 7.78 – 7.69 (m, 3H), 7.03 (t,J = 2.2 Hz, 1H), 6.98 (dd, J = 3.9, 1.7 Hz, 1H), 6.46 (d, J = 7.8 Hz, 1H), 6.19 – 6.17 (m, 1H), 6.09 (s, 2H), 3.74 (d, J = 5.9 Hz, 2H). ESI-MS: m / z385.34 [MH] - , 387.21 [M+2-H] - C 18 H 15 BrN2O3 [386.03].

[0057] Example 2. Preparation of Compound 2

[0058]

[0059] White solid, yield 76.8%, melting point: 160~162℃. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ8.23 – 8.17 (m, 3H), 7.78 – 7.69 (m, 3H), 7.03 (dt, J = 7.6, 1.9 Hz, 2H), 6.48 (d, J = 7.8 Hz, 1H), 6.17 (t, J = 3.3 Hz, 1H), 6.08 (d, J = 15.5 Hz, 2H), 4.22 (t, J = 7.3 Hz, 1H), 1.30 (d, J = 7.3 Hz, 3H). ESI-MS: m / z 399.28[MH] - , 401.21 [M+2-H] - C 19 H 17 BrN2O3[400.04].

[0060] Example 3. Preparation of Compound 3

[0061]

[0062] White solid, yield 77.1%, melting point: 186~188℃. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ12.08 (s, 1H), 8.20 (dd, J = 8.2, 6.1 Hz, 2H), 8.05 (s, 1H), 7.79 – 7.68 (m,3H), 6.97 (dt, J = 8.6, 2.1 Hz, 2H), 6.61 (d, J = 7.8 Hz, 1H), 6.13 (t, J =3.3 Hz, 1H), 6.06 (s, 2H), 1.36 (s, 6H). ESI-MS: m / z 413.30 [MH] - , 415.34 [M+2-H] - C 20 H 19 BrN2O3 [414.06].

[0063] Preparation of compounds 4a-6a

[0064] II-3 (0.20 g, 0.69 mmol) was placed in a 25 mL flask, dissolved in 15 mL of DCM, and then HATU (0.39 g, 1.03 mmol) was added. The mixture was stirred in an ice bath for 30 min, and then DIPEA (0.27 g, 2.06 mmol) was added. After stirring for another 10 min, glycine methyl hydrochloride (0.12 g, 0.82 mmol), D / L-alanine methyl hydrochloride (0.12 g, 0.82 mmol), or 2-aminoisobutyrate methyl hydrochloride (0.12 g, 0.82 mmol) was added. The ice bath was removed, and the mixture was stirred at room temperature for 12 h before TLC analysis. After the reaction was complete, 50 mL of EA and 50 mL of water were added. The mixture was extracted and separated, and the organic phase was washed with saturated NaCl aqueous solution (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then subjected to column chromatography (EA:PE = 1:5) to obtain the product. Recrystallization of EA yielded the target compounds 4a-6a. Compound 4a was a white solid with a yield of 71.8%, a melting point of 112–114 °C, and an ESI-MS value of m / z 363.46 [M+H]. + . C 22 H 22 N₂O₃ [362.16]. Compound 5a, white solid, yield: 73.0%, melting point: 118–120 °C, ESI-MS: m / z 377.23 [M+H] + . C 23 H 24 N₂O₃ [376.18]. Compound 6a, white solid, yield: 72.5%, melting point: 135–137 °C, ESI-MS: m / z 391.07 [M+H] + . C 24 H 26 N2O3 [390.19].

[0065] Preparation of compounds 4-6

[0066] Compound 4a (0.13 g, 0.36 mmol) was placed in a 25 mL flask and dissolved in a mixture of 5 mL tetrahydrofuran and 5 mL methanol. Lithium hydroxide (0.09 g, 3.60 mmol) was dissolved in a small amount of water and added dropwise to the above solution. The mixture was then stirred at room temperature for 4 h. After the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure. 10 mL of water was added to the residue, and the pH was adjusted to 2-3 by adding 1 M HCl solution dropwise. The product was collected by filtration and recrystallized from ethanol to give compound 4. The preparation of compounds 5 and 6 was carried out in the same manner.

[0067] Example 4. Preparation of Compound 4

[0068]

[0069] White solid, yield 74.0%, melting point: 142~144℃. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6)δ 8.47 – 8.42 (m, 1H), 8.34 (t, J = 5.9 Hz, 1H), 8.14 – 8.09 (m, 1H), 7.60(dq, J = 12.7, 6.5 Hz, 2H), 7.13 (d, J = 7.3 Hz, 1H), 6.97 – 6.92 (m, 2H), 6.56 (d, J = 7.4 Hz, 1H), 6.13 (t, J = 3.2 Hz, 1H), 6.06 (s, 2H), 3.76 (d, J= 5.9 Hz, 2H), 2.39 – 2.33 (m, 1H), 1.05 – 0.99 (m, 2H), 0.68 (dt, J = 5.6,2.9 Hz, 2H). ESI-MS: m / z 347.29 [MH] - C 21 H 20 N2O3 [348.15].

[0070] Example 5. Preparation of Compound 5

[0071]

[0072] White solid, yield 77.2%, melting point: 144~146℃. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ8.44 (d, J = 8.1 Hz, 1H), 8.22 (d, J = 7.4 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.61 (p, J = 6.9 Hz, 2H), 7.13 (d, J = 7.4 Hz, 1H), 7.02 (d, J = 3.9 Hz, 1H), 6.93 (s, 1H), 6.58 (d, J = 7.4 Hz, 1H), 6.13 (t, J = 3.4 Hz, 1H), 6.08 (s,1H), 6.03 (s, 1H), 4.28 (q, J = 7.3 Hz, 1H), 2.39 – 2.33 (m, 1H), 1.32 (d, J= 7.3 Hz, 3H), 1.02 (dd, J = 9.0, 4.6 Hz, 2H), 0.68 (t, J = 4.9 Hz, 2H). ESI-MS: m / z 361.39 [MH] - C 22 H 22 N2O3 [362.16].

[0073] Example 6. Preparation of Compound 6

[0074]

[0075] White solid, yield 80.1%, melting point: 162~164℃. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ12.06 (s, 1H), 8.45 – 8.42 (m, 1H), 8.20 – 8.09 (m, 2H), 7.64 – 7.56 (m, 2H),7.14 (dd, J = 7.4, 2.7 Hz, 1H), 6.97 – 6.88 (m, 2H), 6.64 (d, J = 7.3 Hz, 1H), 6.09 (ddd, J = 7.8, 3.9, 2.7 Hz, 1H), 6.05 – 6.00 (m, 2H), 2.36 (q, J =5.3, 4.2 Hz, 1H), 1.37 (d, J = 4.4 Hz, 6H), 1.05 – 1.01 (m, 2H), 0.67 (dt, J= 5.5, 2.6 Hz, 2H). ESI-MS: m / z 375.37 [MH] - C 23 H 24 N2O3 [376.18].

[0076] Synthesis of compounds 7-36:

[0077]

[0078] Reagents and conditions: (i) NBS, BPO, n-hexane, 70℃; (ii) methyl 2-pyrrolecarboxylate, cesium carbonate, acetonitrile, 70℃; (iii) lithium hydroxide, tetrahydrofuran, methanol, room temperature; (iv) sulfonamide, DMAP, EDCI, DCM, 0℃ to room temperature; (v) tricyclohexylphosphine, cyclopropylboronic acid, palladium acetate, potassium phosphate, toluene, 100℃, nitrogen.

[0079] Preparation of compound 7-21

[0080] II-2 (0.20 g, 0.60 mmol) was placed in a 25 mL flask, dissolved in 15 mL of DCM, and then DMAP (0.11 g, 0.91 mmol) and EDCI (0.18 g, 0.91 mmol) were added sequentially. After stirring and activating in an ice bath for 15 min, different substituted sulfonamide groups (0.72 mmol) were added. The ice bath was removed, and the reaction was stirred at room temperature for 12 h before TLC detection. After the reaction was complete, 10 mL of DCM was added, and the mixture was washed successively with saturated NaHCO3, 1 M HCl, and saturated NaCl solution (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography (EA : PE : glacial acetic acid = 1:5:2%) to obtain the target compound 7-21.

[0081] Example 7. Preparation of Compound 7

[0082]

[0083] Following experimental step II-2 above, benzenesulfonamide (0.11 g, 0.82 mmol) was reacted to yield a white solid product in 80.2% yield, with a melting point of 224–226 °C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.84 – 7.81 (m, 2H), 7.75 – 7.57 (m, 5H), 7.52 (d, J = 7.7 Hz, 1H), 7.35 (q,J = 1.9 Hz, 1H), 7.23 (t, J = 2.1 Hz, 1H), 6.30 – 6.22 (m, 2H), 5.91 (s, 2H).ESI-MS: m / z 467.23 [MH] - 469.36 [M+2-H] - C 22 H 17 BrN2O3S [468.01].

[0084] Example 8. Preparation of Compound 8

[0085]

[0086] Following experimental step II-2 above, 0.20 g (0.60 mmol) was reacted with 4-bromobenzenesulfonamide (0.17 g, 0.82 mmol) to give a white solid product in 81.1% yield, with a melting point of 227–229 °C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.80 – 7.65 (m, 7H), 7.33 (d, J = 4.0 Hz, 1H), 7.25 (s, 1H), 6.34 – 6.21 (m,2H), 5.91 (s, 2H). ESI-MS: m / z 544.53 [MH] - 547.26 [M+2-H] - C 22 H 16 Br2N2O3S [545.92].

[0087] Example 9. Preparation of Compound 9

[0088]

[0089] Following experimental step II-2 above, 0.20 g (0.60 mmol) was reacted with 4-chlorobenzenesulfonamide (0.14 g, 0.82 mmol) to give a white solid product in 76.2% yield, with a melting point of 235–237 °C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.76 – 7.64 (m, 3H), 7.58 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 4.1 Hz, 1H), 7.26 (t, J = 2.1 Hz, 1H), 6.30 – 6.23 (m, 2H), 5.91 (s,2H). ESI-MS: m / z 500.83 [MH] - 503.02 [M+2-H] - C 22 H 16 BrClN2O3S [501.98].

[0090] Example 10. Preparation of Compound 10

[0091]

[0092] Following experimental step II-2 above, 0.20 g (0.60 mmol) was reacted with 4-fluorobenzenesulfonamide (0.13 g, 0.82 mmol) to give a white solid product in 85.0% yield, with a melting point of 231–233 °C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.88 (ddd, J = 9.0, 5.2, 2.1 Hz, 3H), 7.73 (t, J = 7.6 Hz, 1H), 7.67(dd, J = 7.9, 5.4 Hz, 2H), 7.40 (t, J = 4.4 Hz, 1H), 7.35 – 7.32 (m, 2H), 7.25 (t, J = 2.2 Hz, 1H), 6.29 – 6.23 (m, 2H), 5.91 (s, 2H). ESI-MS: m / z 485.38 [MH] - , 487.21 [M+2-H] - C 22 H 16 BrFN2O3S [486.00].

[0093] Example 11. Preparation of Compound 11

[0094]

[0095] Following experimental step II-2 above, 0.20 g, 0.60 mmol was reacted with p-methoxybenzenesulfonamide (0.14 g, 0.82 mmol) to give a white solid product in 74.4% yield, with a melting point of 211–213 °C. Spectroscopic data: 1H NMR (400MHz, DMSO-d6) δ 11.86 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.79 – 7.72 (m, 3H), 7.67 (t, J = 7.3 Hz, 2H), 7.34 (d, J = 4.1 Hz, 1H), 7.23 (s, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.31 – 6.21 (m, 2H), 5.92 (s, 2H).ESI-MS: m / z 497.23 [MH] - , 499.36 [M+2-H] - C 23 H 19 BrN2O4S [498.02].

[0096] Example 12. Preparation of Compound 12

[0097]

[0098] Following experimental step II-2 above, 0.20 g (0.60 mmol) was reacted with m-nitrobenzenesulfonamide (0.15 g, 0.82 mmol) to give a white solid product in 81.2% yield, with a melting point of 215–217 °C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.49 (t, J = 2.1 Hz, 1H), 8.42 (dd, J = 8.2, 2.3Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.4Hz, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.64 (d, J = 7.8Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.36 – 7.29 (m, 2H), 6.27 (dd, J = 4.1,2.5 Hz, 1H), 6.19 (d, J = 7.8 Hz, 1H), 5.88 (s, 2H). ESI-MS: m / z 512.26 [MH] - , 514.31 [M+2-H]- C 22 H 16 BrN3O5S [513.00].

[0099] Example 13. Preparation of Compound 13

[0100]

[0101] Following experimental step II-2 above, 0.20 g (0.60 mmol) was reacted with 2-nitrobenzenesulfonamide (0.15 g, 0.82 mmol) to give a pale yellow solid product in 74.6% yield, with a melting point of 207–209 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ 12.47 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.05 (dd, J = 15.1,8.1 Hz, 2H), 7.94 (d, J = 7.9 Hz, 1H), 7.83 (t, J = 7.7 Hz, 1H), 7.72 (dt, J= 8.0, 4.2 Hz, 3H), 7.65 (d, J = 7.7 Hz, 1H), 7.50 (d, J = 4.2 Hz, 1H), 7.27(s, 1H), 6.32 – 6.27 (m, 2H), 5.92 (s, 2H). ESI-MS: m / z 512.16 [MH] - , 514.27[M+2-H] - C 22 H 16 BrN3O5S [513.00].

[0102] Example 14. Preparation of Compound 14

[0103]

[0104] Following experimental step II-2 above, 0.20 g (0.60 mmol) was reacted with m-bromobenzenesulfonamide (0.17 g, 0.82 mmol) to give a white solid product in 83.8% yield, with a melting point of 195–197 °C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.83 (dd, J = 10.7, 8.1 Hz, 2H), 7.73 (t, J = 7.6Hz, 1H), 7.66 (dd, J = 7.8, 2.5 Hz, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.37 –7.33 (m, 1H), 7.28 (t, J = 2.2 Hz, 1H), 6.26 (dd, J = 6.7, 2.8 Hz, 2H), 5.91(s, 2H). ESI-MS: m / z 544.91 [MH] - 547.15 [M+2-H] - C 22 H 16 Br2N2O3S [545.92].

[0105] Example 15. Preparation of Compound 15

[0106]

[0107] Following experimental step II-2 above, 0.20 g (0.60 mmol) was reacted with 5-chlorothiophene-2-sulfonamide (0.14 g, 0.82 mmol) to give a white solid product in 72.4% yield, with a melting point of 211–213 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ 12.35 (s, 1H), 8.23 ​​– 8.17 (m, 2H), 7.77 – 7.67 (m, 3H), 7.49(d, J = 4.1 Hz, 1H), 7.23 (d, J = 3.2 Hz, 2H), 7.11 (d, J = 4.1 Hz, 1H), 6.38 (d, J = 7.8 Hz, 1H), 6.23 (t, J = 3.3 Hz, 1H), 6.02 (s, 2H). ESI-MS: m / z506.69 [MH] - , 509.21 [M+2-H] - C 20 H 14BrClN2O3S2[507.93].

[0108] Example 16. Preparation of Compound 16

[0109]

[0110] Following experimental step II-2 described above, 0.20 g (0.60 mmol) was reacted with 4-(2-hydroxy-2-propyl)furan-2-sulfonamide (0.15 g (0.82 mmol)) to give a white solid product in 71.2% yield, with a melting point of 169–171 °C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 11.98 (s, 1H), 8.19 (dd, J = 8.4,1.4 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.77 – 7.66 (m, 4H), 7.34 (s, 1H),7.23 (s, 1H), 7.08 (s, 1H), 6.31 (d, J = 7.8 Hz, 1H), 6.24 (dd, J = 4.1, 2.5Hz, 1H), 5.99 (s, 2H), 1.29 (s, 6H) ESI-MS: m / z 515.38 [MH] - 517.48 [M+2-H] - C 23 H 21 BrN2O5S [516.04].

[0111] Example 17. Preparation of Compound 17

[0112]

[0113] Following experimental step II-2 above, 0.20 g (0.60 mmol) was reacted with methanesulfonamide (0.07 g, 0.82 mmol) to give a white solid product in 86.3% yield, with a melting point of 199–201 °C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.24 – 8.17 (m, 2H), 7.81 – 7.72 (m, 3H), 7.38 (dd,J = 4.1, 1.6 Hz, 1H), 7.28 (t, J = 2.1 Hz, 1H), 6.39 (d, J = 7.8 Hz, 1H), 6.27 (dd, J = 4.2, 2.5 Hz, 1H), 6.05 (s, 2H), 3.21 (s, 3H). ESI-MS: m / z405.24 [MH] - 407.36 [M+2-H] - C 17 H 15 BrN2O3S [406.00].

[0114] Example 18. Preparation of Compound 18

[0115]

[0116] Following experimental step II-2 above, 0.20 g (0.60 mmol) was reacted with ethylsulfonamide (0.08 g, 0.82 mmol) to give a white solid product in 83.9% yield, with a melting point of 195–197 °C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​– 8.17 (m, 2H), 7.80 – 7.72 (m, 3H), 7.38 (dd, J = 4.2, 1.7Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 6.38 (d, J = 7.7 Hz, 1H), 6.27 (dd, J =4.1, 2.5 Hz, 1H), 6.04 (s, 2H), 3.30 (d, J = 7.3 Hz, 2H), 1.13 (d, J = 7.3Hz, 3H). ESI-MS: m / z 419.33 [MH] - , 421.25 [M+2-H] - C 18 H 17 BrN2O3S [420.01].

[0117] Example 19. Preparation of Compound 19

[0118]

[0119] Following experimental step II-2 above, 0.20 g (0.60 mmol) was reacted with tert-butylsulfonamide (0.10 g, 0.82 mmol) to give a white solid product in 86.1% yield, with a melting point of 187–189 °C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.20 (d, J = 2.9 Hz, 1H), 7.78 – 7.73 (m, 3H), 7.38 (dd, J = 4.2, 1.7 Hz, 1H), 7.31 (t, J = 2.1 Hz, 1H), 7.20 (t, J = 2.2Hz, 1H), 6.35 (s, 1H), 6.27 (dd, J = 4.1, 2.6 Hz, 1H), 6.02 (s, 2H), 1.24 (s,9H). ESI-MS: m / z 447.26 [MH] - 449.55 [M+2-H] - C 20 H 21 BrN2O3S [448.05].

[0120] Example 20. Preparation of Compound 20

[0121]

[0122] Following experimental step II-2 above, 0.20 g (0.60 mmol) was reacted with cyclopropylsulfonamide (0.09 g, 0.82 mmol) to give a white solid product in 82.4% yield, with a melting point of 173–175 °C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 8.24 – 8.17 (m, 2H), 7.81 – 7.70 (m, 3H), 7.37 (dd,J = 4.1, 1.7 Hz, 1H), 7.32 (t, J = 2.1 Hz, 1H), 6.37 (dd, J = 7.8, 2.5 Hz, 1H), 6.28 (dd, J = 4.1, 2.6 Hz, 1H), 6.05 (d, J = 10.6 Hz, 2H), 3.63 – 3.53(m, 1H), 3.54 (s, 1H), 1.19 (d, J = 6.9 Hz, 4H). ESI-MS: m / z 431.16 [MH] - 433.26 [M+2-H] - C 19 H 17 BrN2O3S [432.01].

[0123] Example 21. Preparation of Compound 21

[0124]

[0125] Following experimental step II-2 above, 0.20 g (0.60 mmol) was reacted with propylsulfonamide (0.09 g, 0.82 mmol) to give a white solid product in 80.6% yield, with a melting point of 195–197 °C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.20 (t, J = 8.7 Hz, 2H), 7.80 – 7.71 (m, 3H), 7.38– 7.34 (m, 1H), 7.31 (t, J = 2.2 Hz, 1H), 6.35 (d, J = 7.8 Hz, 1H), 6.27 (dd,J = 4.2, 2.5 Hz, 1H), 6.04 (s, 2H), 3.28 – 3.22 (m, 2H), 1.56 (q, J = 7.5 Hz,2H), 0.84 (t, J = 7.4 Hz, 3H). ESI-MS: m / z 433.26 [MH] - 435.36 [M+2-H] - C 19 H 19BrN2O3S [434.03].

[0126] Preparation of compounds 22-36

[0127] II-3 (0.20 g, 0.69 mmol) was placed in a 25 mL flask, dissolved in 15 mL of DCM, and then DMAP (0.12 g, 1.03 mmol) and EDCI (0.20 mg, 1.03 mmol) were added sequentially. After stirring and activating in an ice bath for 15 min, different substituted sulfonamide groups (0.82 mmol) were added. The ice bath was removed, and the reaction was stirred at room temperature for 12 h before TLC detection. After the reaction was complete, 10 mL of DCM was added, and the mixture was washed successively with saturated NaHCO3, 1 M HCl, and saturated NaCl solution (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography (EA:PE:glacial acetic acid = 1:5:2%) to obtain the target compound 22-36.

[0128] Example 22. Preparation of Compound 22

[0129]

[0130] Following experimental step II-3 above, benzenesulfonamide (0.13 g, 0.82 mmol) was reacted to yield a white solid product in 76.4% yield, with a melting point of 185–187 °C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.43 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.90 – 7.86 (m, 2H), 7.86 – 7.80 (m, 1H), 7.70 – 7.50 (m, 6H), 7.40 – 7.30 (m, 2H), 7.05 (d, J = 7.4 Hz, 1H), 6.39 (d, J = 7.4 Hz, 1H), 6.20 (dd, J =4.1, 2.6 Hz, 1H), 5.88 (s, 2H), 2.39 – 2.29 (m, 1H), 1.10 – 0.95 (m, 2H),0.74 – 0.58 (m, 2H). ESI-MS: m / z 429.31 [MH] - C 25 H 22 N2O3S [430.14].

[0131] Example 23. Preparation of compound 23

[0132]

[0133] Following experimental step II-3 above, 0.20 g (0.69 mmol) was reacted with 4-bromobenzenesulfonamide (0.19 g, 0.82 mmol) to give a white solid product in 82.6% yield, with a melting point of 183–185 °C. Spectroscopic data: 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 8.44 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.84 – 7.74 (m, 5H), 7.62 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.32 (dd, J = 4.2, 1.7 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.39 (d, J = 7.4 Hz, 1H), 6.21 (dd, J = 4.1, 2.6 Hz, 1H), 5.88 (s, 2H), 2.36 (td, J = 8.8, 4.4 Hz,1H), 1.11 – 0.96 (m, 2H), 0.78 – 0.59 (m, 2H). ESI-MS: m / z 507.13 [MH] - 509.20 [M+2-H] - C 25 H 21 BrN2O3S [508.05].

[0134] Example 24. Preparation of compound 24

[0135]

[0136] Following experimental step II-3 above, 0.20 g (0.69 mmol) was reacted with 4-chlorobenzenesulfonamide (0.16 g, 0.82 mmol) to give a white solid product in 83.2% yield, with a melting point of 195–196 °C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.92 – 7.82 (m, 2H), 7.69 – 7.49 (m, 4H), 7.33 (dd, J = 4.1, 1.7 Hz, 1H), 7.20 (t, J = 2.1 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 6.37 (d, J = 7.4 Hz, 1H), 6.21 (dd, J = 4.1, 2.5 Hz, 1H), 5.88 (s, 2H), 2.35 (td, J = 8.4, 4.3 Hz, 1H), 1.09 – 0.97 (m, 2H), 0.78 – 0.50 (m, 2H). ESI-MS: m / z 463.13 [MH] - 465.26[M+2-H] - C 25 H 21 ClN2O3S [464.10].

[0137] Example 25. Preparation of compound 25

[0138]

[0139] Following experimental step II-3 above, 0.20 g (0.69 mmol) was reacted with 4-fluorobenzenesulfonamide (0.14 g, 0.82 mmol) to give a white solid product in 84.5% yield, with a melting point of 179–181 °C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.37 (dd, J = 28.5, 8.5 Hz, 3H), 8.09 (d, J = 8.7Hz, 2H), 7.98 (d, J = 8.3 Hz, 1H), 7.58 (dt, J = 24.1, 7.3 Hz, 2H), 7.34 (dd,J = 4.1, 1.6 Hz, 1H), 7.22 (t, J = 2.2 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.33 (d, J = 7.4 Hz, 1H), 6.24 (dd, J = 4.1, 2.5 Hz, 1H), 5.87 (s, 2H), 2.32(td, J = 8.5, 4.2 Hz, 1H), 1.08 – 0.97 (m, 2H), 0.70 – 0.56 (m, 2H). ESI-MS: m / z 447.32 [MH] - , 449.21 [M+2-H] - C 25 H 21 FN2O3S [448.13].

[0140] Example 26. Preparation of Compound 26

[0141]

[0142] Following experimental step II-3 above, 0.20 g (0.69 mmol) was reacted with p-methoxybenzenesulfonamide (0.15 g, 0.82 mmol) to give a white solid product in 84.0% yield, with a melting point of 179–180 °C. Spectroscopic data: 1H NMR (400MHz, DMSO-d6) δ 11.87 (s, 1H), 8.43 (dd, J = 8.5, 2.6 Hz, 1H), 8.01 (dd, J =8.1, 2.6 Hz, 1H), 7.82 (ddt, J = 7.5, 5.2, 2.8 Hz, 2H), 7.68 – 7.51 (m, 2H), 7.32 (dt, J = 4.2, 2.0 Hz, 1H), 7.19 – 7.00 (m, 4H), 6.39 (dd, J = 7.7, 2.5Hz, 1H), 6.19 (td, J = 4.1, 2.1 Hz, 1H), 5.90 (s, 2H), 3.93 – 3.78 (m, 3H), 2.34 (t, J = 7.3 Hz, 1H), 1.02 (ddt, J = 8.6, 4.3, 2.3 Hz, 2H), 0.67 (dp, J =5.9, 2.7, 2.0 Hz, 2H). ESI-MS: m / z 459.03 [MH] - C 26 H 24 N2O4S [460.15].

[0143] Example 27. Preparation of Compound 27

[0144]

[0145] Following experimental step II-3 above, 0.20 g (0.69 mmol) was reacted with m-nitrobenzenesulfonamide (0.16 g, 0.82 mmol) to give a white solid product in 82.6% yield, with a melting point of 177–179 °C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.56 (t, J = 2.0 Hz, 1H), 8.51 – 8.38 (m, 2H), 8.27(d, J = 7.8 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.57 (dt, J = 31.4, 7.4 Hz, 2H), 7.33 (dd, J = 4.2, 1.6 Hz, 1H), 7.22 (t, J = 2.1Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H), 6.33 (d, J = 7.4 Hz, 1H), 6.23 (dd, J =4.1, 2.6 Hz, 1H), 5.86 (s, 2H), 2.33 (td, J = 8.5, 4.2 Hz, 1H), 1.02 (dt, J =8.9, 3.1 Hz, 2H), 0.69 – 0.62 (m, 2H). ESI-MS: m / z 474.35 [MH] - C 25 H 21 N3O5S [475.12].

[0146] Example 28. Preparation of compound 28

[0147]

[0148] Following experimental step II-3 above, 0.20 g (0.69 mmol) was reacted with 2-nitrobenzenesulfonamide (0.16 g, 0.82 mmol) to give a pale yellow solid product in 80.2% yield, with a melting point of 185–187 °C. Spectroscopic data: 1H NMR (400MHz, DMSO-d6) δ 12.49 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.83 (dt, J = 35.8, 7.7 Hz, 2H), 7.68 – 7.46(m, 3H), 7.20 (s, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.37 (d, J = 7.4 Hz, 1H), 6.31 – 6.21 (m, 1H), 5.89 (s, 2H), 2.34 (d, J = 7.6 Hz, 1H), 1.02 (d, J = 8.0Hz, 2H), 0.67 (d, J = 5.4 Hz, 2H). ESI-MS: m / z 474.35 [MH] - C 25 H 21 N3O5S [475.12].

[0149] Example 29. Preparation of compound 29

[0150]

[0151] Following experimental step II-3 above, 0.20 g (0.69 mmol) was reacted with m-bromobenzenesulfonamide (0.19 g, 0.82 mmol) to give a white solid product in 84.8% yield, with a melting point of 153–155 °C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.04 – 7.95 (m, 2H), 7.88(t, J = 7.9 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.54 (dt, J = 7.2, 3.5 Hz, 2H), 7.32 (dd, J = 4.2, 1.5 Hz, 1H), 7.21 (t, J = 2.1 Hz, 1H), 7.04 (d, J =7.4 Hz, 1H), 6.38 (d, J = 7.4 Hz, 1H), 6.22 (dd, J = 4.1, 2.6 Hz, 1H), 5.88(s, 2H), 2.34 (td, J = 8.5, 4.2 Hz, 1H), 1.07 – 0.98 (m, 2H), 0.66 (dt, J =6.1, 3.0 Hz, 2H). ESI-MS: m / z 507.23 [MH] - 509.32 [M+2-H] - C 25 H 21 BrN2O3S [508.05].

[0152] Example 30. Preparation of compound 30

[0153]

[0154] Following experimental step II-3 above, 0.20 g (0.69 mmol) was reacted with 5-chlorothiophene-2-sulfonamide (0.15 g, 0.82 mmol) to give a white solid product in 78.9% yield, with a melting point of 175–177 °C. Spectroscopic data: 1H NMR (400MHz, DMSO-d6) δ 12.33 (s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.61 (tt, J = 13.8, 7.2 Hz, 3H), 7.30 (dd, J = 4.2, 1.6 Hz, 1H), 7.25 –7.18 (m, 2H), 7.08 (d, J = 7.3 Hz, 1H), 6.45 (d, J = 7.4 Hz, 1H), 6.22 (dd, J= 4.1, 2.6 Hz, 1H), 5.96 (s, 2H), 2.36 (ddd, J = 13.7, 8.5, 5.3 Hz, 1H), 1.08– 1.00 (m, 2H), 0.67 (dt, J = 5.6, 2.9 Hz, 2H). ESI-MS: m / z 469.42 [MH] - 471.17 [M+2-H] - C 23 H 19 ClN2O3S2[470.05].

[0155] Example 31. Preparation of compound 31

[0156]

[0157] Following experimental step II-3 above (0.20 g, 0.69 mmol), 4-(2-hydroxy-2-propyl)furan-2-sulfonamide (0.17 g, 0.82 mmol) was reacted to give a white solid product in 74.2% yield, with a melting point of 177–179 °C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ 12.12 (d, J = 93.0 Hz, 1H), 8.44 (dd, J = 8.3,1.3 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.64 – 7.54 (m, 2H),7.34 – 7.23 (m, 1H), 7.11 (d, J = 6.9 Hz, 3H), 6.43 (d, J = 7.4 Hz, 1H), 6.24– 6.16 (m, 1H), 5.96 (s, 2H), 5.09 (s, 1H), 2.35 (td, J = 8.4, 4.2 Hz, 1H),1.32 (s, 6H), 1.01 (dt, J = 8.6, 3.0 Hz, 2H), 0.67 (dt, J = 6.0, 3.0 Hz, 2H).ESI-MS: m / z 477.47 [MH] - C 26 H 26 N2O5S [478.16].

[0158] Example 32. Preparation of compound 32

[0159]

[0160] Following experimental step II-3 above, 0.20 g (0.69 mmol) was reacted with methanesulfonamide (0.08 g, 0.82 mmol) to give a white solid product in 83.6% yield, with a melting point of 174–176 °C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.51 – 8.43 (m, 1H), 8.14 – 8.07 (m, 1H), 7.69 –7.59 (m, 2H), 7.39 – 7.34 (m, 1H), 7.20 (t, J = 2.2 Hz, 1H), 7.15 (d, J = 7.4Hz, 1H), 6.44 (d, J = 7.4 Hz, 1H), 6.24 (t, J = 3.2 Hz, 1H), 6.03 (s, 2H), 3.24 (s, 3H), 2.38 (dd, J = 13.1, 7.0 Hz, 1H), 1.03 (dq, J = 6.4, 4.2 Hz, 2H), 0.69 (dt, J = 5.5, 2.7 Hz, 2H). ESI-MS: m / z 367.31 [MH] - C 20 H 20 N2O3S [368.12].

[0161] Example 33. Preparation of compound 33

[0162]

[0163] Following experimental step II-3 above, 0.20 g (0.69 mmol) was reacted with ethylsulfonamide (0.09 g, 0.82 mmol) to give a white solid product in 84.6% yield, with a melting point of 167–169 °C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.45 (dd, J = 7.5, 2.0 Hz, 1H), 8.09 (dd, J = 7.6,2.0 Hz, 1H), 7.63 (tt, J = 6.8, 5.2 Hz, 2H), 7.35 (dd, J = 4.1, 1.7 Hz, 1H), 7.23 (t, J = 2.1 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 6.44 (d, J = 7.4 Hz, 1H), 6.23 (dd, J = 4.1, 2.5 Hz, 1H), 6.01 (s, 2H), 3.32 (t, J = ESI-MS: m / z 381.32 [MH] - C 21 H 22 N2O3S [382.14].

[0164] Example 34. Preparation of compound 34

[0165]

[0166] Following experimental step II-3 above, 0.20 g (0.69 mmol) was reacted with tert-butylsulfonamide (0.11 g, 0.82 mmol) to give a white solid product in 78.4% yield, with a melting point of 153–155 °C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.45 (dt, J = 8.0, 1.7 Hz, 1H), 8.10 (ddd, J = 7.5,4.0, 1.5 Hz, 1H), 7.62 (tt, J = 7.5, 1.5 Hz, 2H), 7.33 (dd, J = 4.1, 1.7 Hz,1H), 7.23 (t, J = 2.1 Hz, 1H), 7.14 – 7.10 (m, 1H), 6.42 (t, J = 7.2 Hz, 1H), 6.21 (ddd, J = 13.1, 4.0, 2.6 Hz, 1H), 5.99 (s, 2H), 2.35 (td, J = 8.4, 4.2Hz, 1H), 1.25 (s, 9H), 1.04 – 1.01 (m, 2H), 0.68 – 0.65 (m, 2H). ESI-MS: m / z409.36 [MH] - C 23 H 26 N2O3S [410.17].

[0167] Example 35. Preparation of compound 35

[0168]

[0169] Following experimental step II-3 above, 0.20 g (0.69 mmol) was reacted with cyclopropylsulfonamide (0.10 g, 0.82 mmol) to give a white solid product in 81.4% yield, with a melting point of 179–181 °C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.49 – 8.42 (m, 1H), 8.12 – 8.06 (m, 1H), 7.64 (q,J = 7.6, 7.0 Hz, 2H), 7.33 (d, J = 4.2 Hz, 1H), 7.24 (d, J = 2.6 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H), 6.44 (d, J = 7.5 Hz, 1H), 6.26 – 6.21 (m, 1H), 6.01(s, 2H), 3.60 (h, J = 6.9 Hz, 1H), 2.36 (h, J = 5.9, 5.1 Hz, 1H), 1.19 (d, J= 6.9 Hz, 6H), 1.02 (h, J = 4.1 Hz, 2H), 0.67 (t, J = 5.1 Hz, 2H). ESI-MS: m / z 393.36 [MH] - C 22 H 22 N2O3S [394.14].

[0170] Example 36. Preparation of compound 36

[0171]

[0172] Following experimental step II-3 above, 0.20 g (0.69 mmol) was reacted with propylsulfonamide (0.10 g, 0.82 mmol) to give a white solid product in 84.6% yield, with a melting point of 191–193 °C. Spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.49 – 8.43 (m, 1H), 8.15 – 8.07 (m, 1H), 7.63 (tt,J = 6.9, 5.2 Hz, 2H), 7.34 (dd, J = 4.1, 1.7 Hz, 1H), 7.23 (t, J = 2.1 Hz,1H), 7.13 (d, J = 7.4 Hz, 1H), 6.41 (d, J = 7.4 Hz, 1H), 6.23 (dd, J = 4.1,2.6 Hz, 1H), 6.02 (s, 2H), 3.32 – 3.25 (m, 2H), 2.37 (td, ESI-MS: m / z 395.34 [MH] - C 22 H 24 N2O3S [396.15].

[0173] Example 37. In vivo uric acid-lowering activity assay of the target compound

[0174] Test materials and methods:

[0175] (1) Experimental animals: Male Kunming mice weighing approximately 20 g were provided by Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0176] (2) Sample preparation: Before use, the compound to be tested is prepared with sodium carboxymethyl cellulose (CMC-Na) and DMSO to an appropriate concentration.

[0177] (3) Modeling drugs: hypoxanthine, potassium oxonate.

[0178] (4) Positive control drugs: Lesinurad, Benzbromarone.

[0179] (5) Testing instruments: Huihao Yousu uric acid tester and uric acid test strips.

[0180] (6) Experimental principle: A mouse model of acute hyperuricemia was established by subcutaneous injection of potassium oxonate combined with gavage administration of hypoxanthine. Then, positive control drugs and test compounds were administered by gavage. By measuring the changes in serum uric acid levels in mice after administration, compounds with excellent in vivo activity were screened.

[0181] (7) Test method:

[0182] Mice were randomly divided into 5 groups after one week of acclimatization. For the first 12 hours of the experiment, mice were fasted but allowed free access to water. The experimental group received 0.2 mL of hypoxanthine suspension (60 mg / mL) by gavage, 0.2 mL of potassium oxonate suspension (40 mg / mL) subcutaneously, and 0.2 mL of a compound solution (0.2 mg / mL) by gavage. The control group received 0.2 mL of hypoxanthine suspension (60 mg / mL) by gavage, 0.2 mL of potassium oxonate suspension (40 mg / mL) subcutaneously, and 0.2 mL of Lesinurad or Benzbromarone solution (0.2 mg / mL) by gavage. The model group received 0.2 mL of hypoxanthine suspension (60 mg / mL) by gavage, 0.2 mL of potassium oxonate suspension (40 mg / mL) subcutaneously, and 0.2 mL of a blank solution by gavage. The blank control group received 0.4 mL of a blank solution by gavage and 0.2 mL of a blank solution subcutaneously. Four hours later, mice were anesthetized, their eyeballs were enucleated to collect blood, and they were euthanized by spinal dislocation. After clotting for 30 minutes, the blood was centrifuged, and the supernatant serum was collected. The serum uric acid concentration was measured using a uric acid analyzer. The serum uric acid concentration reduction rate (DR)% = (model value - experimental value) / (model value - blank value) × 100%. The higher the DR value, the better the activity.

[0183] Table 2. Uric acid-lowering activity of compounds 1-36

[0184]

[0185] The structures of compounds 1-36 are shown in Table 1. (Where: A indicates a DR value of 85% or higher; B indicates a DR value in the range of 65% to 85%; C indicates a DR value in the range of 45% to 65%; D indicates a DR value of less than 45%)

[0186] Conclusion: As shown in Table 2, 23 compounds exhibited significant uric acid-lowering activity, which was superior to the positive control drugs Lesinurad and Benzbromarone. Among them, the representative compounds 2, 4, 23, 24, 25, 27, 32, and 33 all showed a uric acid reduction rate of over 85% in animal activity tests, demonstrating excellent uric acid-lowering activity and can be used as lead compounds for uric acid-lowering drugs.

Claims

1. A pyrrole derivative or a pharmaceutically acceptable salt thereof, having the structure shown in general formulas I and II: in, R1 is cyclopropyl or bromine; R2 is methylene, isopropylene, or tert-butylene; R3 is selected from phenyl, 4-bromophenyl, 4-chlorophenyl, 4-fluorophenyl, 5-chlorothiophene, 4-methoxyphenyl, 4-ethylphenyl, 3-nitrophenyl, 2-nitrophenyl, 3-bromophenyl, 4-(2-hydroxy-2-propyl)furanyl, ethyl, methyl, tert-butyl, cyclopropyl, or propyl.

2. A pyrrole derivative, characterized in that, It is one of the following compounds: 。 3. The method for preparing pyrrole derivatives as described in claim 2, characterized in that, One of the following methods: (1) Synthesis of compounds 1-6: Starting with I-0, i.e. 1-bromo-4-methylnaphthalene, N-bromosuccinimide (NBS) reacted with benzoyl peroxide (BPO) in hexane at 70°C to give intermediate I-1, i.e. 1-bromo-4-(bromomethyl)naphthalene. Subsequently, I-1 reacted with methyl 2-pyrrolecarboxylate in an acetonitrile system at 70°C under the catalysis of cesium carbonate to generate the key intermediate II-0, namely methyl 1-((4-bromonaphth-1-yl)methyl)-1H-pyrrole-2-carboxylate; II-0 was hydrolyzed with lithium hydroxide at room temperature in a mixed solution of tetrahydrofuran, methanol, and water to give II-2, namely 1-((4-bromonaphth-1-yl)methyl)-1H-pyrrole-2-carboxylic acid; in dichloromethane, under conditions from 0°C to room temperature... Below, II-2 undergoes a condensation reaction with one of the following amino acid ester hydrochlorides: glycine methyl ester hydrochloride, DL-alanine methyl ester hydrochloride, or 2-aminoisobutyrate methyl ester hydrochloride, under the combined action of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA), to give 1a-3a; subsequently, it is hydrolyzed with lithium hydroxide at room temperature in a mixed solution of tetrahydrofuran, methanol, and water to give compounds 1-3. The synthesis of compounds 4-6 is based on the synthesis of compounds 1-3, except that II-0 reacts with cyclopropylboronic acid in toluene at 100°C under nitrogen protection in the presence of tricyclohexylphosphine, potassium phosphate, and palladium acetate to generate intermediate II-1, namely methyl 1-((4-cyclopropylnaphth-1-yl)methyl)-1H-pyrrole-2-carboxylic acid. Subsequently, II-1 is hydrolyzed with lithium hydroxide at room temperature in a mixed solution of tetrahydrofuran, methanol, and water to give II-3, namely 1-((4-cyclopropylnaphth-1-yl)methyl)-1H-pyrrole-2-carboxylic acid. In dichloromethane, under conditions from 0°C to room temperature, II-3 undergoes a condensation reaction with different amino acid ester hydrochlorides in the presence of HATU and DIPEA to give 4a-6a. Then, it is hydrolyzed with lithium hydroxide at room temperature in a mixed solution of tetrahydrofuran, methanol, and water to give compounds 4-6. Route 1: Reagents and conditions: (i) NBS, BPO, n-hexane, 70℃; (ii) methyl 2-pyrrolecarboxylate, cesium carbonate, acetonitrile, 70℃; (iii) lithium hydroxide, tetrahydrofuran, methanol, water, room temperature; (iv) glycine methyl hydrochloride or DL-alanine methyl hydrochloride or methyl 2-aminoisobutyrate hydrochloride, HATU, DIPEA, dichloromethane, 0℃ to room temperature; (v) lithium hydroxide, tetrahydrofuran, methanol, water, room temperature; (vi) tricyclohexylphosphine, cyclopropylboronic acid, palladium acetate, potassium phosphate, toluene, 100℃, nitrogen atmosphere; Wherein R2 is the same as the substituent at the corresponding position in compounds 1-6 of claims 2; (2) Synthesis of compounds 7-36: The synthesis of intermediates 1-((4-bromonaphth-1-yl)methyl)-1H-pyrrole-2-carboxylic acid (II-2) and 1-((4-cyclopropylnaphth-1-yl)methyl)-1H-pyrrole-2-carboxylic acid (II-3) is consistent with steps (i), (ii), (iii), and (vi) of route one above. Subsequently, in dichloromethane at 0°C to room temperature, II-2 undergoes a condensation reaction with different sulfonamide groups in the presence of 4-dimethylaminopyridine (DMAP) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) to give compound 7-21. Replacing intermediate II-2 with the above-mentioned II-3, under the same reaction reagents and conditions as compound 7-21, intermediate II-2 undergoes a condensation reaction with different sulfonamide groups to give compounds 22-36. Route 2: Reagents and conditions: (i) NBS, BPO, n-hexane, 70℃; (ii) methyl 2-pyrrolecarboxylate, cesium carbonate, acetonitrile, 70℃; (iii) lithium hydroxide, tetrahydrofuran, methanol, water, room temperature; (iv) sulfonamide, DMAP, EDCI, dichloromethane, 0℃ to room temperature; (v) tricyclohexylphosphine, cyclopropylboronic acid, palladium acetate, potassium phosphate, toluene, 100℃, nitrogen atmosphere; R3 is the same as the substituent at the corresponding position in compounds 7-36 of claim 2.

4. The use of the pyrrole derivative of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a lead compound for a urate-lowering drug.

5. The use of the pyrrole derivatives according to claim 2 in the preparation of lead compounds for uric acid-lowering drugs.

6. A uric acid-lowering drug lead compound composition comprising a pyrrole derivative as described in any one of claims 1-2, and a pharmaceutically acceptable excipient.

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