CN116874406A - Indolyl sulfonamide compound and preparation method and application thereof - Google Patents

Abstract

The invention relates to an indolylsulfonamide compound and its preparation method and application. The compound has the structure shown in Formula I. The present invention also relates to preparation methods and pharmaceutical compositions containing compounds having the structure of formula I. The present invention also provides the use of the above-mentioned compounds in the preparation of uric acid-lowering drugs.

Description

Indole acyl sulfonamide compound and preparation method and application thereof

Technical Field

The present invention belongs to the technical field of organic compound synthesis and pharmaceutical application. Specifically, the present invention relates to an indole acyl sulfonamide compound and a preparation method thereof or a drug combination containing the same, and the use thereof in medicine.

Background Art

Hyperuricemia (HUA) refers to fasting blood uric acid levels >420μmol/L on two different days under a normal purine diet. Gout refers to a crystal-related arthropathy caused by monosodium urate (MSU) deposition with a blood uric acid concentration exceeding 6.8mg/dL. It is directly related to hyperuricemia caused by purine metabolism disorders or reduced uric acid excretion, specifically acute characteristic arthritis and chronic tophi. Gout and hyperuricemia are both related to the level of uric acid in the human body. A normal adult produces about 750mg of uric acid per day, of which 1/3 is metabolized by the intestines and 2/3 is excreted by the kidneys, thereby maintaining the stability of uric acid levels in the body. Currently, there are two main types of drugs for the treatment of gout: one is xanthine oxidase inhibitors that inhibit uric acid production, and the other is URAT1 inhibitors that promote uric acid excretion. Uric acid transporter 1 (URAT1) is located on the brush border of human renal proximal tubular epithelial cells and mainly mediates the reabsorption of uric acid in the kidney. Increased URAT1 activity or gene expression caused by its gene mutation is one of the important pathogenesis of hyperuricemia. Lesinurad is a URAT1 inhibitor used to treat hyperuricemia and gout. Its therapeutic dose is large and has serious toxic side effects. Therefore, further structural modification is expected to obtain a new uric acid-lowering drug with better activity and safety and independent intellectual property rights.

Summary of the invention

In view of the deficiencies in the prior art, the present invention provides a method for preparing an indoleyl sulfonamide compound. The present invention also provides the activity screening results of the above-mentioned compound as a uric acid-lowering drug and its application.

The technical solution of the present invention is as follows:

1. Indoleylsulfonamide compounds

The indole acyl sulfonamide compounds of the present invention, or pharmaceutically acceptable salts thereof, have a structure as shown in the following general formula I:

Wherein, _R1 is cyclopropyl or bromine; _R2 is selected from C1-C5 alkyl or cycloalkyl, phenyl or substituted phenyl, aromatic heterocycle or substituted aromatic heterocycle; the aromatic heterocycle is selected from naphthyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, pyridyl, furyl, thienyl, pyrrolyl or pyrimidinyl, and the substituent is selected from halogen, hydroxyl, amino, nitro, hydroxyl, cyano, trifluoromethyl, C1-C5 alkyl or cycloalkyl.

According to the present invention, preferably, the indole acyl sulfonamide compound is one of the following:

Table 1. Structural formula of compounds 1-47

2. Preparation method of indole acyl sulfonamide compounds

The preparation method of the indole acyl sulfonamide compound of the present invention is one of the following methods:

(1) Synthesis of compounds 1 to 24:

First, 1-bromo-4-methylnaphthalene is used as a starting material, and reacts with N-bromosuccinimide in n-hexane under the catalytic action of dibenzoyl peroxide to generate ZS-A, i.e., 1-bromo-4-(bromomethyl)naphthalene; in acetonitrile, the intermediate ZS-A reacts with 1H-indole-2-carboxylic acid methyl ester under the catalytic action of cesium carbonate to generate the intermediate ZS-B, i.e., 1-(4-bromonaphthalene-1-yl)methyl-1H-indole-2-carboxylic acid methyl ester; the intermediate ZS-B is hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to obtain compound ZS-C, i.e., 1-(4-bromonaphthalene-1-yl)methyl-1H-indole-2-carboxylic acid; ZS-C is condensed with different types of sulfonamides under the action of 4-dimethylaminopyridine (DMAP) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) to obtain target products 1 to 24.

Route 1:

Reagents and conditions: (i) N-bromosuccinimide, dibenzoyl peroxide, n-hexane, 70°C; (ii) 1H-indole-2-carboxylic acid methyl ester, cesium carbonate, acetonitrile, 70°C; (iii) lithium hydroxide, tetrahydrofuran, methanol, room temperature; (iv) sulfonamide, DMAP, EDCI, dichloromethane, 0°C to room temperature;

Wherein R ₂ is the same as the above general formula I, and the structures of compounds 1 to 24 are shown in 1 to 24 in Table 1;

(2) Synthesis of Compounds 25 to 47

The synthesis of compound ZS-B, i.e., 1-(4-bromonaphthalene-1-yl)methyl-1H-indole-2-carboxylic acid methyl ester, is consistent with the synthesis of the above compounds 1 to 24, except that ZS-B reacts with cyclopropylboric acid in toluene under the action of tricyclohexylphosphine, potassium phosphate and palladium acetate to generate intermediate SZ-B, i.e., 1-(4-cyclopropyl-1-yl)methyl-1H-indole-2-carboxylic acid methyl ester; intermediate SZ-B is hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to obtain SZ-C, i.e., 1-(4-cyclopropyl-1-yl)methyl-1H-indole-2-carboxylic acid; SZ-C is condensed with different types of sulfonamides under the catalysis of DMAP and EDCI to obtain target products 25 to 47;

Route 2:

Reagents and conditions: (i) N-bromosuccinimide, dibenzoyl peroxide, n-hexane, 70°C; (ii) 1H-indole-2-carboxylic acid methyl ester, cesium carbonate, acetonitrile, 70°C; (iii) tricyclohexylphosphine, cyclopropylboric acid, palladium acetate, potassium phosphate, toluene, 100°C, nitrogen; (iv) lithium hydroxide, tetrahydrofuran, methanol, room temperature; (v) sulfonamide, DMAP, EDCI, dichloromethane, 0°C to room temperature;

Wherein R ₂ is the same as the above general formula I, and the structures of compounds 25 to 47 are shown as 25 to 47 in Table 1;

The room temperature described in the present invention refers to 20-30°C.

3. Application of indole acyl sulfonamide compounds

The present invention discloses the results of screening for the uric acid lowering activity of indole acyl sulfonamide compounds and their first application in preparing uric acid lowering drugs. Experiments prove that the indole acyl sulfonamide compounds of the present invention can be used as uric acid lowering drugs. Specifically, they can be used as uric acid lowering compounds for preparing uric acid lowering drugs. The present invention also provides the application of the above compounds in preparing uric acid lowering drugs.

Uric acid-lowering activity of target compounds:

According to the above method, 47 compounds were synthesized (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 Tables 2 and 3, with Lesinurad being a positive drug.

It can be seen from Tables 2 and 3 that 39 compounds showed significant uric acid-lowering activity, which was stronger than or equivalent to the positive drug Lesinurad. Among them, representative compounds 1, 9, 12, 15, 24, 25, 27, 29, 34, 35, 44, 45, and 47 had a blood uric acid reduction rate of more than 70% in the in vivo activity test in animals, showing excellent uric acid-lowering activity and can be used as candidate uric acid-lowering drugs.

Therefore, the indole acyl sulfonamide compounds in the present invention are a class of compounds with novel structures and uric acid lowering activity, and can be used as candidate drugs for lowering uric acid and used for preparing uric acid lowering drugs.

A uric acid-lowering pharmaceutical composition comprises the indole acyl sulfonamide compound of the present invention and one or more pharmaceutically acceptable carriers or excipients.

DETAILED DESCRIPTION

The following examples are helpful for understanding the present invention, but they cannot limit the content of the present invention. In the following examples, the numbers of all target compounds are the same as those in Table 1.

Synthesis route of compounds 1 to 24:

Reagents and conditions: (i) N-bromosuccinimide, dibenzoyl peroxide, n-hexane, 70°C; (ii) 1H-indole-2-carboxylic acid methyl ester, cesium carbonate, acetonitrile, 70°C; (iii) lithium hydroxide, tetrahydrofuran, methanol, room temperature; (iv) sulfonamide, DMAP, EDCI, dichloromethane, 0°C to room temperature;

Preparation of compound ZS-A

Mix N-bromosuccinimide (4.00g, 33.93mmol) and dibenzoyl peroxide (0.16g, 0.68mmol) in a 250mL round-bottom flask, add 100mL of n-hexane, then drop the raw material 1-bromo-4-methylnaphthalene (5.00g, 22.62mmol) into the flask, heat to 70℃ and react for 12h; TLC monitors the reaction to be complete, stop heating, wait for the reaction liquid to cool to room temperature, and filter to collect the filter cake. Place the filter cake in a 250mL beaker, add 150mL of saturated NaHCO ₃ aqueous solution to the beaker, stir for 10min, filter, collect the filter cake, repeat the above operation twice, wash with clean water for the last time, and filter again. Collect the filter cake, place it in a 100 mL flask, add 50 mL of n-hexane and heat to reflux. After heating for 1 h, stop heating, cool to room temperature, filter, and vacuum dry to obtain a light yellow powder with a yield of 49.3% and a melting point of 102-104°C. ESI-MS: m/z 301.24 [M+2+H] ⁺ , 303.53 [M+4+H] ⁺ , C ₁₁ H ₈ Br ₂ [297.90].

Preparation of compound ZS-B

Add 1-bromo-4-(bromomethyl)naphthalene (3.00g, 10.00mmol) to a 250mL round-bottom flask, then add about 50mL acetonitrile to dissolve it, add cesium carbonate (6.54g, 20.00mmol) to the flask, then dissolve 1H-indole-2-carboxylic acid methyl ester (2.10g, 12.00mmol) in 50mL acetonitrile and slowly drop it into the flask. Heat to 70°C, and solids will precipitate continuously during stirring. After 12h, monitor by TLC. After the reaction is completed, filter and collect the filter cake. Place the filter cake in a 250mL beaker, add 150mL water to the beaker, stir for 10min, filter, collect the filter cake, and repeat the above operation twice. Finally, the filter cake was placed in a 100 mL flask, 50 mL of ethanol was added and heated to 80 °C. After stirring for 1 h, the heating was stopped, the mixture was cooled to room temperature and filtered. The filter cake was vacuum dried to obtain a white solid with a yield of 87.0% and a melting point of 153-155 °C. ESI-MS: m/z 393.90 [M+H] ⁺ , 396.12 [M+2+H] ⁺ , C ₂₁ H ₁₆ BrNO ₂ [393.04].

Preparation of compound ZS-C

ZS-B (2.00 g, 5.08 mmol) was placed in a 100 mL flask, and 20 mL of tetrahydrofuran and 20 mL of methanol were added to completely dissolve it. Lithium hydroxide (1.22 g, 50.80 mmol) was weighed and dissolved in water, and slowly added to the flask. After stirring for 4 hours, TLC detected that the reaction was complete. 10 mL of water was added, and the tetrahydrofuran and methanol in the mixed solution were evaporated under reduced pressure. 1 mol/L HCl was slowly added to the remaining aqueous solution. Solids precipitated during the addition process. When the pH of the solution was 2-3, the solids no longer increased. Filter and vacuum dry the filter cake to obtain a white solid with a yield of 76.9% and a melting point of 175-177°C. ¹ HNMR (400MHz, DMSO-d ₆ ) δ12.96(s,1H),8.42–8.33(m,1H),8.27–8.18(m,1H),7.79(d,J＝7.8Hz,3H),7.66–7.60(m,1H),7.45(s,1H),7.42(d,J＝8.5Hz ,1H),7.26(t,J＝7.7Hz,1H),7.17(t,J＝7.5Hz,1H),6.37(s,2H),5.96(d,J＝7.7Hz,1H).ESI-MS: m/z 378.10[MH] ^- ,380.11[M+2-H] ^- ,C ₂₀ H ₁₄ BrNO ₂ [379 .02].

Example 1. Preparation of Compound 1

ZS-C (0.10 g, 0.26 mmol) was placed in a 25 mL flask, 10 mL of dichloromethane was added to dissolve, DMAP (48 mg, 0.39 mmol) and EDCI (75 mg, 0.39 mmol) were added, and benzenesulfonamide (49 mg, 0.32 mmol) was added after stirring for 15 min under ice bath, and the ice bath was removed, and the mixture was stirred for 12 h at room temperature and then detected by TLC. After the reaction was complete, 10 mL of dichloromethane was added, and the mixture was washed with saturated NaHCO ₃ , 1 mol/L dilute hydrochloric acid, and saturated NaCl solution (20 mL×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was separated by column chromatography (ethyl acetate: petroleum ether: glacial acetic acid = 1:10:2%) to obtain a white solid product with a yield of 74.8% and a melting point of 243-245°C. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.61(s,1H),8.22(dd,J＝14.5,8.0Hz,2H),7.88–7.70(m,6H),7.61–7.52(m,2H),7.47(t,J＝7.8Hz,2H),7.41(d,J＝8.4 Hz,1H),7.28(t,J＝7.1Hz,1H),7.18(t,J＝7.5Hz,1H),6.15(s,2H),5.88(d,J＝7.8Hz,1H).ESI-MS: m/z 517.39[MH] ^- ,519.31[M+2-H] ^- ,C ₂₆ H ₁₉ BrN ₂ O ₃ S[518.03].

Example 2. Preparation of Compound 2

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with p-bromobenzenesulfonamide (75 mg, 0.32 mmol) to obtain a white solid with a yield of 71.0% and a melting point of 245-247°C. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.61 (s, 1H), 8.29–8.19 (m, 2H), 7.80 (t, J = 8.0Hz, 2H), 7.76 (d, J = 8.4Hz, 2H), 7.72 (s, 2H), 7.68 (d, J = 8.5Hz, 2H), 7.57 (d ,J＝7.8Hz,1H),7.44(d,J＝8.5Hz,1H),7.29(t,J＝7.7Hz,1H),7.19(t,J＝7.5Hz,1H),6.16(s,2H),5.88(d,J＝7.7Hz,1H).ESI-MS:m/z597.30[M+2-H] ^- ,595 .37[MH] ^- ,599.19[M+4-H] ^- ,C ₂₆ H ₁₈ Br ₂ N ₂ O ₃ S[595.94].

Example 3. Preparation of Compound 3

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with p-toluenesulfonamide (55 mg, 0.32 mmol) to obtain a white solid with a yield of 61.8% and a melting point of 250-252°C.波谱数据： ¹ H NMR(400MHz,DMSO-d ₆ )δ12.51(s,1H),8.25(d,J＝7.6Hz,1H),8.21(d,J＝6.7Hz,1H),7.81(d,J＝7.9Hz,1H),7.74–7.67(m,4H),7.55(d,J＝7.8Hz,1H),7.42(d,J＝8.5Hz,1H),7.37(d,J＝8.0Hz,1H),7.28(s,1H),7.24(d,J＝8.3Hz,2H),7.18(t,J＝7.5Hz,1H),6.16(s,2H),5.86(d,J＝7.7Hz,1H),2.30(s,3H).ESI-MS:m/z 531.31[MH] ^- ,533.30[M+2-H] ^- ,C ₂₇ H ₂₁ BrN ₂ O ₃ S[532.05].

Example 4. Preparation of Compound 4

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with 4-chlorobenzenesulfonamide (61 mg, 0.32 mmol) to obtain a white solid with a yield of 74.4% and a melting point of 252-254°C. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.74 (s, 1H), 8.23 (dd, J = 13.5, 8.1Hz, 2H), 7.81 (d, J = 8.6Hz, 4H), 7.74 (d, J = 10.3Hz, 2H), 7.56 (d, J = 7.8Hz, 1H), 7.54–7.48 (m,2H),7.43(d,J＝8.5Hz,1H),7.29(t,J＝7.7Hz,1H),7.19(t,J＝7.4Hz,1H),6.16(s,2H),5.88(d,J＝7.7Hz,1H).ESI-MS:m/z551.48[MH] ^- ,553.33[M+2-H] ^- ,C ₂₆ H ₁₈ BrClN ₂ O ₃ S[551.99].

Example 5. Preparation of Compound 5

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with 4-fluorobenzenesulfonamide (56 mg, 0.32 mmol) to obtain a white solid with a yield of 72.3% and a melting point of 219-221°C.波谱数据： ¹ H NMR(400MHz,DMSO-d ₆ )δ12.75(s,1H),8.25(d,J＝8.1Hz,1H),8.20(d,J＝8.2Hz,1H),7.88(dd,J＝8.9,4.9Hz,2H),7.81(d,J＝8.3Hz,1H),7.77(d,J＝8.9Hz,1H),7.72(s,1H),7.55(d,J＝7.8Hz,1H),7.42(t,J＝9.6Hz,2H),7.28(q,J＝8.8,7.7Hz,3H),7.19(t,J＝7.5Hz,1H),6.16(s,2H),5.86(d,J＝7.8Hz,1H).ESI-MS:m/z 535.58[MH] ^- ,537.38[MH] ^- ,C ₂₆ H ₁₈ BrFN ₂ O ₃ S[536.02].

Example 6. Preparation of Compound 6

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with p-nitrobenzenesulfonamide (65 mg, 0.32 mmol) to give a pale yellow solid with a yield of 77.4% and a melting point of 251-253°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.20(dd, J＝9.0,2.4 Hz, 3H),8.16–8.12(m, 1H),8.02(s, 1H),8.00(s, 1H),7.82(d, J＝8.0 Hz, 1H),7.76–7.69(m, 3H),7.53(d, J＝7.8 Hz, 1H),7.46(d, J＝8.4 Hz, 1H),7.30(t, J＝7.7 Hz, 1H),7.19(t, J＝7.2 Hz, 1H),6.15(s, 2H),5.82(d, J＝7.8 Hz, 1H).ESI-MS:m/z562.31[MH] ^- ,564.23[M+2-H] ^- ,C ₂₆ H ₁₈ BrN ₃ O ₅ S[563.02].

Example 7. Preparation of Compound 7

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with 2,4-difluorobenzenesulfonamide (62 mg, 0.32 mmol) to obtain a white solid with a yield of 80.3% and a melting point of 253-255°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.06 (s, 1H), 8.21 (t, J = 9.2 Hz, 2H), 7.89–7.69 (m, 5H), 7.58 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.38–7.25 (m, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.15–7.06 (m, 1H), 6.16 (s, 2H), 5.85 (d, J = 7.8 Hz, 1H). ESI-MS: m/z 553.29 [MH] ^- , 555.25 [M+2-H] ^- , C ₂₆ H ₁₇ BrF ₂ N ₂ O ₃ S [554.01].

Example 8. Preparation of Compound 8

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with 4-tert-butylbenzenesulfonamide (68 mg, 0.32 mmol) to obtain a white solid with a yield of 78.2% and a melting point of 259-261°C. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.59 (s, 1H), 8.26 (d, J = 7.9Hz, 1H), 8.21 (d, J = 9.7Hz, 1H), 7.81 (d, J = 8.0Hz, 1H), 7.78–7.71 (m, 5H), 7.59 (d, J = 7.9Hz, 1H) ,7.49(d,J＝8.6Hz,2H),7.41(d,J＝8.4Hz,1H),7.30–7.25(m,1H),7.22–7.14(m,1H),6.18(s,2H),5.90(d,J＝7.8Hz,1H),1.21(s,9H).ESI-MS: m/z 573.4 1[MH] ^- ,575.33[M+2-H] ^- ,C ₃₀ H ₂₇ BrN ₂ O ₃ S[574.09].

Example 9. Preparation of Compound 9

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with 4-(trifluoromethyl)benzenesulfonamide (72 mg, 0.32 mmol) to obtain a white solid with a yield of 65.9% and a melting point of 270-272°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.60 (s, 1H), 8.23 (d, J = 8.2 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.83 (t, J = 8.5 Hz, 3H), 7.74 (d, J = 17.3 Hz, 3H), 7.57 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 6.15 (s, 2H), 5.88 (d, J = 7.8 Hz, 1H). ESI-MS: m/z 585.54 [MH] ^- ,587.32[M+2-H] ^- ,C ₂₇ H ₁₈ BrF ₃ N ₂ O ₃ S[586.02].

Example 10. Preparation of Compound 10

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with 5-chlorothiophene-2-sulfonamide (63 mg, 0.32 mmol) to obtain a white solid with a yield of 70.3% and a melting point of 252-254°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.36–8.29 (m, 1H), 8.23 (dd, J = 6.9, 2.6 Hz, 1H), 7.84–7.74 (m, 3H), 7.67 (s, 1H), 7.60–7.51 (m, 2H), 7.46 (d, J = 8.5 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.10 (s, 1H), 6.26 (s, 2H), 5.94 (d, J = 7.8 Hz, 1H). ESI-MS: m/z 557.60 [MH] ^- , 559.34 [M+2-H] ^- , 561.19 [M+4-H] ^- , C ₂₄ H ₁₆ BrClN ₂ O ₃ S ₂ [557.95].

Example 11. Preparation of Compound 11

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with 4-methoxybenzenesulfonamide (60 mg, 0.32 mmol) to obtain a white solid with a yield of 74.4% and a melting point of 264-266°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.49 (s, 1H), 8.26 (dd, J = 7.9, 1.6 Hz, 1H), 8.21 (dd, J = 8.0, 1.6 Hz, 1H), 7.85–7.69 (m, 6H), 7.56 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.32–7.24 (m, 1H), 7.18 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.17 (s, 2H), 5.88 (d, J = 7.8 Hz, 1H), 3.78 (s, 3H). ESI-MS: m/z 547.37 [MH] ^- ,549.32[M+2-H] ^- ,C ₂₇ H ₂₁ BrN ₂ O ₄ S[548.04].

Example 12. Preparation of Compound 12

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with 4-(2-hydroxy-2-propyl)furan-2-sulfonamide (66 mg, 0.32 mmol) to give a white solid with a yield of 66.7% and a melting point of 232-234°C. Spectral data: ¹ HNMR (600MHz, DMSO-d ₆ )δ12.96(s,1H),8.27(d,J＝7.2Hz,1H),8.19(d,J＝7.2Hz,1H),7.83–7.71(m,4H),7.66(d,J＝5.3Hz,1H),7.59(d,J＝7.0Hz,1H),7.41(t,J＝7.1Hz,1H),7.28(q,J＝7.5,7.1Hz,1H),7.16(dd,J＝16.0,6.8Hz,2H),6.21(s,2H),5.90(d,J＝7.1Hz,1H),5.02(s,1H),1.25(s,6H).ESI-MS:m/z 565.90[MH] ^- ,567.40[M+2-H] ^- ,C ₂₇ H ₂₃ BrN ₂ O ₅ S[566.05].

Example 13. Preparation of Compound 13

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with 4-ethylbenzenesulfonamide (59 mg, 0.32 mmol) to obtain a white solid with a yield of 69.2% and a melting point of 240-242°C. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.53 (s, 1H), 8.25 (d, J = 7.6Hz, 1H), 8.20 (d, J = 8.2Hz, 1H), 7.80 (t, J = 7.4Hz, 2H), 7.74–7.71 (m, 3H), 7.57 (d, J = 7.8Hz, 1H) ,7.41(t,J＝7.8Hz,2H),7.29(d,J＝8.3Hz,3H),7.18(t,J＝7.5Hz,1H),6.17(s, 2H),5.87(d,J＝7.8Hz,1H),2.60(q,J＝7.6Hz,2H),1.12(t,J＝7.6Hz,3H).ESI- MS:m/z 545.61[MH] ^- ,547.39[M+2-H] ^- ,C ₂₈ H ₂₃ BrN ₂ O ₃ S[546.06].

Example 14. Preparation of Compound 14

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with 3,5-difluorobenzenesulfonamide (62 mg, 0.32 mmol) to obtain a white solid with a yield of 70.0% and a melting point of 238-240°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.26(d, J＝7.5 Hz, 1H),8.20(d, J＝8.1 Hz, 1H),7.82(d, J＝8.0 Hz, 1H),7.80–7.70(m, 3H),7.55–7.50(m, 2H),7.50–7.43(m, 3H),7.30(t, J＝7.6 Hz, 1H),7.19(t, J＝7.5 Hz, 1H),6.18(s, 2H),5.86(d, J＝7.7 Hz, 1H).ESI-MS:m/z 553.85[MH] ^- ,555.39[M+2-H] ^- ,C ₂₆ H ₁₇ BrF ₂ N ₂ O ₃ S[554.01].

Example 15. Preparation of Compound 15

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with m-nitrobenzenesulfonamide (65 mg, 0.32 mmol) to give a pale yellow solid with a yield of 72.3% and a melting point of 243-245°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.61(t, J＝2.0 Hz, 1H),8.53–8.43(m, 1H),8.42–8.31(m, 1H),8.28–8.11(m, 3H),7.85–7.77(m, 1H),7.77–7.65(m, 3H),7.49–7.39(m, 2H),7.34–7.24(m, 1H),7.18(q, J＝7.5 Hz, 1H),6.15(s, 2H),5.80(d, J＝7.8 Hz, 1H).ESI-MS:m/z 562.80[MH] ^- ,564.38[M+2-H] ^- ,C ₂₆ H ₁₈ BrN ₃ O ₅ S[563.02].

Example 16. Preparation of Compound 16

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with 2-nitrobenzenesulfonamide (65 mg, 0.32 mmol) to give a pale yellow solid with a yield of 72.3% and a melting point of 234-236°C. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.30 (d, J = 8.1Hz, 1H), 8.24–8.14 (m, 1H), 7.90 (d, J = 7.8Hz, 1H), 7.73 (dt, J = 17.8, 7.5Hz, 3H), 7.65 (d, J = 7.8Hz, 1H), 7.58 ( dd,J＝11.5,7.7Hz,2H),7.50(t,J＝7.6Hz,1H),7.31(s,1H),7.21(d,J＝8.1Hz, 1H),7.10(dt,J＝17.7,7.0Hz,2H),6.37(s,2H),6.03(d,J＝7.8Hz,1H).ESI-MS: m/z 562.75[MH] ^- ,564.37[M+2-H] ^- ,C ₂₆ H ₁₈ BrN ₃ O ₅ S[563.02].

Example 17. Preparation of Compound 17

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with m-bromobenzenesulfonamide (75 mg, 0.32 mmol) to obtain a white solid with a yield of 62.8% and a melting point of 241-243°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.82 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.86–7.72 (m, 6H), 7.53 (d, J = 7.8 Hz, 1H), 7.47–7.38 (m, 2H), 7.29 (t, J = 7.7 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 6.17 (s, 2H), 5.87 (d, J = 7.8 Hz, 1H). ESI-MS: m/z 597.35 [M+2-H] ^- , 595.87 [MH] ^- , 599.20 [M+4-H] ^- ,C ₂₆ H ₁₈ Br ₂ N ₂ O ₃ S[595.94].

Example 18. Preparation of Compound 18

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with tert-butylsulfonamide (44 mg, 0.32 mmol) to give a pale yellow solid with a yield of 75.5% and a melting point of 270-272°C. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.62 (s, 1H), 8.43–8.28 (m, 1H), 8.27–8.20 (m, 1H), 7.86–7.72 (m, 3H), 7.64 (d, J = 7.8Hz, 1H), 7.56–7.38 (m, 1H), 7.3 0(t,J＝7.9Hz,1H),7.19(t,J＝7.5Hz,1H),6.28(s,2H),6.01(d,J＝7.8Hz,1H),2.51(p,J＝1.8Hz,9H).ESI-MS: m/z 497.38[MH] ^- , _499.32 [M+2-H] ^- ,C ₂₄ H _{2 3BrN2O3} S[498.06].

Example 19. Preparation of Compound 19

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with ethanesulfonamide (35 mg, 0.32 mmol) to obtain a white solid with a yield of 79.7% and a melting point of 215-217°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.42–8.32 (m, 1H), 8.28–8.17 (m, 1H), 7.86–7.76 (m, 3H), 7.72 (s, H), 7.65 (d, J＝7.8 Hz, 1H), 7.54–7.37 (m, 2H), 7.36–7.23 (m, 1H), 7.19 (dt, J＝10.2, 7.5 Hz, 1H), 6.31 (s, 2H), 6.07–5.92 (m, 2H), 1.11 (t, J＝7.3 Hz, 3H).ESI-MS: m/z 469.55 [MH] ^- , 471.35 [M+2-H] ^- , C ₂₂ H ₁₉ BrN ₂ O ₃ S[470.03].

Example 20. Preparation of Compound 20

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with methylsulfonamide (30 mg, 0.32 mmol) to give a white solid with a yield of 55.8% and a melting point of 235-237°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.19 (s, 1H), 8.40–8.31 (m, 1H), 8.26–8.20 (m, 1H), 7.86–7.74 (m, 4H), 7.65 (d, J=7.8 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.34–7.26 (m, 1H), 7.20 (t, J=7.4 Hz, 1H), 6.31 (s, 2H), 6.02 (d, J=7.8 Hz, 1H), 3.25 (s, 3H). ESI-MS: m/z 455.50 [MH] ^- , 457.31 [M+2-H] ^- , C ₂₁ H ₁₇ BrN ₂ O ₃ S [456.01].

Example 21. Preparation of Compound 21

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with propylsulfonamide (39 mg, 0.32 mmol) to give a white solid with a yield of 59.5% and a melting point of 205-207°C. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.14(s,1H),8.39–8.31(m,1H),8.27–8.19(m,1H),7.86–7.76(m,3H),7.73(s,1H),7.64(d,J＝7.8Hz,1H),7.50(d,J＝8 .5Hz,1H),7.32(t,J＝7.6Hz,1H),7.20(t,J＝7.5Hz,1H),6.31(s,2H),5.98(d ,J＝7.8Hz,1H),3.31–3.22(m,2H),1.53(h,J＝7.4Hz,2H),0.79(t,J＝7.4Hz,3H ).ESI-MS:m/z 483.46[MH] ^- ,485.32[M+2-H] ^- ,C ₂₃ H ₂₁ BrN ₂ O ₃ S[484.05].

Example 22. Preparation of Compound 22

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with cyclopropanesulfonamide (39 mg, 0.32 mmol), and a white solid was obtained with a yield of 59.7% and a melting point of 220-222°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.16(s,1H),8.36(dt,J＝8.1,2.8Hz,1H),8.27–8.20(m,1H),7.84–7.75(m,3H),7.72(s,1H),7.66(d,J＝7.8Hz,1H),7.46(d,J＝8.5Hz,1H),7.31(t ,J＝7.7Hz,1H),7.20(t,J＝7.4Hz,1H),6.32(s,2H),6.03(d,J＝7.8Hz,1H),2.95(ddd,J＝12.9,8.0,4.7Hz,1H),1.06(dd,J＝4.7,2.5Hz,2H),1.00–0.92(m, 2H).ESI-MS:m/z 481.30[MH] ^- ,483.24[M+2-H] ^- ,C ₂₃ H ₂₁ BrN ₂ O ₃ S[482.03].

Example 23. Preparation of Compound 23

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with isopropylsulfonamide (39 mg, 0.32 mmol) to obtain a white solid with a yield of 61.8% and a melting point of 210-212°C. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.04(s,1H),8.39–8.28(m,1H),8.27–8.20(m,1H),7.85–7.75(m,3H),7.73(s,1H),7.65(d,J＝7.8Hz,1H),7.49(d,J＝8 .1Hz,1H),7.32(t,J＝7.1Hz,1H),7.21(t,J＝7.5Hz,1H),6.29(s,2H),6.02(d,J＝7.8Hz,1H),3.56(p,J＝6.9Hz,1H),1.23(d,J＝6.8Hz,1H),1.18(d,J＝6.9Hz, 5H).ESI-MS:m/z 483.29[MH] ^- ,485.27[M+2-H] ^- ,C ₂₃ H ₂₁ BrN ₂ O ₃ S[484.05].

Example 24. Preparation of Compound 24

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) was reacted with 2-thiophene amide (52 mg, 0.32 mmol) to obtain a white solid with a yield of 77.4% and a melting point of 225-227°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.83(s,1H),8.30(d,J＝7.5Hz,1H),8.22(d,J＝7.7Hz,1H),7.90(d,J＝6.4Hz,1H),7.84–7.71(m,4H),7.68(d,J＝3.8Hz,1H),7.57(d,J＝7.7Hz,1H),7.43(d,J＝8.4Hz,1H),7.33–7.24(m,1H),7.18(t,J＝7.5Hz,1H),7.08–7.03(m,1H),6.21(s,2H),5.94(d,J＝7.8Hz,1H).ESI-MS:m/z 523.75[MH] ^- ,525.16[M+2-H] ^- ,C ₂₄ H ₁₇ BrN ₂ O ₃ S ₂ [523.99].

Synthesis route of compounds 25 to 47:

Reagents and conditions: (i) N-bromosuccinimide, dibenzoyl peroxide, n-hexane, 70°C; (ii) 1H-indole-2-carboxylic acid methyl ester, cesium carbonate, acetonitrile, 70°C; (iii) tricyclohexylphosphine, cyclopropylboric acid, palladium acetate, potassium phosphate, toluene, 100°C, nitrogen; (iv) lithium hydroxide, tetrahydrofuran, methanol, room temperature; (v) sulfonamide, DMAP, EDCI, dichloromethane, 0°C to room temperature;

Preparation of compound SZ-B

ZS-B (5.00 g, 12.70 mmol), cyclopropylboronic acid (1.64 g, 19.00 mmol), tricyclohexylphosphine (0.70 g, 2.54 mmol), potassium phosphate (9.4 g, 44.45 mmol), palladium acetate (0.28 g, 1.27 mmol) were added to a 250 mL flask in sequence, and 100 mL toluene and 16 mL distilled water were added. The mixture was heated to 100 °C in a _N2 atmosphere. After 15 h, the reaction was completed by TLC monitoring. The reaction solution was cooled to room temperature and filtered through diatomaceous earth. The solvent was evaporated under reduced pressure. The residue was dissolved in 100 mL ethyl acetate, and then washed with saturated NaCl aqueous solution (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate for 2 h and filtered. The filtrate was concentrated under reduced pressure and then subjected to column chromatography (EA:PE = 1:5) to obtain a white solid with a yield of 93.3% and a melting point of 135-137 °C. ESI-MS: m/z 356.36[M+H] ⁺ ,C ₂₄ H ₂₁ NO ₂ [355.16].

Preparation of compound SZ-C

The intermediate SZ-B (4.2g, 11.80mmol) was placed in a 250mL flask, and 80mL tetrahydrofuran and 25mL methanol were added to completely dissolve it. Lithium hydroxide (2.90g, 0.12mmol) was weighed and dissolved in water, and slowly added to the flask. After stirring for 4h, the reaction was detected by TLC. 20mL of clean water was added, and tetrahydrofuran and methanol in the mixed solution were evaporated. 1mol/L HCl was slowly added to the remaining aqueous solution. Solids precipitated during the addition. When the pH of the solution was 2-3, the solids no longer increased. Filter and vacuum dry the filter cake to obtain a white solid with a yield of 95.0% and a melting point of 105-107°C. ¹ H NMR (600MHz, DMSO-d ₆ )δ12.89(s,1H),8.50–8.41(m,1H),8.33–8.24(m,1H),7.77(d,J＝8.0Hz,1H),7.70–7.66(m,2H),7.42(s,1H),7.36(d,J＝8.4Hz,1H),7.27–7.20(m,1 H),7.14(t,J＝7 .5Hz,1H),6.98(d,J＝7.5Hz,1H),6.35(s,2H),5.94(d,J＝7.5Hz,1H),2.32(ddd,J＝13.8,8.5,5.4Hz,1H),1.03–0.92(m,2H),0.61(td,J＝5.9,4.0Hz,2H) .ESI-MS: m/z 340.4[MH] ^- ,C ₂₃ H ₁₉ NO ₂ [341.14].

Example 25. Preparation of Compound 25

SZ-C (0.20 g, 0.59 mmol) was placed in a 50 mL flask, 20 mL of dichloromethane was added to dissolve, DMAP (0.11 g, 0.89 mmol) and EDCI (0.17 g, 0.89 mmol) were added, and benzenesulfonamide (0.11 g, 0.70 mmol) was added after stirring for 15 min under ice bath, and the ice bath was removed, and the mixture was stirred for 12 h at room temperature and then detected by TLC. After the reaction was complete, 20 mL of dichloromethane was added, and the mixture was washed with saturated NaHCO ₃ , 1 mol/L dilute hydrochloric acid, and saturated NaCl solution (20 mL×2 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The product was separated by column chromatography (ethyl acetate: petroleum ether: glacial acetic acid = 1:10:2%) to obtain a white solid product with a yield of 75.8% and a melting point of 220-222°C. Spectral data: ¹ HNMR (400 MHz, DMSO-d ₆ )δ12.62(s,1H),8.50–8.42(m,1H),8.22–8.14(m,1H),7.88(d,J＝7.8Hz,2H),7.80(d,J＝8.0Hz,1H),7.75(s,1H),7.71–7.57(m,4H),7.51(t,J＝7.7Hz ,2H),7.34(d,J＝8.4Hz,1H),7 .25(t,J＝7.6Hz,1H),7.16(t,J＝7.4Hz,1H),6.91(d,J＝7.4Hz,1H),6.14(s,2H),5.89(d,J＝7.4Hz,1H),2.37–2.27(m,1H),0.98(q,J＝6.2Hz,2H),0.61( t, J＝4.8Hz, 2H).ESI-MS: m/z 479.11[MH] ^- ,C ₂₉ H ₂₄ N ₂ O ₃ S[480.15].

Example 26. Preparation of Compound 26

The operation was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) was reacted with p-bromobenzenesulfonamide (0.165 g, 0.70 mmol) to obtain a white solid with a yield of 77.0% and a melting point of 225-227°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.73(s,1H),8.45(d,J＝7.9Hz,1H),8.18(d,J＝7.7Hz,1H),7.83–7.62(m,8H),7.36(d,J＝8.5Hz,1H),7.26(t,J＝7.7Hz,1H),7.17(t,J＝7.5Hz,1H),6.92(d,J＝7.5Hz,1H),6.14(s,2H),5.89(d,J＝7.4Hz,1H),2.40–2.24(m,1H),1.07–0.92(m,2H),0.68–0.53(m,2H).ESI-MS:m/z 557.66[MH] ^- ,559.40[M+2-H] ^- ,C ₂₉ H ₂₃ BrN ₂ O ₃ S[558.06].

Example 27. Preparation of Compound 27

The operation was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) was reacted with p-toluenesulfonamide (0.12 g, 0.70 mmol), and a white solid was obtained with a yield of 73.5% and a melting point of 215-217°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.51(s,1H),8.45(d,J＝8.9Hz,1H),8.17(d,J＝7.2Hz,1H),7.79(d,J＝8.0Hz,1H),7.75(s,1H),7.73(s,3H),7.70(s,1H),7.68–7.60(m,2H),7.36( d,J＝8.0Hz,2H),7.15(t,J＝7.4Hz,1H),6.91(d,J＝7.4Hz,1H),6.14(s,2H),5.88(d,J＝7.4Hz,1H),2.31(s,4H),1.03–0.92(m,2H),0.64–0.57(m,2H).ES I-MS:m/z 493.16[MH] ^- ,C ₃₀ H ₂₆ N ₂ O ₃ S[494.17].

Example 28. Preparation of Compound 28

The operation was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) was reacted with 4-chlorobenzenesulfonamide (0.13 g, 0.70 mmol) to give a white solid with a yield of 70.2% and a melting point of 210-212°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.75 (s, 1H), 8.45 (d, J = 9.0 Hz, 1H), 8.17 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.73 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.49 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H) ,7.26(t,J＝7.7Hz,1H),7.17(t,J＝7.4Hz,1H),6.91(d,J＝7.4Hz,1H),6.14(s,2H),5.88(d,J＝7.4Hz,1H),2.37–2.27(m,1H),1.04–0.94(m,2H),0.62( t, J＝4.7Hz, 2H).ESI-MS: m/z 513.73[MH] ^- ,515.48[M+2-H] ^- ,C ₂₉ H ₂₃ ClN ₂ O ₃ S[514.11].

Example 29. Preparation of Compound 29

The operation was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) was reacted with 4-fluorobenzenesulfonamide (0.12 g, 0.70 mmol) to give a white solid with a yield of 80.7% and a melting point of 208-210°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.62 (s, 1H), 8.49–8.40 (m, 1H), 8.20–8.13 (m, 1H), 7.92 (dd, J=8.9, 5.1 Hz, 2H), 7.80 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.65 (p, J=6.9 Hz, 2H), 7.43 (d, J=2.9 Hz, 1H), 7.34 (d, J=3.8 Hz, 1H) ,7.32(s,1H),7.25(t,J＝7.7Hz,1H),7.16(t,J＝7.4Hz,1H),6.90(d,J＝7.4Hz,1H),6.14(s,2H),5.87(d,J＝7.4Hz,1H),2.36–2.26(m,1H),1.03–0.95(m ,2H),0.63–0.56(m,2H).ESI-MS:m/z 497.08[MH] ^- ,C ₂₉ H ₂₃ FN ₂ O ₃ S[498.14].

Example 30. Preparation of Compound 30

The operation was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) was reacted with p-nitrobenzenesulfonamide (0.14 g, 0.70 mmol) to give a pale yellow solid with a yield of 79.2% and a melting point of 220-222°C. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.41 (dd, J = 11.8, 7.7Hz, 2H), 8.23–8.04 (m, 4H), 7.82–7.61 (m, 4H), 7.41–7.14 (m, 4H), 6.89 (d, J = 7.5Hz, 1H), 6.13 (s, 2H) ),1.23(s,1H),0.98(d,J＝8.2Hz,2H),0.59(d,J＝5.2Hz,2H).ESI-MS: m/z 524.10[MH] ^- ,C ₂₉ H ₂₃ N ₃ O ₅ S[525.14].

Example 31. Preparation of Compound 31

The operation was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) was reacted with 2,4-difluorobenzenesulfonamide (0.14 g, 0.70 mmol) to obtain a white solid with a yield of 81.2% and a melting point of 215-217°C. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ13.09 (s, 1H), 8.47–8.11 (m, 2H), 7.92–7.80 (m, 3H), 7.64 (t, J = 7.9Hz, 2H), 7.41–7.14 (m, 6H), 6.92 (d, J = 7.4Hz, 1H), 6. 14(s,2H),1.92(s,1H),0.99(d,J＝8.1Hz,2H),0.61(d,J＝5.4Hz,2H).ESI-MS: m/z 514.99[MH] ^- ,C ₂₉ H ₂₂ F ₂ N ₂ O ₃ S[516.13].

Example 32. Preparation of Compound 32

The operation was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) was reacted with 4-tert-butylbenzenesulfonamide (0.15 g, 0.70 mmol) to obtain a white solid with a yield of 72.0% and a melting point of 225-227°C. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.57 (s, 1H), 8.20–8.16 (m, 1H), 7.78–7.74 (m, 4H), 7.67–7.57 (m, 4H), 7.51 (d, J = 8.6Hz, 2H), 7.33–7.16 (m, 4H), 6.16 (s,2H),1.00–0.96(m,2H),0.61(dd,J＝5.6,1.8Hz,2H).ESI-MS:m/z 535.11[MH] ^- ,C ₃₃ H ₃₂ N ₂ O ₃ S[536.21].

Example 33. Preparation of Compound 33

The operation was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) was reacted with 4-(trifluoromethyl)benzenesulfonamide (0.16 g, 0.70 mmol) to obtain a white solid with a yield of 71.9% and a melting point of 205-207°C. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.18–8.14(m,1H),8.08–7.99(m,4H),7.90–7.77(m,4H),7.64(d,J＝2.1Hz,2H),7.38–7.15(m,4H),6.14(s,2H),2.30 (td,J＝8.5,4.3Hz,1H),1.01–0.95(m,2H),0.60(dt,J＝6.1,3.1Hz,2H).ESI-MS: m/z 547.08[MH] ^- ,C ₃₀ H ₂₃ F ₃ N ₂ O ₃ S[548.14].

Example 34. Preparation of Compound 34

The operation was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) was reacted with 5-chlorothiophene-2-sulfonamide (0.14 g, 0.70 mmol) to obtain a white solid with a yield of 84.0% and a melting point of greater than 250°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49–8.45 (m, 1H), 8.26–8.22 (m, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.71–7.62 (m, 3H), 7.55 (d, J=4.2 Hz, 1H), 7.41–7.08 (m, 5H), 6.93 (d, J=7.5 Hz, 1H), 6.25 (s, 2H), 2.32 (dq, J=8.7, 4.4 Hz, 1H), 0.98 (dt, J=9.0, 3.1 Hz, 2H), 0.61 (dt, J=6.1, 3.1 Hz, 2H). ESI-MS: m/z 519.83 [MH] ^- , 521.36 [M+2-H] ^- ,C ₂₇ H ₂₁ ClN ₂ O ₃ S ₂ [520.07].

Example 35. Preparation of Compound 35

The operation was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) was reacted with 4-methoxybenzenesulfonamide (0.13 g, 0.70 mmol) to obtain a white solid with a yield of 74.8% and a melting point of 215-217°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.46(s,1H),8.48–8.42(m,1H),8.21–8.17(m,1H),7.82–7.74(m,4H),7.27–7.13(m,4H),7.12–6.98(m,4H),6.92(d,J＝7.4Hz,1H),6.16(s,2H),3.79(s,3H),2.31(td,J＝8.5,4.4Hz,1H),0.99(dt,J＝8.4,3.2Hz,2H),0.64–0.59(m,2H).ESI-MS:m/z 509.27[MH] ^- ,C ₃₀ H ₂₆ N ₂ O ₄ S[510.16].

Example 36. Preparation of Compound 36

The operation was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) was reacted with 4-ethylbenzenesulfonamide (67 mg, 0.36 mmol) to give a white solid with a yield of 76.0% and a melting point of 208-210°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.52 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 7.7 Hz, 1H), 7.79-7.72 (m, 5H), 7.66 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 7.29 (s, 1H), 7.27-7.19 (m, 1H), 7.16 (t, J = 7.4 Hz, 1H),6.92(d,J＝7.4Hz,1H),6.15(s,2H),5.89(d,J＝7.4Hz,1H),2.61(q,J＝7.8Hz,2H),2.37–2.27(m,1H),1.13(t,J＝7.6Hz,3H),1.03–0.94(m,2H),0. 64–0.57(m,2H).ESI-MS:m/z 507.13[MH] ^- ,C ₃₁ H ₂₈ N ₂ O ₃ S[508.18].

Example 37. Preparation of Compound 37

The operation was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) was reacted with 3,5-difluorobenzenesulfonamide (70 mg, 0.36 mmol) to give a white solid with a yield of 70.0% and a melting point of 206-208°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.74 (s, 1H), 8.44 (d, J = 7.0 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.66 (q, J = 6.8 Hz, 2H), 7.54 (dd, J = 25.0, 7.1 Hz, 3H), 7.39 (d, J = 8.5 Hz, 1H), 7.27 ( t,J＝7.6Hz,1H),7.17(t,J＝7.5Hz,1H),6.90(d,J＝7.5Hz,1H),6.16(s,2H),5.88(d,J＝7.4Hz,1H),2.32(p,J＝7.9,7.3Hz,1H),0.99(t,J＝6.1Hz,2H),0.6 4–0.54(m,2H).ESI-MS:m/z 515.09[MH] ^- ,C ₂₉ H ₂₂ F ₂ N ₂ O ₃ S[516.13].

Example 38. Preparation of Compound 38

The operation was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) was reacted with m-nitrobenzenesulfonamide (73 mg, 0.36 mmol) to give a pale yellow solid with a yield of 76.1% and a melting point of 220-222°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.98 (s, 1H), 8.54 (s, 1H), 8.40 (dd, J = 13.4, 9.7 Hz, 2H), 8.24 (d, J = 7.6 Hz, 1H), 8.13 (d, J = 7.5 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.78-7.71 (m, 2H), 7.68-7.55 (m, 2H), 7.38 (d, J = 8.5 Hz,1H),7.26(t,J＝7.7Hz,1H),7.17(t,J＝7.5Hz,1H),6.84(d,J＝7.4Hz,1H),6.13(s,2H),5.83(d,J＝7.4Hz,1H),2.35–2.25(m,1H),1.03–0.93(m,2H), 0.62–0.54(m,2H).ESI-MS:m/z 524.10[MH] ^- ,C ₂₉ H ₂₃ N ₃ O ₅ S[525.14].

Example 39. Preparation of Compound 39

The operation was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) was reacted with 2-nitrobenzenesulfonamide (73 mg, 0.36 mmol) to give a pale yellow solid with a yield of 72.3% and a melting point of >250°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.44 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 9.2 Hz, 3H), 7.68 (dt, J = 23.8, 8.0 Hz, 3H), 7.35 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 7. .6Hz,1H),7.18(t,J＝7.5Hz,1H),6.93(d,J＝7.4Hz,1H),6.17(s,2H),5.91(d,J＝7.4Hz,1H),2.37–2.27(m,1H),0.99(t,J＝6.3Hz,2H),0.60(t,J＝5.2Hz,2 H).ESI-MS: m/z524.00[MH] ^- ,C ₂₉ H ₂₃ N ₃ O ₅ S[525.14].

Example 40. Preparation of Compound 40

The operation was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) was reacted with m-bromobenzenesulfonamide (85 mg, 0.36 mmol) to give a white solid with a yield of 70.0% and a melting point of 210-212°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.74 (s, 1H), 8.44 (d, J=8.0 Hz, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.98 (s, 1H), 7.92–7.77 (m, 3H), 7.74 (s, 1H), 7.64 (p, J=6.9 Hz, 2H), 7.45 (t, J=8.0 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 7. 25(t,J＝7.7Hz,1H),7.16(t,J＝7.5Hz,1H),6.90(d,J＝7.5Hz,1H),6.15(s,2H),5.89(d,J＝7.5Hz,1H),2.37–2.13(m,1H),0.98(d,J＝8.2Hz,2H),0.60(d ,J＝5.2Hz,2H).ESI-MS: m/z 557.91[MH] ^- ,559.37[M+2-H] ^- ,C ₂₉ H ₂₃ BrN ₂ O ₃ S[558.06].

Example 41. Preparation of Compound 41

The operation was the same as in Example 1, except that ZS-C (0.10 g, 0.29 mmol) was reacted with tert-butylsulfonamide (49 mg, 0.36 mmol) to give a pale yellow solid with a yield of 78.8% and a melting point of 215-217° C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.62 (s, 1H), 8.46 (dd, J = 6.6, 3.3 Hz, 1H), 8.25 (dd, J = 6.5, 3.3 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.69–7.64 (m, 3H), 7.44 (d, J = 8.5 Hz, 1H), 7.27 (t, J = 7.1 Hz, 1H), 7.17 (d, J = 7.3 Hz, 1H). z,1H),6.97(d,J＝7.4Hz,1H),6.25(s,2H),5.99(d,J＝7.4Hz,1H),2.32(q,J＝8.4,6.9Hz,1H),1.21(s,9H),0.99(dd,J＝8.4,2.0Hz,2H),0.65–0.56(m,3H ).ESI-MS:m/z449.13[MH] ^- ,C ₂₇ H ₂₈ N ₂ O ₃ S[460.18].

Example 42. Preparation of Compound 42

The operation was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) was reacted with ethanesulfonamide (39 mg, 0.36 mmol) to give a white solid with a yield of 82.3% and a melting point of 200-202°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.09 (s, 1H), 8.46 (dd, J = 6.4, 3.4 Hz, 1H), 8.26 (dd, J = 6.5, 3.3 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.68 (dd, J = 6.5, 3.3 Hz, 2H), 7.42 (d, J = 8.4 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H). .5Hz,1H),6.98(d,J＝7.4Hz,1H),6.28(s,2H),5.99(d,J＝7.4Hz,1H),3.31(t,J＝7.3Hz,2H),2.32(q,J＝8.5,6.8Hz,1H),1.09(t,J＝7.3Hz,3H),0.99(t,J ＝6.3Hz,2H),0.65–0.57(m,2H).ESI-MS:m/z 431.16[MH] ^- ,C ₂₅ H ₂₄ N ₂ O ₃ S[432.15].

Example 43. Preparation of Compound 43

The operation was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) was reacted with methylsulfonamide (34 mg, 0.36 mmol) to give a white solid with a yield of 60.7% and a melting point of 195-197°C. Spectral data: ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.22 (s, 1H), 8.47 (d, J = 7.7Hz, 1H), 8.37–8.19 (m, 1H), 7.88–7.73 (m, 2H), 7.73–7.65 (m, 2H), 7.37 (d, J = 8.7Hz, 1H), 7.2 2(dt,J＝33.0,7.2Hz,2H),6.98(d,J＝7.7Hz,1H),6.30(s,2H),6.01(d,J＝7.7Hz,1H),3.39(s,3H),2.33(s,1H),0.98(d,J＝8.7Hz,2H),0.71–0.48(m,2H) .ESI-MS:m/z 417.11[MH] ^- ,C ₂₄ H ₂₂ N ₂ O ₃ S[418.14].

Example 44. Preparation of Compound 44

The operation was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) was reacted with propylsulfonamide (44 mg, 0.36 mmol) to give a white solid with a yield of 55.3% and a melting point of 192-194°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.11 (s, 1H), 8.53–8.43 (m, 1H), 8.31–8.22 (m, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.76–7.63 (m, 3H), 7.44 (d, J=8.5 Hz, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 6.22 (d, J=7.8 Hz, 1H). .29(s,2H),5.96(d,J＝7.4Hz,1H),3.32–3.22(m,2H),2.34(dq,J＝9.1,4.4,3.0Hz,1H),1.54(q,J＝7.6Hz,2H),0.99(d,J＝6.5Hz,2H),0.79(t,J＝7.5Hz, 3H), 0.61 (d, J＝5.5Hz, 2H).ESI-MS: m/z 445.14[MH] ^- ,C ₂₆ H ₂₆ N ₂ O ₃ S[446.17].

Example 45. Preparation of Compound 45

The operation was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) was reacted with cyclopropanesulfonamide (44 mg, 0.36 mmol) to give a white solid with a yield of 64.3% and a melting point of 180-182°C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.15 (s, 1H), 8.51–8.43 (m, 1H), 8.32–8.24 (m, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.75–7.65 (m, 3H), 7.40 (d, J=8.5 Hz, 1H), 7.28 (t, J=7.7 Hz, 1H), 7.18 (t, J=7.5 Hz, 1H), 6.99 (d, J=7.5 Hz, 1 H),6.31(s,2H),6.01(d,J＝7.5Hz,1H),2.96(tt,J＝8.4,4.8Hz,1H),2.38–2.28(m,1H),1.06(q,J＝4.7,4.0Hz,2H),1.02–0.93(m,4H),0.62(q,J＝5.0,4 .2Hz,2H).ESI-MS:m/z443.06[MH] ^- ,C ₂₆ H ₂₄ N ₂ O ₃ S[446.17].

Example 46. Preparation of Compound 46

The operation was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) was reacted with isopropylsulfonamide (44 mg, 0.36 mmol) to give a white solid with a yield of 61.8% and a melting point of 206-208° C. Spectral data: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.03 (s, 1H), 8.53–8.40 (m, 1H), 8.31–8.20 (m, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.76–7.64 (m, 3H), 7.43 (d, J=8.4 Hz, 1H), 7.28 (t, J=7.7 Hz, 1H), 7.18 (t, J=7.4 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H). z,1H),6.27(s,2H),5.99(d,J＝7.1Hz,1H),3.57(p,J＝6.9Hz,1H),2.33(d,J＝7.5Hz,1H),1.17(d,J＝6.6Hz,6H),0.98(d,J＝8.4Hz,2H),0.60(d,J＝5.5Hz,2 H).ESI-MS: m/z445.36[MH] ^- ,C ₂₆ H ₂₆ N ₂ O ₃ S[446.17].

Example 47. Preparation of Compound 47

The operation was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) was reacted with 2-thiophene to exchange amide (59 mg, 0.36 mmol) to give a white solid with a yield of 76.6% and a melting point of 212-214°C. Spectral data: ¹ H NMR (400 MH z, DMSO-d ₆ ) δ 12.78 (s, 1H), 8.46 (d, J = 7.8 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 4.9 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.75-7.58 (m, 4H), 7.36 (d, J = 8.3 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.1 7(d,J＝7.6Hz,1H),7.08(t,J＝4.5Hz,1H),6.93(d,J＝7.5Hz,1H),6.20(s,2H),5.93(d,J＝7.2Hz,1H),2.40–2.25(m,1H),0.98(d,J＝8.1Hz,2H),0.61(d, J＝5.2Hz,2H).ESI-MS:m/z 485.17[MH] ^- ,C ₂₇ H ₂₂ N ₂ O ₃ S ₂ [486.11].

Example 48. In vivo uric acid-lowering activity test of target compounds

Test Materials and Methods:

(1) Experimental animals: Adult male Kunming mice weighing approximately 20 g were provided by the Experimental Animal Center of Shandong University.

(2) Modeling drugs: hypoxanthine, potassium oxalate, and carboxymethylcellulose sodium (CMC-Na).

(3) Positive control drug: Lesinurad

(4) Testing instruments: Huihao Uric Acid Tester and Uric Acid Test Strips

(5) Experimental principle: An acute hyperuricemia model in mice was established by subcutaneous injection of potassium oxonate combined with oral administration of hypoxanthine. Then, 2 mg/kg of the positive control drug and the test compound were administered. The changes in the blood uric acid levels of the mice were measured 4 hours later to screen out the compounds with excellent in vivo activity.

(6) Sample processing:

First, weigh 0.5g CMC-Na and place it in a 250mL flask. Add 100mL distilled water and heat at 100℃ for 2h. Stop heating after the solution becomes clear and cool for later use.

Preparation of 60mg/mL hypoxanthine suspension: Add 1.2g hypoxanthine to 20mL of 0.5% CMC-Na solution, mix well under ultrasound, and set aside. The hypoxanthine gavage volume for Kunming mice is 0.2mL, and the corresponding animal dosage is 600mg/kg.

Preparation of 40mg/mL potassium oxonate suspension: add 0.8g potassium oxonate to 12mL distilled water and 8mL CMC-Na solution, mix well under ultrasound, and set aside. The subcutaneous injection volume of potassium oxonate in Kunming mice is 0.2mL, and the corresponding animal dosage is 400mg/kg.

Preparation of 0.2 mg/mL solution of Resinade or the compound to be tested: weigh 1 mg of Resinade or the compound to be tested, add 100 μl DMSO to dissolve, then add 4.9 mL 0.5% CMC-Na solution and mix well, and set aside. The corresponding animal dose is 2 mg/kg, 0.2 mL/animal by gavage.

Preparation of blank solution for intragastric administration: Mix 3 mL of 0.5% CMC-Na solution and 1 mL of distilled water, vortex and sonicate, mix well and set aside.

Preparation of blank solution for subcutaneous injection: 3 mL of distilled water, 0.88 mL of 0.5% CMC-Na solution and 0.12 mL of dimethyl sulfoxide were mixed, vortexed and ultrasonicated, and mixed evenly for use. Before use, the test compound was prepared with DMSO and CMC-Na to an appropriate concentration.

(7) Test method:

After 1 week of adaptation, the mice were randomly divided into 4 groups. The mice were fasted but not watered 12 h before the experiment. The experimental group was gavaged with 0.2 mL hypoxanthine suspension (60 mg/mL), subcutaneously injected with 0.2 mL potassium oxonate suspension (40 mg/mL), and gavaged with 0.2 mL compound solution (0.2 mg/mL); the control group was gavaged with 0.2 mL hypoxanthine suspension (60 mg/mL), subcutaneously injected with 0.2 mL potassium oxonate suspension (40 mg/mL), and gavaged with 0.2 mL lesinade solution (0.2 mg/mL); the model group was gavaged with 0.2 mL hypoxanthine suspension (60 mg/mL), subcutaneously injected with 0.2 mL potassium oxonate suspension (40 mg/mL), and gavaged with 0.2 mL blank solution; the blank group was gavaged with 0.4 mL blank solution and subcutaneously injected with 0.2 mL blank solution. After 4 hours, the mice were anesthetized, their eyeballs were removed and blood was collected. The mice were then killed by spinal dislocation, and the serum was separated to detect the blood uric acid concentration.

The decrease rate of blood uric acid concentration (DR) % = (modeling value - experimental value) / (modeling value - blank value) × 100%. The larger the decrease rate value, the better the activity.

Table 2. Uric acid lowering activity of compounds 1 to 24

The structures of compounds 1 to 24 are shown in Table 1 1 to 24;

Table 3. Structures and uric acid-lowering activities of compounds 25-47

The structures of compounds 25 to 47 are shown in Table 1 as 25 to 47;

Conclusion: It can be seen from Tables 2 and 3 that 39 compounds showed uric acid-lowering activity, which was stronger than or equivalent to the positive drug Lesinurad. Among them, representative compounds 1, 9, 12, 15, 24, 25, 27, 29, 34, 35, 44, 45, and 47 showed a blood uric acid reduction rate of more than 70% in the in vivo activity test in animals, showing excellent uric acid-lowering activity and can be used as candidate uric acid-lowering drugs.

Claims (5)

1. Indolylsulfonamide compounds, or pharmaceutically acceptable salts thereof, have a structure represented by the following general formula I: Wherein, R ₁ is cyclopropyl or bromine; R ₂ is selected from C1-C5 alkyl or cycloalkyl, phenyl or substituted phenyl, aromatic heterocycle or substituted aromatic heterocycle; the aromatic heterocycle is selected from naphthalene base, quinolyl, isoquinolyl, quinazolinyl, indolyl, pyridyl, furyl, thienyl, pyrrolyl or pyrimidinyl, the substituent is selected from halogen, hydroxyl, amino, nitro, Hydroxy, cyano, trifluoromethyl, C1-C5 alkyl or cycloalkyl. 2. The indolylsulfonamide compound according to claim 1, which is one of the following compounds: 3. The preparation method of indolylsulfonamide compounds as claimed in claim 2, which is one of the following methods: (1) Synthesis of compounds 1 to 24: First, 1-bromo-4-methylnaphthalene is used as the starting material, and under the catalysis of dibenzoyl peroxide, it reacts with N-bromosuccinimide in n-hexane to generate ZS-A, which is 1 -Bromo-4-(bromomethyl)naphthalene; in acetonitrile, intermediate ZS-A reacts with 1H-indole-2-carboxylic acid methyl ester under the catalysis of cesium carbonate to generate intermediate ZS-B, which is 1-( 4-Bronaphthyl-1-yl)methyl-1H-indole-2-carboxylic acid methyl ester; intermediate ZS-B is hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to obtain compound ZS-C, that is, 1-( 4-Bromonaphthyl)methyl-1H-indole-2-carboxylic acid; ZS-C in 4-dimethylaminopyridine (DMAP) and 1-ethyl-(3-dimethylaminopropyl) Condensation with different types of sulfonamides under the catalysis of carbodiimide hydrochloride (EDCI) gives target products 1 to 24; Route one: Reagents and conditions: (i) N-bromosuccinimide, dibenzoyl peroxide, n-hexane, 70°C; (ii) 1H-indole-2-carboxylic acid methyl ester, cesium carbonate, acetonitrile, 70°C ; (iii) Lithium hydroxide, tetrahydrofuran, methanol, room temperature; (iv) Sulfonamide, in DMAP, EDCI, dichloromethane, 0°C ~ room temperature; Wherein R ₂ is the same as the above general formula I, and the structures of compounds 1 to 24 are as shown in claim 2; (2) Synthesis of compounds 25 to 47 The synthesis of compound ZS-B, namely 1-(4-bromonaphthyl-1-yl)methyl-1H-indole-2-carboxylic acid methyl ester, is consistent with the synthesis of the above-mentioned compounds 1 to 24, except that ZS-B is in tricyclohexyl Under the action of phosphine, potassium phosphate, and palladium acetate, it reacts with cyclopropylboronic acid in toluene to form the intermediate SZ-B, which is 1-(4-cyclopropyl-1-yl)methyl-1H-indole-2-carboxylic acid. Methyl ester; intermediate SZ-B is hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to obtain SZ-C, which is 1-(4-cyclopropyl-1-yl)methyl-1H-indole-2-carboxylic acid. ;SZ-C is condensed with different types of sulfonamides under the catalysis of DMAP and EDCI to obtain target products 25~47; Route two: Reagents and conditions: (i) N-bromosuccinimide, dibenzoyl peroxide, n-hexane, 70°C; (ii) 1H-indole-2-carboxylic acid methyl ester, cesium carbonate, acetonitrile, 70°C ; (iii) Tricyclohexylphosphine, cyclopropylboronic acid, palladium acetate, potassium phosphate, toluene, 100°C, nitrogen; (iv) Lithium hydroxide, tetrahydrofuran, methanol, room temperature; (v) Sulfonamide, in DMAP, EDCI , dichloromethane, 0℃~room temperature; Wherein R ₂ is the same as the above general formula I, and the structures of compounds 25 to 47 are as shown in claim 2; The room temperature mentioned in the present invention refers to 20 to 30°C. 4. Application of the indolylsulfonamide compound according to any one of claims 1 to 2 in the preparation of uric acid-lowering drugs. 5. A uric acid-lowering pharmaceutical composition, comprising the indolylsulfonamide compound according to any one of claims 1-2 and one or more pharmaceutically acceptable carriers or excipients.