An indole acyl sulfonamide compound, a preparation method and application thereof

Abstract

This invention relates to an indoleylsulfonamide compound, its preparation method, and its application. The compound has the structure shown in Formula I. This invention also relates to a method for preparing a compound containing the structure of Formula I and pharmaceutical compositions thereof. This invention also provides the application of the above-mentioned compound in the preparation of uric acid-lowering drugs.

Description

Technical Field

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

[0002] Hyperuricemia (HUA) is defined as a fasting serum uric acid level >420 μmol / L on two separate occasions under normal purine dietary conditions. Gout is a crystal-related arthropathy caused by the deposition of monosodium urate (MSU) with a serum uric acid concentration exceeding 6.8 mg / dL. It is directly related to hyperuricemia caused by purine metabolism disorders or reduced uric acid excretion, specifically referring to acute characteristic arthritis and chronic tophi. Both gout and hyperuricemia are related to the level of uric acid in the body. A normal adult produces approximately 750 mg of uric acid daily, of which one-third is metabolized in the intestines and two-thirds is excreted by the kidneys, thus maintaining stable uric acid levels in the body. Currently, there are two main types of drugs for treating gout: one is xanthine oxidase inhibitors, which inhibit uric acid production, and the other is URAT1 inhibitors, which promote uric acid excretion. Uric acid transporter 1 (URAT1) is located on the brush border of proximal tubular epithelial cells in the human kidney and mainly mediates the reabsorption of uric acid in the kidney. Increased URAT1 activity or expression due to gene mutations is one of the important pathogenic mechanisms of hyperuricemia. Lesinurad is a URAT1 inhibitor used to treat hyperuricemia and gout, but its therapeutic dose is high and it has serious toxic side effects. Therefore, further structural modification of URAT1 is expected to yield novel uric acid-lowering drugs with better activity and safety, and with independent intellectual property rights. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention provides a method for preparing indoleylsulfonamide compounds. This invention also provides the activity screening results of the above compounds as uric acid-lowering drugs and their applications.

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

[0005] I. Indoleylsulfonamides

[0006] The indoleylsulfonamide compounds of the present invention, or pharmaceutically acceptable salts thereof, have the structure shown in general formula I:

[0007]

[0008] Wherein, R1 is cyclopropyl or bromine; R2 is selected from C1-C5 alkyl or cycloalkyl, phenyl or substituted phenyl, aromatic heterocyclic or substituted aromatic heterocyclic; the aromatic heterocyclic is selected from naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, indolyl, pyridyl, furanyl, thiophenyl, pyrroleyl or pyrimidinyl, and the substituent is selected from halogen, hydroxyl, amino, nitro, hydroxyl, cyano, trifluoromethyl, C1-C5 alkyl or cycloalkyl.

[0009] According to the present invention, the indoleylsulfonamide compound is one of the following:

[0010] Table 1. Structural formulas of compounds 1-47

[0011]

[0012]

[0013] II. Preparation methods of indoleylsulfonamide compounds

[0014] The preparation method of the indoleylsulfonamide compounds of the present invention is one of the following methods:

[0015] (1) Synthesis of compounds 1-24:

[0016] First, using 1-bromo-4-methylnaphthalene as the starting material, it reacts with N-bromosuccinimide in n-hexane under the catalysis of benzoyl peroxide to generate ZS-A, namely 1-bromo-4-(bromomethyl)naphthalene. In acetonitrile, intermediate ZS-A reacts with methyl 1H-indole-2-carboxylate under the catalysis of cesium carbonate to generate intermediate ZS-B, namely methyl 1-(4-bromonaphth-1-yl)methyl-1H-indole-2-carboxylate. Intermediate ZS-B is hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to obtain compound ZS-C, namely 1-(4-bromonaphth-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 1-24.

[0017] Route 1:

[0018]

[0019] Reagents and conditions: (i) N-bromosuccinimide, benzoyl peroxide, n-hexane, 70℃; (ii) methyl 1H-indole-2-carboxylate, cesium carbonate, acetonitrile, 70℃; (iii) lithium hydroxide, tetrahydrofuran, methanol, room temperature; (iv) sulfonamide, DMAP, EDCI, dichloromethane, 0℃~room temperature;

[0020] R2 is the same as the general formula I above, and the structures of compounds 1 to 24 are shown in Table 1.

[0021] (2) Synthesis of compounds 25-47

[0022] The synthesis of compound ZS-B, i.e., methyl 1-(4-bromonaphth-1-yl)methyl-1H-indole-2-carboxylate, is consistent with the synthesis of compounds 1-24 above, except that ZS-B reacts with cyclopropylboronic acid in toluene under the action of tricyclohexylphosphine, potassium phosphate, and palladium acetate to generate intermediate SZ-B, i.e., methyl 1-(4-cyclopropyl-1-yl)methyl-1H-indole-2-carboxylate; 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 the target products 25-47;

[0023] Route 2:

[0024]

[0025] Reagents and conditions: (i) N-bromosuccinimide, benzoyl peroxide, n-hexane, 70℃; (ii) methyl 1H-indole-2-carboxylate, cesium carbonate, acetonitrile, 70℃; (iii) tricyclohexylphosphine, cyclopropylboronic acid, palladium acetate, potassium phosphate, toluene, 100℃, nitrogen; (iv) lithium hydroxide, tetrahydrofuran, methanol, room temperature; (v) sulfonamide, DMAP, EDCI, dichloromethane, 0℃~room temperature;

[0026] R2 is the same as the general formula I above, and the structures of compounds 25-47 are shown in Table 1.

[0027] The room temperature mentioned in this invention refers to 20–30°C.

[0028] III. Applications of Indoleylsulfonamide Compounds

[0029] This invention discloses the screening results of indoleylsulfonamide compounds for lowering uric acid activity and their first application in the preparation of uric acid-lowering drugs. Experiments demonstrate that the indoleylsulfonamide compounds of this invention can be used as uric acid-lowering drugs. Specifically, they can be used as uric acid-lowering compounds in the preparation of uric acid-lowering drugs. This invention also provides the application of the above compounds in the preparation of uric acid-lowering drugs.

[0030] Uric acid-lowering activity of the target compound:

[0031] Forty-seven 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 Tables 2 and 3, with Lesinurad as the positive drug.

[0032] As shown in Tables 2 and 3, 39 compounds exhibited significant uric acid-lowering activity, which was stronger than or comparable to the positive control drug Lesinurad. Among them, the representative compounds 1, 9, 12, 15, 24, 25, 27, 29, 34, 35, 44, 45, and 47 all showed a uric acid reduction rate of over 70% in in vivo animal activity tests, demonstrating excellent uric acid-lowering activity and can be considered as candidate drugs for uric acid reduction.

[0033] Therefore, the indoleylsulfonamide compounds in this invention are a novel class of compounds with uric acid-lowering activity, which can be used as candidate drugs for lowering uric acid and for preparing uric acid-lowering drugs.

[0034] A uric acid-lowering pharmaceutical composition comprising an indoleylsulfonamide compound of the present invention and one or more pharmaceutically acceptable carriers or excipients. Detailed Implementation

[0035] 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.

[0036] Synthetic routes for compounds 1–24:

[0037]

[0038] Reagents and conditions: (i) N-bromosuccinimide, benzoyl peroxide, n-hexane, 70℃; (ii) methyl 1H-indole-2-carboxylate, cesium carbonate, acetonitrile, 70℃; (iii) lithium hydroxide, tetrahydrofuran, methanol, room temperature; (iv) sulfonamide, DMAP, EDCI, dichloromethane, 0℃~room temperature;

[0039] Preparation of compound ZS-A

[0040] N-bromosuccinimide (4.00 g, 33.93 mmol) and benzoyl peroxide (0.16 g, 0.68 mmol) were mixed in a 250 mL round-bottom flask, and 100 mL of n-hexane was added. Then, 1-bromo-4-methylnaphthalene (5.00 g, 22.62 mmol) was added dropwise to the flask. The mixture was heated to 70 °C and reacted for 12 h. The reaction was monitored by TLC until complete. Heating was stopped, and the reaction mixture was allowed to cool to room temperature. The filter cake was collected. The filter cake was placed in a 250 mL beaker, and 150 mL of saturated NaHCO3 aqueous solution was added. The mixture was stirred for 10 min and then filtered. The filter cake was collected. The above operation was repeated twice. The last time, the mixture was washed with water and filtered again. Collect the filter cake and place it in a 100 mL flask. Add 50 mL of n-hexane and heat to reflux for 1 hour. After heating, stop the heating, cool to room temperature, filter, and vacuum dry to obtain a pale 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 H8Br2[297.90].

[0041] Preparation of compound ZS-B

[0042] 1-Bromo-4-(bromomethyl)naphthalene (3.00 g, 10.00 mmol) was added to a 250 mL round-bottom flask, followed by approximately 50 mL of acetonitrile to dissolve it. Cesium carbonate (6.54 g, 20.00 mmol) was then added to the flask, followed by methyl 1H-indole-2-carboxylate (2.10 g, 12.00 mmol) dissolved in 50 mL of acetonitrile, which was slowly added dropwise to the flask. The mixture was heated to 70 °C, and solids continuously precipitated during stirring. After 12 h, TLC monitoring was performed. After the reaction was complete, the mixture was filtered, and the filter cake was collected. The filter cake was placed in a 250 mL beaker, and 150 mL of water was added. The mixture was stirred for 10 min, then filtered, and the filter cake was collected. This process was repeated twice. Finally, the filter cake was placed in a 100 mL flask, 50 mL of ethanol was added, and the mixture was heated to 80 °C and stirred for 1 hour. Heating was then stopped, and the mixture was cooled to room temperature and filtered. The filter cake was then 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 BrNO2 [393.04].

[0043] Preparation of compound ZS-C

[0044] 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 dissolve it completely. Lithium hydroxide (1.22 g, 50.80 mmol) was weighed, dissolved in water, and slowly added dropwise to the flask. After stirring for 4 h, the reaction was monitored by TLC to confirm completion. 10 mL of water was added to the mixture, and the tetrahydrofuran and methanol in the mixture were evaporated under reduced pressure. 1 mol / L HCl was slowly added dropwise to the remaining aqueous solution. During the addition, a solid precipitated, and the amount of solid decreased when the pH of the solution was 2-3. The mixture was filtered, and the filter cake was dried under vacuum to obtain a white solid with a yield of 76.9% and a melting point of 175-177 °C. 1 HNMR(400MHz,DMSO-d6)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 BrNO2 [379.02].

[0045] Example 1. Preparation of Compound 1

[0046]

[0047] ZS-C (0.10 g, 0.26 mmol) was placed in a 25 mL flask, dissolved in 10 mL of dichloromethane, and then DMAP (48 mg, 0.39 mmol) and EDCI (75 mg, 0.39 mmol) were added. The mixture was stirred in an ice bath for 15 min, followed by the addition of benzenesulfonamide (49 mg, 0.32 mmol). The ice bath was removed, and the mixture was stirred at room temperature for 12 h before TLC analysis. After the reaction was complete, 10 mL of dichloromethane was added, and the mixture was washed successively with saturated NaHCO3, 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 filtrate was then 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. Spectroscopic data: 1H NMR(400MHz, DMSO-d6)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=7.8H z,2H),7.41(d,J=8.4Hz,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 BrN2O3S[518.03].

[0048] Example 2. Preparation of Compound 2

[0049]

[0050] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with p-bromobenzenesulfonamide (75 mg, 0.32 mmol). The product was a white solid, yield 71.0%, melting point: 245-247 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) 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 Br2N2O3S[595.94].

[0051] Example 3. Preparation of Compound 3

[0052]

[0053] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with p-toluenesulfonamide (55 mg, 0.32 mmol). The product was a white solid, yield 61.8%, melting point: 250-252 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) 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 BrN2O3S[532.05].

[0054] Example 4. Preparation of Compound 4

[0055]

[0056] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with 4-chlorobenzenesulfonamide (61 mg, 0.32 mmol). The product was a white solid with a yield of 74.4% and a melting point of 252-254 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) 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 BrClN2O3S[551.99].

[0057] Example 5. Preparation of Compound 5

[0058]

[0059] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with 4-fluorobenzenesulfonamide (56 mg, 0.32 mmol). The product was a white solid with a yield of 72.3% and a melting point of 219-221 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) 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=8.8,7.7 Hz,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 BrFN2O3S[536.02].

[0060] Example 6. Preparation of Compound 6

[0061]

[0062] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with p-nitrobenzenesulfonamide (65 mg, 0.32 mmol). The product was a pale yellow solid with a yield of 77.4% and a melting point of 251-253 °C. Spectroscopic data: 1H NMR(400MHz, DMSO-d6)δ8.20(dd,J=9.0,2.4Hz,3H),8.16–8.12(m,1H),8.02(s,1H),8.00(s,1H),7.82(d,J=8.0Hz,1H),7.76–7.69(m,3H),7.53 (d,J=7.8Hz,1H),7.46(d,J=8.4Hz,1H),7.30(t,J=7.7Hz,1H),7.19(t,J=7.2Hz,1H),6.15(s,2H),5.82(d,J=7.8Hz,1H).ESI-MS: m / z562.31[MH] - 564.23[M+2-H] - C 26 H 18 BrN3O5S[563.02].

[0063] Example 7. Preparation of Compound 7

[0064]

[0065] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with 2,4-difluorobenzenesulfonamide (62 mg, 0.32 mmol). The product was a white solid with a yield of 80.3% and a melting point of 253-255 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ13.06(s,1H),8.21(t,J=9.2Hz,2H),7.89–7.69(m,5H),7.58(d,J=7.8Hz,1H),7.46(d,J=8.5 Hz,1H),7.38–7.25(m,2H),7.20(t,J=7.4Hz,1H),7.15–7.06(m,1H),6.16(s,2H),5.85(d,J=7.8Hz,1H).ESI-MS:m / z 553.29[MH] - 555.25[M+2-H] - C 26 H 17 BrF2N2O3S[554.01].

[0066] Example 8. Preparation of Compound 8

[0067]

[0068] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with 4-tert-butylbenzenesulfonamide (68 mg, 0.32 mmol). The product was a white solid with a yield of 78.2% and a melting point of 259-261 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) 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 573.41[MH] - 575.33[M+2-H] - C 30 H 27 BrN2O3S[574.09].

[0069] Example 9. Preparation of Compound 9

[0070]

[0071] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with 4-(trifluoromethyl)benzenesulfonamide (72 mg, 0.32 mmol). The product was a white solid with a yield of 65.9% and a melting point of 270-272 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ12.60(s,1H),8.23(d,J=8.2Hz,1H),8.19(d,J=8.2Hz,1H),8.02(d,J=8.4Hz,2H),7.83(t,J=8.5Hz,3H),7.74(d,J=17.3H z,3H),7.57(d,J=7.8Hz,1H),7.43(d,J=8.4Hz,1H),7.29(t,J=7.7Hz,1H),7.19(t,J=7.5Hz,1H),6.15(s,2H),5.88(d,J=7.8Hz,1H).ESI-MS: m / z 585.54[MH] - 587.32[M+2-H] - C 27 H 18 BrF3N2O3S[586.02].

[0072] Example 10. Preparation of Compound 10

[0073]

[0074] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with 5-chlorothiophene-2-sulfonamide (63 mg, 0.32 mmol). The product was a white solid with a yield of 70.3% and a melting point of 252-254 °C. Spectroscopic data: 1 H NMR(400MHz, DMSO-d6)δ8.36–8.29(m,1H),8.23(dd,J=6.9,2.6Hz,1H),7.84–7.74(m,3H),7.67(s,1H),7.60–7.51(m,2H),7. 46(d,J=8.5Hz,1H),7.30(t,J=7.7Hz,1H),7.19(t,J=7.4Hz,1H),7.10(s,1H),6.26(s,2H),5.94(d,J=7.8Hz,1H).ESI-MS:m / z 557.60[MH] - 559.34[M+2-H] - 561.19[M+4-H] - C 24 H 16 BrClN2O3S2[557.95].

[0075] Example 11. Preparation of Compound 11

[0076]

[0077] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with 4-methoxybenzenesulfonamide (60 mg, 0.32 mmol). The product was a white solid with a yield of 74.4% and a melting point of 264-266 °C. Spectroscopic data: 1H NMR(400MHz, DMSO-d6)δ12.49(s,1H),8.26(dd,J=7.9,1.6Hz,1H),8.21(dd,J=8.0,1.6Hz,1H),7.85–7.69(m,6H),7.56(d,J=7.8Hz,1H),7.40 (d,J=8.4Hz,1H),7.32–7.24(m,1H),7.18(t,J=7.5Hz,1H),6.98(d,J=9.0Hz,2H),6.17(s,2H),5.88(d,J=7.8Hz,1H),3.78(s,3H).ESI-MS:m / z 547.37[MH] - 549.32[M+2-H] - C 27 H 21 BrN2O4S[548.04].

[0078] Example 12. Preparation of Compound 12

[0079]

[0080] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with 4-(2-hydroxy-2-propyl)furan-2-sulfonamide (66 mg, 0.32 mmol). The product was a white solid, yield 66.7%, melting point: 232-234 °C. Spectroscopic data: 1 HNMR (600MHz, DMSO-d6) δ12.96 (s, 1H), 8.27 (d, J = 7.2 Hz, 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 BrN2O5S[566.05].

[0081] Example 13. Preparation of Compound 13

[0082]

[0083] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with 4-ethylbenzenesulfonamide (59 mg, 0.32 mmol). The product was a white solid with a yield of 69.2% and a melting point of 240-242 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ12.53(s,1H),8.25(d,J=7.6Hz,1H),8.20(d,J=8.2H z,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 BrN2O3S[546.06].

[0084] Example 14. Preparation of Compound 14

[0085]

[0086] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with 3,5-difluorobenzenesulfonamide (62 mg, 0.32 mmol). The product was a white solid with a yield of 70.0% and a melting point of 238-240 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ8.26(d,J=7.5Hz,1H),8.20(d,J=8.1Hz,1H),7.82(d,J=8.0Hz,1H),7.80–7.70(m,3H),7.55–7.5 0(m,2H),7.50–7.43(m,3H),7.30(t,J=7.6Hz,1H),7.19(t,J=7.5Hz,1H),6.18(s,2H),5.86(d,J=7.7Hz,1H).ESI-MS:m / z 553.85[MH] - 555.39[M+2-H] - C 26 H 17 BrF2N2O3S[554.01].

[0087] Example 15. Preparation of Compound 15

[0088]

[0089] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with m-nitrobenzenesulfonamide (65 mg, 0.32 mmol), producing a pale yellow solid with a yield of 72.3% and a melting point of 243-245 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ8.61(t,J=2.0Hz,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=7.5Hz,1H),6.15(s,2H),5.80(d,J=7.8Hz,1H).ESI-MS:m / z 562.80[MH] - 564.38[M+2-H] - C 26 H 18 BrN3O5S[563.02].

[0090] Example 16. Preparation of Compound 16

[0091]

[0092] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with 2-nitrobenzenesulfonamide (65 mg, 0.32 mmol). The product was a pale yellow solid with a yield of 72.3% and a melting point of 234-236 °C. Spectroscopic data: 1 H NMR(400MHz, DMSO-d6)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 BrN3O5S[563.02].

[0093] Example 17. Preparation of Compound 17

[0094]

[0095] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with m-bromobenzenesulfonamide (75 mg, 0.32 mmol). The product was a white solid with a yield of 62.8% and a melting point of 241-243 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ12.82(s,1H),8.25(d,J=8.0Hz,1H),8.21(d,J=9.0Hz,1H),7.93(d,J=2.1Hz,1H),7.86–7.72(m,6H),7.53 (d,J=7.8Hz,1H),7.47–7.38(m,2H),7.29(t,J=7.7Hz,1H),7.19(t,J=7.4Hz,1H),6.17(s,2H),5.87(d,J=7.8Hz,1H).ESI-MS:m / z 597.35[M+2-H] - 595.87 [MH] - 599.20[M+4-H] - C 26 H 18 Br2N2O3S[595.94].

[0096] Example 18. Preparation of Compound 18

[0097]

[0098] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with tert-butylsulfonamide (44 mg, 0.32 mmol). The product was a pale yellow solid with a yield of 75.5% and a melting point of 270-272 °C. Spectroscopic data: 1H NMR (400MHz, DMSO-d6) 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),7.30(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 23 BrN2O3S[498.06].

[0099] Example 19. Preparation of Compound 19

[0100]

[0101] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with ethanesulfonamide (35 mg, 0.32 mmol). The product was a white solid with a yield of 79.7% and a melting point of 215-217 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) 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=7.8Hz,1H),7.54–7.3 7(m,2H),7.36–7.23(m,1H),7.19(dt,J=10.2,7.5Hz,1H),6.31(s,2H),6.07–5.92(m,2H),1.11(t,J=7.3Hz,3H).ESI-MS:m / z 469.55[MH] - 471.35[M+2-H] - C 22 H 19 BrN2O3S[470.03].

[0102] Example 20. Preparation of Compound 20

[0103]

[0104] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with methanesulfonamide (30 mg, 0.32 mmol). The product was a white solid with a yield of 55.8% and a melting point of 235-237 °C. Spectroscopic data: 1 H NMR(400MHz,DMSO-d6)δ12.19(s,1H),8.40–8.31(m,1H),8.26–8.20(m,1H),7.86–7.74(m,4H),7.65(d,J=7.8Hz,1H),7.4 3(d,J=8.4Hz,1H),7.34–7.26(m,1H),7.20(t,J=7.4Hz,1H),6.31(s,2H),6.02(d,J=7.8Hz,1H),3.25(s,3H).ESI-MS:m / z 455.50[MH] - 457.31[M+2-H] - C 21 H 17 BrN2O3S[456.01].

[0105] Example 21. Preparation of compound 21

[0106]

[0107] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with propylsulfonamide (39 mg, 0.32 mmol). The product was a white solid with a yield of 59.5% and a melting point of 205-207 °C. Spectroscopic data: 1 H NMR(400MHz,DMSO-d6)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 BrN2O3S[484.05].

[0108] Example 22. Preparation of compound 22

[0109]

[0110] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with cyclopropanesulfonamide (39 mg, 0.32 mmol). The product was a white solid with a yield of 59.7% and a melting point of 220-222 °C. Spectroscopic data: 1 H NMR(400MHz, DMSO-d6)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 BrN2O3S[482.03].

[0111] Example 23. Preparation of compound 23

[0112]

[0113] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with isopropyl sulfonamide (39 mg, 0.32 mmol). The product was a white solid with a yield of 61.8% and a melting point of 210-212 °C. Spectroscopic data: 1H NMR(400MHz,DMSO-d6)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),7.3 2(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 BrN2O3S[484.05].

[0114] Example 24. Preparation of compound 24

[0115]

[0116] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.26 mmol) reacted with 2-thiopheneamide (52 mg, 0.32 mmol). The product was a white solid with a yield of 77.4% and a melting point of 225-227 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ12.83(s,1H),8.30(d,J=7.5Hz,1H),8.22(d,J=7.7 Hz,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 BrN2O3S2[523.99].

[0117] Synthetic routes for compounds 25–47:

[0118]

[0119] Reagents and conditions: (i) N-bromosuccinimide, benzoyl peroxide, n-hexane, 70℃; (ii) methyl 1H-indole-2-carboxylate, cesium carbonate, acetonitrile, 70℃; (iii) tricyclohexylphosphine, cyclopropylboronic acid, palladium acetate, potassium phosphate, toluene, 100℃, nitrogen; (iv) lithium hydroxide, tetrahydrofuran, methanol, room temperature; (v) sulfonamide, DMAP, EDCI, dichloromethane, 0℃~room temperature;

[0120] Preparation of compound SZ-B

[0121] 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), and palladium acetate (0.28 g, 1.27 mmol) were added sequentially to a 250 mL flask. 100 mL of toluene and 16 mL of distilled water were added. The mixture was heated to 100 °C under a nitrogen atmosphere. After 15 h, the reaction was monitored by TLC to indicate completion. 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 washed with saturated NaCl aqueous solution (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate for 2 h and then filtered. The filtrate was concentrated under reduced pressure and then subjected to rapid column chromatography (EA:PE = 1:5) to give 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 NO2[355.16].

[0122] Preparation of compound SZ-C

[0123] Intermediate SZ-B (4.2 g, 11.80 mmol) was placed in a 250 mL flask, and 80 mL of tetrahydrofuran and 25 mL of methanol were added to dissolve it completely. Lithium hydroxide (2.90 g, 0.12 mmol) was weighed, dissolved in water, and slowly added dropwise to the flask. After stirring for 4 h, the reaction was monitored by TLC to confirm completion. 20 mL of water was added to the mixture to evaporate the tetrahydrofuran and methanol. 1 mol / L HCl was slowly added dropwise to the remaining aqueous solution. A solid precipitated during the addition, but the amount of solid decreased when the pH of the solution reached 2-3. The solution was filtered, and the filter cake was vacuum dried to obtain a white solid with a yield of 95.0% and a melting point of 105–107 °C. 1H NMR(600MHz,DMSO-d6)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,1H),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(d dd,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 NO2[341.14].

[0124] Example 25. Preparation of compound 25

[0125]

[0126] SZ-C (0.20 g, 0.59 mmol) was placed in a 50 mL flask, dissolved in 20 mL of dichloromethane, and then DMAP (0.11 g, 0.89 mmol) and EDCI (0.17 g, 0.89 mmol) were added. The mixture was stirred in an ice bath for 15 min, followed by the addition of benzenesulfonamide (0.11 g, 0.70 mmol). The ice bath was removed, and the mixture was stirred at room temperature for 12 h before TLC analysis. After the reaction was complete, 20 mL of dichloromethane was added, and the mixture was washed successively with saturated NaHCO3, 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 filtrate was then 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. Spectroscopic data: 1HNMR(400MHz,DMSO-d6)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),5.8 9(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 N₂O₃S[480.15].

[0127] Example 26. Preparation of compound 26

[0128]

[0129] The procedure was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) reacted with p-bromobenzenesulfonamide (0.165 g, 0.70 mmol). The product was a white solid, yield 77.0%, melting point: 225-227 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) 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 BrN2O3S[558.06].

[0130] Example 27. Preparation of compound 27

[0131]

[0132] The procedure was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) reacted with p-toluenesulfonamide (0.12 g, 0.70 mmol). The product was a white solid, yield 73.5%, melting point: 215-217 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) 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).ESI-MS:m / z 493.16[MH] - C 30 H 26 N2O3S[494.17].

[0133] Example 28. Preparation of compound 28

[0134]

[0135] The procedure was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) reacted with 4-chlorobenzenesulfonamide (0.13 g, 0.70 mmol). The product was a white solid with a yield of 70.2% and a melting point of 210-212 °C. Spectroscopic data: 1H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.45(d,J=9.0Hz,1H),8.17(d,J=8.9Hz,1H),7.85(d,J= 8.5Hz,2H),7.73(s,1H),7.66(d,J=8.8Hz,2H),7.56(d,J=8.5Hz,2H),7.49(s,1H),7.36(d,J= 8.4Hz,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 ClN2O3S[514.11].

[0136] Example 29. Preparation of compound 29

[0137]

[0138] The procedure was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) reacted with 4-fluorobenzenesulfonamide (0.12 g, 0.70 mmol). The product was a white solid with a yield of 80.7% and a melting point of 208-210 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ12.62(s,1H),8.49–8.40(m,1H),8.20–8.13(m,1H),7.92(dd,J=8.9,5.1H z,2H),7.80(d,J=8.0Hz,1H),7.73(s,1H),7.65(p,J=6.9Hz,2H),7.43(d,J=2.9Hz,1H),7.34(d,J= 3.8Hz,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 H23 FN2O3S[498.14].

[0139] Example 30. Preparation of compound 30

[0140]

[0141] The procedure was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) reacted with p-nitrobenzenesulfonamide (0.14 g, 0.70 mmol). The product was a pale yellow solid with a yield of 79.2% and a melting point of 220-222 °C. Spectroscopic data: 1 H NMR(400MHz, DMSO-d6)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 N3O5S[525.14].

[0142] Example 31. Preparation of compound 31

[0143]

[0144] The procedure was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) reacted with 2,4-difluorobenzenesulfonamide (0.14 g, 0.70 mmol). The product was a white solid with a yield of 81.2% and a melting point of 215-217 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) 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 F2N2O3S[516.13].

[0145] Example 32. Preparation of compound 32

[0146]

[0147] The procedure was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) reacted with 4-tert-butylbenzenesulfonamide (0.15 g, 0.70 mmol). The product was a white solid, yield 72.0%, melting point: 225-227 °C. Spectroscopic data: 1 H NMR(400MHz,DMSO-d6)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 N2O3S[536.21].

[0148] Example 33. Preparation of compound 33

[0149]

[0150] The procedure was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) reacted with 4-(trifluoromethyl)benzenesulfonamide (0.16 g, 0.70 mmol). The product was a white solid with a yield of 71.9% and a melting point of 205-207 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) 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 F3N2O3S[548.14].

[0151] Example 34. Preparation of compound 34

[0152]

[0153] The procedure was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) reacted with 5-chlorothiophene-2-sulfonamide (0.14 g, 0.70 mmol). The product was a white solid with a yield of 84.0% and a melting point greater than 250 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ8.49–8.45(m,1H),8.26–8.22(m,1H),7.78(d,J=8.0Hz,1H),7.71–7.62(m,3H),7.55(d,J=4.2Hz,1H),7.41–7.08(m,5H), 6.93(d,J=7.5Hz,1H),6.25(s,2H),2.32(dq,J=8.7,4.4Hz,1H),0.98(dt,J=9.0,3.1Hz,2H),0.61(dt,J=6.1,3.1Hz,2H).ESI-MS: m / z519.83[MH] - 521.36[M+2-H] - C 27 H 21 ClN2O3S2[520.07].

[0154] Example 35. Preparation of compound 35

[0155]

[0156] The procedure was the same as in Example 25, except that SZ-C (0.20 g, 0.59 mmol) reacted with 4-methoxybenzenesulfonamide (0.13 g, 0.70 mmol). The product was a white solid with a yield of 74.8% and a melting point of 215-217 °C. Spectroscopic data: 1 H NMR(400MHz,DMSO-d6)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 N₂O₄S[510.16].

[0157] Example 36. Preparation of compound 36

[0158]

[0159] The procedure was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) reacted with 4-ethylbenzenesulfonamide (67 mg, 0.36 mmol). The product was a white solid, yield 76.0%, melting point: 208-210 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),8.45(d,J=8.0Hz,1H),8.18(d,J=7.7Hz,1H),7.79–7.7 2(m,5H),7.66(d,J=7.7Hz,1H),7.40(d,J=8.1Hz,2H),7.29(s,1H),7.27–7.19(m,1H),7.16(t ,J=7.4Hz,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 N₂O₃S[508.18].

[0160] Example 37. Preparation of compound 37

[0161]

[0162] The procedure was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) reacted with 3,5-difluorobenzenesulfonamide (70 mg, 0.36 mmol). The product was a white solid, yield 70.0%, melting point: 206-208 °C. Spectroscopic data: 1H NMR (400MHz, DMSO-d6) δ12.74(s,1H),8.44(d,J=7.0Hz,1H),8.18(d,J=8.5Hz,1H),7.81(d,J= 8.0Hz,1H),7.72(s,1H),7.66(q,J=6.8Hz,2H),7.54(dd,J=25.0,7.1Hz,3H),7.39(d,J=8.5Hz, 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),0.64–0.54(m,2H).ESI-MS:m / z 515.09[MH] - C 29 H 22 F2N2O3S[516.13].

[0163] Example 38. Preparation of compound 38

[0164]

[0165] The procedure was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) reacted with m-nitrobenzenesulfonamide (73 mg, 0.36 mmol), producing a pale yellow solid with a yield of 76.1% and a melting point of 220-222 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ12.98(s,1H),8.54(s,1H),8.40(dd,J=13.4,9.7Hz,2H),8.24(d,J=7.6 Hz,1H),8.13(d,J=7.5Hz,1H),7.81(d,J=8.0Hz,1H),7.78–7.71(m,2H),7.68–7.55(m,2H),7.3 8(d,J=8.5Hz,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 N3O5S[525.14].

[0166] Example 39. Preparation of compound 39

[0167]

[0168] The procedure was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) reacted with 2-nitrobenzenesulfonamide (73 mg, 0.36 mmol), producing a pale yellow solid with a yield of 72.3% and a melting point >250 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ8.44(d,J=8.0Hz,1H),8.18(d,J=7.9Hz,1H),8.07(d,J=7.9Hz,1H),7.9 5(d,J=7.9Hz,1H),7.83(d,J=9.2Hz,3H),7.68(dt,J=23.8,8.0Hz,3H),7.35(d,J=8.4Hz,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=7.4H z,1H),2.37–2.27(m,1H),0.99(t,J=6.3Hz,2H),0.60(t,J=5.2Hz,2H).ESI-MS:m / z524.00[MH] - C 29 H 23 N3O5S[525.14].

[0169] Example 40. Preparation of Compound 40

[0170]

[0171] The procedure was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) reacted with m-bromobenzenesulfonamide (85 mg, 0.36 mmol). The product was a white solid, yield 70.0%, melting point: 210-212 °C. Spectroscopic data: 1H NMR (400MHz, DMSO-d6) δ12.74(s,1H),8.44(d,J=8.0Hz,1H),8.17(d,J=8.0Hz,1H),7.98(s,1H ),7.92–7.77(m,3H),7.74(s,1H),7.64(p,J=6.9Hz,2H),7.45(t,J=8.0Hz,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 BrN2O3S[558.06].

[0172] Example 41. Preparation of compound 41

[0173]

[0174] The procedure was the same as in Example 1, except that ZS-C (0.10 g, 0.29 mmol) reacted with tert-butylsulfonamide (49 mg, 0.36 mmol). The product was a pale yellow solid with a yield of 78.8% and a melting point of 215-217 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.46(dd,J=6.6,3.3Hz,1H),8.25(dd,J=6.5,3.3Hz,1H ),7.81(d,J=8.0Hz,1H),7.69–7.64(m,3H),7.44(d,J=8.5Hz,1H),7.27(t,J=7.1Hz,1H),7.17 (d,J=7.3Hz,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 N₂O₃S[460.18].

[0175] Example 42. Preparation of compound 42

[0176]

[0177] The procedure was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) reacted with ethanesulfonamide (39 mg, 0.36 mmol). The product was a white solid with a yield of 82.3% and a melting point of 200-202 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),8.46(dd,J=6.4,3.4Hz,1H),8.26(dd,J=6.5,3.3Hz,1H),7.80(d ,J=8.0Hz,1H),7.73(s,1H),7.68(dd,J=6.5,3.3Hz,2H),7.42(d,J=8.4Hz,1H),7.28(t,J=7.9Hz,1H),7 .18(t,J=7.5Hz,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 N2O3S[432.15].

[0178] Example 43. Preparation of compound 43

[0179]

[0180] The procedure was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) reacted with methanesulfonamide (34 mg, 0.36 mmol). The product was a white solid with a yield of 60.7% and a melting point of 195-197 °C. Spectroscopic data: 1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),8.47(d,J=7.7Hz,1H),8.37–8.19(m,1 H),7.88–7.73(m,2H),7.73–7.65(m,2H),7.37(d,J=8.7Hz,1H),7.22(dt,J=3 3.0,7.2Hz,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 N2O3S[418.14].

[0181] Example 44. Preparation of compound 44

[0182]

[0183] The procedure was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) reacted with propylsulfonamide (44 mg, 0.36 mmol). The product was a white solid, yield 55.3%, melting point: 192-194 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H),8.53–8.43(m,1H),8.31–8.22(m,1H),7.81(d,J=8.0Hz,1H), 7.76–7.63(m,3H),7.44(d,J=8.5Hz,1H),7.29(t,J=7.7Hz,1H),7.19(t,J=7.5Hz,1H),6.98(d,J=7. 5Hz,1H),6.29(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 N2O3S[446.17].

[0184] Example 45. Preparation of compound 45

[0185]

[0186] The procedure was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) reacted with cyclopropanesulfonamide (44 mg, 0.36 mmol). The product was a white solid with a yield of 64.3% and a melting point of 180-182 °C. Spectroscopic data: 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),8.51–8.43(m,1H),8.32–8.24(m,1H),7.81(d,J=8.0Hz,1H ),7.75–7.65(m,3H),7.40(d,J=8.5Hz,1H),7.28(t,J=7.7Hz,1H),7.18(t,J=7.5Hz,1H),6.99(d, J=7.5Hz,1H),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 N2O3S[446.17].

[0187] Example 46. Preparation of compound 46

[0188]

[0189] The procedure was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) reacted with isopropyl sulfonamide (44 mg, 0.36 mmol). The product was a white solid with a yield of 61.8% and a melting point of 206-208 °C. Spectroscopic data: 1H NMR(400MHz,DMSO-d6)δ12.03(s,1H),8.53–8.40(m,1H),8.31–8.20(m,1H),7.80(d,J=7.9Hz,1 H),7.76–7.64(m,3H),7.43(d,J=8.4Hz,1H),7.28(t,J=7.7Hz,1H),7.18(t,J=7.4Hz,1H),6.97 (d,J=7.2Hz,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,1 H),1.17(d,J=6.6Hz,6H),0.98(d,J=8.4Hz,2H),0.60(d,J=5.5Hz,2H).ESI-MS:m / z445.36[MH] - C 26 H 26 N2O3S[446.17].

[0190] Example 47. Preparation of compound 47

[0191]

[0192] The procedure was the same as in Example 25, except that SZ-C (0.10 g, 0.29 mmol) reacted with 2-thiopheneamide (59 mg, 0.36 mmol). The product was a white solid, yield 76.6%, melting point: 212-214 °C. Spectroscopic data: 1 H NMR(400MH z,DMSO-d6)δ12.78(s,1H),8.46(d,J=7.8Hz,1H),8.22(d,J=7.6Hz,1H),7.93(d,J=4.9Hz, 1H),7.79(d,J=7.9Hz,1H),7.75–7.58(m,4H),7.36(d,J=8.3Hz,1H),7.25(t,J=7.6Hz,1H) ,7.17(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 N2O3S2[486.11].

[0193] Example 48. In vivo uric acid-lowering activity test of the target compound

[0194] Test materials and methods:

[0195] (1) Experimental animals: Adult male Kunming mice weighing about 20g were provided by the Experimental Animal Center of Shandong University.

[0196] (2) Modeling drugs: hypoxanthine, potassium oxonate, sodium carboxymethylcellulose (CMC-Na).

[0197] (3) Positive control drug: Lesinurad

[0198] (4) Testing instruments: Huihao Yousu uric acid tester and uric acid test strips

[0199] (5) Experimental principle: A mouse model of acute hyperuricemia was established by subcutaneous injection of potassium oxonate combined with gavage administration of hypoxanthine. Then, 2 mg / kg of positive control drug and test compound were given. By measuring the change in serum uric acid level in mice after 4 hours, compounds with excellent in vivo activity were screened.

[0200] (6) Sample processing:

[0201] First, weigh 0.5g of CMC-Na and place it in a 250mL flask. Add 100mL of distilled water and heat at 100℃ for 2 hours. After the solution becomes clear, stop heating and let it cool before use.

[0202] Preparation of 60 mg / mL hypoxanthine suspension: Add 1.2 g hypoxanthine to 20 mL of 0.5% CMC-Na solution, mix thoroughly under sonication, and set aside. The intragastric administration volume of hypoxanthine to Kunming mice is 0.2 mL, corresponding to an animal dose of 600 mg / kg.

[0203] Preparation of 40 mg / mL potassium oxonate suspension: Add 0.8 g potassium oxonate to 12 mL of distilled water and 8 mL of CMC-Na solution, mix thoroughly under sonication, and set aside for use. The subcutaneous injection volume of potassium oxonate in Kunming mice is 0.2 mL, corresponding to an animal dose of 400 mg / kg.

[0204] Preparation of 0.2 mg / mL Recinard or test compound solution: Weigh 1 mg of Recinard or test compound, add 100 μl of DMSO to dissolve, then add 4.9 mL of 0.5% CMC-Na solution and mix well. The corresponding animal dosage is 2 mg / kg, 0.2 mL / animal administered by gavage.

[0205] Preparation of blank solution for gavage: Mix 3 mL of 0.5% CMC-Na solution with 1 mL of distilled water, vortex and sonicate, and mix thoroughly before use.

[0206] Preparation of blank solution for subcutaneous injection: Mix 3 mL of distilled water, 0.88 mL of 0.5% CMC-Na solution, and 0.12 mL of dimethyl sulfoxide. Vortex and sonicate until homogeneous. Before use, prepare an appropriate concentration of the test compound using DMSO and CMC-Na.

[0207] (7) Test method:

[0208] Mice were randomly divided into four groups after acclimatizing for one week. 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 Recinard 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, the mice were anesthetized, their eyeballs were removed to collect blood, and they were euthanized by spinal cord dislocation. Serum was separated, and the serum uric acid concentration was measured.

[0209] The rate of decrease in serum uric acid concentration (DR)% = (model value - experimental value) / (model value - blank value) × 100%. The higher the rate of decrease, the better the activity.

[0210] Table 2. Uric acid-lowering activity of compounds 1–24

[0211]

[0212] The structures of compounds 1–24 are shown in Table 1 (1–24);

[0213] Table 3. Structures and uric acid-lowering activities of compounds 25–47

[0214]

[0215]

[0216] The structures of compounds 25–47 are shown in Table 1.

[0217] Conclusion: As shown in Tables 2 and 3, 39 compounds exhibited uric acid-lowering activity, which was stronger than or comparable to the positive control drug Lesinurad. Among them, the representative compounds 1, 9, 12, 15, 24, 25, 27, 29, 34, 35, 44, 45, and 47 all showed a uric acid reduction rate of over 70% in in vivo animal activity tests, demonstrating excellent uric acid-lowering activity and can be considered as candidate drugs for uric acid reduction.

Claims

1. Indoleylsulfonamide compounds, or pharmaceutically acceptable salts thereof, having the structure shown in general formula I: in, R1 is cyclopropyl or bromine; R2 is selected from C1-C5 alkyl or cyclopropyl, phenyl or substituted phenyl, aromatic heterocyclic or substituted aromatic heterocyclic; the aromatic heterocyclic is selected from furanyl or thiophene, and the substituent is selected from halogen, hydroxyl, nitro, trifluoromethyl, C1-C5 alkyl.

2. Indoleylsulfonamide compounds, characterized in that, It is one of the following compounds:

3. The method for preparing indoleylsulfonamide compounds as described in claim 2, characterized in that, One of the following methods: (1) Synthesis of compounds 1-24: First, using 1-bromo-4-methylnaphthalene as the starting material, it reacts with N-bromosuccinimide in n-hexane under the catalysis of benzoyl peroxide to generate ZS-A, namely 1-bromo-4-(bromomethyl)naphthalene. In acetonitrile, intermediate ZS-A reacts with methyl 1H-indole-2-carboxylate under the catalysis of cesium carbonate to generate intermediate ZS-B, namely methyl 1-(4-bromonaphthyl-1-yl)methyl-1H-indole-2-carboxylate. Intermediate ZS-B is hydrolyzed with lithium hydroxide in a mixed solution of tetrahydrofuran and methanol to obtain compound ZS-C, namely 1-(4-bromonaphthyl-1-yl)methyl-1H-indole-2-carboxylic acid. ZS-C is condensed with different types of sulfonamides under the catalysis of 4-dimethylaminopyridine (DMAP) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) to obtain target products 1-24. Route 1: Reagents and conditions: (i) N-bromosuccinimide, benzoyl peroxide, n-hexane, 70℃; (ii) methyl 1H-indole-2-carboxylate, cesium carbonate, acetonitrile, 70℃; (iii) lithium hydroxide, tetrahydrofuran, methanol, room temperature; (iv) sulfonamide, in DMAP, EDCI, dichloromethane, 0℃ to room temperature; Wherein R2 is as defined in claim 1, and compounds 1 to 24 have the structures shown in claim 2; (2) Synthesis of compounds 25-47 The synthesis of compound ZS-B, i.e., methyl 1-(4-bromonaphth-1-yl)methyl-1H-indole-2-carboxylate, is consistent with the synthesis of compounds 1-24 above, except that ZS-B reacts with cyclopropylboronic acid in toluene under the action of tricyclohexylphosphine, potassium phosphate, and palladium acetate to generate intermediate SZ-B, i.e., methyl 1-(4-cyclopropyl-1-yl)methyl-1H-indole-2-carboxylate; 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 the target products 25-47; Route 2: Reagents and conditions: (i) N-bromosuccinimide, benzoyl peroxide, n-hexane, 70°C; (ii) methyl 1H-indole-2-carboxylate, 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°C to room temperature; Wherein R2 is as defined in claim 1, and compounds 25-47 have the structures shown in claim 2; The room temperature mentioned refers to 20–30°C.

4. The use of the indoleylsulfonamide compound according to any one of claims 1-2 in the preparation of a uric acid-lowering drug.

5. A uric acid-lowering pharmaceutical composition comprising an indoleylsulfonamide compound as described in any one of claims 1-2 and one or more pharmaceutically acceptable carriers or excipients.

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