Substituted benzenesulfonamide compounds and their applications

Abstract

The present invention relates to the field of medicinal chemistry, specifically to a class of substituted benzenesulfonamide compounds and their applications. Pharmacological experiments have shown that the benzenesulfonamide compounds of the present invention have strong inhibitory activity against GSTP1-1 protein. Some compounds have anti-proliferative effects on tumor cells, including human lung cancer and cisplatin-resistant lung cancer, and have a certain degree of ability to reverse cisplatin resistance.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of substituted benzenesulfonamide compounds, pharmaceutical compositions thereof and applications thereof. Background Art

[0002] Cisplatin (CDDP) is one of the most widely used platinum-based anti-tumor drugs. After cisplatin enters the body, one of its chlorine atoms is replaced by a water molecule, forming [PtCl(H2O)(NH3)2] ＋ , the water molecule readily dissociates, allowing platinum to coordinate with DNA bases. Subsequently, another chlorine atom dissociates, allowing platinum to cross-link with two points within a single DNA strand or with both strands, inhibiting DNA replication in cancer cells and leading to cell apoptosis. CDDP primarily binds to the N7 site of purine bases on DNA, forming various types of adducts, the vast majority of which are intrastrand crosslinks.

[0003] CDDP is primarily used in chemotherapy to treat various types of cancer, including sarcomas, lung cancer, head and neck cancer, ovarian cancer, and lymphoma. CDDP is a highly effective but also highly toxic chemotherapeutic drug. Its broad anticancer spectrum and strong anticancer activity make it an important treatment for various cancers, but it also poses challenges with side effects and drug resistance. Long-term use of CDDP can cause toxic side effects such as ototoxicity, nephrotoxicity, cardiotoxicity, and neurotoxicity. The development of CDDP resistance may be related to platinum compounds failing to reach effective intracellular levels or being inactivated before reacting with DNA, such as reduced drug uptake in tumor cells and increased drug efflux from endothelial cells. Molecular mechanisms of resistance include reduced intracellular drug accumulation, enhanced drug inactivation, DNA repair, DNA damage response, and alterations in apoptosis pathways.

[0004] There is a correlation between CDDP resistance and the GSTP1-1 protein (glutathione S-transferase P1). GSTP1-1 is a crucial detoxification enzyme that plays a crucial role in tumorigenesis and the development of anticancer drug resistance in tumor cells. Hypermethylation of the GSTP1-1 gene promoter can lead to promoter inactivation and gene silencing, affecting the functions of the encoded protein involved in tumor suppression, DNA damage repair, and cell cycle regulation. These functional alterations are closely linked to cancer.

[0005] In studies of CDDP resistance, elevated GSTP1-1 expression and the associated increase in glutathione (GSH) concentrations suggest that enzymatic CDDP inactivation plays a key role in the clinically manifested resistance phenotype. In CDDP-resistant tumor cells, elevated GST expression is associated with CDDP resistance. GST catalyzes the conjugation of CDDP with GSH, forming a Pt-GSH conjugate. This conjugate is more readily transported out of the cell by multidrug resistance-associated proteins (such as MRP2), promoting resistance. Furthermore, overexpression of GSTP1-1 can lead to increased resistance to CDDP. Overexpression of GSTP1-1 in sensitive cell lines that underexpress specific genes can induce resistance. In head and neck cancer patients, low GSTP1-1 expression correlates with effective CDDP treatment, while patients with high GSTP1-1 expression have a two-fold decreased survival rate. In summary, GSTP1-1 protein plays a key role in CDDP resistance, and its overexpression is directly associated with the formation of CDDP resistance.

[0006] Gliquidone is a drug classified as a second-generation sulfonylurea. Its mechanism of action involves stimulating the release of endogenous insulin from pancreatic beta cells, thereby achieving a blood sugar-lowering effect. It is considered a primary treatment option for managing mild to moderate renal impairment in patients with diabetic nephropathy. Furthermore, gliquidone has demonstrated the ability to lower blood sugar levels by enhancing insulin sensitivity in hepatocytes. The structural formula of gliquidone is as follows:

[0007] .

[0008] Patent CN114469963A discloses the application of gliquidone combined with cisplatin in the preparation of anti-tumor drugs. The present invention found that the inhibitory effect of gliquidone and cisplatin on lung cancer cells was significantly enhanced when the two drugs were used in combination. The IC of cisplatin in A549 and A549 / CDDP was 50 were 7.29±1.11μM and 32.32±0.17μM, respectively, while the IC 50 The results were 4.00±0.14μM and 18.16±1.03μM, respectively. Gliquidone can, to a certain extent, reverse the resistance of the drug-resistant cell line A549 / CDDP to CDDP. However, studies on gliquidone derivatives targeting GSTP1-1 to achieve anti-tumor effects and reverse tumor resistance have not been reported. Summary of the Invention

[0009] The technical problem solved by the present invention is to provide a class of substituted benzenesulfonamide compounds, a pharmaceutical composition thereof and an application thereof.

[0010] In order to solve the technical problems of the present invention, the present invention provides the following technical solutions:

[0011] The first aspect of the technical solution of the present invention is to provide a substituted benzenesulfonamide compound as shown in general formula (I) or a pharmaceutically acceptable salt, isomer or solvate thereof.

[0012]

[0013] Formula (I)

[0014] Among them, R 1 H, R 3 for , X is O,

[0015] R 2 for:

[0016]

[0017] or, R 1 、R 2 for , X is O, S,

[0018] R 3 for:

[0019] .

[0020] Preferably, the structural formula of the above-mentioned substituted benzenesulfonamide compound or its pharmaceutically acceptable salt, isomer or solvate is as follows:

[0021]

[0022] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed with a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0023] Another preferred salt is a salt of the compound of the present invention formed with a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0024] The term "solvate" refers to a complex in which the compound of the present invention is coordinated with solvent molecules to form a specific ratio.

[0025] The second aspect of the technical solution of the present invention is to provide a method for preparing the compound described in the first aspect. The compound of general formula (I) of the present invention can be prepared by the following method:

[0026]

[0027] Among them, R 1 =H,R 3 = , X = O,

[0028] R 2 for:

[0029]

[0030] 4-(2-aminoethyl)benzenesulfonamide (1) is used as a raw material to undergo a nucleophilic substitution reaction with di-tert-butyl dicarbonate to generate tert-butyl (4-sulfonamide phenylethyl) carbamate (2). The intermediate (2) undergoes a nucleophilic addition reaction with cyclohexyl isocyanate to generate tert-butyl (4-( N -(cyclohexylcarbamoyl)sulfonyl)phenethyl)carbamate (3), compound (3) was desorbed from the Boc group in 20% hydrochloric acid isopropanol to generate the key intermediate 4-(2-aminoethyl)- N -(cyclohexylcarbamoyl)benzenesulfonamide (4), the key intermediate (4) reacts with different carboxylic acids or substituted benzenesulfonyl chloride reagents to obtain the target compound represented by general formula (I).

[0031] Alternatively, it can be prepared by the following method:

[0032]

[0033] X = O, S,

[0034] R 3 for:

[0035] .

[0036] Compound m-methoxybenzoic acid (7) is used as a raw material and reacts with chloral hydrate under the action of concentrated sulfuric acid to produce 6-methoxy-3-(trichloromethyl)isobenzofuran-1(3H)-one (8). Compound (8) is reduced to 2-(2,2-dichlorovinyl)-5-methoxybenzoic acid (9) under the action of Zn, and then oxidized with concentrated sulfuric acid to produce 2-(carboxymethyl)-5-methoxybenzoic acid (10). Compound (10) reacts with raw material (1) to produce 4-(2-(7-methoxy-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)benzenesulfonamide (11). Compound (11) reacts with CH3I under the action of NaH to produce a key intermediate (12). The key intermediate (12) reacts with an isocyanate compound or an isothiocyanate compound to obtain the target compound.

[0037] The third aspect of the technical solution of the present invention is to provide the use of the substituted benzenesulfonamide compounds or pharmaceutically acceptable salts, isomers or solvates thereof described in the first aspect in the preparation of GSTP1-1 inhibitors.

[0038] The fourth aspect of the technical solution of the present invention is to provide a pharmaceutical composition comprising the substituted benzenesulfonamide compound or its pharmaceutically acceptable salt, isomer, or solvate according to the first aspect and one or more pharmaceutical carriers and / or diluents, in any clinically or pharmaceutically acceptable dosage form, preferably an oral preparation or an injection. The pharmaceutical composition contains a physiologically effective amount of 0.01g to 10g of the compound represented by general formula (I), which may be 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.04g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g, 0.6g, 0.75g, 1g, 1.25g, 1.5g, 1.75g, 2g, 2.5g, 3g, 4g, 5g, 6g, 7g, 8g, 9g, 10g, etc.

[0039] Any compound of the present invention can be administered orally or parenterally to a patient in need of such treatment.

[0040] For parenteral administration, the drug can be formulated as an injection. Conventional methods in the pharmaceutical field can be used for production of injections, with either aqueous or non-aqueous solvents. The most commonly used aqueous solvent is water for injection, though 0.9% sodium chloride solution or other suitable aqueous solutions can also be used. Common non-aqueous solvents are vegetable oils, primarily soybean oil for injection, as well as aqueous solutions of ethanol, propylene glycol, and polyethylene glycol. When formulating an injection, additives may be omitted or, depending on the drug's properties, may be added, such as osmotic pressure regulators, pH regulators, solubilizers, fillers, antioxidants, antibacterial agents, emulsifiers, and suspending agents. For oral administration, conventional solid preparations such as tablets, capsules, pills, and granules can be prepared. Liquid oral preparations such as oral solutions, oral suspensions, and syrups can also be prepared. Suitable fillers, binders, disintegrants, and lubricants may be added to the formulation.

[0041] The compounds of the present invention can be added with pharmaceutically acceptable carriers to prepare common pharmaceutical preparations, such as tablets, capsules, powders, syrups, liquids, suspensions, and injections, and can be added with common pharmaceutical excipients such as flavorings, sweeteners, liquid or solid fillers or diluents.

[0042] The compounds of the present invention can be administered clinically by oral administration, injection, or the like.

[0043] The clinical dosage of the compound of the present invention is 0.01-1000 mg / day, and may deviate from this range depending on the severity of the disease or the dosage form.

[0044] The fifth aspect of the technical solution of the present invention is to provide use of the composition described in the fourth aspect in the preparation of a GSTP1-1 inhibitor.

[0045] The sixth aspect of the technical solution of the present invention is to provide the use of the substituted benzenesulfonamide compounds or pharmaceutically acceptable salts, isomers, solvates thereof described in the first aspect or the composition described in the fourth aspect in the preparation of drugs for preventing and / or treating cisplatin-resistant diseases.

[0046] The cisplatin-resistant disease is lung cancer.

[0047] The seventh aspect of the technical solution of the present invention is to provide the use of the substituted benzenesulfonamide compound or its pharmaceutically acceptable salt, isomer, solvate or the composition described in the first aspect in the preparation of a drug for treating lung cancer.

[0048] Beneficial technical effects:

[0049] (1) The present invention uses gliquidone as the lead compound and optimizes its structure to synthesize a series of novel substituted benzenesulfonamide compounds, which have high inhibitory activity against GSTP1-1 protein and ideal anti-tumor cell resistance activity.

[0050] (2) The compounds of the present invention have high inhibitory activity against GSTP1-1 protease, which is higher than that of the positive drug gliquidone, and the inhibition rate against GSTP1-1 is above 50%.

[0051] (3) IC of the compounds of the present invention against GSTP1-1 protein 50 All of them were below 10 μM, among which compounds S6, S7, S18, S19, S28, S31, S36, S67 and S71 had IC 50 The values ​​were all between 3-4 μM. The experimental results showed that the compounds of the present invention had a certain inhibitory effect on GSTP1-1 protein.

[0052] (4) Gliquidone, as an anti-diabetic drug, has no inhibitory effect on tumor cells. Experimental findings (Table 3) show that after structural optimization of gliquidone, compounds S6, S13, S34, S46, and S77 have stronger inhibitory effects on A549 / CDDP than on A549. That is, compared with A549, A549 / CDDP tumor cells are more sensitive to S6, S13, S34, S46, and S77. Compounds S71 and S77 have strong inhibitory activity on tumor cells A549 and A549 / CDDP, showing anti-tumor effects, and are potential clinical candidate drugs. DETAILED DESCRIPTION

[0053] The present invention will be further described below in conjunction with specific embodiments so that those skilled in the art can better understand the present invention, but the present invention is not limited thereto.

[0054] Unless otherwise specified, the experimental materials and reagents used in the examples of the present invention are conventional consumables and reagents available from commercial channels.

[0055] In the following examples, the experimental methods without specific conditions are generally based on conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0056] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0057] Example 1: N -(4-(N -(cyclohexylcarbamoyl)aminosulfonyl)phenethyl)-3,5-difluorobenzamide (S6):

[0058]

[0059] Procedure: 4-(2-Aminoethyl)benzenesulfonamide 1 (4 g, 20 mmol) and di-tert-butyl dicarbonate (4.8 g, 22 mmol) were dissolved in DMF (100 mL) and reacted at room temperature under nitrogen for 2 h. TLC (developing solvent: dichloromethane-methanol = 20:1) confirmed the reaction was complete. The reaction solution was poured into 300 mL of water, whereupon a white solid precipitated. This solid was filtered and dried to yield compound 2 (5.6 g, 93%) as a white solid. Compound 2 (5.6 g, 18.7 mmol) and potassium carbonate (3.09 g, 22.4 mmol) were dissolved in acetone (200 mL) and refluxed for 6 h. Cyclohexyl isocyanate (4.67 g, 37.3 mmol) was added and refluxed for 6 h. TLC (developing solvent: dichloromethane-methanol = 20:1) confirmed the reaction was complete. The reaction solution was filtered, and the solid was transferred to a 500 mL beaker. A small amount of water was added, and the pH was adjusted to 5-6 with 1 N HCl. The solution was filtered, washed with water, and dried to obtain compound 3 (7 g, 88%) as a white solid. Compound 3 (5 g, 11.8 mmol) was dissolved in 20% hydrochloric acid in isopropanol and allowed to react at room temperature for 12 h. The reaction was complete when the starting material spot disappeared by TLC (developing solvent: dichloromethane-methanol = 10:1). The solvent was evaporated under reduced pressure, and the crude product was washed with dichloromethane and filtered to obtain key intermediate 4 (3.5 g, 84%).

[0060] The carboxylic acid reagent 3,5-difluorobenzoic acid (0.46 mmol, 1.0 eq), key intermediate 4 (0.46 mmol, 1.0 eq), 1-hydroxybenzotriazole (0.69 mmol, 1.5 eq), 1-ethyl-(3-dimethylaminopropyl)carbonic acid diimide hydrochloride (0.69 mmol, 1.5 eq), and triethylamine (1.15 mmol, 2.5 eq) were dissolved in DMF (20 mL). The reaction was allowed to proceed at room temperature under nitrogen for 8 h. TLC (developing solvent: dichloromethane-methanol = 10:1) confirmed the completion of the reaction. The reaction solution was poured into 100 mL of ice water, and a white solid precipitated. The resulting crude product was filtered and recrystallized from methanol to obtain compound S6.

[0061] S6 was obtained as a white solid powder in 69% yield. mp: 189.4-190.9 °C. 1 H NMR (800 MHz, DMSO- d6)δ 10.31 (s, 1H), 8.77 (t, J = 5.6 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.52 – 7.43(m, 5H), 6.33 (d, J = 7.8 Hz, 1H), 3.54 (q, J = 6.8 Hz, 2H), 3.27 (dtd, J = 10.5,7.0, 3.9 Hz, 1H), 2.95 (t, J = 7.3 Hz, 2H), 1.67 – 1.46 (m, 5H), 1.24 – 1.07(m, 5H). 13 C NMR (200 MHz, DMSO- d 6) δ 164.14, 163.31 (d, J =12.44 Hz, 1C), 162.08(d, J =11.96 Hz, 1C), 150.90, 145.60, 138.64, 138.43 (t, J =8.28 Hz, 1C), 129.73(2C), 127.79 (2C), 111.04 (d, J =4.42 Hz, 1C), 110.93 (d, J =4.04 Hz, 1C), 107.14(t, J =25.82 Hz, 1C), 48.52, 40.89, 35.07, 32.72 (2C), 25.44, 24.64 (2C). IR(KBr, cm -1 ): 443.39, 540.19, 573.26, 606.56, 685.32, 768.67, 845.99, 881.46,984.41, 1032.16, 1089.16, 1118.59, 1164.37, 1195.17, 1221.99, 1339.39,1445.22, 1536.44, 1593.82, 1642.32, 1683.74, 2859.69, 2939.46, 3078.77,3229.56, 3309.88, 3595.65, 3864.76. HRMS (ESI): m / z calcd for C22 H 25 F2N3O4S [M+Na] + : 488.1432 found: 488.1417.

[0062] The preparation methods of the compounds in Examples 2-11 are the same as those in Example 1, except that different carboxylic acid reagents are used. The specific acid reagents used in each example are indicated in the corresponding example:

[0063] Example 2: N -(4-( N -(cyclohexylcarbamoyl)aminosulfonyl)phenethyl)cyclopropanecarboxamide (S7):

[0064]

[0065] The carboxylic acid used was cyclopropanecarboxylic acid. S7 was obtained as a white solid powder in 32% yield. mp: 169.1-170.3 °C. 1 HNMR (800 MHz, DMSO- d 6) δ 10.30 (s, 1H), 8.15 (t, J = 5.7 Hz, 1H), 7.82 – 7.80(m, 2H), 7.43 (d, J = 8.2 Hz, 2H), 6.34 (d, J = 7.8 Hz, 1H), 3.33 – 3.26 (m, 3H), 2.81 (t, J = 7.3 Hz, 2H), 1.65 (dd, J = 12.7, 4.1 Hz, 2H), 1.58 (dd, J = 9.3, 4.3Hz, 2H), 1.49 (dddd, J = 15.7, 11.2, 8.0, 4.4 Hz, 2H), 1.21 (ddt, J = 25.0, 11.7,3.5 Hz, 2H), 1.14 – 1.08 (m, 3H), 0.66 – 0.59 (m, 4H). 13 C NMR (200 MHz, DMSO- d6) δ 171.11, 148.98, 143.89, 136.63, 127.74 (2C), 125.82 (2C), 46.61, 38.52,33.57, 30.81 (2C), 23.52, 22.73 (2C), 12.08, 4.65 (2C). IR (KBr, cm -1 ):443.91, 537.88, 595.31, 655.95, 687.35, 817.68, 841.74, 904.38, 1036.72,1091.13, 1165.90, 1245.72, 1339.45, 1448.98, 1543.16, 1640.41, 1679.58,2855.63, 2937.49, 3009.18, 3215.59, 3302.17, 3864.79. HRMS (ESI): m / z calcd for C 19 H 27 N3O4S [M+Na] + : 416.1620 found: 416.1596.

[0066] Example 3: N -(4-( N -(cyclohexylcarbamoyl)aminosulfonyl)phenethyl)-6-oxo-6-phenylhexanamide (S12):

[0067]

[0068] The carboxylic acid used was 5-benzoylvaleric acid. S12 was obtained as a white solid powder in 66% yield. mp: 166.5-168.2 °C. 1 H NMR (800 MHz, DMSO- d 6) δ 10.30 (s, 1H), 7.96 (d, J = 7.7 Hz, 2H), 7.91 (t, J =5.7 Hz, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.6Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 6.33 (d, J= 7.8 Hz, 1H), 3.30 (q, J = 6.7 Hz,2H), 3.01 (t, J = 6.9 Hz, 2H), 2.79 (t, J = 7.1 Hz, 2H), 2.08 (t, J = 7.1 Hz, 2H), 1.68 – 1.45 (m, 10H), 1.24 – 1.17 (m, 2H), 1.15 – 1.07 (m, 3H). 13 C NMR (200MHz, DMSO- d 6) δ 198.17, 170.17, 148.62, 143.54, 136.26, 134.89, 131.24,127.40 (2C), 126.75 (2C), 126.07 (2C), 125.44 (2C), 46.24, 38.16, 35.78,33.39, 33.14, 30.45 (2C), 23.14, 23.05, 22.35 (2C), 21.57. IR (KBr, cm -1 ):432.40, 540.12, 579.02, 600.81, 686.47, 727.67, 811.32, 846.23, 901.24,979.19, 1035.60, 1086.26, 1158.25, 1193.90, 1224.22, 1262.02, 1335.08,1372.73, 1451.25, 1535.07, 1594.17, 1679.06, 2859.01, 2936.26, 3064.99,3203.97, 3300.60, 3381.80, 3864.81. HRMS (ESI): m / z calcd for C 27 H 35 N3O5S [M+Na] + : 536.2195 found: 536.2183.

[0069] Example 4: N -(4-( N -(cyclohexylcarbamoyl)aminosulfonyl)phenethyl)-6-phenylhexanamide (S13):

[0070]

[0071] The carboxylic acid used was 6-phenylhexanoic acid. S13 was obtained as a white solid powder in 69% yield. mp: 136.7-138.5°C. 1 HNMR (800 MHz, DMSO- d 6) δ 10.30 (s, 1H), 7.87 (t, J = 5.7 Hz, 1H), 7.81 (d, J =8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.26 (t, J = 7.5 Hz, 2H), 7.20 – 7.14 (m,3H), 6.33 (d, J = 7.9 Hz, 1H), 3.29 (p, J = 8.0, 7.4 Hz, 3H), 2.78 (t, J = 7.1 Hz,2H), 2.54 (t, J = 7.7 Hz, 2H), 2.01 (t, J = 7.4 Hz, 2H), 1.65 (dd, J = 12.8, 4.1Hz, 2H), 1.57 (dt, J = 13.8, 7.0 Hz, 2H), 1.53 (q, J = 7.7 Hz, 2H), 1.49 (p, J =7.5 Hz, 3H), 1.21 (dd, J = 15.4, 8.1 Hz, 4H), 1.11 (pd, J = 11.5, 9.6, 3.4 Hz,3H). 13 C NMR (200 MHz, DMSO- d 6) δ 170.53 (2C), 148.88, 143.83, 140.72 (2C), 136.51, 127.65, 126.73 (2C), 126.66 (2C), 125.70, 124.05, 46.52, 38.44,33.74, 33.47, 33.39, 30.72 (2C), 29.19, 26.68, 23.53, 23.42, 22.63 (2C). IR(KBr, cm -1): 432.40, 540.12, 579.02, 600.81, 686.47, 727.67, 811.32, 846.23,901.24, 979.19, 1035.60, 1086.26, 1158.25, 1193.90, 1224.22, 1262.02,1335.08, 1372.73, 1451.25, 1535.07, 1594.17, 1679.06, 2859.01, 2936.26,3064.99, 3203.97, 3300.60, 3381.80, 3864.81. HRMS (ESI): m / z calcd for C 27 H 37 N3O4S [M+H] + : 500.2583 found: 500.2562.

[0072] Example 5: N -(4-( N -(Cyclohexylcarbamoyl)aminosulfonyl)phenethyl)cinnamamide (S18):

[0073]

[0074] The carboxylic acid used was trans-cinnamic acid. S18 was obtained as a white solid powder in 69% yield. mp: 168.5-169.9 °C. 1 HNMR (800 MHz, DMSO- d 6) δ 10.31 (s, 1H), 8.23 ​​(t, J = 5.7 Hz, 1H), 7.85 – 7.80(m, 2H), 7.55 (d, J = 7.4 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.44 – 7.39 (m, 3H), 7.37 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 15.8 Hz, 1H), 6.34 (d, J = 7.9 Hz, 1H), 3.47(q, J = 6.8 Hz, 2H), 3.28 (tdt, J = 11.0, 7.2, 3.7 Hz, 1H), 2.89 (t, J= 7.2 Hz,2H), 1.64 (dd, J = 12.8, 4.1 Hz, 2H), 1.57 (dt, J = 13.6, 4.1 Hz, 2H), 1.47 (dq, J = 12.7, 4.1 Hz, 1H), 1.20 (tdd, J = 14.6, 7.0, 3.5 Hz, 2H), 1.14 – 1.06 (m,3H). 13 C NMR (200 MHz, DMSO- d 6) δ 165.47, 150.90, 145.76, 139.15, 138.61,135.35, 129.91, 129.69 (2C), 129.40 (2C), 127.99 (2C), 127.79 (2C), 122.55,49.07, 48.53, 35.35, 32.73 (2C), 25.43, 24.64 (2C). IR (KBr, cm -1 ): 446.10,482.89, 568.13, 611.87, 683.65, 716.50, 763.70, 842.60, 905.02, 979.57,1025.99, 1088.14, 1160.43, 1225.19, 1337.95, 1451.06, 1547.47, 1609.80,1655.36, 1709.63, 2856.82, 2932.42, 3091.98, 3326.69, 3369.36, 3864.47. HRMS(ESI): m / z calcd for C 24 H 29 N3O4S [M+Na] + : 478.1776 found: 478.1748.

[0075] Example 6: N -(4-( N -(cyclohexylcarbamoyl)aminosulfonyl)phenethyl)pentanamide (S19):

[0076]

[0077] The carboxylic acid used was n-valeric acid. S19 was obtained as a white solid powder in 75% yield. mp: 169.3-170.1°C.1 H NMR(800 MHz, DMSO- d 6) δ 10.29 (s, 1H), 7.87 (t, J = 5.7 Hz, 1H), 7.83 – 7.78 (m,2H), 7.43 – 7.40 (m, 2H), 6.33 (d, J = 7.8 Hz, 1H), 3.30 (tt, J = 10.6, 5.3 Hz,3H), 2.79 (t, J = 7.1 Hz, 2H), 2.02 (t, J = 7.5 Hz, 2H), 1.65 (dd, J = 12.8, 4.1Hz, 2H), 1.58 (dt, J = 13.5, 4.1 Hz, 2H), 1.48 (dt, J = 13.2, 4.1 Hz, 1H), 1.45 –1.40 (m, 2H), 1.24 – 1.18 (m, 4H), 1.13 – 1.08 (m, 3H), 0.83 (t, J = 7.4 Hz,3H). 13 C NMR (200 MHz, DMSO- d 6) δ 172.58, 150.90, 145.83, 138.53, 129.67 (2C),127.13 (2C), 48.53, 40.45, 35.52, 35.38, 32.73 (2C), 27.86, 25.44, 24.65(2C), 22.19,14.15. IR (KBr, cm -1 ): 441.51, 471.59, 516.32, 547.19, 569.61,614.67, 712.00, 847.93, 909.03, 1022.93, 1092.71, 1118.33, 1163.01, 1338.99,1454.02, 1560.16, 1629.67, 1712.77, 2310.68, 2857.49, 2930.52, 3122.88,3188.87, 3298.51, 3868.88. HRMS (ESI): m / z calcd for C 20 H31 N3O4S [M+Na] + :432.1933 found: 432.1912.

[0078] Example 7: 3-cyclohexyl- N -(4-( N -(cyclohexylcarbamoyl)aminosulfonyl)phenethyl)propionamide (S23):

[0079]

[0080] The carboxylic acid used was 3-cyclohexylpropionic acid. S23 was obtained as a white solid powder in 47% yield. mp: 176.6-178.3°C. 1 H NMR (800 MHz, DMSO- d 6) δ 10.29 (s, 1H), 7.87 (t, J = 5.7 Hz, 1H), 7.80 (d, J =8.1 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 6.33 (d, J = 7.7 Hz, 1H), 3.30 (q, J = 6.7Hz, 3H), 2.79 (t, J = 7.1 Hz, 2H), 2.05 – 2.01 (m, 2H), 1.64 (d, J = 12.3 Hz,6H), 1.59 (dt, J = 9.1, 4.3 Hz, 3H), 1.48 (d, J = 13.0 Hz, 1H), 1.35 (q, J = 7.3Hz, 2H), 1.21 (q, J = 12.4, 12.0 Hz, 2H), 1.17 – 1.08 (m, 7H), 0.82 (q, J = 11.7 Hz, 2H). 13 C NMR (200 MHz, DMSO- d6) δ 171.65, 149.70, 144.67, 137.34, 128.47(2C), 126.51 (2C), 47.35, 39.27, 35.92, 34.17, 32.19, 32.08, 31.85 (2C),31.56 (2C), 25.41, 25.03 (2C), 24.26, 23.47 (2C). IR (KBr, cm -1 ): 422.80,447.59, 543.04, 573.74, 606.25, 660.32, 840.40, 904.09, 970.27, 1032.03,1089.78, 1160.16, 1341.87, 1450.38, 1537.87, 1634.74, 1689.90, 2310.96,2377.84, 2853.28, 2926.08, 3093.32, 3309.76, 3876.39. HRMS (ESI): m / z calcd for C 24 H 37 N3O4S [M+H] + : 464.2583 found: 464.2545.

[0081] Example 8: N -(4-( N -(cyclohexylcarbamoyl)aminosulfonyl)phenethyl)-2-cyclopropylacetamide (S28):

[0082]

[0083] The carboxylic acid used was cyclopropylacetic acid. S28 was obtained as a white solid powder in 42% yield. mp: 188.6-189.8°C. 1 HNMR (800 MHz, DMSO- d 6) δ 10.24 (s, 1H), 7.77 – 7.71 (m, 3H), 7.37 (d, J = 8.4Hz, 2H), 6.27 (d, J = 7.8 Hz, 1H), 3.28 – 3.24 (m, 2H), 3.24 – 3.20 (m, 1H), 2.75 (t, J = 7.1 Hz, 2H), 1.87 (d, J = 7.1 Hz, 2H), 1.59 (dd,J = 12.8, 4.1 Hz,2H), 1.55 – 1.50 (m, 2H), 1.45 – 1.41 (m, 1H), 1.19 – 1.12 (m, 2H), 1.05 (q, J = 11.5, 10.2 Hz, 3H), 0.89 – 0.79 (m, 1H), 0.35 – 0.31 (m, 2H), 0.02 – -0.02(m, 2H). 13 C NMR (200 MHz, DMSO- d 6) δ 172.07, 150.88, 145.83, 138.52, 129.74(2C), 127.69 (2C), 48.53, 40.95, 35.33, 32.73 (2C), 25.44, 24.66 (2C), 8.22(2C), 4.59(2C). IR (KBr, cm -1 ): 515.85, 546.89, 571.37, 612.27, 710.97,823.82, 907.07, 1023.48, 1092.63, 1122.84, 1163.78, 1196.83, HRMS (ESI): m / z calcd for C 20 H 29 N3O4S [M+Na] + : 430.1776 found: 430.1745.

[0084] Example 9: N -(4-( N -(cyclohexylcarbamoyl)aminosulfonyl)phenethyl)methacrylamide (S31):

[0085]

[0086] The carboxylic acid used was α-methacrylic acid. S31 was obtained as a white solid powder in 30% yield. mp: 169.9-171.6°C. 1 H NMR (800 MHz, DMSO- d6) δ 10.30 (s, 1H), 8.03 (t, J = 5.7 Hz, 1H), 7.81 (d, J =8.3 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 6.33 (d, J = 7.9 Hz, 1H), 5.59 (s, 1H),5.30 (t, J = 1.6 Hz, 1H), 3.37 (dd, J = 12.8, 7.5 Hz, 2H), 3.30 – 3.25 (m, 1H),2.86 (t, J = 7.3 Hz, 2H), 1.82 (s, 3H), 1.65 (dd, J = 12.8, 4.0 Hz, 2H), 1.58(dd, J = 9.3, 4.3 Hz, 2H), 1.51 – 1.46 (m, 1H), 1.24 – 1.18 (m, 2H), 1.14 –1.07 (m, 3H). 13 C NMR (200 MHz, DMSO- d 6) δ 167.98, 150.88, 145.84, 140.45,138.53, 129.68 (2C), 127.74 (2C), 119.35, 48.53, 40.45, 35.24, 32.73 (2C),25.44, 24.65 (2C), 19.08. IR (KBr, cm -1 ): 444.73, 539.36, 600.92, 646.43,686.61, 743.20, 843.25, 876.83, 907.13, 1032.36, 1088.43, 1120.33, 1168.86,1225.11, 1341.67, 1449.78, 1536.72, 1616.13, 1679.57, 1727.28, 2311.44,2856.47, 2929.47, 3056.04, 3239.35, 3305.96, 3874.18. HRMS (ESI): m / z calcd forC 19 H 27 N3O4S [M+Na] +: 416.1620 found: 416.1603.

[0087] Example 10: N -(4-( N -(cyclohexylcarbamoyl)aminosulfonyl)phenethyl)-2-methylquinoline-6-carboxamide (S34):

[0088]

[0089] The carboxylic acid used was 2-methyl-6-quinolinecarboxylic acid. S34 was obtained as a white solid powder in 48% yield. mp: 209.7-211.1°C. 1 H NMR (800 MHz, DMSO- d 6) δ 10.30 (s, 1H), 8.80 (t, J = 5.6 Hz, 1H),8.40 (d, J = 2.1 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.08 (dd, J = 8.7, 2.0 Hz, 1H),7.96 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.52 – 7.48 (m, 3H), 6.33 (d, J = 7.7 Hz, 1H), 3.61 – 3.56 (m, 2H), 3.30 – 3.24 (m, 1H), 3.00 (t, J = 7.3 Hz, 2H), 2.69 (s, 3H), 1.63 (dd, J = 12.8, 4.1 Hz, 2H), 1.59 – 1.54 (m, 2H), 1.49 –1.45 (m, 1H), 1.22 – 1.16 (m, 2H), 1.13 – 1.05 (m, 3H). 13 C NMR (200 MHz, DMSO- d6) δ 166.42, 160.98, 150.89, 148.73, 145.82, 138.59, 137.58, 132.01, 129.75(2C), 128.63, 128.07 (2C), 127.81 (2C), 125.83, 123.35, 48.52, 40.87, 35.32,32.72 (2C), 25.43 (2C), 24.63 (2C). IR (KBr, cm -1 ): 423.88, 446.52, 542.89,581.54, 612.54, 656.81, 689.82, 843.04, 903.43, 1025.74, 1090.96, 1166.12,1195.46, 1223.51, 1293.51, 1343.60, 1445.32, 1533.10, 1638.67, 1687.91, 2310.38, 2376.77, 2858.32, 2933.41, 3305.49, 3878.37. HRMS (ESI): m / z calcd for C 26 H 30 N4O4S [M+H] + : 495.2066 found: 495.2029.

[0090] Example 11: N -(4-( N -(cyclohexylcarbamoyl)aminosulfonyl)phenethyl)-3-oxocyclobutane-1-carboxamide (S36):

[0091]

[0092] The carboxylic acid used was 3-oxocyclobutanecarboxylic acid. S36 was obtained as a white solid powder in 26% yield. mp: 189.1-190.6°C. 1 H NMR (800 MHz, DMSO- d 6) δ 10.30 (s, 1H), 8.24 (t, J = 5.6 Hz, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 6.33 (d, J = 7.9 Hz, 1H), 3.37 (q, J=6.8 Hz, 2H), 3.30 – 3.25 (m, 1H), 3.17 – 3.12 (m, 2H), 3.09 – 3.02 (m, 3H), 2.83 (t, J = 7.1 Hz, 2H), 1.65 (dd, J = 12.7, 4.1 Hz, 2H), 1.58 (dd, J = 9.3, 4.3Hz, 2H), 1.48 (dd, J = 8.8, 4.3 Hz, 1H), 1.21 (q, J = 11.6 Hz, 2H), 1.10 (q, J =11.5, 9.8 Hz, 3H). 13 C NMR (200 MHz, DMSO- d 6) δ 205.98, 173.68, 150.88, 145.68,138.57, 129.73 (2C), 127.72 (2C), 51.35 (3C), 48.53, 35.26, 32.74 (2C),27.68, 25.44, 24.65 (2C). IR (KBr, cm -1 ): 447.20, 514.73, 543.39, 573.16,599.52, 666.06, 841.66, 902.31, 1035.84, 1088.87, 1159.17, 1193.78, 1235.09,1337.84, 1372.96, 1448.13, 1536.50, 1637.87, 1678.80, 1787.18, 2309.60,2376.93, 2858.16, 2936.28, 3201.54, 3296.67, 3596.19, 3721.97, 3834.04,3877.03, 3945.98. HRMS (ESI): m / z calcd for C 20 H 27 N3O5S [M+Na] + : 444.1569 found:444.1533.

[0093] Example 12: N -(Cyclohexylcarbamoyl)-4-(2-(phenylsulfonamido)ethyl)benzenesulfonamide (S46):

[0094]

[0095] Procedure: Dissolve the substituted benzenesulfonyl chloride reagent (benzenesulfonyl chloride) (0.62 mmol, 1.0 eq), key intermediate 4 (0.62 mmol, 1.0 eq), and triethylamine (0.65 mmol, 1.05 eq) in DMF (20 mL). React at room temperature under nitrogen for 5 h. TLC (developing solvent: dichloromethane-methanol = 20:1) indicates completion of the reaction. The reaction solution is extracted with ethyl acetate, and the organic phase is washed sequentially with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent removed under reduced pressure. The crude product is purified by silica gel column chromatography (mobile phase: n-hexane-ethyl acetate = 3:1) to obtain compound S46.

[0096] S46 was obtained as a white solid powder in 24% yield. mp: 133.7-135.4 °C. 1 H NMR (800 MHz, DMSO- d 6) δ 10.31 (s, 1H), 7.79 – 7.74 (m, 5H), 7.65 – 7.62 (m, 1H), 7.58 (dd, J =8.5, 6.9 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 6.34 (d, J = 7.8 Hz, 1H), 3.28 (dtd, J = 10.5, 6.9, 3.8 Hz, 1H), 3.02 (q, J = 7.1 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H),1.65 (dd, J = 12.9, 4.0 Hz, 2H), 1.58 (dt, J = 13.7, 4.3 Hz, 2H), 1.48 (dt, J =12.8, 4.1 Hz, 1H), 1.24 – 1.18 (m, 2H), 1.14 – 1.07 (m, 3H). 13 C NMR (200 MHz, DMSO- d6) δ 150.90, 144.94, 140.76, 138.71, 132.88, 129.75 (2C), 129.70 (2C), 127.73 (2C), 126.92 (2C), 48.53, 43.83, 35.46, 32.73 (2C), 25.44, 24.64 (2C).IR (KBr, cm -1 ): 446.25, 569.17, 602.62, 658.81, 685.55, 753.02, 843.86,904.21, 1036.29, 1092.27, 1160.11, 1225.30, 1319.01, 1453.46, 1533.45,1658.27, 2857.70, 2933.18, 3084.43, 3264.19, 3350.30. HRMS (ESI): m / z calcd for C 21 H 27 N3O5S2[M+H] + : 466.1470 found: 466.1435.

[0097] Example 13: N -(Ethylcarbamoyl)-4-(2-(7-methoxy-4,4-dimethyl-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)benzenesulfonamide (S64):

[0098]

[0099] Procedure: Dissolve starting material 7 (10 g, 65.72 mmol) in concentrated H₂SO₄ (40 mL), add chloral hydrate (13.045 g, 78.87 mmol), and stir at room temperature for 16 h. TLC analysis (developing solvent: dichloromethane-methanol = 10:1) reveals the disappearance of the starting material spot. The reaction solution was poured into ice water, whereupon a white solid precipitated. The solid was collected by filtration, washed with saturated sodium bicarbonate solution and water to pH 7, and dried to afford the crude product. The crude product was stirred in anhydrous ethanol for 4 h, filtered, and dried to afford pure compound 8 (14.29 g, 77%). Compound 8 (4 g, 14.18 mmol) was added to glacial acetic acid, and Zn powder (1.84 g, 28.36 mmol) was added in small portions. The reaction solution was stirred at room temperature for 30 min, then heated to reflux for 5 min. The hot solution was immediately filtered and cooled to room temperature to afford white needle-shaped crystals. The crystals were collected by filtration, and the filtrate was poured into ice water, whereupon a white solid precipitated. This solid was then filtered and recrystallized from acetic acid. The two crystals were combined to yield compound 9 (2.87 g, 82.3%). Compound 9 (2.83 g, 12.2 mmol) was dissolved in concentrated H₂SO₄ (9 mL). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was poured into ice water, whereupon a precipitate formed. This precipitate was filtered, washed with cold water, and recrystallized from a 3:1 mixture of acetone and water. The resulting mixture was filtered to yield pure compound 10 (1.3 g, 51%). A mixture of compound 10 (1 g, 4.762 mmol) and starting material 1 (1.05 g, 5.238 mmol) was placed in a microwave reactor and reacted at 160°C for 2 h. Upon completion of the reaction, the brown melt solidified. The solid was dissolved in ethyl acetate and extracted with 1N HCl. The ethyl acetate layer was dried over anhydrous MgSO₄, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase: dichloromethane-methanol = 150:1) to afford intermediate 11 (1.02 g, 57%). NaH (0.642 g, 16.055 mmol) was dissolved in an appropriate amount of DMF and activated under nitrogen at -10°C for 30 min. A DMF solution of intermediate 11 (3.16 g, 8.45 mmol) was then added dropwise to the reaction mixture. The reaction was continued for 30 min. CHCl (2.4 g, 16.9 mmol) was then added to the reaction mixture. After 10 min, the reaction mixture was brought to room temperature and allowed to react for 12 h. The disappearance of the starting material spot indicated completion by TLC analysis (developing solvent: dichloromethane-methanol = 20:1). The reaction solution was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase: dichloromethane-methanol = 100:1) to obtain the key intermediate 12 (2.72 g, 80%).

[0100] The key intermediate 12 (0.5 mmol, 1.0 eq), the isocyanate reagent ethyl isocyanate (1 mmol, 2.0 eq), and K₂CO₃ (1 mmol, 2.0 eq) were dissolved in acetone (40 mL) and refluxed at 65°C for 6 h. TLC (developing solvent: dichloromethane-methanol = 10:1) detected the disappearance of the starting material spot. The K₂CO₃ was removed by filtration, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase: dichloromethane-methanol = 100:1) or PTLC (dichloromethane-methanol = 10:1) to obtain the target compound S64.

[0101] S64 is a white solid powder with a yield of 30%. mp: 170.7-172.2 °C. 1 H NMR (800 MHz, DMSO- d 6) δ 10.53 (s, 1H), 7.81 – 7.76 (m, 2H), 7.59 (d, J = 8.7 Hz, 1H), 7.53 (d, J =2.9 Hz, 1H), 7.44 – 7.41 (m, 2H), 7.30 (dd, J = 8.7, 2.9 Hz, 1H), 6.44 (t, J =5.7 Hz, 1H), 4.18 – 4.14 (m, 2H), 3.84 (s, 3H), 2.98 – 2.93 (m, 4H), 1.41 (s,6H), 0.93 (t, J = 7.2 Hz, 3H). 13 C NMR (200 MHz, DMSO- d 6) δ 175.86, 162.68,157.52, 150.50, 143.59, 137.79, 136.67, 128.79 (2C), 126.91, 126.70 (2C),123.59, 120.97, 110.00, 54.83, 41.81, 39.65, 33.48, 32.50, 28.29 (2C), 14.25.IR (KBr, cm -1): 418.15, 460.12, 521.63, 576.68, 658.38, 714.17, 781.56,835.53, 868.01, 931.28, 1002.01, 1038.89, 1089.05, 1161.70, 1244.40, 1276.24,1349.30, 1380.26, 1437.35, 1464.62, 1503.21, 1544.53, 1608.22, 1663.03,1711.09, 2308.95, 2873.52, 2975.26, 3343.70, 3723.19, 3874.22. HRMS (ESI): m / z calcd for C 23 H 27 N3O6S [M+Na] + : 496.1518 found: 496.1480.

[0102] The preparation methods of the compounds in Examples 14-17 are the same as those in Example 13, except that different isocyanate reagents are used for the synthesis. The specific isocyanate reagents used in each example are indicated in the corresponding example:

[0103] Example 14: N -(allylcarbamoyl)-4-(2-(7-methoxy-4,4-dimethyl-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)benzenesulfonamide (S65):

[0104]

[0105] The isocyanate reagent used was 3-isocyanatopropylene. S65 was obtained as a white solid powder in 50% yield. mp: 148.3-150.1°C. 1 H NMR (800 MHz, DMSO- d 6) δ 10.62 (s, 1H), 7.80 (d, J = 8.4 Hz,2H), 7.59 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 2.9 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H),7.30 (dd, J = 8.6, 2.9 Hz, 1H), 6.57 (t, J= 5.9 Hz, 1H), 5.72 (ddt, J = 17.2,10.3, 5.2 Hz, 1H), 5.03 – 4.99 (m, 2H), 4.17 – 4.13 (m, 2H), 3.84 (s, 3H), 3.57 (t, J = 5.6 Hz, 2H), 2.96 (t, J = 7.5 Hz, 2H), 1.41 (s, 6H). 13 C NMR (200 MHz, DMSO- d 6) δ 175.84, 162.66, 157.50, 150.52, 143.65, 137.67, 136.65, 134.44,128.80 (2C), 126.90, 126.72 (2C), 123.58, 120.96, 114.53, 109.98, 54.82,41.80, 40.78, 39.64, 32.49, 28.28 (2C). IR (KBr, cm -1 ): 449.10, 523.93,559.02, 580.79, 663.42, 719.81, 779.23, 835.34, 869.06, 907.89, 939.77,1030.91, 1090.99, 1164.16, 1275.23, 1348.72, 1434.75, 1469.46, 1501.94,1541.50, 1609.97, 1667.68, 1709.24, 1750.15, 2309.48, 2912.49, 2976.53,3108.87, 3324.39, 3726.19, 3872.53. HRMS (ESI): m / z calcd for C 24 H 27 N3O6S [M+Na] + : 508.1518 found: 508.1490.

[0106] Example 15: N -(tert-Butylcarbamoyl)-4-(2-(7-methoxy-4,4-dimethyl-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)benzenesulfonamide (S67):

[0107]

[0108] The isocyanate reagent used was tert-butyl isocyanate. S67 was obtained as a white solid powder in a 25% yield. mp: 175.6-177.2°C. 1 H NMR (800 MHz, DMSO- d 6) δ 10.11 (s, 1H), 7.80 – 7.76 (m, 2H), 7.59 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 2.9 Hz, 1H), 7.45 – 7.43 (m, 2H), 7.30(dd, J = 8.6, 2.9 Hz, 1H), 6.18 (s, 1H), 4.19 – 4.13 (m, 2H), 3.84 (s, 3H), 2.97 (t, J = 7.4 Hz, 2H), 1.42 (s, 6H), 1.15 (s, 9H). 13 C NMR (200 MHz, DMSO- d 6)δ 176.94, 163.76, 158.59, 150.43, 144.69, 138.84, 137.75, 129.91 (2C), 127.98, 127.71 (2C), 124.66, 122.03, 111.09, 55.90, 55.39, 50.57, 42.90,40.71, 33.57, 29.38 (2C), 28.88 (2C). IR (KBr, cm -1 ): 463.65, 511.22, 606.47,661.77, 688.41, 778.33, 831.72, 876.52, 942.37, 1034.51, 1087.69, 1155.38,1216.10, 1280.03, 1351.27, 1442.66, 1503.61, 1548.55, 1596.84, 1687.96, 2859.86, 2970.97, 3058.52, 3372.77. HRMS (ESI): m / z calcd for C 25 H 31 N3O6S [M+H] + :502.2012 found: 502.2015.

[0109] Example 16: 4-(2-(7-methoxy-4,4-dimethyl-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)- N -(Octylcarbamoyl)benzenesulfonamide (S71)

[0110]

[0111] The isocyanate reagent used was 1-octyl isocyanate. S71 was obtained as a white solid powder with a yield of 32%. mp: 120.2-121.9°C. 1 H NMR (800 MHz, DMSO- d 6) δ 10.48 (s, 1H), 7.80 – 7.77 (m, 2H), 7.59 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 2.9 Hz, 1H), 7.43 – 7.41 (m, 2H), 7.30(dd, J = 8.6, 2.9 Hz, 1H), 6.43 (t, J = 5.8 Hz, 1H), 4.17 – 4.14 (m, 2H), 3.84 (s, 3H), 2.97 – 2.94 (m, 2H), 2.91 (q, J = 6.7 Hz, 2H), 1.41 (s, 6H), 1.30 (t, J = 7.3 Hz, 2H), 1.23 (dd, J = 7.0, 4.6 Hz, 5H), 1.20 – 1.18 (m, 3H), 1.13 (q, J =6.9 Hz, 2H), 0.84 (t, J = 7.3 Hz, 3H). 13 C NMR (200 MHz, DMSO- d6) δ 175.10,161.92, 156.77, 149.83, 142.84, 137.01, 135.92, 128.02 (2C), 126.15, 125.95(2C), 122.85, 120.23, 109.26, 54.66, 54.08, 41.06, 38.92, 31.77, 29.85 (2C),27.81, 27.55 (2C), 26.96, 24.73, 20.66, 12.57. IR (KBr, cm -1 ): 445.48, 493.39,527.38, 578.54, 660.29, 690.92, 777.23, 831.83, 874.98, 1031.59, 1089.53,1163.62, 1276.12, 1347.98, 1462.10, 1505.13, 1573.21, 1616.11, 1669.28,1710.73, 2853.73, 2925.48, 3181.74, 3336.00. HRMS (ESI): m / z calcd for C 29 H 39 N3O6S [M+H] + : 558.2638 found: 558.2637.

[0112] Example 17: N -(Cyclohexylaminomethylthio)-4-(2-(7-methoxy-4,4-dimethyl-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)benzenesulfonamide (S77):

[0113]

[0114] The isothiocyanate reagent used was cyclohexyl isothiocyanate. S77 was obtained as a white solid powder in 53% yield. mp: 190.3-191.5°C. 1 H NMR (800 MHz, DMSO- d 6) δ 11.37 (s, 1H), 8.20 (d, J = 7.9 Hz,1H), 7.81 – 7.75 (m, 2H), 7.59 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 3.0 Hz, 1H),7.46 (d,J = 8.2 Hz, 2H), 7.29 (dd, J = 8.6, 2.9 Hz, 1H), 4.16 (t, J = 7.3 Hz, 2H),3.91 (tq, J = 10.3, 5.4, 4.1 Hz, 1H), 3.84 (s, 3H), 2.98 (t, J = 7.3 Hz, 2H),1.74 (h, J = 6.7, 6.2 Hz, 2H), 1.59 (dq, J = 10.2, 5.1, 4.7 Hz, 2H), 1.53 – 1.49(m, 1H), 1.41 (s, 6H), 1.28 – 1.15 (m, 5H). 13 C NMR (200 MHz, DMSO- d 6) δ177.13, 176.94, 163.74, 158.58, 145.34, 137.72, 137.67, 130.12 (2C), 127.95,127.87 (2C), 124.63, 122.05, 111.07, 55.90 (2C), 53.34, 42.89, 40.63, 33.60,31.21, 29.41 (2C), 25.34, 24.52 (2C). IR (KBr, cm -1 ): 447.48, 501.43, 572.46,611.70, 669.84, 700.67, 778.00, 828.66, 861.28, 895.32, 1030.16, 1081.70,1116.72, 1151.42, 1286.68, 1357.54, 1388.71, 1444.22, 1473.08, 1504.02,1534.93, 1657.26, 1704.88, 2856.68, 2931.06, 3172.13, 3318.20, 3728.34. HRMS(ESI): m / z calcd for C 27 H 33 N3O5S2[M+H] + : 544.1940 found: 544.1951。

[0115] Some pharmacological tests and results of the compounds of the present invention are as follows:

[0116] Experimental Example 1: Inhibition rate and IC of the compounds of the present invention on GSTP1-1 protein 50 Activity experiment

[0117] 1. Experimental methods

[0118] Recombinant human GSTP1-1 (Sigma Chemical Co., St Louis, MO) was used to determine the inhibitory activity of the compounds. Prior to the addition of substrate, 50 μL of GSTP1-1 enzyme (200 μg / mL) was preincubated with 50 μL of GSTP1-1 enzyme (200 μg / mL) in 0.1 M phosphate buffer (pH 7.4) at 30°C for 5 minutes. Then, 50 μL of the chromogenic substrate reagent (1 mM CDNB, 2.5 mM GSH, 1 mM EDTA, and 100 mM potassium dihydrogen phosphate (pH 6.5)) was added. The reaction was stopped after 15 minutes. Absorbance at 340 nm was measured using a BioTek Synergy 2 microplate reader.

[0119] 2. The experimental results are shown in the table below.

[0120] Table 1 Inhibition rate of compounds on GSTP1-1 protein

[0121]

[0122] The results in Table 1 show that the compounds of the present invention have a high inhibitory activity against GSTP1-1 protease, and are higher than the positive drug gliquidone, and the inhibition rate against GSTP1-1 is above 50%. Therefore, the IC values ​​of the compounds against protease inhibitory activity were further determined. 50 value.

[0123] 3. IC of synthetic compounds against GSTP1-1 50

[0124] Table 2 IC values ​​of compounds against GSTP1-1 protein 50

[0125]

[0126] The results in Table 2 show that the IC values ​​of these compounds for GSTP1-1 protein are 50 All of them were below 10 μM, among which compounds S6, S7, S18, S19, S28, S31, S36, S67 and S71 had IC 50The values ​​were all between 3 and 4 μM. The experimental results showed that the target compound had a certain inhibitory effect on GSTP1-1 protein. Therefore, we further investigated the in vitro anti-tumor cell proliferation activity of the target compound.

[0127] Experimental Example 2: Inhibitory activity of the compounds of the present invention on the growth of A549 and A549 / CDDP tumor cells

[0128] 1. Experimental Materials

[0129] A549 cells were cultured in DMEM supplemented with 10% fetal bovine serum; A549 / CDDP cells were cultured in DMEM supplemented with 10% fetal bovine serum, 1% P / S, and 1 μg / mL CDDP. Cells were passaged every 2-3 days. The cell culture incubator was set at 5% CO2 and 37°C. o C, Cells in the logarithmic growth phase were used for experiments.

[0130] 2. Experimental methods:

[0131] A549 and A549 / CDDP tumor cells were seeded into 96-well plates (8 × 10 3 Cells were incubated at 100 μL per well (100 μM per well) for 24 hours. The compounds were then added (100 μM) and incubated for another 48 hours. The supernatant was aspirated, the cells were washed with PBS, and 10 μL of MTT solution (final concentration 0.5 mg / mL) was added to each well. The plates were incubated in an incubator for 4 hours. After aspirating the supernatant, 100 μL of DMSO was added to dissolve the formazan, and the absorbance (OD) at 570 nm was measured using a microplate reader. The cell inhibition rate (100%) was calculated as 100 minus the OD value of the treatment group / the OD value of the blank group × 100%.

[0132] 3. Experimental results:

[0133] Table 3 Inhibitory effects of compounds (100 μM) on various tumor cell lines

[0134]

[0135] Gliquidone, as an anti-diabetic drug, has no inhibitory effect on tumor cells. Experimental findings (Table 3) show that after structural optimization of gliquidone, compounds S6, S13, S34, S46, and S77 have stronger inhibitory effects on A549 / CDDP than on A549. That is, compared with A549, A549 / CDDP tumor cells are more sensitive to S6, S13, S34, S46, and S77. Compounds S71 and S77 have strong inhibitory activity against both tumor cells A549 and A549 / CDDP, demonstrating anti-tumor effects and are potential clinical candidate drugs.

Claims

1. A substituted benzenesulfonamide compound or a pharmaceutically acceptable salt thereof, characterized in that: The structural formula of the compound is as follows:

2. Use of the substituted benzenesulfonamide compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a GSTP1-1 inhibitor.

3. A pharmaceutical composition, characterized in that Contains the substituted benzenesulfonamide compound or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier or excipient.

4. Use of the composition according to claim 3 in the preparation of a GSTP1-1 inhibitor.

5. Use of the substituted benzenesulfonamide compound or a pharmaceutically acceptable salt thereof according to claim 1 or the composition according to claim 3 in the preparation of a drug for preventing and / or treating cisplatin-resistant diseases.

6. The use according to claim 5, characterized in that The cisplatin-resistant disease is lung cancer.

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