4-{[4-(substituted sulfonyl)-1-(homo)piperazinyl]carbonyl}benzenesulfonamides, their preparation and medical use

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to a 4-{[4-(substituted sulfonyl)-1-(high)piperazinyl]carbonyl}benzenesulfonamide compound, its preparation method, and pharmaceutical uses. The compound is the compound shown in formula (1) and its salts and isomers; the substituents are detailed in the specification. The compound of this invention can simultaneously target both CAII and ROCK, achieving a synergistic effect in lowering intraocular pressure and treating glaucoma. Structurally, this type of compound has three active fragments: p-sulfonamide benzoic acid, (high)piperazine, and sulfonyl groups with different substitutions. The sulfonamide moiety can interact with Zn in carbonic anhydrase II. 2+ It forms various interactions with hydrophobic and hydrophilic regions, such as coordination bonds, van der Waals forces, and hydrogen bonds, to inhibit the catalytic activity of enzymes. Meanwhile, substituted (high)piperazine and sulfonyl groups with different substitutions interact with key amino acids of Rho kinase targets. Both targets have potential applications in anti-glaucoma drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a 4-{[4-(substituted sulfonyl)-1-(high)piperazinyl]carbonyl}benzenesulfonamide compound, its preparation method, and its pharmaceutical uses. Background Technology

[0002] Glaucoma is an irreversible neurodegenerative disease of the optic nerve, characterized by progressive damage and apoptosis of retinal ganglion cells. It is one of the most common causes of blindness in clinical practice. The damage to retinal ganglion cells caused by glaucoma is irreparable, leading to progressive vision loss and, in severe cases, permanent blindness. This not only severely reduces the quality of life for patients but also places a heavy burden on global public health systems.

[0003] Elevated intraocular pressure (IOP) is a core risk factor for the development and progression of glaucoma. Currently, the core clinical treatment strategy for glaucoma focuses on targeted IOP regulation and slowing the progression of optic nerve damage. Existing clinically used antiglaucoma drugs all work by lowering IOP through two main pathways: reducing aqueous humor production and increasing aqueous humor outflow. The main drug classes include: parasympathomimetic drugs, α 2-Adrenergic receptor agonists, β - Adrenergic receptor antagonists, prostaglandin drugs, Rho-associated protein kinase (ROCK) inhibitors, hypertonic dehydrating agents, adenosine A1 receptor agonists, carbonic anhydrase II (CA II) inhibitors, etc.

[0004] Carbonic anhydrases (CAs) are a class of zinc-containing metalloenzymes widely distributed in organisms. Their core biological function is to catalyze the reversible hydration of carbon dioxide, making them key regulatory enzymes in acid-base balance, transmembrane ion transport, and fluid secretion processes. CA II is a crucial regulatory target in aqueous humor formation; CA inhibitors can reduce HCO3- levels in the body by targeting and inhibiting the catalytic activity of CA II. - The generation of HCO3- is inhibited. - Na + Cl - This involves the transmembrane transport of water molecules into the aqueous humor, ultimately reducing aqueous humor production and exerting a pharmacological effect of lowering intraocular pressure. It is an important class of drugs in clinical anti-glaucoma treatment. Structural biology studies show that the catalytic domain of CA II is a key region for inhibitor molecule binding. Its catalytic center is located within a cone-shaped cavity in the protein structure, extending from the protein surface to the protein core. This cavity can be divided into two functional regions: a hydrophobic region and a hydrophilic region. Zn2+ The binding site is located at the very bottom of the cavity and is the core site of action for developing CA II inhibitors.

[0005] Rho-associated protein kinases (ROCKs) are a class of serine / threonine protein kinases. Their upstream regulatory molecules include three Rho family GTPases: Rho A, Rho B, and Rho C. The Rho A / ROCK signaling axis mediates several key pathophysiological processes, including cytoskeleton reorganization, cell migration, cell adhesion, proliferation and differentiation, tissue contraction, and growth. ROCK inhibitors are the mainstream clinical anti-glaucoma drugs that promote aqueous humor outflow. They enhance aqueous humor drainage efficiency through dual-pathway regulation: on the one hand, by relaxing trabecular meshwork smooth muscle cells, they widen the aqueous humor drainage gap in the trabecular meshwork-Schlemm canal pathway, directly increasing the amount of aqueous humor drained through the traditional drainage pathway; on the other hand, they reduce the deposition of extracellular matrix in the ciliary body tissue, lowering the resistance to aqueous humor outflow in the uveal-scleral pathway, indirectly promoting aqueous humor drainage through this non-traditional pathway, ultimately achieving efficient reduction of intraocular pressure.

[0006] Currently used antiglaucoma drugs are mostly single-target formulations. However, long-term clinical application still presents challenges such as poor intraocular pressure control in some patients, limited response rates to monotherapy, and adverse reactions associated with long-term use, making it difficult to fully meet the needs of individualized glaucoma treatment. Therefore, developing novel antiglaucoma drugs with multi-target synergistic regulatory effects, excellent intraocular pressure-lowering efficacy, and good safety profile is of significant clinical importance and has broad application prospects. Summary of the Invention

[0007] The purpose of this invention is to design and synthesize a 4-{[4-(substituted sulfonyl)-1-(high)piperazinyl]carbonyl}benzenesulfonamide compound, its preparation method, and its pharmaceutical applications.

[0008] To achieve the objectives of this invention, the following technical solutions can be adopted: A 4-{[4-(substituted sulfonyl)-1-(high)piperazinyl]carbonyl}benzenesulfonamide compound, the compound of formula (1) and its salts and isomers; In formula (1): n = 0 or 1; R1 is selected from H, hydroxyl, unsubstituted or substituted with at least one R2 C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, unsubstituted or substituted with at least one R3 amino, unsubstituted or substituted with at least one R4 thioamide, amide, unsubstituted or substituted with at least one R5 phenyl, benzyl, pyridine ring, pyrazole ring, pyrrole ring, pyrimidine ring, quinoline ring, isoquinoline ring, imidazole ring, morpholine ring, piperazine ring, pyrazine ring, pyrazine ring, piperidine ring, thiophene ring, pyran ring, indole ring, furan ring, biphenyl, naphthyl; R2 is selected from halogen, hydroxyl, cyano, nitro or amino groups; R3 is selected from C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-6 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C2-6 alkenylcarbonyl or C2-6 alkynylcarbonyl. R4 is selected from C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-6 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C2-6 alkenylcarbonyl or C2-6 alkynylcarbonyl. R5 is selected from H, hydroxyl, hydroxymethyl, mercapto, amino, thioamide, carboxyl, ester, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxy, benzyloxycarbonyl, and C1-6 haloalkyl.

[0009] Preferably, the compound is the compound shown in formula (1) and its salts and isomers; In formula (1): n = 0 or 1; R1 is selected from H, hydroxyl, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, amino, thioamide, amide, phenyl, benzyl, pyridine ring, pyrazole ring, pyrrole ring, pyrimidine ring, quinoline ring, isoquinoline ring, imidazole ring, morpholine ring, piperazine ring, pyrazine ring, piperidine ring, thiophene ring, pyran ring, indole ring, furan ring, biphenyl, naphthyl; R5 is selected from H, hydroxyl, hydroxymethyl, mercapto, amino, thioamide, carboxyl, ester, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxy, benzyloxycarbonyl, and C1-6 haloalkyl.

[0010] More preferably, the compound is the compound shown in formula (1) and its salts and isomers; In formula (1): n = 0 or 1; R1 is selected from phenyl, pyridine, pyrazole, pyrrole, pyrimidine, quinoline, isoquinoline, imidazole, morpholine, piperazine, pyridazine, pyrazine, piperidine, thiophene, pyran, indole, furan, biphenyl, and naphthyl groups that are unsubstituted or have been substituted with at least one R5. R5 is selected from H, hydroxyl, hydroxymethyl, mercapto, amino, thioamide, carboxyl, ester, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxy, benzyloxycarbonyl, and C1-6 haloalkyl.

[0011] 4. The 4-{[4-(substituted sulfonyl)-1-(high)piperazinyl]carbonyl}benzenesulfonamide compound according to claim 3, characterized in that: the compound is the compound shown in formula (1) and its salts and isomers; In formula (1): n = 0 or 1; R1 is selected from phenyl, biphenyl, naphthyl, pyridine ring, quinoline ring, isoquinoline ring, indole ring, and furan ring that are unsubstituted or have been substituted with at least one R5; R5 is selected from H, hydroxyl, hydroxymethyl, mercapto, amino, thioamide, carboxyl, ester, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxy, benzyloxycarbonyl, and C1-6 haloalkyl.

[0012] Further preferably, the compound is the compound shown in formula (1) and its salts and isomers; In formula (1): R1 is In the formula, R6, R7, R8, R9, R 10 R 11 It may be selected from H, hydroxyl, hydroxymethyl, mercapto, amino, thioamide, carboxyl, ester, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxy, benzyloxycarbonyl, and C1-6 haloalkyl, either the same or different.

[0013] More preferably, the compound is A method for preparing the compound, wherein the reaction formula is: Reagents and conditions: a. SOCl2, reflux, overnight; b. Pyridine, CH2Cl2, 0 ℃ ~ rt, overnight; c. CF3COOH, CH2Cl2, reflux, 1h; d. sulfonylchloride, CH2Cl2, DIPEA, 0 ℃ ~ rt, 4h. Starting with p-sulfonamide benzoic acid, intermediate 2,2- and 1-Boc-periperazine were obtained via chlorination reaction. N -Acylation reaction yields intermediate 3, which is then deprotected by trifluoroacetic acid to obtain intermediate 4. This intermediate is then sulfonated with different sulfonyl chlorides to obtain compounds of general formula (1).

[0014] A pharmaceutical composition comprising a compound of the general formula (1) and its salts and isomers.

[0015] An application of the compound of general formula (1) and its salts, isomers or compositions in the preparation of an antiglaucoma drug.

[0016] The use of the compound of general formula (1) and its salts, isomers or compositions in the preparation of drugs that inhibit carbonic anhydrase and / or Rho kinase.

[0017] Advantages of this invention: The general formula compounds of this invention can simultaneously target both CAII and ROCK, achieving a synergistic effect in lowering intraocular pressure and treating glaucoma. Structurally, these compounds possess three active fragments: p-sulfonamide benzoic acid, (hyper)piperazine, and sulfonyl groups with varying substitutions. The sulfonamide moiety can interact with Zn in carbonic anhydrase II. 2+ It forms various interactions with hydrophobic and hydrophilic regions, such as coordination bonds, van der Waals forces, and hydrogen bonds, to inhibit the catalytic activity of enzymes. Meanwhile, substituted (high)piperazine and sulfonyl groups with different substitutions interact with key amino acids of Rho kinase targets. Both targets have potential applications in anti-glaucoma drugs. Detailed Implementation

[0018] The compounds of the present invention and their preparation will be better understood by referring to the following examples, which are intended to illustrate rather than limit the scope of the invention.

[0019] Example 1: 4-{[hexahydro-4-(isoquinoline-5-sulfonyl)-1 H -1,4-diaza-1-yl]carbonyl}- N -Benzenesulfonamide (A1) Add 10.00 g (49.75 mmol) of p-sulfonamide benzoic acid and 125 mL of thionyl chloride to a 250 mL round-bottom flask. N , N Add 3 drops of dimethylformamide and reflux overnight with stirring. Then remove the solvent under reduced pressure to obtain crude product 2, a yellow solid, which requires no further purification.

[0020] In a 100 mL round-bottom flask, intermediate 1-Boc-periperazine (2.74 g, 13.66 mmol), pyridine (2.16 g, 27.32 mmol), and 20 mL of dichloromethane were added. Under ice bath and stirring, a 20 mL solution of intermediate 2 (2.00 g, 9.11 mmol) in dichloromethane was slowly added dropwise. After the addition was complete, stirring continued for 30 min, followed by stirring overnight at room temperature. The reaction mixture was poured into 200 mL of water and extracted with dichloromethane (3 x 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was washed with methanol to give crude product 3a, with a yield of 2.70 g (77.36%).

[0021] HRMS (ESI): Calculated for C 17 H 25 N3O5S [M+Na] + : 406.1413, Found 406.1418 [M+ Na] + . Intermediate 3 (2.50 g, 6.52 mmol) and 20 mL of dichloromethane were added to a 100 mL round-bottom flask. Trifluoroacetic acid solution (2.23 g, 19.56 mmol) was slowly added dropwise in portions while stirring at room temperature, and stirring was continued for 60 min. After removing the solvent under reduced pressure, rapid silica gel column chromatography (dichloromethane: anhydrous methanol = 100:1) was performed to obtain 4a as a white solid, with a yield of 1.42 g and a yield of 76.76%. HRMS (ESI): Calcd. for C 12 H 17 N3O3S [M+Na] + : 306.0688, Found306.0872 [M+Na] + . Add intermediate 4a (0.80 g, 2.82 mmol) to a 100 mL round-bottom flask. N,N- Diisopropylethylamine (0.55 g, 4.24 mmol), dichloromethane 15 mL. Isoquinoline-5-sulfonyl chloride (0.96 g, 1.24 mmol) was slowly added dropwise under ice bath and stirring. After the addition was complete, stirring was continued for 4 h. The mixture was filtered with diatomaceous earth as a filter aid. The filtrate was collected, and the solvent was removed under reduced pressure. The solution was then rapidly separated by silica gel column chromatography (dichloromethane:anhydrous methanol = 50:1) to give Al as a white solid, yielding 0.83 g, 61.94% (mp 205.3–208.2 °C). 1 H-NMR (600 MHz, DMSO- d 6) δ 9.52 (d, J = 12.6 Hz, 1H), 8.72 (dd, J =15.8, 6.1 Hz, 1H), 8.49 (dd, J = 21.1, 8.2 Hz, 1H), 8.38 (t, J = 7.2 Hz, 1H),8.33 – 8.28 (m, 1H), 7.88 (dd, J = 8.3, 3.1 Hz, 2H), 7.84 (t, J = 7.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.52 (s, J = 4.5 Hz, 2H), 7.45 (d, J = 7.9 Hz, 1H), 3.78(t, J = 5.5 Hz, 1H), 3.71 (t, J = 5.8 Hz, 1H), 3.51 (dd, J = 11.0, 5.4 Hz, 2H), 3.44 (t, J = 5.7 Hz, 1H), 3.33 (t, J = 6.1 Hz, 1H), 3.12 (dd, J = 7.4, 4.3 Hz, 2H), 1.91 (p, J = 6.1 Hz, 1H), 1.64 (p, J = 5.8 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d6) δ169.73, 154.04, 145.46, 144.01, 140.09, 133.20, 132.87, 130.97, 129.31,127.61, 127.10, 127.01, 126.53, 117.41, 48.30, 47.20, 46.54, 46.41, 28.26.HRMS (ESI): Calcd. for C 21 H 22 N4O5S2[M+Na] + : 497.0924, Found 497.0947 [M+Na] + . Example 2: 4-{[hexahydro-4-(1-methylisoquinoline-5-sulfonyl)-1 H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A2) The compound in Example 2 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and 1-methylisoquinoline-5-sulfonyl chloride (1.02 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A2 was obtained as a white solid, with a yield of 0.91 g and a yield of 65.94%. mp 204.6~206.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.56 (s, 1H),8.55 – 8.50 (m, 1H), 8.32 (dd, J = 46.0, 7.3 Hz, 1H), 8.19 (dd, J = 47.8, 6.1 Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.84 – 7.78 (m, 1H), 7.55 (d, J = 8.0 Hz, 1H),7.50 (s, 2H), 7.45 (d, J = 8.0 Hz, 1H), 3.77 (t, J = 5.5 Hz, 1H), 3.71 (t, J = 5.8Hz, 1H), 3.61 – 3.58 (m, 2H), 3.42 (t, J = 5.7 Hz, 1H), 3.32 (t, J = 6.1 Hz, 1H), 3.12 (dd,J = 7.4, 4.3 Hz, 2H), 2.09 (s, 3H), 1.90 (t, J = 6.0 Hz, 1H), 1.64 (dd, J = 8.4, 3.9 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d 6) δ 169.73, 160.17, 145.04,144.09, 140.19, 132.78, 132.42, 127.95, 127.60, 127.15, 126.77, 126.69,115.89, 48.50, 48.33, 46.61, 46.42, 31.17, 23.34. HRMS (ESI): Calcd. forC 22 H 24 N4O5S2[M+Na] + : 511.1080, Found 511.1090 [M+Na] + .

[0022] Example 3: 4-{[hexahydro-4-(1-chloroisoquinoline-5-sulfonyl)-1 H -1,4-diaza-1-yl]carbonyl}- N - Benzenesulfonamide (A3) The compound in Example 3 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and 1-chloroisoquinoline-5-sulfonyl chloride (1.13 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A3 was obtained as a white solid, with a yield of 1.05 g and a yield of 72.92%. mp 216.3~218.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.64 (dd, J = 21.1, 8.5 Hz, 1H), 8.52 (dd, J = 16.2, 6.0 Hz, 1H), 8.46 (dd, J = 24.6, 6.7 Hz, 1H),8.42 – 8.34 (m, 1H), 7.97 (dt, J = 25.8, 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.57 (d, J= 8.0 Hz, 1H), 7.49 (s, 1H), 7.48 (s, 2H), 3.78 (t, J = 5.5 Hz, 1H), 3.72 (t, J = 5.8 Hz, 1H), 3.62 (t, J = 5.5 Hz, 1H), 3.56 – 3.52 (m, 1H), 3.52 –3.47 (m, 2H), 3.44 (t, J = 5.7 Hz, 1H), 3.34 (d, J = 7.1 Hz, 1H), 1.95 – 1.89 (m,1H), 1.66 (p, J = 4.9, 4.0 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d 6) δ 169.75, 152.01,145.05, 144.09, 140.18, 135.33, 134.02, 128.92, 128.84, 127.62, 127.32,127.18, 126.23, 118.14, 49.18, 48.49, 47.38, 46.60, 28.25. HRMS (ESI): Calcd.for C 21 H 21 ClN4O5S2[M+Na] + : 531.0534, Found 531.0516 [M+Na] + Example 4: 4-{[hexahydro-4-(1-bromoisoquinoline-5-sulfonyl)-1 H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A4) The compound in Example 4 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and 1-bromoisoquinoline-5-sulfonyl chloride (1.30 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A4 was obtained as a white solid, with a yield of 1.23 g and a yield of 77.85%. mp 216.2~219.9℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.59 (dd, J= 20.5,8.6 Hz, 1H), 8.52 – 8.49 (m, 1H), 8.48 – 8.44 (m, 1H), 8.38 (dd, J = 14.0, 6.8Hz, 1H), 7.97 (dt, J = 25.5, 8.0 Hz, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.57 (d, J =8.0 Hz, 1H), 7.48 (s, 3H), 3.78 (t, J = 5.5 Hz, 1H), 3.72 (t, J = 5.8 Hz, 1H), 3.62 (t, J = 5.4 Hz, 1H), 3.52 (d, J = 5.5 Hz, 1H), 3.51 – 3.48 (m, 2H), 3.44 (t, J = 5.4 Hz, 1H), 3.33 (s, 1H), 1.92 (p, J = 5.8 Hz, 1H), 1.66 (t, J = 5.9 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d 6) δ 169.75, 146.05, 144.69, 144.10, 140.18, 134.00,133.06, 129.11, 129.03, 127.62, 127.18, 126.32, 126.23, 118.33, 49.19, 48.48,47.39, 46.60, 28.25. HRMS (ESI): Calcd. for C 21 H 21 BrN4O5S2[MH] - : 551.0064, Found 551.0048 [MH] - . Example 5: 4-{[hexahydro-4-(quinoline-5-sulfonyl)-1 H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A5) The compound in Example 5 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and quinoline-5-sulfonyl chloride (0.96 g, 1.24 mmol) as starting materials, following the synthesis method of A1. A5 was obtained as a white solid, with a yield of 0.97 g and a yield of 72.39%. mp 206.8~208.4 ℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 9.10 – 9.04 (m, 1H),8.55 (dd, J = 10.7, 8.5 Hz, 1H), 8.37 (dd, J = 32.4, 7.2 Hz, 1H), 8.31 (dd, J =15.9, 8.1 Hz, 1H), 7.87 (dd, J = 8.0, 4.8 Hz, 2H), 7.79 – 7.68 (m, 2H), 7.57(d, J = 8.1 Hz, 1H), 7.49 (s, 1H), 7.48 (s, 2H), 3.78 (t, J = 5.4 Hz, 1H), 3.72 –3.68 (m, 2H), 3.56 (t, J = 5.8 Hz, 1H), 3.54 – 3.50 (m, 1H), 3.48 (t, J = 5.9 Hz, 1H), 3.44 (t, J = 5.7 Hz, 1H), 3.35 – 3.31 (m, 1H), 1.89 (p, J = 6.0 Hz, 1H), 1.62 (p, J = 6.0 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d 6) δ 169.74, 151.84, 144.96,143.56, 140.38, 137.39, 132.82, 132.65, 129.22, 127.59, 127.14, 126.30,126.22, 122.94, 48.51, 48.32, 47.35, 47.19, 28.55, 28.50. HRMS (ESI): Calcd.for C 21 H 22 N4O5S2[M+Na]+ : 497.0924, Found 497.0946 [M+Na] + . Example 6: 4-{[hexahydro-4-(2-methylquinoline-5-sulfonyl)-1 H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A6) The compound in Example 6 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and 2-methylquinoline-5-sulfonyl chloride (1.02 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A6 was obtained as a white solid, with a yield of 1.03 g and a yield of 74.64%. mp 212.3~214.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.41 (dd, J =11.5, 8.4 Hz, 1H), 8.34 (ddd, J = 30.2, 7.4, 1.4 Hz, 1H), 8.23 ​​(ddd, J = 15.2,8.1, 1.5 Hz, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.67 (dt, J = 23.2, 7.8 Hz, 1H), 7.58(d, J = 8.8 Hz, 2H), 7.51 – 7.48 (m, 1H), 7.47 (d, J = 4.1 Hz, 2H), 3.78 (t, J =5.5 Hz, 1H), 3.76 – 3.63 (m, 3H), 3.56 (t, J = 5.8 Hz, 1H), 3.52 (d, J = 5.8 Hz,1H), 3.49 – 3.47 (m, 1H), 3.44 (t, J = 5.7 Hz, 1H), 2.09 (s, 3H), 1.90 (t, J =5.8 Hz, 1H), 1.64 (p, J = 6.0 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d6) δ 169.75,160.61, 144.95, 143.16, 140.43, 137.32, 136.38, 133.99, 132.78, 127.61,126.20, 125.24, 125.16, 123.63, 48.54, 48.37, 47.38, 47.25, 30.07, 28.62.HRMS (ESI): Calcd. for C 22 H 24 N4O5S2[M+Na] + : 511.1080, Found 511.1109 [M+Na] + . Example 7: 4-{[hexahydro-4-(3-methylquinoline-5-sulfonyl)-1 H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A7) The compound in Example 7 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and 3-methylquinoline-5-sulfonyl chloride (1.02 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A7 was obtained as a white solid, with a yield of 1.10 g and a yield of 79.71%. mp 205.4~207.2℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.95 – 8.91 (m,1H), 8.35 – 8.26 (m, 2H), 8.25 (d, J = 6.2 Hz, 1H), 8.24 – 8.17 (m, 1H), 7.81(t, J = 7.6 Hz, 2H), 7.70 (dt, J = 24.4, 7.7 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 3.77 (t, J = 5.4 Hz, 1H), 3.70 (q, J = 5.1 Hz, 2H), 3.54(t, J = 5.9 Hz, 1H), 3.49 (t, J = 5.4 Hz, 1H), 3.44 (dt, J= 7.9, 5.9 Hz, 2H), 3.32(d, J = 6.1 Hz, 1H), 3.16 (s, 3H), 1.88 (t, J = 5.8 Hz, 1H), 1.61 (p, J = 6.7, 6.3Hz, 1H). 13 C-NMR (151 MHz, DMSO- d 6) δ 169.74, 160.46, 153.63, 153.57, 140.29,137.03, 136.90, 133.69, 133.64, 132.40, 132.38, 132.35, 127.61, 127.19,48.54, 48.19, 47.25, 47.08, 30.21, 28.45. HRMS (ESI): Calcd. for C 22 H 24 N4O5S2[M+Na] + : 511.1080, Found 511.1119[M+Na] + . Example 8: 4-{[hexahydro-4-(2-chloroquinoline-5-sulfonyl)-1 H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A8) The compound in Example 8 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and 2-chloro-5-quinoline-sulfonyl chloride (1.11 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A8 was obtained as a white solid, yielding 1.14 g, with a yield of 79.17%. mp 213.1~215.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.63 (dd, J = 10.8,8.6 Hz, 1H), 8.46 – 8.33 (m, 2H), 7.90 – 7.86 (m, 2H), 7.84 – 7.76 (m, 2H),7.57 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 2.6 Hz, 2H), 3.78(t, J= 5.5 Hz, 1H), 3.72 (t, J = 5.6 Hz, 1H), 3.67 (t, J = 5.5 Hz, 1H), 3.51 (d, J =5.8 Hz, 3H), 3.44 (t, J = 5.8 Hz, 1H), 3.37 (d, J = 6.6 Hz, 1H), 1.91 (p, J = 5.8Hz, 1H), 1.67 (p, J = 5.8 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d 6) δ 169.75, 151.19,144.98, 142.81, 141.25, 140.34, 136.23, 134.19, 133.88, 127.61, 127.18,126.92, 126.33, 124.13, 49.60, 49.09, 48.52, 48.25, 28.56. HRMS (ESI): Calcd.for C 21 H 21 ClN4O5S2[M+Na] + : 531.0534, Found 531.0561[M+Na] + . Example 9: 4-{[hexahydro-4-(1,3-dichloroisoquinoline-5-sulfonyl)-1} H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A9) The compound in Example 9 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and 1,3-dichloroisoquinoline-5-sulfonyl chloride (1.17 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A9 was obtained as a white solid, with a yield of 1.20 g and a yield of 81.08%. mp 214.3~216.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.64 (dd, J =22.1, 8.5 Hz, 1H), 8.53 – 8.32 (m, 2H), 7.97 (ddd, J= 26.4, 8.6, 7.4 Hz, 1H),7.88 (dd, J = 8.2, 4.1 Hz, 2H), 7.57 (d, J = 8.1 Hz, 1H), 7.50 (s, 1H), 7.48 (s,2H), 3.78 (t, J = 5.5 Hz, 1H), 3.72 (t, J = 5.8 Hz, 1H), 3.61 (dd, J = 6.5, 4.5 Hz, 1H), 3.53 (t, J = 5.6 Hz, 1H), 3.52 – 3.48 (m, 2H), 3.44 (t, J = 5.6 Hz, 1H), 3.35 (d, J = 6.9 Hz, 1H), 1.93 (q, J = 5.2, 4.6 Hz, 1H), 1.68 (p, J = 6.0 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d 6) δ 169.75, 151.91, 144.50, 140.15, 134.99, 134.63,132.15, 129.30, 129.22, 127.63, 127.18, 126.51, 126.34, 117.23, 49.20, 48.51,47.35, 46.57, 28.24. HRMS (ESI): Calcd. for C 21 H 20 Cl2N4O5S 2, [M+Na] + : 565.0144,Found 565.0187 [M+Na] + . Example 10: 4-{[hexahydro-4-(2-bromoquinoline-5-sulfonyl)-1 H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A10) The compound in Example 10 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and 2-bromoquinoline-5-sulfonyl chloride (1.30 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A10 was obtained as a white solid, yielding 1.22 g, with a yield of 78.21%. mp 214.0~216.9℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.57 – 8.48 (m,1H), 8.42 – 8.31 (m, 2H), 7.94 – 7.86 (m, 3H), 7.81 (dt, J = 23.6, 7.8 Hz, 1H),7.60 – 7.56 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 2.3 Hz, 2H), 3.79 (t, J = 5.5 Hz, 1H), 3.73 (t, J = 5.8 Hz, 1H), 3.69 (d, J = 5.6 Hz, 1H), 3.55 (t, J =5.6 Hz, 1H), 3.54 – 3.49 (m, 2H), 3.45 (t, J = 5.8 Hz, 1H), 3.38 (d, J = 6.5 Hz, 1H), 1.91 (p, J = 5.9 Hz, 1H), 1.67 (p, J = 5.9 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d 6)δ 169.75, 144.99, 143.31, 142.94, 140.34, 136.29, 133.85, 128.30, 128.28,127.62, 127.54, 127.18, 127.00, 126.21, 49.11, 48.52, 48.25, 47.19, 28.59.HRMS (ESI): Calcd. for C 21 H 21 BrN4O5S2[M+Na] + : 575.0029, Found 575.0036 [M+Na]+ . Example 11: 4-{[hexahydro-4-(3-bromoquinoline-5-sulfonyl)-1 H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A11) The compound in Example 3 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and 3-bromoquinoline-5-sulfonyl chloride (1.30 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A11 was obtained as a white solid, yielding 1.18 g, with a yield of 75.64%. mp 211.5~214.4℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 9.14 (dd, J = 14.1, 2.4 Hz, 1H), 8.92 (dd, J = 10.0, 2.4 Hz, 1H), 8.39 (dd, J = 32.4, 7.4, 1.4 Hz,1H), 8.27 (dd, J = 15.8, 8.3, 1.4 Hz, 1H), 7.87 (dd, J = 8.4, 2.5 Hz, 2H), 7.81(dt, J = 23.1, 7.8 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H),7.47 (s, 1H), 3.77 (t, J = 5.4 Hz, 1H), 3.71 (dd, J = 7.0, 4.4 Hz, 1H), 3.68 (t, J = 5.5 Hz, 1H), 3.53 (t, J = 5.7 Hz, 1H), 3.52 – 3.49 (m, 1H), 3.49 – 3.46 (m,1H), 3.43 (t, J = 5.7 Hz, 1H), 3.33 (s, 1H), 1.89 (p, J = 5.9 Hz, 1H), 1.62 (p, J =5.9 Hz, 1H). 13 C-NMR (151 MHz, DMSO-d 6) δ 169.73, 152.34, 144.97, 141.66,140.35, 138.76, 137.24, 133.06, 130.27, 127.62, 127.16, 126.22, 118.42,48.52, 48.25, 47.29, 47.14, 28.44. HRMS (ESI): Calcd. for C 21 H 21 BrN4O5S2[M+Na] + :575.0029, Found 575.0054 [M+Na] + . Example 12: 4-{[hexahydro-4-(benzene-4-sulfonyl)-1 H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A12) The compound in Example 3 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and benzene-4-sulfonyl chloride (0.75 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A12 was obtained as a white solid, with a yield of 0.98 g and a yield of 81.67%. mp 213.4~215.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 7.87 (d, J = 3.0 Hz, 1H), 7.86 (d, J = 3.0 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.70(dt, J = 15.3, 7.4 Hz, 1H), 7.63 (dt, J = 20.9, 7.6 Hz, 2H), 7.56 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 9.1 Hz, 2H), 7.46 (s, 1H), 3.74 (t, J = 5.6 Hz, 1H), 3.66 (t, J =5.7 Hz, 1H), 3.43 (d, J = 5.7 Hz, 1H), 3.39 (d,J = 5.5 Hz, 1H), 3.31 (s, 2H), 3.29 (s, 2H), 1.86 (p, J = 5.8 Hz, 1H), 1.63 (p, J = 5.8 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d 6) δ 169.69, 145.03, 140.20, 139.39, 133.38, 127.61, 127.20, 127.03,126.30, 48.31, 47.69, 46.84, 46.45, 28.06. HRMS (ESI): Calcd. for C 18 H 21 N3O5S2[M+Na] + : 446.0815, Found 446.2796[M+Na] + . Example 13: 4-{[hexahydro-4-(naphthalene-2-sulfonyl)-1 H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A13) The compound in Example 13 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and naphthalene-2-sulfonyl chloride (0.96 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A13 was obtained as a white solid, yielding 1.13 g, with a yield of 84.33%. mp 209.3~212.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.50 (dd, J = 28.9, 1.9Hz, 1H), 8.22 – 8.18 (m, 1H), 8.18 – 8.13 (m, 1H), 8.08 (dd, J = 10.7, 8.0 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.81 (dd, J = 19.6, 8.4 Hz, 2H), 7.76 – 7.67 (m,2H), 7.56 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 12.0 Hz, 1H), 7.44 (s,J = 8.1 Hz, 2H), 3.76 (t, J = 5.4 Hz, 1H), 3.67 (t, J = 5.7 Hz, 1H), 3.50 (t, J = 5.5 Hz, 1H), 3.45– 3.37 (m, 3H), 3.36 (s, 1H), 3.29 (t, J = 6.1 Hz, 1H), 1.89 (p, J = 5.8 Hz, 1H), 1.65 (p, J = 5.8 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d 6) δ 169.70, 145.00, 140.17,136.29, 134.77, 132.33, 129.79, 129.74, 129.40, 128.31, 128.18, 128.15,127.60, 127.20, 126.26, 48.32, 47.75, 46.89, 46.49, 28.12. HRMS (ESI): Calcd.for C 22 H 23 N3O5S2[M+Na] + : 496.0971, Found 496.0968 [M+Na] + . Example 14: 4-{[hexahydro-4-(biphenyl-4-sulfonyl)-1 H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A14) The compound in Example 14 was prepared using the same method as in Example 1, with 4a (0.8 g, 2.82 mmol) and biphenyl-4-sulfonyl chloride (1.07 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A14 was obtained as a white solid, yielding 1.17 g, with a yield of 82.98%. mp 211.3~214.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 7.92 (s, 1H), 7.92 –7.88 (dd 2H), 7.88 – 7.86 (m, 2H), 7.85 (d, J = 2.7 Hz, 1H), 7.75 (t, J= 7.2 Hz, 2H), 7.58 (d, J = 8.1 Hz, 1H), 7.55 – 7.49 (m, 3H), 7.48 (s, 1H), 7.47 (s, 2H), 3.77 (t, J = 5.5 Hz, 1H), 3.68 (t, J = 5.8 Hz, 1H), 3.47 (t, J = 5.5 Hz, 1H), 3.42(t, J = 5.7 Hz, 1H), 3.36 (d, J = 5.8 Hz, 2H), 3.34 – 3.30 (m, 2H), 1.89 (p, J =5.8 Hz, 1H), 1.66 (p, J = 6.0 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d 6) δ 169.72,145.04, 140.22, 138.13, 137.91, 129.08, 128.15, 128.12, 127.94, 127.79,127.62, 127.25, 48.30, 47.74, 46.92, 46.51, 28.10. HRMS (ESI): Calcd. forC 24 H 25 N3O5S2[M+Na] - : 522.1128, Found 522.1167 [M+Na] + . Example 15: 4-{[hexahydro-4-(pyridine-3-sulfonyl)-1 H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A15) The compound in Example 15 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and pyridine-3-sulfonyl chloride (0.75 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A15 was obtained as a white solid, yielding 1.01 g, with a yield of 84.17%. mp 214.5~217.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.98 (dd, J= 28.3, 2.5Hz, 1H), 8.87 (dd, J = 15.1, 4.2 Hz, 1H), 8.25 (d, J = 6.3 Hz, 2H), 8.20 (dd, J =8.1, 2.0 Hz, 1H), 7.83 – 7.80 (m, 2H), 7.69 (dd, J = 8.2, 5.0 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 3.75 (t, J = 5.5 Hz, 1H), 3.67 (t, J =5.8 Hz, 1H), 3.47 (t, J = 5.6 Hz, 1H), 3.41 (d, J = 5.6 Hz, 1H), 3.37 (d, J = 5.7Hz, 2H), 3.34 (d, J = 6.1 Hz, 1H), 3.32 (d, J = 5.6 Hz, 1H), 1.87 (p, J = 6.0 Hz, 1H), 1.66 (p, J = 6.1 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d 6) δ 169.72, 153.89,147.43, 144.05, 140.06, 135.32, 135.15, 127.61, 127.26, 125.00, 48.33, 47.54,46.76, 46.35, 28.02. HRMS (ESI): Calcd. for [MH] - C 17 H 20 N4O5S2: 423.0802, Found423.0793 [MH] - . Example 16: 4-{[hexahydro-4-(2-chloropyridine-5-sulfonyl)-1 H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A16) The compound in Example 16 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and 2-chloropyridine-3-sulfonyl chloride (0.90 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A16 was obtained as a white solid, yielding 1.10 g, with a yield of 84.62%. mp 211.3~214.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.84 (dd, J = 27.9,2.6 Hz, 1H), 8.27 (ddd, J = 27.1, 8.4, 2.6 Hz, 1H), 7.87 (dd, J = 8.2, 2.6 Hz, 2H), 7.80 (dd, J = 17.4, 8.4 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.9Hz, 1H), 7.47 (s, 2H), 3.76 (t, J = 5.5 Hz, 1H), 3.68 (t, J = 5.7 Hz, 1H), 3.49(t, J = 5.6 Hz, 1H), 3.39 (s, 3H), 3.36 (s, 1H), 3.31 (s, 1H), 1.88 (p, J = 5.8Hz, 1H), 1.66 (p, J = 5.9 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d 6) δ 169.73, 154.59,148.30, 145.07, 140.15, 138.58, 135.15, 127.61, 127.25, 126.34, 48.34, 47.61,46.78, 46.33, 27.99. HRMS (ESI): Calcd. for C 17 H 19 ClN4O5S2[M+Na] + : 481.0378,Found 481.0383 [M+Na] + . Example 17: 4-{[hexahydro-4-(6-chloro-2-methylpyridine-3-sulfonyl)-1 H- 1,4-Dazacycloheptan-1-yl]carbonyl}- N- Benzenesulfonamide (A17) The compound in Example 17 was prepared using the same method as in Example 1, with 4a (0.80 g, 2.82 mmol) and 6-chloro-2-methylpyridine-3-sulfonyl chloride (0.96 g, 4.24 mmol) as starting materials, following the synthesis method of A1. A17 was obtained as a white solid, yielding 1.12 g, with a yield of 83.58%. mp 205.3~207.9℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.17 (dd, J = 38.8, 8.3 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.61 –7.57 (m, 2H), 7.56 (d, J = 3.8 Hz, 1H), 7.48 (s, 2H), 3.79 (t, J = 5.4 Hz, 1H), 3.72 (t, J = 5.7 Hz, 1H), 3.54 (t, J = 5.5 Hz, 1H), 3.48 (t, J = 5.7 Hz, 1H), 3.43(d, J = 7.1 Hz, 3H), 3.37 (t, J = 6.1 Hz, 1H), 2.70 (d, J = 29.8 Hz, 3H), 1.90 (t, J = 6.4 Hz, 1H), 1.67 (p, J = 5.8 Hz, 1H). 13 C-NMR (151 MHz, DMSO- d6) δ 169.78,158.12, 152.67, 145.05, 140.65, 140.23, 134.25, 127.65, 127.24, 122.84,48.47, 47.35, 46.75, 46.57, 28.26, 23.64, 23.57. HRMS (ESI): Calcd. forC 18 H 21 ClN4O5S2[M+Na] + :495.0534, Found 495.0572 [M+Na] + . Example 18: 4-{[4-(isoquinoline-5-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B1) The compound in Example 18 was prepared using the same method as in Example 2, with 2 (2.00 g, 9.11 mmol) and 1-Boc-piperazine (2.54 g, 13.66 mmol) as starting materials, following the synthesis method of 3a, yielding 3b as a yellow solid, with a yield of 3.20 g and a yield of 87.43%. HRMS (ESI): Calcd. for C 16 H 23 N3O5S [M + Na] + : 392.1256, Found 392. 1259[M + Na] + . Using 3b (2.50 g, 6.77 mmol) as the starting material, and following the same synthesis method as 4a, 4b was obtained as a white solid, yielding 1.56 g in 85.71%. HRMS (ESI): Calcd. for C 11 H 15 N3O3S [M + Na] + : 292.0732,Found 292.0741 [M + Na] + . Using 4b (0.80 g, 2.97 mmol) and isoquinoline-5-sulfonyl chloride (1.01 g, 4.46 mmol) as starting materials, B1 was synthesized following the same method as A1, yielding 1.10 g of a white solid in 80.29% mp 208.3–211.1 °C. 1 H-NMR (600 MHz, DMSO- d 6) δ 9.54 (s, 1H), 8.72 (s, 1H), 8.54 (dd, J= 8.1, 1.1 Hz, 1H), 8.44 (d, J = 6.1 Hz, 1H), 8.38 (dd, J = 7.4, 1.2 Hz, 1H), 7.91 (t, J = 7.8 Hz,1H), 7.85 – 7.80 (m, 2H), 7.56 – 7.50 (m, 2H), 7.46 (s, 2H), 3.69 (s, 2H), 3.34 (s, 2H), 3.25 (s, 2H), 3.18 – 3.08 (m, 2H). 13 C-NMR (151 MHz, DMSO- d 6) δ168.38, 154.00, 145.36, 138.98, 135.02, 134.74, 131.70, 131.55, 129.30,128.11, 127.14, 126.21, 117.60, 55.38, 45.63. HRMS (ESI): Calcd. forC 20 H 20 N4O5S2[M+Na] + : 483.0767, Found 483.0797 [M+Na] + . Example 19: 4-{[4-(1-methylisoquinoline-5-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B2) The compound in Example 19 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and 1-methylisoquinoline-5-sulfonyl chloride (1.08 g, 4.46 mmol) as starting materials, following the synthesis method of B1. B2 was obtained as a white solid, yielding 1.17 g, with a yield of 82.98%. mp 201.3~204.9℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.66 – 8.61(m, 1H), 8.53 (d, J = 6.2 Hz, 1H), 8.37 (dd, J = 7.4, 1.1 Hz, 1H), 8.31 (d, J= 6.2Hz, 1H), 7.90 – 7.86 (m, 1H), 7.86 – 7.81 (m, 2H), 7.56 – 7.51 (m, 2H), 7.48(s, 2H), 3.68 (s, 2H), 3.33 (s, 2H), 3.25 (s, 2H), 3.16 (s, 2H), 2.99 (s,3H). 13 C-NMR (151 MHz, DMSO- d 6) δ 168.39, 160.12, 145.39, 143.95, 138.97,134.32, 132.93, 132.32, 131.83, 128.10, 127.91, 126.79, 126.22, 116.07,45.62, 42.00, 18.42. HRMS (ESI): Calcd. for C 21 H 22 N4O5S2[MH] - : 473.0959, Found473.0952 [MH] - . Example 20: 4-{[4-(1-chloroisoquinoline-5-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B3) The compound in Example 20 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and 1-chloroisoquinoline-5-sulfonyl chloride (1.17 g, 4.46 mmol) as starting materials, following the synthesis method of B1. B3 was obtained as a white solid, with a yield of 1.20 g and a yield of 81.63%. mp 207.3~210.3℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.71 (dd, J = 8.6,1.1 Hz, 1H), 8.51 (s, 2H), 8.48 (dd, J = 7.5, 1.2 Hz, 1H), 8.02 (dd, J = 8.5, 7.4Hz, 1H), 7.85 – 7.82 (m, 2H), 7.54 – 7.52 (m, 2H), 7.46 (s, 2H), 3.69 (s,2H), 3.27 (s, 3H), 3.17 (s, 3H). 13 C-NMR (151 MHz, DMSO- d6) δ 168.34, 152.04,145.38, 144.02, 138.96, 135.61, 133.96, 132.86, 132.58, 128.87, 128.08,127.32, 126.22, 118.28, 47.06, 42.17. HRMS (ESI): Calcd. for C 20 H 19 ClN4O5S2[M+Na] + : 517.0378, Found 517.0370 [M+Na] + . Example 21: 4-{[4-(1-bromoisoquinoline-5-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B4) The compound in Example 21 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and 1-bromoisoquinoline-5-sulfonyl chloride (1.37 g, 4.46 mmol) as starting materials, following the synthesis method of B1. B4 was obtained as a white solid, with a yield of 1.30 g and a yield of 81.25%. mp 202.3~204.7℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.65 (d, J = 8.5 Hz, 1H), 8.52 (d, J = 6.1 Hz, 1H), 8.50 – 8.46 (m, 2H), 8.02 (t, J = 8.0 Hz, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H), 7.46 (s, 2H), 3.69 (s, 2H), 3.27 (s, 3H), 3.22 – 3.11 (m, 3H). 13 C-NMR (151 MHz, DMSO- d 6) δ 168.33, 146.14,145.38, 144.62, 138.97, 135.60, 134.89, 133.61, 132.88, 129.13, 129.05,128.09, 126.22, 118.46, 47.06, 41.52. HRMS (ESI): Calcd. for C 20 H 19BrN4O5S2[M+Na] + : 560.9872, Found 560.9917 [M+Na] + . Example 22: 4-{[4-(quinoline-5-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B5) The compound in Example 22 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and quinoline-5-sulfonyl chloride (1.01 g, 4.46 mmol) as starting materials, following the synthesis method of B1. B5 was obtained as a white solid, yielding 1.05 g, with a yield of 76.66%. mp 206.9~209.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 9.09 (dd, J = 4.2, 1.8Hz, 1H), 8.56 (dd, J = 8.4, 1.8 Hz, 1H), 8.38 (dd, J = 7.4, 1.5 Hz, 1H), 8.33(dd, J = 8.2, 1.4 Hz, 1H), 7.84 (dd, J = 8.4, 1.9 Hz, 2H), 7.77 (t, J = 7.8 Hz, 1H), 7.72 (dd, J = 8.3, 4.2 Hz, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.47 (s, 2H), 3.67(s, 2H), 3.49 (s, 2H), 3.33 (s, 4H). 13 C-NMR (151 MHz, DMSO- d 6) δ 168.45,151.97, 145.33, 143.74, 139.15, 137.35, 136.41, 134.68, 133.05, 129.26,128.10, 126.26, 126.24, 123.04, 47.64, 42.22. HRMS (ESI): Calcd. forC 20 H 20 N4O5S2[M+Na] + : 483.0767, Found 483.0802 [M+Na] + . Example 23: 4-{[4-(2-methylquinoline-5-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B6) The compound in Example 23 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and 2-methylquinoline-5-sulfonyl chloride (1.08 g, 4.46 mmol) as starting materials, following the synthesis method of B1. B6 was obtained as a white solid, yielding 1.15 g, with a yield of 81.56%. mp 198.3~201.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.42 (d, J = 8.5Hz, 1H), 8.33 (dd, J = 7.4, 1.5 Hz, 1H), 8.25 (dd, J = 8.2, 1.4 Hz, 1H), 7.86 –7.83 (m, 2H), 7.68 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.57 – 7.53 (m, 2H), 7.47 (s, 2H), 3.71 – 3.63 (m, 2H), 3.55 – 3.48 (m, 2H), 3.37 (s, 2H), 3.34 – 3.27 (m, 2H), 2.72 (s, 3H). 13 C-NMR (151 MHz, DMSO- d 6) δ 168.47, 160.65,145.32, 143.31, 139.21, 137.24, 136.03, 134.26, 132.82, 128.08, 127.55,126.24, 125.27, 123.73, 47.73, 42.35, 25.51. HRMS (ESI): Calcd. forC 21 H 22 N4O5S2[M+Na] + : 497.0924, Found 497.0910 [M+Na] + . Example 24: 4-{[4-(3-methylquinoline-5-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B7) The compound in Example 24 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and 3-methylquinoline-5-sulfonyl chloride (1.08 g, 4.46 mmol) as starting materials, following the synthesis method of B1. B7 was obtained as a white solid, yielding 1.18 g, with a yield of 83.69%. mp 197.3~200.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.96 (d, J = 2.2 Hz,1H), 8.31 – 8.30 (m, 1H), 8.29 (dd, J = 7.4, 1.4 Hz, 1H), 8.22 (dd, J = 8.2, 1.4Hz, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.72 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 8.2 Hz,2H), 7.47 (s, 2H), 3.67 (s, 2H), 3.47 (s, 2H), 3.31 (s, 4H), 2.53 (s, 3H). 13 C-NMR (151 MHz, DMSO- d 6) δ 168.44, 153.72, 145.33, 141.95, 139.14, 136.19,135.61, 134.00, 132.49, 132.04, 129.14, 128.11, 126.24, 47.62, 42.20, 18.61.HRMS (ESI): Calcd. for C 21 H 22 N4O5S2[M+Na] + : 497.0924, Found 497.0954 [M+Na] + . Example 25: 4-{[4-(2-chloroquinoline-5-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B8) The compound in Example 25 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and 2-chloroquinoline-5-sulfonyl chloride (1.17 g, 4.46 mmol) as starting materials, following the synthesis method of B1. B8 was obtained as a white solid, yielding 1.15 g, with a yield of 78.23%. mp 197.5~200.0℃.1 H-NMR (600 MHz, DMSO- d 6) δ 8.64 (d, J = 8.7 Hz, 1H), 8.41 (dd, J = 7.4, 1.4 Hz, 1H), 8.39 (dd, J = 8.2, 1.4 Hz, 1H), 7.85 (s,1H), 7.85 – 7.83 (m, 1H), 7.82 (d, J = 1.4 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H),7.57 – 7.53 (m, 2H), 7.47 (s, 2H), 3.68 (s, 2H), 3.52 (s, 3H), 3.36 (s, 3H). 13 C-NMR (151 MHz, DMSO-d6) δ 168.41, 151.25, 145.35, 143.01, 141.16, 139.16,135.81, 134.47, 133.96, 128.05, 126.99, 126.25, 124.24, 122.20, 47.63, 42.25.HRMS (ESI): Calcd. for C 20 H 19 ClN4O5S2[M+Na] + : 517.0378, Found 517.0365 [M+Na] + . Example 26: 4-{[4-(1,3-dichloroisoquinoline-5-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B9) The compound in Example 26 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and 1,3-dichloroisoquinoline-5-sulfonyl chloride (1.17 g, 4.46 mmol) as starting materials, following the synthesis method of B1. B9 was obtained as a white solid, yielding 1.18 g, with a yield of 80.27%. mp 203.8~206.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.70 (dd, J =8.6, 1.2 Hz, 1H), 8.51 (s, 1H), 8.50 (dd, J= 7.5, 1.2 Hz, 1H), 8.04 – 8.00 (t,1H), 7.84 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.46 (s, 2H), 3.71 (s, 2H), 3.35 (s, 2H), 3.25 (s, 2H), 3.14 (s, 2H). 13 C-NMR (151 MHz, DMSO- d 6) δ168.32, 151.85, 145.40, 144.56, 138.93, 136.66, 135.42, 132.81, 132.07,129.21, 128.08, 126.49, 126.23, 117.33, 47.03, 41.50. HRMS (ESI): Calcd. forC 20 H 18 Cl2N4O5S2[M+Na] + : 550.9988 Found 550.9966 [M+Na] + . Example 27: 4-{[4-(2-bromoquinoline-5-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B10) The compound in Example 27 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and 2-bromoquinoline-5-sulfonyl chloride (1.37 g, 4.46 mmol) as starting materials, following the synthesis method of B1. B10 was obtained as a white solid, yielding 1.25 g, with a yield of 78.13%. mp 209.3~212.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.52 (d, J = 8.6 Hz, 1H), 8.40 (dd, J = 7.4, 1.5 Hz, 1H), 8.39 – 8.36 (m, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 7.8 Hz, 1H), 7.56 (d, J= 8.0 Hz, 2H), 7.47 (s, 2H), 3.69 (s, 2H), 3.52 (s, 2H), 3.39 (s, 2H), 3.32 (s, 2H). 13 C-NMR (151 MHz, DMSO- d 6) δ 168.41, 145.35, 143.53, 143.03, 140.54, 139.16, 135.94,134.63, 133.88, 128.36, 128.06, 127.62, 127.07, 126.26, 47.65, 42.27. HRMS(ESI): Calcd. for C 20 H 19 BrN4O5S2[M+Na] + : 560.9872. Found 560.9891 [M+Na] + . Example 28: 4-{[4-(3-bromoquinoline-5-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B11) The compound in Example 28 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and 3-bromoquinoline-5-sulfonyl chloride (1.37 g, 1.00 mmol) as starting materials, following the synthesis method of B1. B11 was obtained as a white solid, with a yield of 1.30 g and a yield of 81.25%. mp 204.7~207.1℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 9.15 (s, 1H), 8.93 (s, 1H), 8.39 (d, J = 7.3 Hz, 1H), 8.29 (d, J = 8.2 Hz, 1H), 7.84 (t, J = 6.8 Hz, 3H), 7.55 (d, J = 8.0 Hz, 2H), 7.47 (s, 2H), 3.66 (s, 2H), 3.46 (s, 2H), 3.34(s, 4H). 13 C-NMR (151 MHz, DMSO- d6) δ 168.41, 152.46, 145.33, 141.86, 139.14,138.71, 136.54, 133.92, 133.42, 130.33, 128.11, 127.59, 126.23, 118.55,47.61, 42.16. HRMS (ESI): Calcd. for C 20 H 19 BrN4O5S2[M+Na] + : 560.9872. Found560.9919 [M+Na] + . Example 29: 4-{[4-(naphthalene-2-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B12) The compound in Example 29 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and naphthalene-2-sulfonyl chloride (1.01 g, 4.46 mmol) as starting materials, following the synthesis method of B1. B12 was obtained as a white solid, yielding 1.10 g, with a yield of 80.29%. mp 196.6~199.4℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.46 – 8.43 (m, 1H),8.22 (d, J = 8.1 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.83– 7.80 (m, 2H), 7.76 (ddd, J = 8.2, 5.7, 1.6 Hz, 2H), 7.72 (ddd, J = 8.1, 6.8,1.3 Hz, 1H), 7.53 – 7.50 (m, 2H), 7.46 (s, 2H), 3.73 (s, 2H), 3.38 (s, 2H), 3.07 (d, J = 62.1 Hz, 4H). 13 C-NMR (151 MHz, DMSO- d6) δ 168.45, 145.31, 138.91,135.03, 132.83, 132.34, 130.01, 129.90, 129.64, 129.30, 128.38, 128.22,128.13, 126.19, 123.28, 46.16, 41.33. HRMS (ESI): Calcd. for C 21 H 21 N3O5S2[M+Na] + :482.0815. Found 482.0812 [M+Na] + . Example 30: 4-{[4-(biphenyl-4-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B13) The compound in Example 30 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and biphenyl-4-sulfonyl chloride (1.13 g, 4.46 mmol) as starting materials, following the synthesis method of B1. B13 was obtained as a white solid, yielding 1.20 g, with a yield of 83.33%. mp 203.3~206.7℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 7.97 (s, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.83 (d, J = 4.9 Hz, 2H), 7.81 (s, 1H), 7.78 (d, J = 1.5Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 7.6 Hz,2H), 7.47 (s, 3H), 3.74 (s, 2H), 3.39 (s, 2H), 3.09 (s, 2H), 3.01 (s, 2H). 13 C-NMR (151 MHz, DMSO- d 6) δ 168.44, 145.40, 138.96, 138.73, 134.31, 129.68,129.20, 128.72, 128.16, 128.13, 127.61, 126.22, 46.15, 41.32. HRMS (ESI):Calcd. for C23 H 23 N3O5S2[M+Na] + : 508.0971, Found 508.0951 [M+Na] + . Example 31: 4-{[4-(pyridine-3-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B14) The compound in Example 31 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and pyridine-3-sulfonyl chloride (0.79 g, 4.46 mmol) as starting materials, following the synthesis method of B1. B14 was obtained as a white solid, yielding 1.00 g, with a yield of 81.97%. mp 196.6~199.5℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.93 (dd, J = 4.9, 1.6 Hz, 1H), 8.91 (d, J = 2.4 Hz, 1H), 8.17 (dt, J = 8.1, 2.0 Hz, 1H), 7.86 (d, J =8.1 Hz, 2H), 7.73 (dd, J = 8.1, 4.8 Hz, 1H), 7.58 – 7.53 (m, 2H), 7.51 (s, 2H), 3.73 (s, 2H), 3.39 (s, 2H), 3.38 (s, 2H), 3.04 (s, 2H). 13 C-NMR (151 MHz, DMSO- d 6) δ 168.40, 154.39, 148.21, 144.38, 138.88, 136.15, 132.37, 128.12, 126.52,125.08, 45.91, 41.43. HRMS (ESI): Calcd. for C 16 H 18 N4O5S2[M+Na] + :433.0611. Found433.0616[M+Na] + . Example 32: 4-{[4-(2-chloropyridine-5-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B15) The compound in Example 32 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and 2-chloropyridine-3-sulfonyl chloride (0.94 g, 4.46 mmol) as starting materials, following the synthesis method of B1. B15 was obtained as a white solid, with a yield of 1.03 g and a recovery rate of 78.03%. mp 204.9~207.3℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.76 (dd, J =4.0, 2.1 Hz, 1H), 8.19 (dd, J = 8.4, 2.6 Hz, 1H), 7.86 (d, 1H), 7.84 (d, J = 8.0Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.47 (s, 2H), 3.73 (s, 2H), 3.37 (s, 2H), 3.14 (s, 2H), 3.06 (s, 2H). 13 C-NMR (151 MHz, DMSO- d 6) δ 168.33, 155.12,149.01, 145.40, 139.45, 138.99, 131.87, 128.09, 126.24, 125.94, 46.78, 41.19.HRMS (ESI): Calcd. for C 16 H 17 ClN4O5S2[M+Na] + :467.0221. Found 467.0236 [M+Na] + . Example 33: 4-{[4-(6-chloro-2-methylpyridine-3-sulfonyl)-1-piperazinyl]carbonyl}benzenesulfonamide (B16) The compound in Example 33 was prepared using the same method as in Example 18, with 4b (0.80 g, 2.97 mmol) and 6-chloro-2-methylpyridine-3-sulfonyl chloride (1.01 g, 4.46 mmol) as starting materials, following the synthesis method of B1. B16 was obtained as a white solid, yielding 1.11 g, with a yield of 81.62%. mp 199.6~202.3℃. 1 H-NMR (600 MHz, DMSO- d 6) δ 8.17(d, J= 8.4 Hz, 1H), 7.88 – 7.85 (m, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.59 (d, J =8.3 Hz, 2H), 7.48 (s, 2H), 3.72 (s, 2H), 3.37 (s, 2H), 3.26 – 3.20 (m, 2H), 3.17 (d, J = 9.4 Hz, 2H), 2.74 (s, 3H). 13 C-NMR (151 MHz, DMSO- d 6) δ 168.38,158.59, 153.19, 145.42, 141.85, 139.02, 131.75, 128.15, 128.12, 126.32,126.26, 122.99, 47.07, 41.52, 24.10. HRMS (ESI): Calcd. for C 17 H 19 ClN4O5S2[M+Na] + :481.0378. Found 481.0414[M+Na] + . Pharmacological studies of the present invention The inhibitory effect of the compound of the general formula obtained in this invention on carbonic anhydrase II was determined by the esterase method; the inhibitory effect of the compound on ROCK II was determined by the ADP-Glo ​​kinase assay kit.

[0023] The above compounds were dissolved in dimethyl sulfoxide to prepare a 20 mM stock solution, which was then diluted with PBS to the target concentration. Fasudil was used as a positive control to test the in vitro enzyme inhibitory activity of the target compounds against ROCK II. Acetazolamide was used as a positive control to test the in vitro enzyme inhibitory activity of the target compounds against CA II. IC50 was calculated based on the inhibition rate. 50 value.

[0024] The formula for calculating the inhibition rate is as follows: % inhibition = (1- sample activity / total activity) 100

[0025] As can be seen from the table above, the ROCK II and CA dual-target compounds of the present invention exhibit clear inhibitory effects on both targets, indicating that they possess good dual-target inhibitory activity; and some compounds of the present invention have more prominent inhibitory activity than positive control drugs.

[0026] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A 4-{[4-(substituted sulfonyl)-1-(high)piperazinyl]carbonyl}benzenesulfonamide compound, characterized in that: The compounds are those shown in formula (1) and their salts and isomers; In formula (1): n = 0 or 1; R1 is selected from H, hydroxyl, unsubstituted or substituted by at least one R2 C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkoxy, C2-6 alkenyloxy, C2-6 alkoxy, unsubstituted or substituted by at least one R3 amino, unsubstituted or substituted by at least one R4 thioamide, amide, unsubstituted or substituted by at least one R5 phenyl, benzyl, pyridine ring, pyrazole ring, pyrrole ring, pyrimidine ring, quinoline ring, isoquinoline ring, imidazole ring, morpholine ring, piperazine ring, pyrazine ring, pyrazine ring, piperidine ring, thiophene ring, pyran ring, indole ring, furan ring, biphenyl, naphthyl; R2 is selected from halogen, hydroxyl, cyano, nitro or amino groups; R3 is selected from C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-6 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C2-6 alkenylcarbonyl or C2-6 alkynylcarbonyl. R4 is selected from C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-6 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C2-6 alkenylcarbonyl or C2-6 alkynylcarbonyl. R5 is selected from H, hydroxyl, hydroxymethyl, mercapto, amino, thioamide, carboxyl, ester, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxy, benzyloxycarbonyl, and C1-6 haloalkyl.

2. The 4-{[4-(substituted sulfonyl)-1-(high)piperazinyl]carbonyl}benzenesulfonamide compound according to claim 1, characterized in that: The compound represented by compound formula (1) and its salts and isomers; In formula (1): n = 0 or 1; R1 is selected from H, hydroxyl, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, amino, thioamide, amide, phenyl, benzyl, pyridine ring, pyrazole ring, pyrrole ring, pyrimidine ring, quinoline ring, isoquinoline ring, imidazole ring, morpholine ring, piperazine ring, pyrazine ring, piperidine ring, thiophene ring, pyran ring, indole ring, furan ring, biphenyl, naphthyl; R5 is selected from H, hydroxyl, hydroxymethyl, mercapto, amino, thioamide, carboxyl, ester, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxy, benzyloxycarbonyl, and C1-6 haloalkyl.

3. The 4-{[4-(substituted sulfonyl)-1-(high)piperazinyl]carbonyl}benzenesulfonamide compound according to claim 2, characterized in that: The compound is the compound shown in formula (1) and its salts and isomers; In formula (1): n = 0 or 1; R1 is selected from phenyl, pyridine, pyrazole, pyrrole, pyrimidine, quinoline, isoquinoline, imidazole, morpholine, piperazine, pyridazine, pyrazine, piperidine, thiophene, pyran, indole, furan, biphenyl, and naphthyl groups that are unsubstituted or have been substituted with at least one R5. R5 is selected from H, hydroxyl, hydroxymethyl, mercapto, amino, thioamide, carboxyl, ester, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxy, benzyloxycarbonyl, and C1-6 haloalkyl.

4. The 4-{[4-(substituted sulfonyl)-1-(high)piperazinyl]carbonyl}benzenesulfonamide compound according to claim 3, characterized in that: The compound is the compound shown in formula (1) and its salts and isomers; In formula (1): n = 0 or 1; R1 is selected from phenyl, biphenyl, naphthyl, pyridine ring, quinoline ring, isoquinoline ring, indole ring, and furan ring that are unsubstituted or have been substituted with at least one R5; R5 is selected from H, hydroxyl, hydroxymethyl, mercapto, amino, thioamide, carboxyl, ester, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxy, benzyloxycarbonyl, and C1-6 haloalkyl.

5. The 4-{[4-(substituted sulfonyl)-1-(high)piperazinyl]carbonyl}benzenesulfonamide compound according to claim 4, characterized in that: The compound is the compound shown in formula (1) and its salts and isomers; In formula (1): R1 is In the formula, R6, R7, R8, R9, R 10 R 11 It may be selected from H, hydroxyl, hydroxymethyl, mercapto, amino, thioamide, carboxyl, ester, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxy, benzyloxycarbonyl, and C1-6 haloalkyl, either the same or different.

6. The 4-{[4-(substituted sulfonyl)-1-(high)piperazinyl]carbonyl}benzenesulfonamide compound according to claim 5, characterized in that: The compound is 。 7. A method for preparing the compound according to claim 1, characterized in that: The reaction formula is Starting with p-sulfonamide benzoic acid, intermediate 2,2- and 1-Boc-periperazine were obtained via chlorination reaction. N -Acylation reaction yields intermediate 3, which is then deprotected by trifluoroacetic acid to obtain intermediate 4. This intermediate is then sulfonated with different sulfonyl chlorides to obtain compounds of general formula (1).

8. A pharmaceutical composition, characterized in that: The composition contains a compound of general formula (1) as claimed in claim 1, and its salts and isomers.

9. An application according to claim 1 or 8, characterized in that: The use of the compound of general formula (1) of claim 1 and its salts, isomers or the composition of claim 8 in the preparation of antiglaucoma drugs.

10. The application according to claim 9, characterized in that: The use of the compound of general formula (1) of claim 1 and its salts, isomers or the composition of claim 8 in the preparation of a drug that inhibits carbonic anhydrase and / or Rho kinase.

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