Arylsulfonamide derivatives, processes for their preparation and use thereof

Abstract

The present application relates to the technical field of medicine, in particular to a kind of aryl sulfonamide derivative and its preparation method and application.The aryl sulfonamide derivative provided by the present application can be combined with androgen receptor (AR) and glucocorticoid receptor (GR) efficiently, show excellent double-target point antagonistic activity, and some compounds can significantly inhibit castration-resistant prostate cancer cell proliferation, with outstanding potential for drug development.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to an arylsulfonamide derivative, its preparation method, and its application. Background Technology

[0002] As a core member of the nuclear receptor superfamily, the androgen receptor (AR)-mediated signaling pathway plays a decisive role in the occurrence and development of prostate cancer. Androgens activate downstream target genes by binding to AR, thereby driving the proliferation and survival of tumor cells. Therefore, androgen deprivation therapy (ADT), which aims to block the androgen-AR signaling axis, has become a basic clinical intervention for prostate cancer.

[0003] However, the vast majority of patients who receive second-generation anti-androgen drugs such as ADT or enzalutamide inevitably develop fatal castration-resistant prostate cancer (CRPC) and develop clinical drug resistance. The resistance mechanisms induced by long-term drug use are very complex, mainly including AR ligand-binding domain mutations leading to antagonist inactivation, overexpression of AR splice variants, and compensatory activation of glucocorticoid receptor (GR).

[0004] In the aforementioned mechanisms, the compensatory role of GR is particularly crucial. GR and AR belong to the same nuclear receptor superfamily and are highly homologous in sequence and spatial structure. When AR signaling is potently inhibited by drugs, GR can replace AR to drive the transcription of tumor proliferation-related genes. This compensatory activation not only counteracts the efficacy of AR antagonists but is also an important driving force for maintaining tumor cell survival and proliferation.

[0005] Therefore, developing dual-target antagonists that can simultaneously target both AR and GR is of great practical significance in overcoming resistance to existing antiandrogen drugs, delaying the progression of CRPC, and prolonging the clinical benefits for patients. Summary of the Invention

[0006] To overcome the above problems, the present invention provides an arylsulfonamide derivative, its preparation method and application.

[0007] To achieve the above technical objectives, the present invention adopts the following technical solution: In a first aspect, the present invention provides an arylsulfonamide derivative having the structural formula shown in formula (I).

[0008] Equation (I); In equation (Ⅰ), R a and R b Independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl groups, substituted or unsubstituted C3-C4 alkyl groups. 10 Cycloalkyl, substituted or unsubstituted C5~C13 aryl, substituted or unsubstituted 4-13 heteroaryl, substituted or unsubstituted C1-C8 acyl, substituted or unsubstituted C6-C 10 Arylformyl, substituted or unsubstituted 4-10 membered heteroarylformyl; Ar represents substituted or unsubstituted aryl or heteroaryl groups.

[0009] In one or more embodiments, R a and R b Substitution refers to substitution by one or more of the following groups: halogen, cyano, nitro, amino, hydroxyl, mercapto, carboxyl, ketone, aldehyde, ester, oxo (=O), C1-C8 alkyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, C1-C8 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, 4-10 membered heteroaryl or 4-8 membered heterocyclic; Ar represents aromatic or fused heterocyclic skeletons such as benzofuranyl, benzopyranoneyl, benzothiopheneyl, indolyl, naphthyl, benzodioxaneyl, tetrahydropyridinylpyrazoloneyl, and xanthineyl.

[0010] Preferably, the arylsulfonamide derivative has the structural formula shown in formulas (II) to (VII).

[0011] Formula (II); In formula (II), R1 is selected from , -CH2CH3 (Et) or -CH3 (Me); R2 is selected from , , , , , , , , , or ;

[0012] Formula (Ⅲ); In equation (Ⅲ), R3 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;

[0013] Formula (Ⅳ); In formula (Ⅳ), R4 is selected from H or -CH3(Me); R5 is selected from , , , , , , , , , , , , , , , , , , , , or ;

[0014] Formula (V); In equation (V), Ar1 is selected from , , , , , , , , , , , , , , , or ; R6 is selected from , , , , , , , , , , , , , , , , , , , , , , , , or ;

[0015] Formula (VI); In equation (VI), Ar2 is selected from , , , , , , , , , , , , , , or ; R7 is selected from , , , , H , , , , , , , , , , , , , , , , or ; Ar3 is selected from , , , , or ;

[0016] Formula (VII); In equation (VII), Ar4 is selected from , , , , , , , , , , , , , , , , or ; R8 is selected from , , , , , , , , , , , , , , , , , , , , , or .

[0017] More preferably, the compound shown in formula (II) includes compounds X1 to X11, and the structural formulas of compounds X1 to X11 are shown below;

[0018] More preferably, the compound shown in formula (Ⅲ) includes compounds X12 to X41, and the structural formulas of compounds X12 to X41 are shown below;

[0019] More preferably, the compound shown in formula (Ⅳ) includes compounds X42~X63, and the structural formulas of compounds X42~X63 are shown below;

[0020] More preferably, the compound shown in formula (V) includes compounds X64 to X107, and the structural formulas of compounds X64 to X107 are shown below;

[0021] More preferably, the compound shown in formula (VI) includes compounds X108 to X135, and the structural formulas of compounds X108 to X135 are shown below;

[0022] More preferably, the compound shown in formula (VII) includes compounds X136 to X158, and the structural formulas of compounds X136 to X158 are shown below;

[0023] In one or more embodiments, the compound represented by formula (I) further includes a pharmaceutically acceptable salt, stereoisomer, isotope label, solvate, polycrystalline material, or prodrug.

[0024] "Pharmaceutically acceptable salts" refers to conventional, non-toxic salts, including inorganic acid salts such as hydrochlorides, hydrobroms, sulfates, phosphates, and nitrates; organic acid salts such as acetates, propionates, oxalates, succinates, lactates, malates, tartrates, citrates, maleates, fumarates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, and ascorbic acid salts; inorganic base salts such as sodium, potassium, calcium, zinc, magnesium, and aluminum salts; and organic base salts such as arginine salts, benzyl benzoate salts, choline salts, diethylamine salts, diolamine salts, glycine salts, lysine salts, meglumine salts, ethanolamine salts, and aminobutanetriol salts.

[0025] A second aspect of the present invention provides a method for preparing the arylsulfonamide derivative described in the first aspect, comprising the following steps: Compound 1 and compound 2 were subjected to a sulfonation reaction to obtain compound 3; Compound 3 and compound 4 were reacted to obtain an arylsulfonamide derivative; The structural formula of compound 1 is shown below: ; The structural formula of compound 2 is shown below: ; The structural formula of compound 3 is shown below: ; The structural formula of compound 4 is shown below: ; In compounds 1 and 3, R a Selected from hydrogen, substituted or unsubstituted C1-C4 alkyl groups, substituted or unsubstituted C3-C4 alkyl groups. 10 Cycloalkyl, substituted or unsubstituted C5~C 13 aryl, substituted or unsubstituted 4-13 heteroaryl, substituted or unsubstituted C1-C8 acyl, substituted or unsubstituted C6-C 10 Arylformyl, substituted or unsubstituted 4-10 membered heteroarylformyl; In compounds 2 and 3, Ar is a substituted or unsubstituted aryl or heteroaryl group; In compound 4, R b Selected from hydrogen, substituted or unsubstituted C1-C4 alkyl groups, substituted or unsubstituted C3-C4 alkyl groups. 10 Cycloalkyl, substituted or unsubstituted C5~C 13 aryl, substituted or unsubstituted 4-13 heteroaryl, substituted or unsubstituted C1-C8 acyl, substituted or unsubstituted C6-C 10 Arylformyl, substituted or unsubstituted 4-10 heteroarylformyl groups.

[0026] In one or more embodiments, R a and R b Substitution refers to substitution by one or more of the following groups: halogen, cyano, nitro, amino, hydroxyl, mercapto, carboxyl, ketone, aldehyde, ester, oxo (=O), C1-C8 alkyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, C1-C8 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 Aryl, 4-10 membered heteroaryl or 4-8 membered heterocyclic; Ar represents aromatic or fused heterocyclic skeletons such as benzofuranyl, benzopyranoneyl, benzothiopheneyl, indolyl, naphthyl, benzodioxaneyl, tetrahydropyridinylpyrazoloneyl, and xanthineyl.

[0027] A third aspect of the present invention provides the use of the arylsulfonamide derivatives described in the first aspect or the arylsulfonamide derivatives prepared by the preparation method described in the second aspect as androgen receptor antagonists and / or glucocorticoid receptor antagonists.

[0028] A fourth aspect of the invention provides the use of the arylsulfonamide derivatives described in the first aspect or prepared by the preparation method described in the second aspect in the preparation of medicaments for preventing, alleviating, treating, or resolving diseases related to androgen receptor and / or glucocorticoid receptor activity.

[0029] In one or more embodiments, the disease is caused by androgen imbalance; preferably, the disease is caused by androgen hyperactivity.

[0030] More preferably, the diseases include prostate cancer, benign prostatic hyperplasia, acne, hirsutism, excessive sebum production, and hair loss; The prostate cancer mentioned is either hormone-sensitive prostate cancer or hormone-resistant prostate cancer; The hormone-resistant prostate cancer is preferably hydroxyflutamide-resistant prostate cancer or castration-resistant prostate cancer with high expression of glucocorticoid receptors. The glucocorticoid receptor-overexpressing, drug-resistant castration-resistant prostate cancer is preferably enzalutamide-resistant or abiraterone-resistant prostate cancer.

[0031] A fifth aspect of the present invention provides a medicament for preventing, alleviating, treating, or resolving diseases related to androgen receptor and / or glucocorticoid receptor activity, comprising the arylsulfonamide derivatives described in the first aspect or the arylsulfonamide derivatives prepared by the preparation method described in the second aspect.

[0032] In one or more embodiments, the disease is caused by androgen imbalance; preferably, the disease is caused by androgen hyperactivity.

[0033] More preferably, the diseases include prostate cancer, benign prostatic hyperplasia, acne, hirsutism, excessive sebum production, and hair loss; The prostate cancer mentioned is either hormone-sensitive prostate cancer or hormone-resistant prostate cancer; The hormone-resistant prostate cancer is preferably hydroxyflutamide-resistant prostate cancer or castration-resistant prostate cancer with high expression of glucocorticoid receptors. The glucocorticoid receptor-overexpressing, drug-resistant castration-resistant prostate cancer is preferably enzalutamide-resistant or abiraterone-resistant prostate cancer.

[0034] In one or more embodiments, the drug further includes pharmaceutically acceptable carriers, excipients, and diluents.

[0035] The non-pharmaceutical active ingredients that may be included, such as carriers, excipients, and diluents, are well known in the art, and those skilled in the art can determine that they meet clinical standards.

[0036] Preferably, the carrier, excipients, and diluents include, but are not limited to, lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil.

[0037] Preferably, the dosage form of the drug is a suspension, emulsion, granules, spray, injection, transdermal absorbent, a dosage form suitable for transfection, tablet, powder, granules or capsule.

[0038] A sixth aspect of the present invention provides a pharmaceutical composition comprising the pharmaceuticals described in the fifth aspect.

[0039] The beneficial effects of this invention are as follows: The aryl sulfonamide derivatives provided by this invention can efficiently bind to androgen receptors (AR) and glucocorticoid receptors (GR), exhibiting excellent dual-target antagonistic activity. Some compounds can significantly inhibit the proliferation of castration-resistant prostate cancer cells, demonstrating outstanding drug potential. Attached Figure Description

[0040] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0041] Figure 1 The preparation process of compound X64; Figure 2 The image shows the 1H NMR spectrum of compound X64. Figure 3 The image shows the carbon NMR spectrum of compound X64. Figure 4 The preparation process of compound X12; Figure 5 The effect of compound X64 on the expression of AR-regulated genes in LNCaP-EnzR cells is shown in Figures A through E, representing AR, prostate-specific antigen (PSA), FK506-binding protein 5 (FKBP5), transmembrane serine protease 2 (TMPRSS2), and ubiquitin-binding enzyme E2C (UBE2C), respectively. Figure 6The inhibitory activity of compound X64 against clinically resistance-associated AR mutants is given; where A-D represent the inhibitory activities of the second-generation antagonist darolutamide (DARO), the second-generation antagonist enzalutamide (ENZ), the first-generation antagonist bicalutamide (BIC), and compound X64 against the F877L mutant, respectively; E-H represent the inhibitory activities of the second-generation antagonist darolutamide (DARO), the second-generation antagonist enzalutamide (ENZ), the first-generation antagonist bicalutamide (BIC), and compound X64 against the F877L / Inhibitory activity against the T878A mutant; I~L represent the inhibitory activities of the second-generation antagonist darolutamide (DARO), the second-generation antagonist enzalutamide (ENZ), the first-generation antagonist bicalutamide (BIC), and compound X64 against the H875Y / T878A mutant, respectively; M~P represent the inhibitory activities of the second-generation antagonist darolutamide (DARO), the second-generation antagonist enzalutamide (ENZ), the first-generation antagonist bicalutamide (BIC), and compound X64 against the W742C mutant, respectively. Figure 7 The study investigated the inhibitory activity of compound X64 on the proliferation of human prostate cancer cells and its anti-drug resistance effect. In this study, A represents the inhibitory effect of X64 and enzalutamide (ENZ) on LNCaP cell colony formation, B represents the quantification of A, C represents the inhibitory effect of X64 and enzalutamide (ENZ) on 22Rv1 (ENZ-resistant) cell colony formation, and D represents the quantification of C. Figure 8 The in vivo antitumor activity of compound X64 in a 22Rv1 cell xenograft model in nude mice is shown in Figure A, where A represents the change in 22Rv1 xenograft volume over time under different administration methods; B represents the quantitative statistics of tumor weight in each group at the experimental endpoint; and C represents the change in body weight of mice in each group during the administration period. Detailed Implementation

[0042] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0043] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0044] Terminology Explanation: C1~C8 refers to having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on.

[0045] "4-10 rings" refers to rings with 4, 5, 6, 7, 8, 9, or 10 ring atoms, and so on.

[0046] C1-C8 alkyl refers to straight-chain or branched alkyl groups having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0047] C2~C6 alkenyl refers to alkenyl groups with 2~6 carbon atoms that are straight or branched, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl or similar groups.

[0048] C2~C6 alkynyl refers to a straight-chain or branched alkynyl group with 2 to 6 carbon atoms, such as ethynyl, propynyl or similar groups.

[0049] C3-C6 cycloalkyl refers to cyclic alkyl groups having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or similar groups.

[0050] C1~C8 alkoxy groups refer to straight-chain or branched alkoxy groups having 1 to 8 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, or similar groups.

[0051] "Halogen": refers to fluorine, chlorine, bromine, or iodine. The term "halogenated" refers to a group substituted with one or more of the same or different halogen atoms, such as trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl, or similar groups.

[0052] "alkyl": refers to a group formed by removing one hydrogen atom from an alkane molecule.

[0053] "alkylene": refers to a group formed by removing two hydrogen atoms from an alkane molecule.

[0054] "Aryl": refers to a hydrocarbon moiety containing one or more aromatic rings. For example, the term C6~C 10Aryl refers to an aromatic cyclic group with 6 to 10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl and naphthyl.

[0055] "Heteroaryl": refers to a heteroaromatic system containing 1 to 4 heteroatoms, including nitrogen, oxygen, and sulfur. For example, 4-8-membered heteroaryl refers to a heteroaromatic system containing 4 to 8 ring atoms, and 4-10-membered heteroaryl refers to a heteroaromatic system containing 4 to 10 ring atoms, including but not limited to pyrroleyl, furanyl, thiopheneyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridinyl, pyranyl, pyridazinyl, benzimidazolyl, triazolyl, indoleyl, etc.

[0056] "Heterocyclic group": refers to a cyclic group containing at least one cyclic heteroatom (e.g., N, O, or S). Typically, the heterocycle contains no more than 4 nitrogen atoms, no more than 2 oxygen atoms, and / or no more than 2 sulfur atoms. Unless otherwise specified, the heterocyclic group can be a saturated, partially unsaturated, or fully unsaturated ring. Exemplary heterocyclic groups include, but are not limited to, morpholino, hexahydroisoindolyl, tetrahydrofuranyl, and tetrahydropyrroleyl.

[0057] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0058] Example 1 Figure 1 For the preparation process of compound X64, refer to... Figure 1 Synthesize X64.

[0059] (1) Under 0℃ ice bath conditions, 10 mmol of p-aminophenol was dissolved in 75 mL of a dichloromethane-pyridine mixture (volume ratio 1:2). After stirring and dissolving, 13 mmol of compound 5 was slowly added in three batches. After the addition was complete, the mixture was naturally heated to room temperature and stirred for 4 h. After the reaction was complete, the solvent was removed by thin-layer chromatography (TLC). The residue was dissolved in ethyl acetate, the organic phase was washed with dilute sulfuric acid, and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate-n-hexane (volume ratio 1:6) to obtain compound 6. The product did not require purification and was used directly in the next reaction.

[0060] (2) At room temperature, 10.0 mmol of compound 6 was dissolved in 200 mL of dichloromethane. After stirring and dissolving, a NaIO4 / SiO2 loading reagent containing 15 mmol of sodium periodate was added and the mixture was stirred at room temperature for 2 h. After the reaction was complete as monitored by TLC, the solid was removed by filtration, the filter cake was washed with dichloromethane, the filtrates were combined and concentrated under reduced pressure, and the crude product was recrystallized from ethyl acetate to obtain the orange-red product compound 7.

[0061] (3) Under anhydrous conditions at room temperature, 10.0 mmol of compound 7 and 11.0 mmol of compound 8 were dissolved in 250 mL of anhydrous 1,4-dioxane, and 2% molar amount of sodium methoxide was added. The mixture was stirred at 25 °C for 2 h. TLC monitoring showed that the raw materials were completely consumed and the system solution was completely decolorized. 100 mL of water was added and stirred for 1 h. The mixture was filtered, the filter cake was washed with water 3 times, and recrystallized from anhydrous ethanol to obtain the white solid product compound 9.

[0062] (4) Add a stir bar to a dry 50 mL reaction flask, and add 1.0 mmol of compound 9, 2.0 mmol of compound 10 and 0.1 mmol of DMAP in sequence. After purging with nitrogen three times, add 2.0 mL of anhydrous dichloromethane, stir to dissolve, and then add 3.5 mmol of Et3N. Stir the reaction under nitrogen protection at 25 °C for 22 h. The reaction is monitored by TLC to ensure complete reaction. Dilute the reaction solution with 8 mL of dichloromethane, wash with 10 mL each of 1.0 M hydrochloric acid, saturated sodium bicarbonate solution and saturated saline solution in sequence, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (eluent: 30% ethyl acetate / n-hexane) to obtain white solid product X64.

[0063] Figure 2 The image shows the 1H NMR spectrum of compound X64. Figure 3 This is the carbon NMR spectrum of compound X64.

[0064] Example 2 Figure 4 For the preparation process of compound X12, refer to... Figure 4 Synthesize X12.

[0065] (1) 10.0 mmol of 1-methylindoline-2-one, 20.0 mmol of acetone, 50 mg of p-toluenesulfonic acid and 50 mL of toluene were added to a dry reaction flask equipped with a water separator. The mixture was heated under reflux for 4 h. After the reaction was completed by TLC monitoring, the solvent was removed by vacuum distillation. The crude product was recrystallized from ethanol-water to obtain a yellow solid compound 11. 10.0 mmol of compound 11 was dissolved in 50 mL of methanol. Using 10% palladium on carbon as a catalyst, the mixture was evacuated and replaced with hydrogen three times. The mixture was stirred at room temperature and under 1 atm of hydrogen for 6 h. After the reaction was completed by TLC monitoring, the palladium on carbon was removed by filtration. The filtrate was concentrated under vacuum and the crude product was recrystallized to obtain a white solid product compound 12.

[0066] (2) Under nitrogen protection and ice bath conditions of 0~5℃, 10.0 mmol of compound 12 was dissolved in 40 mL of anhydrous dichloromethane, and 40.0 mmol of compound 13 was slowly added dropwise. After the addition was completed, the mixture was stirred and reacted for 3 h. The mixture was then quenched with ice water, separated, washed, dried and concentrated. The crude product was recrystallized from n-hexane-dichloromethane to obtain the white solid target product compound 14.

[0067] (3) Under 0℃ ice bath conditions, 10 mmol of 4-isopropylaniline was dissolved in 75 mL of dichloromethane-pyridine (volume ratio 1:2). After stirring and dissolving, 13 mmol of compound 14 was slowly added in three batches. After the addition was completed, the mixture was naturally heated to room temperature and stirred for 4 h. After the reaction was complete by TLC monitoring, the solvent was removed by vacuum concentration. The residue was dissolved in ethyl acetate, the organic phase was washed with dilute sulfuric acid, and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried with anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude product was recrystallized from ethyl acetate-n-hexane (volume ratio 1:6) to obtain compound X12.

[0068] 1 H NMR (400 MHz, Chloroform- d ) δ 8.70 (s, 1H), 7.85 (m, 1H), 7.75 (d,J = 7.5 Hz, 1H), 7.68 (m, 1H), 7.32 (d, J = 7.5 Hz, 2H), 6.90 (d, J = 7.5 Hz,2H), 3.24 (s, 3H), 2.87 (m, 1H), 2.07 (s, 6H), 1.20 (d, J = 6.8 Hz, 6H). 13 CNMR (101 MHz, Chloroform- d ) δ 168.00, 147.80, 138.40, 135.20, 134.90, 128.60,128.50, 126.90, 122.90, 119.40, 119.30, 109.30, 33.20, 30.40, 23.30, 21.00.ESI-MS: m / z 385.15 [M+H] + C 21 H 24 N2O3S (384.15). Example 3 Preparation of compound X65: The preparation process of X65 is the same as in Example 1, except that compound 5 in step (1) is replaced with benzenesulfonyl chloride.

[0069] 1 H NMR (400 MHz, Chloroform- d ) 8.69 (d, J = 1.5 Hz, 1H), 8.31 (d, J =7.5 Hz, 2H), 8.11 (d, J = 7.5 Hz, 2H), 7.83 (m, 2H), 7.70 (d, J = 7.5 Hz,1H), 7.63 (m, 1H), 7.59 (m, 2H), 7.44 (dd, J = 7.5, 1.5 Hz, 1H), 2.85 (s,3H), 2.49 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 194.2, 164.8, 152.3,151.3, 150.4, 145.3, 140.3, 139.7, 132.9, 131.9, 129.6, 129.6, 129.0, 129.0,127.3, 127.3, 124.0, 124.0, 124.0, 117.5, 113.5, 111.7, 29.0, 14.4. ESI-MS: m / z 479.09 [M+H] + C 24 H 18 N2O7S (478.08). Example 4 Preparation of compound X66: The preparation process of X66 is the same as in Example 1, except that compound 5 in step (1) is replaced with p-chlorobenzenesulfonyl chloride. In step (4), 4-nitrobenzoyl chloride is replaced with 3-nitrobenzoyl chloride.

[0070] 1 H NMR (600 MHz, DMSO- d 6) δ 8.72 (m, 1H), 8.69 (d, J = 1.5 Hz, 1H), 8.46 (m, 1H), 8.34 (m, 1H), 7.85 (t, J = 7.5 Hz, 1H), 7.74 (d, J = 7.5 Hz,2H), 7.70 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 7.5 Hz, 2H), 7.44 (dd, J = 7.5,1.5 Hz, 1H), 2.85 (s, 3H), 2.49 (s, 3H).13 C NMR (151 MHz, DMSO- d 6) δ 194.2,164.8, 152.3, 150.4, 148.0, 145.3, 137.8, 137.5, 135.1, 133.6, 132.9, 129.7,129.1, 129.1, 128.7, 128.7, 127.3, 124.0, 123.3, 117.5, 113.5, 111.7, 29.0,14.4. ESI-MS: m / z 514.04 [M+H] + C 24 H 17 ClN2O7S (512.04). Example 5 Preparation of compound X109: The preparation process of X109 is the same as in Example 1, except that: in step (1), p-aminophenol is replaced with 6,7,8,9-tetrahydrodibenzo[b,d]furan-2-amine, and compound 5 is replaced with 4-methyl-3-nitrobenzenesulfonyl chloride; in step (4), 4-nitrobenzenesulfonyl chloride is replaced with benzoyl chloride.

[0071] 1 H NMR (600 MHz, DMSO-d6) δ 8.69 (d, J = 1.5 Hz, 1H), 8.68 (d, J = 1.5 Hz, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.95 (m, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.67 (d, J =7.5 Hz, 1H), 7.62 (m, 1H), 7.54 (m, 2H), 7.44 (dd, J = 7.5, 1.5 Hz, 1H), 2.81(t, J = 7.1 Hz, 4H), 2.54 (s, 3H), 1.87 (m, 4H). 13C NMR (151 MHz, DMSO-d6) δ164.8, 156.6, 149.6, 148.3, 137.6, 136.6, 134.4, 134.2, 132.9, 132.1, 130.2,130.1, 128.8, 128.8, 127.5, 127.5, 123.0, 117.5, 113.5, 112.5, 111.7, 23.9,23.8, 22.8, 22.6, 18.3. ESI-MS: m / z 491.12 [M+H] + C 26 H 22 N2O6S (490.12). Example 6 Preparation of compound X87: The preparation process of X87 is the same as in Example 1, except that: in step (1), compound 5 is replaced with benzenesulfonyl chloride, and in step (4), 4-nitrobenzoyl chloride is replaced with benzoyl chloride.

[0072] 1 H NMR (600 MHz, DMSO-d6) δ 8.69 (m, 1H), 7.95 (m, 2H), 7.83 (m, 2H), 7.70 (m, 1H), 7.63 (m, 1H), 7.62 (m, 1H), 7.59 (m, 2H), 7.54 (m, 2H), 7.44(m, 1H), 2.85 (s, 3H), 2.49 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 194.20,164.80, 152.30, 150.40, 145.30, 139.70, 134.20, 132.90, 132.10, 131.90,129.00, 128.80, 127.50, 127.30, 124.00, 117.50, 113.50, 111.70, 29.00, 14.40.ESI-MS: m / z 434.10 [M+H] + C 24 H 19 NO5S (433.10). Example 7 Preparation of compound X47: The preparation process of X47 is the same as in Example 2, except that in step (2), compound 12 is replaced with compound 16. In step (3), 4-isopropylaniline is replaced with 6,7,8,9-tetrahydrodibenzo[b,d]furan-2-amine.

[0073] Preparation of compound 16:

[0074] Under nitrogen protection, 10 mmol of compound 15, 20 mmol of potassium carbonate, and 15 mL of anhydrous DMF were added to a dry three-necked flask and dissolved, and the mixture was stirred until homogeneous. 15 mmol of iodomethane was slowly added dropwise, and the reaction was stirred at room temperature for 4 h. TLC monitoring was performed until the reactants had completely reacted. The reaction was quenched by pouring ice water into the reaction solution, and a solid precipitated. The solid was filtered, washed with ice water, and the crude product was recrystallized from ethanol-water (2:1) to give a white solid product, compound 16.

[0075] Characterization of X47: 1 H NMR (600 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.94 (m, 1H), 8.24 (m, 1H), 7.84 (m, 1H), 7.76 (m, 1H), 7.73 (m, 1H), 7.46 (m, 1H), 7.45 (m, 1H), 6.59(m, 1H), 3.89 (s, 3H), 2.81 (m, 4H), 1.87 (m, 4H). 13 C NMR (151 MHz, DMSO-d6) δ167.00, 156.60, 142.70, 141.40, 137.20, 136.60, 134.60, 130.70, 130.00,128.20, 128.00, 126.30, 125.80, 117.80, 112.50, 112.30, 112.20, 108.20,37.60, 23.90, 23.80, 22.80, 22.60. ESI-MS: m / z 433.12 [M+H] + C 24 H 20 N2O4S(432.11). Example 8 Preparation of compound X44: The preparation process of X44 is the same as in Example 2, except that in step (2), compound 12 is replaced with benzo[cd]indole-2(1H)-one. In step (3), 4-isopropylaniline is replaced with 4-aminobiphenyl.

[0076] Characterization of X44: 1 H NMR (600 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.86 (s, 1H), 8.94 (m, 1H), 8.09 (m, 1H), 7.76 (m, 1H), 7.75 (m, 2H), 7.73 (m, 1H), 7.49 (m, 2H), 7.46(m, 1H), 7.44 (m, 2H), 7.41 (m, 1H), 6.99 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ169.60, 140.80, 137.20, 136.60, 134.60, 133.80, 130.00, 129.20, 128.70,128.20, 128.00, 127.90, 127.60, 126.30, 125.80, 117.80, 116.80. ESI-MS: m / z401.09 [M+H] + C 23 H 16 N2O3S (400.09). Example 9 Preparation of compound X45: The preparation process of X45 is the same as in Example 2, except that in step (2), compound 12 is replaced with benzo[cd]indole-2(1H)-one. In step (3), 4-isopropylaniline is replaced with compound 19.

[0077] Preparation of compound 19:

[0078] Under nitrogen protection, 10 mmol of compound 17 and 20 mL of glacial acetic acid were added to a dry reaction flask. After cooling to 0-5°C, 12 mmol of fuming nitric acid was slowly added dropwise. The mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC until complete. The reaction solution was crystallized by ice water, filtered, washed with water, and recrystallized from ethanol to obtain compound 18. 10 mmol of compound 18, 0.1 g of 10% Pd / C and 30 mL of methanol were placed in an autoclave and stirred at room temperature and 1 atm of hydrogen for 6 h. After the reaction was monitored by TLC until complete, palladium on carbon was removed by filtration. The filtrate was concentrated under reduced pressure, and the crude product was recrystallized to obtain the white solid product compound 19.

[0079] Characteristic of X45: 1H NMR (600 MHz, DMSO-d6) δ 10.72 (s,1H), 9.86 (s,1H), 8.94 (m,1H), 8.09 (m,1H), 7.84 (m,1H), 7.76 (m,1H), 7.73 (m,1H), 7.46 (m,1H), 7.45 (m,1H), 6.59 (m,1H), 3.90 (s,3H), 2.68 (s,3H). 13 C NMR (151 MHz, DMSO-d6) δ 169.60,159.40, 147.00, 145.70, 141.40, 137.20, 136.60, 134.60, 130.00, 128.20,128.00, 127.30, 126.30, 125.80, 117.80, 112.30, 112.20, 110.00, 108.20,51.50, 14.30. ESI-MS: m / z 437.08 [M+H] + C 22 H 16 N2O6S (436.07). Example 10 Preparation of compound X1: The preparation process of X1 is the same as in Example 2, except that in step (2), compound 12 is replaced with cyclopropyl(3,3-dimethylindoline-1-yl) methyl ketone. In step (3), 4-isopropylaniline is replaced with N,N-diethyl-3-methyl-1,4-phenylenediamine.

[0080] Characterization of X1: 1 H NMR (600 MHz, DMSO-d6) δ 9.67 (s,1H), 7.90 (m,1H), 7.55 (m,1H), 7.41 (m,1H), 6.65 (m,1H), 6.57 (m,1H), 6.55 (m,1H), 3.59 (m,2H), 3.40 (m,4H),2.12 (s,3H), 1.41 (m,1H), 1.40 (s,6H), 1.12 (d,6H), 0.78, 0.53 (m,4H). 13C NMR(151 MHz, DMSO-d6) δ 180.70, 143.50, 141.50, 140.80, 134.90, 129.90, 126.30,125.60, 122.90, 121.50, 117.10, 114.80, 110.60, 60.30, 47.10, 41.90, 26.20,17.30, 12.90, 12.70, 7.90. ESI-MS: m / z 456.23 [M+H] + C 25 H 33 N3O3S (455.22). Example 11 Preparation of compound X140: The preparation process of X140 is the same as in Example 2, except that in step (2), compound 12 is replaced with 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline-5-one. In step (3), 4-isopropylaniline is replaced with 3,3-diphenylprop-1-amine.

[0081] Characterization of X140: 1 H NMR (600 MHz, DMSO-d6) δ 7.69 (m, 2H), 7.29 (m, 4H), 7.22 (m, 2H), 7.18 (m, 4H), 7.26 (br s, 1H), 4.06 (m, 2H), 3.96 (m, 1H), 3.38 (m, 2H), 2.86(m, 2H), 2.79 (m, 2H), 2.49 (m, 2H), 2.17 (m, 2H), 1.51 (m, 2H). 13 C NMR (151MHz, DMSO-d6) δ 169.80, 145.10, 143.20, 135.30, 131.30, 129.70, 129.20,128.20, 126.20, 123.20, 122.90, 44.60, 40.60, 39.80, 33.60, 27.30, 27.10,26.90, 22.30. ESI-MS: m / z 461.19 [M+H] + C 27 H 28 N2O3S (460.18). Example 12 Preparation of compound X43: The preparation process of X43 is the same as in Example 2, except that in step (2), compound 12 is replaced with benzo[cd]indole-2(1H)-one. In step (3), 4-isopropylaniline is replaced with methyl p-aminobenzoate.

[0082] Characterization of X43: 1 H NMR (600 MHz, DMSO-d6) δ 10.72 (s,1H), 9.86 (s,1H), 8.94 (m,1H), 8.09 (m,1H), 7.76 (m,1H), 7.73 (m,1H), 7.63 (m,2H), 7.46 (m,1H), 7.09 (m,2H),3.89 (s,3H). 13 C NMR (151 MHz, DMSO-d6) δ 169.6, 165.9, 142.0, 137.2, 136.6,134.6, 130.7, 130.0, 128.2, 128.0, 126.3, 125.8, 123.6, 117.8, 116.2, 51.5.ESI-MS: m / z 383.07 [M+H] + C 19 H 14 N2O5S (382.06). Example 13 Preparation of compound X46: The preparation process of X46 is the same as in Example 2, except that in step (2), compound 12 is replaced with benzo[cd]indol-2(1H)-one. In step (3), 4-isopropylaniline is replaced with 2,4-dimethylaniline.

[0083] Characterization of X46: 1 H NMR (600 MHz, DMSO-d6) δ 10.72 (s,1H), 9.67 (s,1H), 8.94 (m,1H), 8.09 (m,1H), 7.76 (m,1H), 7.73 (m,1H), 7.46 (m,1H), 6.94 (m,1H), 6.76 (m,1H), 6.70 (m,1H), 2.24 (s,3H), 2.12 (s,3H). 13C NMR (151 MHz, DMSO-d6) δ 169.6,137.8, 137.2, 136.6, 134.6, 133.1, 131.7, 130.0, 128.9, 128.2, 128.2, 128.0,126.8, 126.3, 125.8, 117.8, 116.1, 21.6, 17.6. ESI-MS: m / z 353.09 [M+H] + C 19 H 16 N2O3S (352.09). Example 14 Preparation of compound X147: The preparation process of X147 is the same as in Example 2, except that in step (2), compound 12 is replaced with N-phenylpropionamide. In step (3), 6-amino-1-propionyl-1,2,3,4-tetrahydroquinoline is replaced with 2,4-dimethylaniline.

[0084] Characterization of X46: 1 H NMR (600 MHz, DMSO-d6) δ 10.13 (s,1H), 9.86 (s,1H), 7.72 (m,2H),7.69 (m,2H), 6.96 (m,2H), 6.75 (m,1H), 4.06 (t,2H), 2.79 (t,2H), 2.35 (m,2H), 2.32 (m,2H), 1.51 (m,2H), 1.12 (d,3H), 1.04 (d,3H). 13 C NMR (151 MHz, DMSO-d6)δ 173.7, 172.4, 141.7, 135.3, 133.4, 130.3, 129.4, 129.3, 122.5, 118.0,115.3, 113.8, 44.6, 30.6, 28.3, 27.0, 22.3, 10.3, 10.0. ESI-MS: m / z 416.16 [M+H] + C 21 H 25 N3O4S (415.16). Example 15 Preparation of compound X67: The preparation process of X67 is the same as that in Example 1, except that in step (1), compound 5 is replaced with 4-ethylbenzenesulfonyl chloride, and in step (4), compound 10 is replaced with 3-nitrobenzoyl chloride.

[0085] Characterization of X67: 1 H NMR (600 MHz, DMSO-d6) δ 8.72 (m, 1H), 8.69 (d, J = 1.5 Hz, 1H), 8.46(m, 1H), 8.34 (m, 1H), 7.85 (t, J = 7.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 2H), 7.70(d, J = 7.5 Hz, 1H), 7.45 (d, J = 7.5 Hz, 2H), 7.44 (dd, J = 7.5, 1.5 Hz, 1H), 2.85(s, 3H), 2.72 (q, J = 8.0 Hz, 2H), 2.49 (s, 3H), 1.18 (t, J = 8.0 Hz, 3H). 13 C NMR(151 MHz, DMSO-d6) δ 194.2, 164.8, 152.3, 150.4, 148.0, 147.5, 145.3, 136.9,135.1, 133.6, 132.9, 129.7, 128.3, 128.3, 128.0, 128.0, 127.3, 124.0, 123.3,117.5, 113.5, 111.7, 29.0, 28.2, 14.5, 14.4. ESI-MS: m / z 507.12 [M+H] + C 26 H 22 N2O7S (506.11). Example 16 Preparation of compound X69: The preparation process of X69 is the same as that in Example 1, except that in step (4), compound 10 is replaced with 3-nitrobenzoyl chloride.

[0086] Characterization of X69: 1H NMR (600 MHz, DMSO-d6) δ 8.72 (m, 1H), 8.69 (d, J = 1.5 Hz, 1H), 8.46(m, 1H), 8.34 (m, 1H), 7.85 (t, J = 7.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.5 Hz, 2H), 7.44 (dd, J = 7.5, 1.5 Hz, 1H), 7.38 (d, J = 7.5 Hz, 2H), 2.85(s, 3H), 2.49 (s, 3H), 2.43 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 194.2, 164.8,152.3, 150.4, 148.0, 145.3, 137.6, 136.7, 135.1, 133.6, 132.9, 129.7, 129.3,129.3, 128.3, 128.3, 127.3, 124.0, 123.3, 117.5, 113.5, 111.7, 29.0, 21.3,14.4. ESI-MS: m / z 493.10 [M+H] + C 25 H 20 N2O7S (492.10). Example 17 Preparation of compound X72: The preparation process of X72 is the same as that in Example 1, except that in step (1), compound 5 is replaced with 4-methyl-3-nitrobenzenesulfonyl chloride, and in step (4), compound 10 is replaced with benzoyl chloride.

[0087] Characterization of X72: 1 H NMR (600 MHz, DMSO-d6) δ 8.69 (d, J = 1.5 Hz, 1H), 8.68 (d, J = 1.5 Hz, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.95 (m, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.67 (d,J =7.5 Hz, 1H), 7.62 (m, 1H), 7.54 (m, 2H), 7.44 (dd, J = 7.5, 1.5 Hz, 1H), 2.85(s, 3H), 2.54 (s, 3H), 2.49 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 194.2, 164.8,152.3, 150.4, 149.6, 145.3, 137.6, 136.6, 134.4, 134.2, 132.9, 132.1, 130.2,128.8, 128.8, 127.5, 127.5, 124.0, 123.0, 117.5, 113.5, 111.7, 29.0, 18.3,14.4. ESI-MS: m / z 493.10 [M+H] + C 25 H 20 N2O7S (492.10). Example 18 Preparation of compound X76: The preparation process of X76 is the same as that in Example 1, except that in step (1), compound 5 is replaced with 3-nitrobenzenesulfonyl chloride, and in step (4), compound 10 is replaced with 4-methylbenzoyl chloride.

[0088] Characterization of X76: 1 H NMR (600 MHz, DMSO-d6) δ 8.69 (d, J = 1.5 Hz, 1H), 8.54 (m, 1H), 8.43(m, 1H), 8.22 (m, 1H), 7.97 (t, J = 7.5 Hz, 1H), 7.84 (d, J = 7.5 Hz, 2H), 7.70(d, J = 7.5 Hz, 1H), 7.44 (dd, J = 7.5, 1.5 Hz, 1H), 7.32 (d, J = 7.5 Hz, 2H), 2.85(s, 3H), 2.49 (s, 3H), 2.41 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 194.2, 164.8,152.3, 150.4, 148.2, 145.3, 141.8, 140.6, 133.4, 132.9, 131.2, 129.9, 129.1,129.1, 127.4, 127.4, 127.1, 124.0, 123.1, 117.5, 113.5, 111.7, 29.0, 21.3,14.4. ESI-MS: m / z 493.10 [M+H] + C 25 H 20 N2O7S (492.10). Example 19 Preparation of compound X76: The preparation process of X78 is the same as that in Example 18, except that in step (4), 4-methylbenzoyl chloride is replaced with benzoyl chloride.

[0089] Characterization of X78: 1 H NMR (600 MHz, DMSO-d6) δ 9.30 (m, 1H), 8.69 (d, J = 1.5 Hz, 1H), 8.01(m, 1H), 7.95 (m, 2H), 7.83 (m, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.62 (m, 1H),7.60 (t, J = 7.5 Hz, 1H), 7.54 (m, 2H), 7.44 (dd, J = 7.5, 1.5 Hz, 1H), 2.85 (s, 3H), 2.49 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 194.2, 164.8, 152.3, 150.4,148.2, 145.3, 140.6, 134.2, 133.4, 132.9, 132.1, 129.9, 128.8, 128.8, 127.5,127.5, 127.1, 124.0, 123.1, 117.5, 113.5, 111.7, 29.0, 14.4. ESI-MS: m / z479.09 [M+H] + C 24 H 18N2O7S (478.08). Example 20 Preparation of compound X82: The preparation process of X82 is the same as that in Example 1, except that in step (4), compound 10 is replaced with cinnamoyl chloride.

[0090] Characterization of X82: 1 H NMR (600 MHz, DMSO-d6) δ 8.69 (d, J=1.5 Hz, 1H), 7.70 (d, J=7.5 Hz, 1H), 7.68 (m, 2H), 7.62 (m, 2H), 7.44 (dd, J=7.5, 1.5 Hz, 1H), 7.38 (m, 5H), 7.37 (d, J=15.1 Hz, 1H), 7.33 (m, 1H), 6.89 (d, J=15.1 Hz, 1H), 2.85 (s, 3H), 2.49 (s, 3H), 2.43 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 194.2, 164.2, 152.3,150.4, 145.3, 141.7, 137.6, 136.7, 135.2, 132.9, 129.3, 128.6, 128.5, 128.3,127.9, 124.0, 118.8, 117.5, 113.5, 111.7, 29.0, 21.3, 14.4. ESI-MS: m / z474.13 [M+H] + C 27 H 23 NO5S (473.13). Example 21 Preparation of compound X83: The preparation process of X83 is the same as that in Example 1, except that in step (1), compound 5 is replaced with naphthalene-2-sulfonyl chloride.

[0091] Characterization of X83: 1 H NMR (600 MHz, DMSO-d6) δ 8.80 (m, 1H), 8.69 (d, J = 1.5 Hz, 1H), 8.31(d, J = 7.5 Hz, 2H), 8.30 (m, 1H), 8.13 (d, J= 7.5 Hz, 1H), 8.11 (d, J = 7.5 Hz,2H), 8.02 (m, 1H), 8.01 (m, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.59 (m, 2H), 7.44(dd, J = 7.5, 1.5 Hz, 1H), 2.85 (s, 3H), 2.49 (s, 3H). 13 C NMR (151 MHz, DMSO-d6)δ 194.2, 164.8, 152.3, 151.3, 150.4, 145.3, 140.3, 137.0, 136.7, 134.1,132.9, 129.6, 129.6, 129.4, 128.1, 128.1, 126.2, 126.2, 126.0, 124.0, 124.0,124.0, 123.4, 117.5, 113.5, 111.7, 29.0, 14.4. ESI-MS: m / z 529.10 [M+H] + C 28 H 20 N2O7S (528.10). Example 22 Preparation of compound X84: The preparation process of X84 is the same as that in Example 18, except that in step (4), 4-methylbenzoyl chloride is replaced with phenyl chloroformate.

[0092] Characterization of x84: 1 H NMR (600 MHz, DMSO-d6) δ 8.69 (d, J=1.5 Hz, 1H), 8.54 (dd, J=7.5,1.5 Hz, 1H), 8.43 (m, 1H), 8.22 (dd, J=7.5, 1.5 Hz, 1H), 7.97 (t, J=7.5 Hz,1H), 7.70 (d, J=7.5 Hz, 1H), 7.49 (m, 2H), 7.44 (dd, J=7.5, 1.5 Hz, 1H), 7.32(m, 2H), 7.31 (m, 1H), 2.85 (s, 3H), 2.49 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ194.2, 153.1, 152.3, 151.3, 150.4, 148.2, 145.3, 140.6, 133.4, 132.9, 129.9,129.1, 127.1, 125.5, 124.0, 123.1, 121.6, 117.5, 113.5, 111.7, 29.0, 14.4.ESI-MS: m / z 495.08 [M+H] + C 24 H 18 N2O8S (494.08). Example 23 Preparation of compound X111: The preparation process of X111 is the same as that in Example 1, except that in step (1), compound 5 is replaced with 3-nitrobenzenesulfonyl chloride and p-aminophenol is replaced with compound 19; in step (4), 4-methylbenzoyl chloride is replaced with butyryl chloride.

[0093] Characterization of x84: 1 H NMR (600 MHz, DMSO-d6) δ 8.69 (d, J = 1.5 Hz, 1H), 8.54 (m, 1H), 8.43(m, 1H), 8.22 (m, 1H), 7.97 (t, J = 7.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.44(dd, J = 7.5, 1.5 Hz, 1H), 3.90 (s, 3H), 2.68 (s, 3H), 2.39 (t, J = 7.1 Hz, 2H),1.74 (m, 2H), 0.96 (d, J = 8.0 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 170.3,159.4, 151.3, 148.2, 147.0, 140.6, 135.5, 133.4, 129.9, 127.1, 126.7, 123.1,117.5, 113.5, 111.7, 110.0, 51.5, 34.7, 19.0, 14.3, 13.1. ESI-MS: m / z 461.10[M+H] +C 21 H 20 N2O8S (460.09). Example 24 Preparation of compound X86: The preparation process of X86 is the same as that in Example 1, except that in step (1), compound 5 is replaced with 4-tert-butylbenzenesulfonyl chloride.

[0094] Characterization of x86: 1 H NMR (600 MHz, DMSO-d6) δ 8.69 (d, J = 1.5 Hz, 1H), 8.31 (d, J = 7.5 Hz, 2H), 8.11 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 7.5 Hz, 2H), 7.56 (d, J = 7.5 Hz, 2H), 7.44 (dd, J = 7.5, 1.5 Hz, 1H), 2.85 (s, 3H), 2.49 (s,3H), 1.33 (s, 9H). 13 C NMR (151 MHz, DMSO-d6) δ 194.2, 164.8, 154.5, 152.3,151.3, 150.4, 145.3, 140.3, 136.6, 132.9, 129.6, 128.0, 125.3, 124.0, 117.5,113.5, 111.7, 34.2, 31.3, 29.0, 14.4. ESI-MS: m / z 535.15 [M+H] + C 28 H 26 N2O7S(534.15). Example 25 Preparation of compound X68: The preparation process of X68 is the same as that in Example 1, except that in step (1), compound 5 is replaced with benzenesulfonyl chloride; in step (4), compound 10 is replaced with 3-nitrobenzoyl chloride.

[0095] Characterization of X68: 1H NMR (600 MHz, DMSO-d6) δ 8.72 (m, 1H), 8.69 (d, J = 1.5 Hz, 1H), 8.46(m, 1H), 8.34 (m, 1H), 7.85 (t, J = 7.5 Hz, 1H), 7.83 (d, J = 7.5 Hz, 2H), 7.70(d, J = 7.5 Hz, 1H), 7.63 (m, 1H), 7.59 (m, 2H), 7.44 (dd, J = 7.5, 1.5 Hz, 1H), 2.85 (s, 3H), 2.49 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 194.2, 164.8, 152.3,150.4, 148.0, 145.3, 139.7, 135.1, 133.6, 132.9, 131.9, 129.7, 129.0, 127.3,124.0, 123.3, 117.5, 113.5, 111.7, 29.0, 14.4. ESI-MS: m / z 479.09 [M+H] + C 24 H 18 N2O7S (478.08). Example 26 Preparation of compound X71: The preparation process of X71 is the same as that in Example 1, except that in step (4), compound 10 is replaced with benzoyl chloride.

[0096] Characterization of X71: 1 H NMR (600 MHz, DMSO-d6) δ 8.69 (d, J = 1.5 Hz, 1H), 7.95 (m, 2H), 7.70(d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.5 Hz, 2H), 7.62 (m, 1H), 7.54 (m, 2H), 7.44(dd, J = 7.5, 1.5 Hz, 1H), 7.38 (d, J= 7.5 Hz, 2H), 2.85 (s, 3H), 2.49 (s, 3H), 2.43 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 194.2, 164.8, 152.3, 150.4, 145.3,137.6, 136.7, 134.2, 132.9, 132.1, 129.3, 128.8, 128.3, 127.5, 124.0, 117.5,113.5, 111.7, 29.0, 21.3, 14.4. ESI-MS: m / z 462.13 [M+H] + C 26 H 23 NO5S (461.13). Example 27 Preparation of compound X73: The preparation process of X73 is the same as that in Example 1, except that in step (1), compound 5 is replaced with 2-methyl-5-nitrobenzenesulfonyl chloride; and in step (4), compound 10 is replaced with benzoyl chloride.

[0097] Characterization of X73: 1 H NMR (600 MHz, DMSO-d6) δ 8.69 (d, J = 1.5 Hz, 1H), 8.68 (m, 1H), 8.47(d, J = 7.5 Hz, 1H), 7.95 (m, 2H), 7.70 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.5 Hz,1H), 7.62 (m, 1H), 7.54 (m, 2H), 7.44 (dd, J = 7.5, 1.5 Hz, 1H), 2.85 (s, 3H), 2.64 (s, 3H), 2.49 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 194.2, 164.8, 152.3,150.4, 145.3, 145.2, 142.7, 139.8, 134.2, 132.9, 132.1, 130.2, 128.8, 128.8,127.5, 127.5, 127.0, 124.0, 123.0, 117.5, 113.5, 111.7, 29.0, 22.0, 14.4.ESI-MS: m / z 493.10 [M+H] + C 25 H 20 N2O7S (492.10). Example 28 Preparation of compound X79: The preparation process of X79 is the same as that in Example 1, except that in step (1), compound 5 is replaced with 3-nitrobenzenesulfonyl chloride; and in step (4), compound 10 is replaced with 4-chlorobenzoyl chloride.

[0098] Characterization of X79: 1 H NMR (600 MHz, DMSO-d6) δ 8.69 (d, J = 1.5 Hz, 1H), 8.54 (m, 1H), 8.43(m, 1H), 8.22 (m, 1H), 7.97 (t, J = 7.5 Hz, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.70(d, J = 7.5 Hz, 1H), 7.55 (d, J = 7.5 Hz, 2H), 7.44 (dd, J = 7.5, 1.5 Hz, 1H), 2.85(s, 3H), 2.49 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 194.2, 164.8, 152.3, 150.4,148.2, 145.3, 140.6, 137.7, 133.4, 132.9, 132.3, 130.1, 129.9, 128.9, 127.1,124.0, 123.1, 117.5, 113.5, 111.7, 29.0, 14.4. ESI-MS: m / z 514.04 [M+H] +C 24 H 17 ClN2O7S (512.04). Example 29 Preparation of compound X80: The preparation process of X80 is the same as that in Example 29, except that in step (4), 4-chlorobenzoyl chloride is replaced with 2-chlorobenzoyl chloride.

[0099] Characteristic of X80: 1 H NMR (600 MHz, DMSO-d6) δ 8.69 (d, J = 1.5 Hz, 1H), 8.54 (m, 1H), 8.43(m, 1H), 8.22 (m, 1H), 7.97 (t, J = 7.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.44(dd, J = 7.5, 1.5 Hz, 1H), 7.43 (m, 4H), 2.85 (s, 3H), 2.49 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ 194.2, 164.8, 152.3, 150.4, 148.2, 145.3, 140.6, 134.6,133.5, 133.4, 132.9, 132.3, 130.1, 129.9, 128.9, 127.1, 126.9, 124.0, 123.1,117.5, 113.5, 111.7, 29.0, 14.4. ESI-MS: m / z 514.04 [M+H] + C 24 H 17 ClN2O7S(512.04). Experimental Example 1 (1) Evaluation experiment on the ability of androgen receptor transcriptional repression Prostate cancer cells infused with the ARR2PB promoter express the androgen receptor-regulated green fluorescent protein EGFP. Inhibiting androgen receptor transcription with compounds reduces the protein's fluorescence intensity. LNCaP-ARR2PB-EGFP cells were first cultured in androgen-free complete medium for 3-5 days until the background fluorescence value decreased to a low level. Then, they were inoculated at 3.5 × 10⁻⁶ cells / year. 4Cells were seeded at a density of 10 cells / well in 96-well plates. After stable cell adhesion, dihydrotestosterone (DHT) and compounds of different concentration gradients were administered. After incubation for 72 hours, the fluorescence intensity near 530 nm was detected using a multi-mode microplate reader under excitation light at 485 nm, and the half-inhibitory concentration (IC50) of the compounds antagonizing androgen receptors was quantitatively calculated. 50 Enzalutamide (ENZ), a positive control, was used as a reference. Results for some compounds are shown in Tables 1-6. The IC50 values ​​of some compounds antagonizing androgen receptors are... 50 The results are shown in Table 7.

[0100] (2) Evaluation experiment on the transcriptional repression capacity of glucocorticoid receptors HeLa cells stably transfected with pGL4-MMTV-hygro (HeLa-MMTV) were used. MMTV-HeLa cells were then introduced at a rate of 1×10⁻⁶. 4 Each sample was seeded onto a 96-well white plate. Different concentrations of the test compound were added in the presence of 100 nM dexamethasone (DEX). After 24 h of incubation, the luciferase activity of fireflies was measured using the One-Lumi™ firefly luciferase assay kit. The IC50 of the compound antagonizing glucocorticoid receptor was then quantitatively calculated. 50 Mifepristone (MIF) was used as a positive control. Results for some compounds are shown in Tables 1-6. The IC50 of some compounds antagonizing glucocorticoid receptors is... 50 The results are shown in Table 7.

[0101] Experiment Example 2 (1) The MTT assay was used to detect the inhibitory activity of the compound on the proliferation of castration-resistant prostate cancer cell line (22Rv1 cell line). Detection method: Succinate dehydrogenase in the mitochondria of live cells can reduce exogenous MTT to water-insoluble blue-purple formazan crystals. Measuring the absorbance of formazan can quantitatively reflect the number of live cells. Human prostate cancer cells in the logarithmic growth phase (22Rv1) were selected. After trypsin digestion, centrifugation, and discarding the supernatant, the cells were resuspended in complete culture medium and counted. After adjusting the cell concentration with culture medium, they were then cultured at 3 × 10⁻⁶ cells / mL. 3The sample was seeded at a density of 90 μL per well in a 96-well plate, with a zeroing well and a control well. The plate was placed in a humidified, 37°C, 5% CO2 incubator. After 24 h of incubation, 10 μL of culture medium containing the test compound was added, with enzalutamide (ENZ) as a positive control. The final concentrations of the test compounds were 50, 16.667, 5.556, 1.852, 0.617, 0.206, 0.069, and 0.023 μM, respectively, in triplicate. The plates were incubated for another 5 days. 10 μL of MTT solution (5 mg / mL) was added to each well, and the plates were incubated for 3–5 h until crystals formed. 100 μL of triplet solution was added, and the plates were incubated overnight to completely dissolve the formazan crystals. The OD values ​​were measured at 570 nm using a microplate reader. The results for some compounds are shown in Table 8.

[0102] (2) Detection of the effect of the compound on the expression of AR regulatory genes in ENZ-resistant LNCaP-EnzR cells by quantitative real-time PCR (qPCR). Detection method: Select LNCaP in the logarithmic growth phase EnzR cells were seeded and cultured. After cell adhesion, the test compound X64 and the positive control drug enzalutamide (ENZ) were added at a final concentration of 10 μM, respectively. A DMSO blank control group was also set up. After culture, total RNA was extracted from the cells using the Trizol method and reverse transcribed into cDNA. Using GAPDH as an internal control, the mRNA expression levels of AR, PSA, FKBP5, TMPRSS2, and UBE2C genes were detected by qPCR. Results of some compounds are shown below. Figure 5 .

[0103] Table 1. AR / GR transcriptional repression activities of the compounds shown in formula (II)

[0104] Formula (II);

[0105] Table 2 shows the AR / GR transcriptional repression activities of the compounds represented by formula (III).

[0106] Formula (Ⅲ);

[0107] Table 3 shows the AR / GR transcriptional repression activities of the compounds represented by formula (Ⅳ).

[0108] Formula (Ⅳ);

[0109] Table 4 shows the AR / GR transcriptional repressive activities of the compounds represented by formula (V).

[0110] Formula (V);

[0111] Table 5 shows the AR / GR transcriptional repression activities of the compounds represented by formula (VI).

[0112] Formula (VI);

[0113] Table 6 shows the AR / GR transcriptional repressive activities of the compounds represented by formula (VII).

[0114] Formula (VII);

[0115] Table 7. AR / GR bioactivity test results of some compounds.

[0116] Table 8 shows the results of the anti-castration resistance prostate cancer activity tests for some compounds.

[0117] Experimental Example 3 Detecting the inhibitory activity of compounds against clinically drug-resistant AR mutants: Detection Principle: Amino acid mutations in the AR ligand binding pocket lead to abnormal activation of the AR signaling pathway by AR antagonists or nonspecific ligands, thereby promoting tumor progression. The T878A mutation is associated with resistance to the first-generation anti-androgen drug hydroxyfluramide and can promote the growth of prostate cancer cells. The W742C mutation mediates the agonist effect of bicalutamide. The F877L mutation is found in the plasma DNA of patients with CRPC treated with enzalutamide / apalutamide. In addition, the H875Y / T878A double mutation can synergistically expand the androgen receptor ligand binding pocket and remodel the H12 activation conformation, not only causing strong resistance to first-generation anti-androgen drugs such as hydroxyfluramide and bicalutamide and converting them into agonists, but also significantly weakening the inhibitory activity of second-generation antagonists such as enzalutamide and apalutamide, and even inducing their agonist effects. Based on this, this invention uses a dual-luciferase reporter gene system to detect the effects of compounds on drug-resistant AR mutants (containing AR... F877L AR F877L / T878A AR W742C and AR H875Y / T878A The inhibitory effect of mutants.

[0118] Detection method: HEK293T cells were cultured at a concentration of 1 × 10⁻⁶. 4 Cells were seeded per well in 96-well white plates. After 24 h of cell adhesion, 50 ng hAR was added to each well. F877L hAR F877L / T878A hAR H875Y / T878A and hAR W742C Mutant plasmid, 20 ng pGL4-ARR2PB-Luc plasmid, and 5 ng Renilla plasmid, 0.25 μL transfection reagent, and 25 μL serum-free medium were used. After transfection for 24 hours, different concentrations of the test compound were added and incubated for 24 hours with or without DHT. Luciferase activity was then measured according to the instructions of the dual-luciferase reporter gene assay kit.

[0119] Test results: such as Figure 6 As shown, the first-generation AR antagonist bicalutamide (BIC) exhibits agonistic activity against the W742C mutant, while the second-generation antagonist enzalutamide (ENZ) completely antagonizes the W742C mutant, but shows clear transcriptional agonistic activity against F877L and F877L / T878A, and partial agonistic activity against the H875Y / T878A mutant. In contrast, the compound X64 of this invention shows dose-dependent antagonistic effects against F877L, F877L / T878A, H875Y / T878A, and the W742C mutant, indicating that the compound of this invention can antagonize the activity of representative mutant AR induced by long-term clinical use of first- and second-generation AR antagonists.

[0120] Experiment Example 4 The colony-forming inhibitory activity and anti-drug resistance effect of compound X64 on human prostate cancer cells (LNCaP, 22Rv1) were investigated. Detection principle: Individual tumor cells can proliferate indefinitely in vitro and form visible cell colonies (clones). Clonal formation ability directly reflects cell proliferation viability, tumorigenic potential, and drug sensitivity. By comparing the changes in clonality after treatment with enzalutamide and X64, the inhibitory effect of X64 on the proliferation of prostate cancer cells (especially drug-resistant 22Rv1 cells) was clarified.

[0121] Assay method: Logarithmic growth phase LNCaP cells or 22Rv1 cells were seeded at a density of 1000 cells / well in 6-well cell culture plates and cultured continuously at 37℃, 5% CO2 for approximately 14 days, with fresh medium replaced every 3 days during the culture period. After the cells formed visible clones, the medium in the wells was discarded, and methanol was added for fixation at room temperature for 30 minutes. After fixation, the cells were washed twice with PBS buffer, and crystal violet staining solution was added for staining at room temperature for 20 minutes. After staining, the cells were washed three times with PBS buffer to remove excess dye, and after drying, the number of cell clones in each well was counted and the relative colony formation rate was calculated to evaluate the inhibitory activity of the test compound on tumor cell proliferation.

[0122] Test results: such as Figure 7 As shown, compound X64 significantly inhibits the colony-forming ability of prostate cancer cells. In AR-positive LNCaP cells, the inhibitory effect of X64 on cell colony formation was clearly dose-dependent, with the number of cell colonies decreasing significantly with increasing drug concentration. In 22Rv1 cells, compared with the solvent control group and the enzalutamide treatment group, X64 also significantly reduced the number of cell colonies, indicating that X64 can effectively inhibit the proliferation of castration-resistant prostate cancer cells and has the potential to overcome enzalutamide resistance.

[0123] Experimental Example 5 The in vivo activity of compound X64 against castration-resistant prostate cancer (22Rv1 cell xenograft tumor model in nude mice) was investigated: Detection principle: 22Rv1 cells are castration-resistant prostate cancer cells that highly express AR and its splice variant AR. V7, accompanied by GR activation, exhibits a typical clinical anti-androgen resistance phenotype. A human prostate cancer xenograft model was established in nude mice with T-lymphocyte immunodeficiency by subcutaneous seeding of 22Rv1 cells. The effects of the compound on tumor volume, weight, and plasma PSA levels in mice were observed to evaluate its in vivo antitumor activity and safety.

[0124] Detection method: Six-week-old male Balb / c nude mice were selected. 22Rv1 cells were resuspended in 100 μL PBS and mixed with 100 μL Matrigel. The mixture was then subcutaneously injected into the right axilla of the mice. Tumor volume was measured every 2 days and calculated according to the formula (width). 2 Calculate tumor volume using (×length / 2). When the average tumor volume exceeds 100 mm... 3Mice were randomly divided into three groups: a solvent control group, a compound X64 group (50 mg / kg, administered by gavage), and a compound X64 group (30 mg / kg, administered by intraperitoneal injection). Administered once daily, and body weight was monitored during the experiment to assess toxicity. All test compounds were dissolved in 0.5% sodium carboxymethyl cellulose (CMC-Na) solution. On the day treatment ended, mice were sacrificed, tumor tissue was removed, and weighed.

[0125] Test results: such as Figure 8 As shown, compared with the control group, both the 30 mg / kg intraperitoneal injection group and the 50 mg / kg gavage group significantly inhibited the growth of 22Rv1 tumors, indicating that X64 has a clear anti-tumor activity in vivo. Meanwhile, the body weight of the nude mice in both groups did not change significantly compared with the control group, suggesting good tolerability and safety.

[0126] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. An arylsulfonamide derivative, characterized in that, Its structural formula is shown in equation (Ⅰ). Equation (I); In equation (Ⅰ), R a and R b Independently selected from hydrogen, substituted or unsubstituted C1-C4 alkyl groups, substituted or unsubstituted C3-C4 alkyl groups. 10 Cycloalkyl, substituted or unsubstituted C5~C 13 aryl, substituted or unsubstituted 4-13 heteroaryl, substituted or unsubstituted C1-C8 acyl, substituted or unsubstituted C6-C 10 Arylformyl, substituted or unsubstituted 4-10 membered heteroarylformyl; Ar represents substituted or unsubstituted aryl or heteroaryl groups.

2. The arylsulfonamide derivative as described in claim 1, characterized in that, The compound represented by formula (I) also includes its pharmaceutically acceptable salt, stereoisomer, isotope label, solvate, polycrystalline or prodrug; Alternatively, the arylsulfonamide derivative has the structural formula shown in formulas (II) to (VII). Formula (II); In formula (II), R1 is selected from , -CH2CH3 (Et) or -CH3 (Me); R2 is selected from , , , , , , , , , or ; Formula (Ⅲ); In equation (Ⅲ), R3 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Formula (Ⅳ); In formula (Ⅳ), R4 is selected from H or -CH3(Me); R5 is selected from , , , , , , , , , , , , , , , , , , , , or ; Formula (V); In equation (V), Ar1 is selected from , , , , , , , , , , , , , , , or ; R6 is selected from , , , , , , , , , , , , , , , , , , , , , , , , or ; Formula (VI); In equation (VI), Ar2 is selected from , , , , , , , , , , , , , , or ; R7 is selected from , , , , H , , , , , , , , , , , , , , , , or ; Ar3 is selected from , , , , or ; Formula (VII); In equation (VII), Ar4 is selected from , , , , , , , , , , , , , , , , or ; R8 is selected from , , , , , , , , , , , , , , , , , , , , , or .

3. The arylsulfonamide derivative as described in claim 2, characterized in that, The compounds shown in formula (II) include compounds X1 to X11, and the structural formulas of compounds X1 to X11 are shown below; More preferably, the compound shown in formula (Ⅲ) includes compounds X12 to X41, and the structural formulas of compounds X12 to X41 are shown below; More preferably, the compound shown in formula (Ⅳ) includes compounds X42~X63, and the structural formulas of compounds X42~X63 are shown below; More preferably, the compound shown in formula (V) includes compounds X64 to X107, and the structural formulas of compounds X64 to X107 are shown below; More preferably, the compound shown in formula (VI) includes compounds X108 to X135, and the structural formulas of compounds X108 to X135 are shown below; More preferably, the compound shown in formula (VII) includes compounds X136 to X158, and the structural formulas of compounds X136 to X158 are shown below; 。 4. The method for preparing the arylsulfonamide derivative according to any one of claims 1 to 3, characterized in that, Includes the following steps: Compound 1 and compound 2 were subjected to a sulfonation reaction to obtain compound 3; Compound 3 and compound 4 were reacted to obtain an arylsulfonamide derivative; The structural formula of compound 1 is shown below: ； The structural formula of compound 2 is shown below: ； The structural formula of compound 3 is shown below: ； The structural formula of compound 4 is shown below: ； In compounds 1 and 3, R a Selected from hydrogen, substituted or unsubstituted C1-C4 alkyl groups, substituted or unsubstituted C3-C4 alkyl groups. 10 Cycloalkyl, substituted or unsubstituted C5~C 13 aryl, substituted or unsubstituted 4-13 heteroaryl, substituted or unsubstituted C1-C8 acyl, substituted or unsubstituted C6-C 10 Arylformyl, substituted or unsubstituted 4-10 membered heteroarylformyl; In compounds 2 and 3, Ar is a substituted or unsubstituted aryl or heteroaryl group; In compound 4, R b Selected from hydrogen, substituted or unsubstituted C1-C4 alkyl groups, substituted or unsubstituted C3-C4 alkyl groups. 10 Cycloalkyl, substituted or unsubstituted C5~C 13 aryl, substituted or unsubstituted 4-13 heteroaryl, substituted or unsubstituted C1-C8 acyl, substituted or unsubstituted C6-C 10 Arylformyl, substituted or unsubstituted 4-10 heteroarylformyl groups.

5. The use of the arylsulfonamide derivative according to any one of claims 1 to 3 or the arylsulfonamide derivative prepared by the preparation method according to claim 4 as an androgen receptor antagonist and / or glucocorticoid receptor antagonist.

6. The use of the arylsulfonamide derivative according to any one of claims 1 to 3 or the arylsulfonamide derivative prepared by the preparation method according to claim 4 in the preparation of a medicament for the prevention, mitigation, treatment or remission of diseases related to androgen receptor and / or glucocorticoid receptor activity.

7. The application as described in claim 6, characterized in that, The disease is caused by androgen imbalance; preferably, the disease is caused by androgen hyperactivity.

8. The application as described in claim 7, characterized in that, The diseases mentioned include prostate cancer, benign prostatic hyperplasia, acne, hirsutism, excessive sebum production, and hair loss; The prostate cancer mentioned is either hormone-sensitive prostate cancer or hormone-resistant prostate cancer; The hormone-resistant prostate cancer is preferably hydroxyflutamide-resistant prostate cancer or castration-resistant prostate cancer with high expression of glucocorticoid receptors. The glucocorticoid receptor-overexpressing, drug-resistant castration-resistant prostate cancer is preferably enzalutamide-resistant or abiraterone-resistant prostate cancer.

9. A medicament for preventing, alleviating, treating, or resolving diseases related to androgen receptor and / or glucocorticoid receptor activity, characterized in that, Includes the arylsulfonamide derivatives according to any one of claims 1 to 3 or the arylsulfonamide derivatives prepared by the preparation method according to claim 4.

10. A drug combination, characterized in that, Includes the drug as described in claim 9.

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