Urea derivative containing aryl sulfonamide structure as well as preparation method and application of urea derivative

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a urea derivative containing an aryl sulfonamide structure as well as a preparation method and application of the urea derivative. The urea derivative provided by the invention has a typical urea structure and an aryl sulfonamide structure as primary pharmacophores of sEH, molecular docking shows that the urea structure can be combined with a key catalytic triad of sEH protein, and the aryl sulfonamide structure as a hydrophilic fragment contributes to generating polar interaction with a receptor. Therefore, the urea derivative containing the aryl sulfonamide structure provided by the invention has high inhibitory activity on human source sEH (HsEH) and mouse source sEH (MsEH), has small side effects, and can be used as an sEH inhibitor for preparing drugs for treating soluble epoxide enzyme mediated diseases.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a urea derivative containing an aromatic sulfonamide structure, and a preparation method and application thereof. Background Art

[0002] Epoxide hydrolase is a widely distributed enzyme responsible for the rapid hydrolysis of epoxides to the corresponding vicinal diols (Arch. Toxicol, 2014, 88 (11): 2013-2032). In mammals, soluble epoxide hydrolase (sEH) is an α / β hydrolase fold protein expressed in the cytoplasm and sometimes in peroxisomes, including liver, kidney, lung, heart, brain, spleen, adrenal glands and intestines (Prog Lipid Res, 2005, 44 (1): 1-51). sEH is present in all vertebrates except mammals, but only mammalian sEH has phosphatase activity.

[0003] Mammalian sEH consists of two 62.5 kDa monomers and is a bifunctional enzyme with a 25 kDa N-terminal phosphatase region and a 35 kDa C-terminal hydrolase domain (Annu. Rev Pharmacol. Toxicol, 2005, 45: 311-333.). The C-terminal hydrolase catalyzes the hydrolysis of epoxy fatty acids (EpFA), such as epoxy eicosatrienoic acid (EET) metabolized from arachidonic acid (AA) to the corresponding diol. The hydrolase catalytic pocket of the C-terminal hydrolase consists of two tyrosine residues (Tyr381 and Tyr465), which interact with the oxygen atom of the epoxide through two hydrogen bonds. The nucleophilic carboxylic acid Asp333 in the catalytic triad Asp333-Asp495-His523 is located on the opposite side of Tyr381 and Tyr465, and is directed activated by His523 and Asp495 to attack the epoxide carbon skeleton and form an ester bond with the opened epoxide, which is subsequently hydrolyzed to form the corresponding diol.

[0004] Pain is a complex signal transduction process that originates from the damage of harmful substances and the release of inflammatory mediators, such as cytokines, ions, bradykinins, prostaglandins and leukotrienes, which directly act on pain receptors and drive action potentials to produce a sense of pain (Neuron, 2007, 55(3): 353-364). Although many methods can relieve pain, most of these methods have dose-dependent or restrictive side effects. Therefore, we need new therapies to treat pain. Inflammatory pain is caused by biological or chemical inflammation. Inhibiting sEH activity to relieve inflammatory pain stems from research on the anti-inflammatory effects of sEH inhibitors. In a study of a lipopolysaccharide-induced sepsis model, it was found that inhibition of sEH not only altered the levels of epoxyeicosatrienoic acid (EET) and diol metabolites, but also altered the levels of several other metabolites in the cyclooxygenase (COX) and lipoxygenase (LOX) metabolic pathways of the arachidonic acid cascade (Proc Natl Acad Sci USA, 2005, 102(28):9772-9777). Notably, inhibition of sEH activity with small molecules reduced the levels of prostaglandin 2 (PGE2), an inflammatory mediator and pain-inducing substance. This finding is groundbreaking because it demonstrates that stabilizing endogenous bioactive lipids is a new strategy to limit inflammation. Because previous studies have found that sEH inhibitors have the effect of inhibiting cyclooxygenase 2 (COX-2), the ability of sEH inhibitors to synergize with COX-2 selective inhibitors nonsteroidal anti-inflammatory drugs (NSAIDs) was first studied in an inflammatory pain model (Proc Natl Acad Sci USA, 2006, 103 (37): 13646-13651). The results showed that sEH inhibitors and NSAIDs jointly reduced the levels of PGE2 and COX-2 expression in mice and increased the thermal withdrawal latency. It is worth noting that these improvements occurred without a significant change in the ratio of prostacyclin to thromboxane. The adverse side effect of COX-2 selective inhibitors NSAIDs inducing thrombosis is suspected to be caused by changes in the steady-state balance of COX metabolites (N Engl J Med, 2004, 351: 1709-1711). In subsequent studies, sEH inhibitors were given alone for testing to clarify whether sEH inhibitors can resist hyperalgesia. Inceoglu et al. (Life Sciences, 2006, 79(24): 2311-2319) found that local administration of two different sEH inhibitors can effectively increase the heat withdrawal latency and pain threshold of the lipopolysaccharide (LPS)-induced rat inflammatory pain model. The study also revealed that EpFA metabolites can resist hyperalgesia by increasing the heat withdrawal latency for LPS pain. It can be inferred that inhibiting sEH activity may be an effective method for treating inflammatory pain.

[0005] In 2011, the official academic journal of IASP, PAIN, published a new definition of neuropathic pain (NPP): pain caused directly by damage or disease of the somatic sensory nervous system, which can be secondary to a variety of diseases or injuries, such as stroke, diabetes, etc. The preliminary study on the effect of sEH inhibitors in neuropathy aims to compare the relationship between COX levels and inflammatory pain in pain models. Inceoglu et al. (Proceedings of the National Academy of Sciences of the United States of America, 2008, 105(48):18901-18906) found that sEH inhibition can block diabetic neuropathy in a chronic pain model, so it is proposed as a negative control experimental model. This is exciting because most NSAIDs that block COX have little effect on neuropathic pain (European Journal of Pharmacology, 2013, 700(1-3):93-101). Inceoglu (Proc Natl Acad Sci USA, 2012, 109 (28): 11390-11395) et al. explored the effect of sEH inhibitors on diabetic neuropathy in preclinical models, revealing that sEH inhibitors improve mechanical pain thresholds in a dose-dependent manner, and that sEH inhibitors are superior to standard treatment with gabapentin. This anti-allodynia is unrelated to changes in glucose tolerance, insulin tolerance, and glucose-stimulated insulin secretion. Wagner et al. (Behavioural Brain Research, 2017, 326: 69-76) further studied and demonstrated the effect of sEH inhibitors in a congenital Akita mouse model of type I diabetes. In a study using Akita mice as a model, it was found that sEH inhibitors were effective against diabetic neuropathy in mice, and that sEH activity was associated with the severity of the disease. Guedes A et al. (Equine Veterinary Journal, 2017, 49(3): 345-351) found in a study on the treatment of severe equine laminitis that sEH inhibitors were more effective than previous standard treatments, and sEH inhibitors continued to be successful as a treatment for this disease. It can be inferred that sEH inhibitors may be one of the effective strategies for treating neuropathic pain.

[0006] Given the importance of sEH inhibitors and EpFA in the occurrence and development of inflammation and pain, as well as their protective effects on multiple organs such as the heart, kidneys, and brain, inhibiting sEH activity can increase and stabilize the content of EpFA in the body, such as EETs, thereby exerting analgesic, anti-inflammatory, and protective effects on multiple organs. However, the inhibitory activity of existing sEH inhibitors is insufficient. Summary of the invention

[0007] The object of the present invention is to provide a urea derivative containing an aromatic sulfonamide structure, a preparation method and an application thereof. The urea derivative containing an aromatic sulfonamide structure provided by the present invention has high inhibitory activity against human sEH (HsEH) and mouse sEH (MsEH).

[0008] In order to achieve the above object, the present invention provides the following technical solutions:

[0009] The present invention provides a urea derivative containing an aromatic sulfonamide structure, the structure of which is shown in Formula A or Formula B:

[0010]

[0011] In formula A or formula B, R1 is independently alkyl, substituted alkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heterocyclic group or substituted heterocyclic group;

[0012] R2 is independently -H, alkyl, substituted alkyl, alkoxy or substituted alkoxy;

[0013] Z is independently -NH-, -O- or -S-;

[0014] n is independently 0, 1, 2 or 3.

[0015] Preferably, the alkyl group in R1 includes a straight-chain alkyl group, an adamantyl group or a branched-chain alkyl group; the substituted alkyl group includes a substituted straight-chain alkyl group, a substituted adamantyl group or a substituted branched-chain alkyl group; the heterocyclic group includes pyridine, pyrimidine, pyran, pyrazole, piperidine, thiazole or thiophene; the substituted heterocyclic group includes substituted pyridine, substituted pyrimidine, substituted pyran, substituted pyrazole, substituted piperidine, substituted thiazole or substituted thiophene.

[0016] Preferably, the substituents of the substituted alkyl in R1 independently include halogen groups, hydroxyl groups, amino groups, cyano groups, nitro groups, trifluoromethyl groups, trifluoromethoxy groups, methylamino groups, dimethylamino groups, alkyl groups, aromatic groups, heterocyclic groups, heteroaryl groups, -OR, -SR, -NRR', -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -SO2R, -CONRR', -SO2NRR', -OCOR, -NRCOR' or -NRNRR'; the OR, -SR, -NRR', -C(O)R, -CO2 In R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -SO2R, -CONRR', -SO2NRR', -OCOR, -NRCOR' and -NRNRR', R or R' is independently an alkyl group; the type of the substituent of the substituted phenyl group described in R1 is the same as the type of the substituent of the substituted alkyl group described in R1; the type of the substituent of the substituted naphthyl group described in R1 is the same as the type of the substituent of the substituted alkyl group described in R1; the type of the substituent of the substituted heterocyclic group described in R1 is the same as the type of the substituent of the substituted alkyl group described in R1.

[0017] Preferably, the alkyl group in R2 is a C1-C6 alkyl group; the substituted alkyl group is a substituted C1-C6 alkyl group; the alkoxy group is a C1-C6 alkoxy group; and the substituted alkoxy group is a substituted C1-C6 alkoxy group.

[0018] Preferably, the substituents of the substituted alkyl group in R2 include halogen groups, hydroxyl groups, amino groups, methylamino groups, dimethylamino groups or alkyl groups; the types of substituents of the substituted alkoxy group in R2 are the same as the types of substituents of the substituted alkyl group in R2.

[0019] Preferably, the urea derivatives containing an aromatic sulfonamide structure include N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)cyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3,5-difluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide, 4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, 4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide -methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide,4r)-4-(3-(4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chlorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(2-chloro-4-nitrophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en -1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(1,2,3,5,6,7-hexahydro-s-indol-4-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(3,4- Dioxo-2-(((1r,4r)-4-(3-(p-tolyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-benzhydrylureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluorobenzyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)benzyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl )-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chlorobenzyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethyl)benzyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, 3-(3-chloro-4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(3,4-dioxo-2-((4-(3-(p-tolyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide 1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, ,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chlorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(2-chloro-4-nitrophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1 r,4r)-4-(3-(3-chloro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(1,2,3,5,6,7-hexahydro-s-indole -4-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, 1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(p-tolyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-( -1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3,5-difluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide 1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, 1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(4-(3-(3-chloro-4-methylphenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide,4-dioxo-2-(4-(3-(4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(4-(3-(4-fluoro-3- (trifluoromethyl)phenyl)ureidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(4-(3-(4-chloro-3-fluorophenyl)ureidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethyl)phenyl)ureidin-1-yl) piperidin-1-yl)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, 1-en-1-yl)-1-phenylmethanesulfonamide, N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide or N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide.

[0020] The present invention also provides a method for preparing the urea derivative containing an aromatic sulfonamide structure described in the above scheme. The method for preparing the urea derivative containing an aromatic sulfonamide structure shown in formula A comprises the following steps:

[0021] (1) subjecting compound a to a first nucleophilic substitution reaction with trans-(4-aminocyclohexyl)carbamic acid tert-butyl ester to obtain compound b;

[0022] (2) subjecting the compound b to a second nucleophilic substitution reaction with the compound I to obtain a compound c;

[0023] (3) subjecting the compound c to a first deprotection reaction to obtain a compound d;

[0024] (4) subjecting the compound d to a first acylation reaction with (trichloromethyl) carbonate to obtain a first intermediate compound; subjecting the first intermediate compound to a third nucleophilic substitution reaction with compound II to obtain a urea derivative containing an aromatic sulfonamide structure as shown in formula A;

[0025] The structural formula of the compound I is The structural formula of the compound II is

[0026] The structural formulas of the compound a, compound b, compound c, compound d and the first intermediate compound are:

[0027]

[0028] In the structural formula of compound I, compound II, compound c, compound d or the first intermediate compound, R1, R2 and n are defined the same as in formula A or formula B;

[0029] The preparation method of the urea derivative containing an aromatic sulfonamide structure shown in formula B comprises the following steps:

[0030] (A) subjecting compound a to a fourth nucleophilic substitution reaction with 4-tert-butyloxycarbonylaminopiperidine to obtain compound f;

[0031] (B) subjecting the compound f to a fifth nucleophilic substitution reaction with the compound I to obtain a compound g;

[0032] (C) deprotecting the compound g to obtain compound h;

[0033] (D) subjecting the compound H to a second acylation reaction with (trichloromethyl) carbonate to obtain a second intermediate compound; subjecting the second intermediate compound to a sixth nucleophilic substitution reaction with compound II to obtain a urea derivative containing an aromatic sulfonamide structure as shown in formula B;

[0034] The structural formula of the compound I is The structural formula of the compound II is

[0035] The structural formulas of the compound f, compound g, compound h and the second intermediate compound are:

[0036]

[0037] In the structural formula of compound I, compound II, compound g, compound h or the second intermediate compound, the definitions of R1, R2 and n are the same as those of formula A or formula B.

[0038] Preferably, the first acylation reaction is carried out in triethylamine and dichloromethane; the temperature of the first acylation reaction is -78 to -30°C, and the insulation time is 30 to 60 minutes.

[0039] Preferably, the second acylation reaction is carried out in triethylamine and dichloromethane; the molar ratio of triethylamine to dichloromethane is 1-1.2:1-100; the molar ratio of compound h to triethylamine is 1-1.2:1-10.

[0040] The present invention also provides the use of the urea derivatives containing an aromatic sulfonamide structure described in the above scheme or the urea derivatives containing an aromatic sulfonamide structure obtained by the preparation method described in the above scheme in the preparation of drugs for treating diseases mediated by soluble epoxide enzymes.

[0041] The present invention provides a urea derivative containing an arylsulfonamide structure. The urea derivative provided by the present invention has a typical urea structure and an arylsulfonamide structure as the primary pharmacophore of sEH. Molecular docking shows that the urea structure can bind to the key catalytic triad of the sEH protein, and the arylsulfonamide structure as a hydrophilic fragment helps to produce polar interactions with the receptor. Therefore, the urea derivative containing an arylsulfonamide structure provided by the present invention has high inhibitory activity against human sEH (HsEH) and mouse sEH (MsEH), has little side effects, and can be used as an sEH inhibitor for preparing drugs for treating soluble cyclooxygenase-mediated diseases.

[0042] The present invention also provides a method for preparing the urea derivatives containing an aromatic sulfonamide structure described in the above scheme. The preparation method provided by the present invention has simple steps, convenient operation, high feasibility, and has the prospect of large-scale application.

[0043] The present invention also provides the use of the urea derivatives containing an aromatic sulfonamide structure described in the above scheme or the urea derivatives containing an aromatic sulfonamide structure obtained by the preparation method described in the above scheme in the preparation of drugs for treating diseases mediated by soluble epoxides. The urea derivatives containing an aromatic sulfonamide structure provided by the present invention are prepared into drugs, which have a positive effect on treating diseases mediated by soluble epoxides. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0045] Figure 1 The synthetic route of the urea derivative containing an aromatic sulfonamide structure represented by formula A of the present invention;

[0046] Figure 2 The synthetic route of the urea derivatives containing an aromatic sulfonamide structure as shown in formula B of the present invention is shown in FIG. DETAILED DESCRIPTION

[0047] The present invention provides a urea derivative containing an aromatic sulfonamide structure, the structure of which is shown in Formula A or Formula B:

[0048]

[0049] In formula A or formula B, R1 is independently alkyl, substituted alkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heterocyclic group or substituted heterocyclic group;

[0050] R2 is independently -H, alkyl, substituted alkyl, alkoxy or substituted alkoxy;

[0051] Z is independently -NH-, -O- or -S-;

[0052] n is independently 0, 1, 2 or 3.

[0053] In the present invention, the alkyl group in R1 preferably includes a straight-chain alkyl group, an adamantyl group or a branched-chain alkyl group; the straight-chain alkyl group preferably includes a methyl group, an ethyl group, a propyl group or a butyl group; the adamantyl group preferably includes a memantine group, a 1,3-dihydroxyadamantyl group, a 5-hydroxy-2-adamantanone group or a 4-hydroxy-2-adamantanone group; the branched-chain alkyl group preferably includes an isopropyl group, an isobutyl group or an isopentyl group.

[0054] In the present invention, the substituted alkyl group in R1 preferably includes a substituted straight-chain alkyl group, a substituted adamantyl group or a substituted branched-chain alkyl group; the substituted straight-chain alkyl group preferably includes a substituted methyl group, a substituted ethyl group, a substituted propyl group or a substituted isopropyl group; the substituted adamantyl group preferably includes a substituted memantine group, a substituted 1,3-dihydroxyadamantyl group, a substituted 5-hydroxy-2-adamantanone group or a substituted 4-hydroxy-2-adamantanone group; the substituted branched-chain alkyl group preferably includes a substituted isopropyl group, a substituted isobutyl group or a substituted isopentyl group.

[0055] In the present invention, the substituents of the substituted alkyl group independently preferably include a halogen group, a hydroxyl group (-OH), an amino group (-NH2), a cyano group (-CN), a nitro group (-NO2), a trifluoromethyl group (-CF3), a trifluoromethoxy group (-OCF3), a methylamino group (-NHCH3), a dimethylamino group (-N(CH3)2), an alkyl group, an aromatic group, a heterocyclic group, a heteroaryl group, -OR, -SR, -NRR', -C(O)R, -C02R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S02R, -CONRR', -SO2NRR', -OCOR, -NRCOR' or -NRNRR'; the halogen group is preferably -F, -Cl or -Br; the alkyl group is preferably a straight chain The straight-chain alkyl group preferably includes methyl, ethyl, propyl, butyl or isopropyl; the cycloalkyl group preferably includes cyclopropane, cyclopentane, cyclohexane or cycloheptyl; the aromatic group is preferably phenyl or naphthyl; the heterocyclic group is preferably tetrahydrofuran, hexahydropyridine or hexahydropyran; the heteroaryl group is preferably pyridine, pyrimidine, furan or pyran; in the OR, -SR, -NRR', -C(O)R, -C02R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S02R, -CONRR', -SO2NRR', -OCOR, -NRCOR' and -NRNRR', R or R' is independently preferably an alkyl group; the alkyl group preferably includes methyl, ethyl, propyl, isopropyl, butyl or isobutyl.

[0056] In the present invention, the structure of the substituent of the substituted alkyl group is specifically as follows (wherein the solid five-pointed star represents the connection site):

[0057]

[0058] In the present invention, the type of the substituent of the substituted phenyl group in R1 is preferably the same as the type of the substituent of the substituted alkyl group in R1, and will not be described in detail herein.

[0059] In the present invention, the type of the substituent of the substituted naphthyl group in R1 is preferably the same as the type of the substituent of the substituted alkyl group in R1, and will not be described in detail herein.

[0060] In the present invention, the heterocyclic group in R1 preferably includes pyridine, pyrimidine, pyran, pyrazole, piperidine, thiazole or thiophene.

[0061] In the present invention, the substituted heterocyclic group in R1 preferably includes substituted pyridine, substituted pyrimidine, substituted pyran, substituted pyrazole, substituted piperidine, substituted thiazole or substituted thiophene.

[0062] In the present invention, the type of the substituent of the substituted heterocyclic group in R1 is preferably the same as the type of the substituent of the substituted alkyl group in R1, and will not be described in detail herein.

[0063] In the present invention, the alkyl group in R2 is preferably a C1-C6 alkyl group; the C1-C6 alkyl group preferably includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl or hexyl.

[0064] In the present invention, the substituted alkyl group in R2 is preferably a substituted C1~C6 alkyl group; the substituted C1~C6 alkyl group preferably includes a substituted methyl group, a substituted ethyl group, a substituted propyl group, a substituted isopropyl group, a substituted butyl group, a substituted isobutyl group, a substituted pentyl group, a substituted isopentyl group or a substituted hexyl group.

[0065] In the present invention, the substituent of the substituted alkyl in R2 preferably includes a halogen group, a hydroxyl group (-OH), an amino group (-NH2), a methylamino group (-NHCH3), a dimethylamino group (-N(CH3)2) or an alkyl group; the halogen group is preferably -F, -Cl or -Br; the alkyl group is preferably a C1~C6 alkyl group; the C1~C6 alkyl group preferably includes a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group or a hexyl group.

[0066] In the present invention, the alkoxy group in R2 is preferably a C1-C6 alkoxy group; the C1-C6 alkoxy group preferably includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy or hexyloxy.

[0067] In the present invention, the substituted alkoxy group in R2 is preferably a substituted C1~C6 alkoxy group; the substituted C1~C6 alkoxy group preferably includes a substituted methoxy group, a substituted ethoxy group, a substituted propoxy group, a substituted isopropoxy group, a substituted butoxy group, a substituted isobutoxy group, a substituted pentyloxy group, a substituted isopentyloxy group or a substituted hexyloxy group.

[0068] In the present invention, the type of the substituent of the substituted alkoxy group in R2 is preferably the same as the type of the substituent of the substituted alkyl group in R2, and will not be described in detail herein.

[0069] In the present invention, n is preferably 0, 1 or 2, more preferably 0 or 1.

[0070] In the present invention, the urea derivatives containing an aromatic sulfonamide structure preferably include N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)cyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (denoted as FS-A4), N-(2-(((1r,4r)-4-(3-(3,5-difluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (denoted as FS-B4), N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1 -yl)-4-methylbenzenesulfonamide (denoted as FS-C4), N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-D4), N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-E4), N-(2-(((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobutane -1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-F4), N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-G4), N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-H4), N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS- 1-Butyl)-4-methylbenzenesulfonamide (denoted as FS-I4), N-(2-(((1r,4r)-4-(3-(3-chloro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-J4), N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-L4), N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-M4), N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-N4), N-(2-(((1r,4r)-4-(3-(4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-O4), N-(2-(((1r,4r)-4-(3-(4-chlorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS- 4-(2-(((1r,4r)-4-(3-(2-chloro-4-nitrophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-Q4), N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-R4), N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS- amide (denoted as FS-S4), N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-T4), N-(2-(((1r,4r)-4-(3-(1,2,3,5,6,7-hexahydro-s-indol-4-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-U4), N-(3,4-dioxo-2-(((1r,4r)-4-(3-(p-tolyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-V4), N-(2-(((1r,4r)-4-(3-benzhydrylureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-W4), N-(2-(((1r,4r)-4-(3-(4-fluorobenzyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-X4), N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)benzyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-Y4), N-(2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)benzyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-4r)-4-(3-(4-chlorobenzyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-Z4), N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethyl)benzyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-END4), N-(2-(((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-110), N-(2- (((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-101), N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-102), N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-103), MH-104), N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-105), N-(3,4-dioxo-2-((4-(3-(p-tolyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-106), N-(2-(((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-107), N-(2-(((1r,4 r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-108), N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-109), N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-110), N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-111), N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-111), N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-112), N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-113), N-(2-( ((1r,4r)-4-(3-(4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-114), N-(2-(((1r,4r)-4-(3-(4-chlorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-115), N-(2-(((1r,4r)-4-(3-(2-chloro-4-nitrophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-116), N-(3,4-dioxo-2-(((1r,4 r)-4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-117), N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-118), N-(2-(((1r,4r)-4-(3-(3-chloro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-119), N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide -3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-120), N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-121), N-(2-(((1r,4r)-4-(3-(1,2,3,5,6,7-hexahydro-s-indol-4-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-122), N-(2-(((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-101), N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-102), N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS -103), N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-104), N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-105), N-(3,4-dioxo-2-(((1r,4r)-4-(3-(p-tolyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-106), N-(2-(((1 r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-107), N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-108), N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-109), N-(2-(((1r,4r)-4 -(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-110), N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-111), N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-112), N-(2-(((1r,4r)-4-(3-(3,5-difluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-113), N-(2-(((1r,4r)-4-(3-(3-chloro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-114), N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-115), N-(2-(((1r ,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-116), N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-117), N-(2-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as WG-101), N-( 2-(4-(3-(3-chloro-4-methylphenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as WG-103), N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as WG-105), N-(2-(4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as WG-106), N-(2-(4-(3-(4-fluoro-3-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as WG-107), 4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-A104), N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-A117), N-(2-(4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as WG-108), N-(2-(4-(3-(4-chloro-3-fluorophenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-A104), N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-A117), N-(2-(4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-A102), N-(2-(4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-A112), N-(3,4-dioxo-2-(4-(3-(4- (trifluoromethoxy)phenyl)ureido)piperidin-1-yl)cyclobut-1-ene-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-A113) or N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)cyclobut-1-ene-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-A117), the structural formula is as follows:

[0071]

[0072]

[0073] The present invention also provides a method for preparing the urea derivative containing an aromatic sulfonamide structure as described in the above scheme, wherein the method for preparing the urea derivative containing an aromatic sulfonamide structure as shown in formula A comprises the following steps:

[0074] (1) subjecting compound a to a first nucleophilic substitution reaction with trans-(4-aminocyclohexyl)carbamic acid tert-butyl ester to obtain compound b;

[0075] (2) subjecting the compound b to a second nucleophilic substitution reaction with the compound I to obtain a compound c;

[0076] (3) subjecting the compound c to a first deprotection reaction to obtain a compound d;

[0077] (4) subjecting the compound d to a first acylation reaction with (trichloromethyl) carbonate to obtain a first intermediate compound; subjecting the first intermediate compound to a third nucleophilic substitution reaction with compound II to obtain a urea derivative containing an aromatic sulfonamide structure as shown in formula A;

[0078] The structural formula of the compound I is The structural formula of the compound II is

[0079] The structural formulas of the compound a, compound b, compound c, compound d and the first intermediate compound are:

[0080]

[0081] In the structural formula of compound I, compound II, compound c, compound d or the first intermediate compound, the definitions of R1, R2 and n are the same as those of formula A or formula B.

[0082] In the present invention, compound a and trans-(4-aminocyclohexyl)carbamic acid tert-butyl ester are subjected to a first nucleophilic substitution reaction to obtain compound b. In the present invention, the molar ratio of compound a to trans-(4-aminocyclohexyl)carbamic acid tert-butyl ester is preferably 1:(1-2), more preferably 1:1.

[0083] In the present invention, the first nucleophilic substitution reaction is preferably carried out in the presence of an acid binding agent; the acid binding agent preferably includes one or more of triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, cesium carbonate and sodium carbonate, more preferably N,N-diisopropylethylamine; the molar ratio of the compound a to the acid binding agent is preferably 1:(1-4), more preferably 1:1.2.

[0084] In the present invention, the first nucleophilic substitution reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, ethanol and tetrahydrofuran, more preferably ethanol; the mass ratio of the compound a to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:1-10.

[0085] In the present invention, the temperature of the first nucleophilic substitution reaction is preferably 40-80° C., more preferably 40° C., and the insulation time is preferably 3-8 h, more preferably 3 h.

[0086] In the present invention, after the first nucleophilic substitution reaction, the following steps are preferably performed: adding water to the obtained reaction system, extracting with ethyl acetate, drying, filtering and concentrating.

[0087] In the present invention, the concentration is preferably until dryness.

[0088] After obtaining compound b, the present invention conducts a second nucleophilic substitution reaction between the compound b and compound I to obtain compound c. In the present invention, the molar ratio of the compound b to the compound I is preferably 1:(1-2), more preferably 1:1.

[0089] In the present invention, the second nucleophilic substitution reaction is preferably carried out in the presence of an acid binding agent; the acid binding agent preferably includes one or more of triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, cesium carbonate and sodium carbonate, more preferably N,N-diisopropylethylamine; the molar ratio of the compound b to the acid binding agent is preferably 1:(1-6), more preferably 1:6.

[0090] In the present invention, the second nucleophilic substitution reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, ethanol and tetrahydrofuran; the mass ratio of the compound b to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:1-10.

[0091] In the present invention, the temperature of the second nucleophilic substitution reaction is preferably 40-80° C., more preferably 80° C., and the insulation time is preferably 3-8 h, more preferably 4 h.

[0092] In the present invention, after the second nucleophilic substitution reaction, the steps of sequentially adding water to the obtained reaction system, extracting with ethyl acetate, drying, filtering and concentrating are preferably included.

[0093] In the present invention, the concentration is preferably until dryness.

[0094] After obtaining compound c, the present invention performs a first deprotection reaction on compound c to obtain compound d. In the present invention, the first deprotection reaction is preferably performed under acidic conditions; the acidic conditions are preferably provided by an acidic reagent; the acidic reagent is preferably trifluoroacetic acid; the molar ratio of compound c to the acidic reagent is preferably 1:(3-10), more preferably 1:5.

[0095] In the present invention, the first deprotection reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, dichloromethane and tetrahydrofuran, more preferably dichloromethane.

[0096] In the present invention, the temperature of the first deprotection reaction is preferably -20 to 50°C, more preferably 30°C, and the insulation time is preferably 2 to 8h, more preferably 3h.

[0097] In the present invention, after the first deprotection reaction, the method preferably further comprises concentrating the obtained reaction solution; the concentration is preferably performed under reduced pressure; and the concentration is preferably performed until dryness.

[0098] After obtaining compound d, the present invention conducts a first acylation reaction between the compound d and (trichloromethyl) carbonate to obtain a first intermediate compound. In the present invention, the molar ratio of the compound d to (trichloromethyl) carbonate is preferably 1:(0.3-0.5), more preferably 1:0.5.

[0099] In the present invention, the first acylation reaction is preferably carried out in the presence of an acid binder; the acid binder is preferably triethylamine; the molar ratio of the compound d to the acid binder is preferably 1:(1-4), more preferably 1:1.2.

[0100] In the present invention, the first acylation reaction is preferably carried out in an organic solvent; the organic solvent is preferably dichloromethane; the molar ratio of the acid binding agent to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:1-10.

[0101] In the present invention, the temperature of the first acylation reaction is preferably -78 to -30°C, more preferably -78°C, and the insulation time is preferably 30 to 60 min, more preferably 30 min.

[0102] In the present invention, after the first acylation reaction, the obtained reaction solution is preferably concentrated; the concentration is preferably concentrated under reduced pressure; the concentration temperature is preferably 25-60° C., more preferably 40° C., until it becomes dry.

[0103] After obtaining the first intermediate compound, the present invention conducts a third nucleophilic substitution reaction between the first intermediate compound and compound II to obtain a urea derivative containing an aromatic sulfonamide structure as shown in formula A. In the present invention, the molar ratio of the first intermediate compound to compound II is preferably 1 to 1.2:1 to 3, and more preferably 1 to 1.1:1 to 1.5.

[0104] In the present invention, the third nucleophilic substitution reaction is preferably carried out in the presence of an acid binding agent; the acid binding agent is preferably triethylamine; the molar ratio of the compound II to the acid binding agent is preferably 1:(4-6), more preferably 1:6.

[0105] In the present invention, the third nucleophilic substitution reaction is preferably carried out in an organic solvent; the organic solvent is preferably dichloromethane; the molar ratio of the acid binding agent to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:1-10.

[0106] In the present invention, the temperature of the third nucleophilic substitution reaction is preferably -10 to -30°C, more preferably -25°C, and the insulation time is preferably 30 to 60 min, more preferably 30 min.

[0107] In the present invention, after the third nucleophilic substitution reaction, the steps of sequentially adding water to the obtained reaction system, extracting with ethyl acetate, washing, drying, filtering, concentrating and column chromatography are preferably included.

[0108] In the present invention, the number of extractions is preferably one or more, more preferably three or more.

[0109] In the present invention, the washing is preferably performed sequentially by HCl washing, water washing and saturated salt water washing; the number of HCl washing is preferably more than 1 time, more preferably more than 2 times; the number of water washing is preferably more than 1 time, more preferably more than 2 times; the number of saturated salt water washing is preferably more than 1 time.

[0110] In the present invention, the drying is preferably drying with anhydrous sodium sulfate.

[0111] In the present invention, the concentration is preferably until dryness.

[0112] In the present invention, the column chromatography parameters are preferably: 5 times silica gel column, 1.2 times silica gel sample, eluent is MeOH and DCM, MeOH and DCM volume ratio is 1:50. The synthetic route of the urea derivative containing aromatic sulfonamide structure shown in formula A provided by the present invention is as follows Figure 1 shown.

[0113] In the present invention, the preparation method of the urea derivative containing an aromatic sulfonamide structure represented by formula B comprises the following steps:

[0114] (A) subjecting compound a to a fourth nucleophilic substitution reaction with 4-tert-butyloxycarbonylaminopiperidine to obtain compound f;

[0115] (B) subjecting the compound f to a fifth nucleophilic substitution reaction with the compound I to obtain a compound g;

[0116] (C) deprotecting the compound g to obtain compound h;

[0117] (D) subjecting the compound H to a second acylation reaction with (trichloromethyl) carbonate to obtain a second intermediate compound; subjecting the second intermediate compound to a sixth nucleophilic substitution reaction with compound II to obtain a urea derivative containing an aromatic sulfonamide structure as shown in formula B;

[0118] The structural formula of the compound I is The structural formula of the compound II is

[0119] The structural formulas of the compound f, compound g, compound h and the second intermediate compound are:

[0120]

[0121] In the structural formula of compound I, compound II, compound g, compound h or the second intermediate compound, the definitions of R1, R2 and n are the same as those of formula A or formula B.

[0122] The present invention conducts a fourth nucleophilic substitution reaction between compound a and 4-tert-butoxycarbonylaminopiperidine to obtain compound f. In the present invention, the molar ratio of compound a to 4-tert-butoxycarbonylaminopiperidine is preferably 1:(1.0-2), more preferably 1:1.0.

[0123] In the present invention, the fourth nucleophilic substitution reaction is preferably carried out in the presence of an acid binding agent; the acid binding agent preferably includes one or more of triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, cesium carbonate and sodium carbonate, more preferably N,N-diisopropylethylamine; the molar ratio of the compound a to the acid binding agent is preferably 1:(1-4), more preferably 1:1.2.

[0124] In the present invention, the fourth nucleophilic substitution reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, ethanol and tetrahydrofuran, and more preferably ethanol.

[0125] In the present invention, the temperature of the fourth nucleophilic substitution reaction is preferably 40-80° C., more preferably 40° C., and the insulation time is preferably 3-8 h, more preferably 3 h.

[0126] In the present invention, after the fourth nucleophilic substitution reaction, the following steps are preferably further included: adding water to the obtained reaction system, extracting with ethyl acetate, drying, filtering and concentrating in sequence; the concentration is preferably until dryness.

[0127] After obtaining compound f, the present invention conducts a fifth nucleophilic substitution reaction between compound f and compound I to obtain compound g. In the present invention, the molar ratio of compound f to compound I is preferably 1:(1-2), more preferably 1:1.

[0128] In the present invention, the fifth nucleophilic substitution reaction is preferably carried out in the presence of an acid binding agent; the acid binding agent preferably includes one or more of triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, cesium carbonate and sodium carbonate, more preferably N,N-diisopropylethylamine; the molar ratio of the compound f to the acid binding agent is preferably 1:(1-6), more preferably 1:6.

[0129] In the present invention, the fifth nucleophilic substitution reaction is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, ethanol and tetrahydrofuran.

[0130] In the present invention, the temperature of the fifth nucleophilic substitution reaction is preferably 40-80° C., more preferably 80° C., and the insulation time is preferably 3-8 h, more preferably 4 h.

[0131] In the present invention, after the second nucleophilic substitution reaction, the method preferably further comprises adding water to the obtained reaction system, extracting with ethyl acetate, drying, filtering and concentrating in sequence; the concentration is preferably until dryness.

[0132] After obtaining compound g, the present invention deprotects the compound g to obtain compound h. In the present invention, the deprotection is preferably carried out under acidic conditions; the acidic conditions are preferably provided by an acidic reagent; the acidic reagent is preferably trifluoroacetic acid; the molar ratio of the compound g to the acidic reagent is preferably 1:(3-10), more preferably 1:5.

[0133] In the present invention, the deprotection is preferably carried out in an organic solvent; the organic solvent preferably includes one or more of acetonitrile, dichloromethane and tetrahydrofuran, more preferably dichloromethane.

[0134] In the present invention, the deprotection temperature is preferably -20 to 50°C, more preferably 30°C, and the insulation time is preferably 2 to 8h, more preferably 3h.

[0135] In the present invention, after the deprotection, the obtained reaction solution is preferably concentrated; the concentration is preferably concentrated under reduced pressure; the concentration is preferably until dryness.

[0136] After obtaining compound h, the present invention conducts a second acylation reaction between the compound h and (trichloromethyl) carbonate to obtain a second intermediate compound. In the present invention, the molar ratio of the compound h to (trichloromethyl) carbonate is preferably 1:(0.3-0.5), more preferably 1:0.5.

[0137] In the present invention, the second acylation reaction is preferably carried out in triethylamine and dichloromethane; the molar ratio of triethylamine to dichloromethane is preferably 1-1.2:1-100, more preferably 1-1.2:1-10; the molar ratio of compound h to triethylamine is preferably 1-1.2:1-10, more preferably 1-1.2:1-3.

[0138] In the present invention, the temperature of the second acylation reaction is preferably -78 to -30°C, more preferably -78°C, and the insulation time is preferably 30 to 60 min, more preferably 30 min.

[0139] In the present invention, the second acylation reaction preferably further comprises concentrating the obtained reaction solution; the concentration is preferably concentrated under reduced pressure; the concentration temperature is preferably 25 to 60° C., more preferably 40° C., until it becomes dry.

[0140] After obtaining the second intermediate compound, the present invention conducts a sixth nucleophilic substitution reaction between the second intermediate compound and compound II. In the present invention, the molar ratio of the second intermediate compound to compound II is preferably 1-1.2:1-3, more preferably 1-1.1:1-1.5.

[0141] In the present invention, the sixth nucleophilic substitution reaction is preferably carried out in the presence of an acid binding agent; the acid binding agent is preferably triethylamine; the molar ratio of the compound II to the acid binding agent is preferably 1:(4-6), more preferably 1:6.

[0142] In the present invention, the sixth nucleophilic substitution reaction is preferably carried out in an organic solvent; the organic solvent is preferably dichloromethane; the molar ratio of the acid binding agent to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:1-10.

[0143] In the present invention, the temperature of the sixth nucleophilic substitution reaction is preferably -10 to -30°C, more preferably -25°C, and the insulation time is preferably 30 to 60 min, more preferably 30 min.

[0144] In the present invention, after the sixth nucleophilic substitution reaction, it is preferred that the further steps include adding water, extracting with ethyl acetate, drying, filtering, concentrating and column chromatography to the obtained reaction system in sequence; the extraction, drying, filtering, concentrating and column chromatography are preferably the same as those of the urea derivative containing an aromatic sulfonamide structure shown in formula A, and will not be described in detail here. The specific synthetic route of the urea derivative containing an aromatic sulfonamide structure shown in formula B of the present invention is as follows: Figure 2 shown.

[0145] The present invention also provides the use of the urea derivatives containing an aromatic sulfonamide structure described in the above scheme or the urea derivatives containing an aromatic sulfonamide structure obtained by the preparation method described in the above scheme in the preparation of drugs for treating diseases mediated by soluble epoxide enzymes.

[0146] In the present invention, the soluble cyclooxygenase-mediated diseases preferably include inflammatory diseases, pain, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications, chronic nephritis, renal failure, chronic obstructive pulmonary disease or pulmonary hypertension.

[0147] In order to further illustrate the present invention, the scheme of the present invention is described in detail below in conjunction with the accompanying drawings and embodiments, but they should not be understood as limiting the protection scope of the present invention.

[0148] Example 1 Synthesis of tert-butyl ((1r, 4r)-4-((2-ethoxy-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate (Compound b)

[0149] Add trans-(4-aminocyclohexyl)carbamic acid tert-butyl ester (4.04g, 18.86mmol), diethyl squarate (compound a) (2.92g, 17.15mmol), TEA (2.08g, 20.58mmol), EtOH (30mL) to a 100mL three-necked flask, react at 40℃ for 3h, TLC detection shows that the reaction is complete, and the reaction is stopped. The reaction solution is concentrated and evaporated to dryness, dissolved in DCM (30mL), washed with H2O (25mL×1), and washed with saturated brine (30mL×1). Dry over anhydrous magnesium sulfate, filter after 4h, and concentrate under reduced pressure to obtain tert-butyl ((1r, 4r)-4-((2-ethoxy-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate (compound b) (5.8g pale yellow solid, yield 100.0%).

[0150] Example 2 Synthesis of tert-butyl ((1r, 4r)-4-((2-((4-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate (Compound c)

[0151] To a 100 mL single-necked bottle, tert-butyl ((1r, 4r)-4-((2-ethoxy-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate (compound b) (2.9 g, 8.57 mmol), p-toluenesulfonamide (1.76 g, 10.29 mmol), DBU (2.61 g, 17.15 mmol), and EtOH (20 mL) were added, and the temperature was raised to reflux. After 4 h, solids precipitated. The TLC reaction was complete, and the reaction was stopped. The reaction solution was cooled to room temperature, filtered, and the filter cake was rinsed with EtOH to obtain tert-butyl ((1r, 4r)-4-((2-((4-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate (compound c) (3.65 g white solid, yield 91.94%).

[0152] Example 3 Synthesis of N-(2-(((1r,4r)-4-aminocyclohexyl)amino)-3,4-dioxetane-1-en-1-yl)-4-methylbenzenesulfonamide (Compound d)

[0153] To a 100 mL single-necked bottle was added tert-butyl ((1r, 4r)-4-((2-((4-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate (compound c) (4.40 g, 8.57 mmol), DCM 5 mL, TFA 2 mL, and stirred at room temperature for 2 h. The reaction solution was evaporated to dryness under reduced pressure to give N-(2-(((1r, 4r)-4-aminocyclohexyl)amino)-3,4-dioxetane-1-en-1-yl)-4-methylbenzenesulfonamide (compound d) (yield 4.18 g, yield 102.20%).

[0154] Example 4 Synthesis of N-(2-((1R, 4r)-4-(3-((1r, 3R, 5S, 7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)amino)-3,4-dioxetane-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-110)

[0155] Solid phosgene (0.15 g, 0.51 mmol) and dry DCM (30 mL) were added to a three-necked flask, and the temperature was cooled to below -78 ° C. N-(2-(((1r, 4r)-4-aminocyclohexyl)amino)-3,4-dioxetane-1-en-1-yl)-4-methylbenzenesulfonamide (compound d) (0.3 g, 0.82 mmol) and a dry dichloromethane (20 mL) solution of triethylamine (0.31 g, 3.54 mmol) were added dropwise. After the addition, the mixture was moved to room temperature and stirred for reaction for 0.5 h, and then the reaction was stopped; the obtained reaction solution was concentrated to dryness under reduced pressure, and dry DCM (10 mL) was added to the residue to dissolve it to obtain an isocyanate solution for standby use.

[0156] Memantine (0.18 g, 1.03 mmol), triethylamine (0.63 g, 7.08 mmol), and dry dichloromethane (15 mL) were added to a three-necked flask, and the above isocyanate solution was added dropwise. The reaction was allowed to react at room temperature for 0.5 h. TLC showed that the reaction was complete. The reaction solution was poured into water (20 mL), extracted with EA (20 mL × 3), and then washed with 1 mol / L HCl (40 mL × 2), water (40 mL × 2), saturated brine (40 mL), and dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure. The organic phase was concentrated under reduced pressure to obtain 0.48 g of light yellow oily substance, which was loaded on a 5x silica gel column, mixed with 1.2x silica gel, and eluent (MeOH:DCM=1:50). Column chromatography obtained a white solid, which was FS-110, with a yield of 0.11 g and a yield of 21.58%. mp235~238℃. 1HNMR (400MHz, DMSO-d6): δ (ppm) 7.79 (d, 2H, J = 8.24Hz), 7.38 (d, 2H, J = 9.92Hz) ),7.29(d,1H,J=8.32Hz),5.46(s,1H),5.35(s,1H),3.78-3.71(m,1H),3.25- 3.20(m,1H),2.33(s,3H),1.98-1.96(m,1H),1.81-1.73(m,4H),1.60(s,2H), 1.43(s,4H),1.40-1.32(m,2H),1.19-1.17(m,4H),1.00(s,4H),0.73(s,6H). 13 C NMR (101MHz, DMSO-d6): δ188.10,180.79,170.60,160.13,156.94,144.75,137.35,130.50,127.57, 52.82,51.50,50.85,48.58,47.08,42.90,40.97,32.47,32.35,31.88,30.61,30.09,24.45,21.52.

[0157] Example 5 Synthesis of N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-A4)

[0158] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-trifluoromethoxyaniline to obtain a white solid, namely FS-A4, with a yield of 0.21 g and a yield of 35.0%. mp 245~248℃. 1 HNMR (400MHz, DMSO-d6): δ (ppm) 8.60 (s, 1H), 7.91 (d, 2H, J = 8.24Hz), 7.54-7.50 (m, 4H), 7.44 (d, 1H, J = 8.36Hz), 7.26 (d, 2H, J = 8.6Hz), 6.17(d,1H,J=7.6Hz),3.92-3.87(m,1H),3.54-3.52(m,1H),2.45(s,3H),1.96(d,4H,J=9.88Hz),1.59-1.51(m,2H),1.36-1.27(m,2H). 13CNMR (100MHz, DMSO-d6): δ188.09,180.86,170.63,154.84,144.72,142.42,140. 28,137.41,130.49,127.58,122.06,119.06,52.73,47.45,32.38,31.50,21.52.

[0159] Example 6 Synthesis of N-(2-(((1r,4r)-4-(3-(3,5-difluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-B4)

[0160] The preparation method of this embodiment is the same as that of embodiment 4, except that the memantine in embodiment 4 is replaced by 3,5-difluoroaniline to obtain a white solid, namely FS-B4, with a yield of 0.23 g and a yield of 36.12%. mp 243~245℃. 1 HNMR (400MHz, DMSO-d6): δ (ppm) 8.95 (s, 1H), 7.85 (d, 2H, J = 8.28Hz), 7.81- 7.79(m,1H),7.44(d,1H,J=8.16Hz),7.12-7.09(m,2H),6.66(tt,1H,J1=9. 36Hz,J2=2.36Hz),6.36(d,1H,J=7.56Hz),3.87-3.80(m,1H),3.49-3.46(m ,1H),2.39(s,3H),1.91-1.89(m,4H),1.50-1.42(m,2H),1.31-1.22(m,2H). 13 C NMR (100MHz, DMSO-d6): δ188.12,180.85,170.73,164.34,164.18,161.94,161.78,154.56,144.46,1 43.90,143.76,143.62,137.75,130.39,127.57,100.73,100.44,52.57,47.46,32.31,31.26,21.51.

[0161] Example 7 Synthesis of N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-C4)

[0162] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-chloro-3-fluoroaniline to obtain a white solid, namely FS-C4, with a yield of 0.23 g and a yield of 36.55%. mp 269~271℃. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.70 (s, 1H), 7.86 (d, 2H, J = 8.20Hz), 7.62 (dd, 1H, J1 = 12.44Hz, J2 = 2.32Hz), 7.45 (d, 2H, J = 8.16Hz), 7.40-7.36 (m, 2H), 7.07-7.05(m,1H),6.20(d,1H,J=7.64Hz),3.86-3.82(m,1H),3.49-3.47(m ,1H),2.40(s,3H),1.91-1.89(m,4H),1.54-1.45(m,2H),1.31-1.23(m,2H). 13 C NMR (100MHz, DMSO-d6): δ188.11,180.74,170.61,158.80,156.39,154.61,144.78,141.79,141.68,1 37.33,130.70,130.50,127.59,114.86,110.61,106.10,105.84,52.72,47.51,32.35,31.41,21.52.

[0163] Example 8 Synthesis of N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-D4)

[0164] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-chloro-3-trifluoromethylaniline to obtain a white solid, namely FS-D4, with a yield of 0.24 g and a yield of 36.11%. mp>300℃. 1H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.91(s,1H),8.13(s,1H),7.69(d,J=7.5Hz,2H),7.59(d,J=1.1Hz,2H),7.33(d,J=7.9Hz,3H),6.3 4(d,J=7.8Hz,1H),3.91(d,J=8.3Hz,1H),3.51(d,J=7.4Hz,1H),2.39(s,3H),1.96-1.94(m,4H),1.49-1.41(m,2H),1.39-1.29(m,2H).

[0165] Example 9 Synthesis of N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-E4)

[0166] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-fluoro-4-trifluoromethoxyaniline to obtain a white solid, namely FS-E4, with a yield of 0.27 g and a yield of 36.89%. mp 297~299℃. 1 HNMR(400MHz,DMSO-d6)δ8.78(s,1H),7.86(d,J=8.2Hz,2H),7.69-7.65(m,1 H),7.45(d,J=8.1Hz,2H),7.39(t,J=9.3Hz,2H),7.10(d,J=9.0Hz,1H),6.24 (d,J=7.7Hz,1H),3.86-3.84(m,1H),3.49-3.47(m,1H),2.40(s,3H),1.90(d ,J=8.1Hz,4H),1.49(dd,J=22.2,11.4Hz,2H),1.27(dd,J=22.6,10.0Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ188.1,170.7,155.3,154.6,152.9,144.7,141.9,141.8,137.5,130.5 ,127.6,124.8,122.0,119.4,114.1,114.0,106.2,106.0,52.7,47.5,46.3,32.4,31.4,21.5.

[0167] Example 10 Synthesis of N-(2-(((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-F4)

[0168] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 2-chloro-4-cyanoaniline to obtain a white solid, namely FS-F4, with a yield of 0.25 g and a yield of 36.35%. mp 289~294℃. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 9.10 (s, 1H), 7.89-7.85 (m, 3H), 7.76 (d, 1H, J = 8.60Hz), 7.45 (d, 2H, J = 8.00Hz), 7.39 (d, 1H, J = 8.28Hz), 7.34 (d ,1H,J=8.56Hz),6.43(d,1H,J=7.52Hz),3.87-3.85(m,1H),3.50-3.48( m,1H),2.40(s,3H),1.91(s,4H),1.54-1.46(m,2H),1.33-1.24(m,2H). 13 C NMR (100MHz, DMSO-d6): δ188.1,180.7,170.6,154.1,146.6,144.8,137.3,13 6.5,135.4,130.5,127.6,117.1,116.6,103.2,52.7,47.7,32.3,31.2,21.5.

[0169] Example 11 Synthesis of N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-G4)

[0170] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-fluoro-3-trifluoromethylaniline to obtain a white solid, namely FS-G4, with a yield of 0.16 g and a yield of 22.56%. mp 296~298℃. 1H NMR (400MHz, DMSO-d6) δ8.79 (s, 1H), 7.96 (dd, J=6.4, 2.5Hz, 1H), 7.85 (d, J= 8.2Hz,2H),7.55-7.52(m,2H),7.44(d,J=8.1Hz,2H),7.36(t,J=9.8Hz,1H),6 .25(d,J=7.6Hz,1H),3.86-3.84(m,1H),3.48-3.46(m,1H),2.39(s,3H),1.9 1-1.89(m,4H),1.47(dd,J=22.3,11.4Hz,2H),1.27(dd,J=22.3,11.3Hz,2H). 13 C NMR (100MHz, DMSO-d6) δ188.1,170.8,154.9,144.5,137.88,137.86,130.4,127.5,118.0,117.8,115.6,52.6,47.6,46.2,32.4,31.4,21.5,9.1.

[0171] Example 12 Synthesis of N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-H4)

[0172] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-fluoro-4-methylaniline to obtain a white solid, namely FS-H4, with a yield of 0.21 g and a yield of 33.12%. mp 271~274℃. 1 H NMR (400MHz, DMSO-d6) δ9.55(s,1H),8.56(s,1H),7.85(d,J=8.1Hz,2H),7.77(d,J=8.1H z,1H),7.44(d,J=8.1Hz,2H),7.38(dd,J=12.8,1.6Hz,1H),7.08(t,J=8.6Hz,1H),6.90(d d,J=8.2,1.3Hz,1H),6.17(d,J=7.1Hz,1H),3.83(d,J=7.9Hz,1H),3.44(s,1H),2.39(s,3 H),2.12(s,3H),1.91-1.89(m,4H),1.46(dd,J=22.4,11.1Hz,2H),1.24(d,J=8.1Hz,2H). 13C NMR(100MHz,DMSO-d6)δ188.1,170.8,162.2,159.8,154.8,144.4,140.6,140.5,137.8,131.7, 130.4,127.6,116.2,116.1,113.6,104.8,104.5,52.6,47.4,46.1,32.4,31.4,21.5,13.9,9.0.

[0173] Example 13 Synthesis of N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-I4)

[0174] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-chloro-4-fluoroaniline to obtain a white solid, namely FS-I4, with a yield of 0.22 g and a yield of 35.21%. mp 280~282℃. 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),7.86(d,J=8.2Hz,2H),7.75(dd,J=6.8,2 .5Hz,1H),7.45(d,J=8.2Hz,2H),7.40(d,J=8.4Hz,1H),7.26(t,J=9.0Hz,1H) ,7.21-7.17(m,1H),6.15(d,J=7.6Hz,1H),3.86-3.81(m,1H),3.48-3.46(m,1 H),2.40(s,3H),1.90(d,J=9.0Hz,4H),1.53-1.45(m,2H),1.30-1.22(m,2H). 13 C NMR(100MHz,DMSO-d6)δ188.1,172.4,170.7,154.8,151.1,144.7,138.30,138.28,137.5 2,130.5,127.6,119.3,119.2,118.2,118.1,117.3,117.1.52.7,47.5,32.4,31.5,21.5.

[0175] Example 14 Synthesis of N-(2-(((1r,4r)-4-(3-(3-chloro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-J4)

[0176] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-chloro-4-methylaniline to obtain a white solid, namely FS-J4, with a yield of 0.23 g and a yield of 35.66%. mp 286~288℃. 1 HNMR(400MHz,DMSO-d6)δ9.68(s,1H),8.61(s,1H),7.88(dd,J=15.0,8.3Hz,3H), 7.63(d,J=2.0Hz,1H),7.44(d,J=8.1Hz,2H),7.16(d,J=8.4Hz,1H),7.08(dd,J=8. 3,1.9Hz,1H),6.23(d,J=7.2Hz,1H),3.92-3.74(m,1H),3.44(s,1H),2.39(s,3H), 2.22(s,3H),1.96-1.84(m,4H),1.45(dd,J=22.2,11.1Hz,2H),1.30-1.22(m,2H). 13 C NMR(100MHz,DMSO-d6)δ188.2,170.7,154.9,144.5,140.2,137.7,133.5,131 .5,130.4,127.6,117.9,116.7,52.6,47.4,46.0,32.3,31.4,21.5,19.2,9.0.

[0177] Example 15 Synthesis of N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-L4)

[0178] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-chloro-4-trifluoromethoxyaniline to obtain a white solid, namely FS-L4, with a yield of 0.14 g and a yield of 19.89%. mp 248~251℃. 1HNMR(400MHz, DMSO-d6)δ8.81(s,1H),7.84(dd,J=7.0,5.5Hz,3H),7.56(d,J=8.3Hz,1H),7.46-7.39(m,3H),7.29(dd,J=9.0,2.5Hz,1 H),6.28(d,J=7.7Hz,1H),3.85-3.81(m,1H),3.48-3.46(m,1H),2.39(s,3H),1.91-1.89(m,4H),1.52-1.43(m,2H),1.31-1.23(m,2H). 13 C NMR(100MHz,DMSO-d6)δ188.1,170.7,154.6,144.5,141.4,137.8,130.4,12 7.6,126.5,124.1,122.0,119.4,119.0,117.7,52.6,47.5,32.4,31.4,21.5.

[0179] Example 16 Synthesis of N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-M4)

[0180] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-chloro-3-trifluoromethylaniline to obtain a white solid, namely FS-M4, with a yield of 0.15 g and a yield of 20.06%. mp 289~251℃. 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.07(s,1H),7.85(d,J=8.3Hz,2H),7.71(d,J=8.1Hz,1H),7.53(d,J=1.1Hz,2H),7.44(d,J=8.2Hz,2H) ,6.34(d,J=7.7Hz,1H),3.84(d,J=8.0Hz,1H),3.47(d,J=7.4Hz,1H),2.39(s,3H),1.91-1.89(m,4H),1.50-1.42(m,2H),1.33-1.23(m,2H). 13 C NMR (100MHz, DMSO-d6) δ188.1,170.7,154.7,144.5,140.6,132.3,130.4,127.6,122.7,121.7,116.5,52.6,47.6,46.1,32.3,31.3,21.5,9.0.

[0181] Example 17 Synthesis of N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-N4)

[0182] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-fluoro-4-trifluoromethylaniline to obtain a white solid, namely FS-N4, with a yield of 0.26 g and a yield of 36.22%. mp 265~271℃. 1 H NMR (400MHz, DMSO-d6) δ9.03(s,1H),7.87(d,J=7.0Hz,2H),7.67(d,J=13.8Hz,1H),7.57(d,J=7.9Hz,1H),7.46(d,J=7.1Hz,3H),7.1 9(d,J=7.5Hz,1H),6.35(d,J=5.6Hz,1H),3.85(s,1H),3.49(s,1H),2.40(s,3H),1.90(s,4H),1.52-1.49(m,2H),1.30-1.27(m,2H). 13 CNMR(100MHz,DMSO-d6)δ188.1,180.7,170.6,161.2,160.1,158.7,154.3,147.0,146.9,14 4.8,137.3,130.5,128.0,124.9,122.2,113.3,105.2,104.9,52.7,47.6,32.3,31.3,21.5.

[0183] Example 18 Synthesis of N-(2-(((1r,4r)-4-(3-(4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-O4)

[0184] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-fluoroaniline to obtain a white solid, namely FS-O4, with a yield of 0.24 g and a yield of 35.69%. mp 292~297℃. 1HNMR(400MHz, DMSO-d6)δ8.38(s,1H),7.85(d,J=8.2Hz,2H),7.52(d,J=7.8Hz,1H),7.44(d,J=8.2Hz,2H),7.39-7.35(m,2H),7.04(t,J=8.9 Hz,2H),6.05(d,J=7.3Hz,1H),3.84(d,J=8.7Hz,1H),3.45(s,1H),2.39(s,3H),1.90(d,J=9.7Hz,4H),1.51-1.40(m,2H),1.28-1.23(m,2H). 13 C NMR (100MHz, DMSO-d6) δ188.1,170.8,158.5,156.1,155.0,144.4,137.4,130.4,127.5,119.6,115.4,52.6,47.4,46.2,32.4,31.6,21.5.

[0185] Example 19 Synthesis of N-(2-(((1r,4r)-4-(3-(4-chlorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-P4)

[0186] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-chloroaniline to obtain a white solid, namely FS-P4, with a yield of 0.19 g and a yield of 26.11%. mp 284~287℃. 1 HNMR(400MHz,DMSO-d6)δ9.13(s,1H),8.59(s,1H),7.84(d,J=8.2Hz,2H),7.42-7.40(m,4H),7.23(d,J=8.9Hz,2H),6.60( d,J=6.6Hz,1H),3.80(d,J=8.1Hz,1H),3.43(s,1H),2.38(s,3H),1.91-1.89(m,4H),1.44-1.35(m,2H),1.26-1.22(m,2H). 13 C NMR (100MHz, DMSO-d6) δ188.2,155.1,140.1,140.2,130.2,128.9,127.6,124.5,119.2,52.3,47.2,45.7,32.1,31.1,21.5.

[0187] Example 20 Synthesis of N-(2-(((1r,4r)-4-(3-(2-chloro-4-nitrophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-Q4)

[0188] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 2-chloro-4-nitroaniline to obtain a white solid, namely FS-Q4, with a yield of 0.19 g and a yield of 25.87%. mp 289~292℃. 1 H NMR (400MHz, DMSO-d6) δ8.54-8.52(m,2H),8.29(d,J=2.7Hz,1H),8.16(dd,J =9.4,2.7Hz,1H),7.85(d,J=8.2Hz,2H),7.54(d,J=8.1Hz,1H),7.43(t,J=7. 0Hz,3H),3.87(d,J=8.1Hz,1H),3.51(d,J=7.4Hz,1H),2.39(s,3H),1.94(d, J=9.3Hz, 4H), 1.50 (dd, J=22.3, 11.3Hz, 2H), 1.27 (dd, J=22.5, 10.8Hz, 2H). 13 C NMR (100MHz, DMSO-d6) δ188.1,170.8,153.6,143.7,140.8,130.4,127.5,125.3,124.1,120.4,118.8,52.5,47.8,46.1,32.2,31.2,21.5.

[0189] Example 21 Synthesis of N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-R4)

[0190] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-trifluoromethylaniline to obtain a white solid, namely FS-R4, with a yield of 0.11 g and a yield of 14.23%. mp 295~299℃. 1H NMR (400MHz, DMSO-d6) δ9.36(s,1H),8.46(s,1H),7.85(d,J=8.2Hz,2H),7.56(q,J=8.9Hz,4H),7.42(d,J=8.1Hz,2H),6.68(d ,J=7.4Hz,1H),3.81(d,J=8.3Hz,1H),3.46(s,1H),2.38(s,3H),1.91(d,J=9.8Hz,4H),1.46-1.38(m,2H),1.29-1.22(m,2H). 13 C NMR(100MHz,DMSO-d6)δ188.2,170.9,154.8,144.9,130.3,127.6,126.5,126.3 9,126.36,123.8,121.3,120.9,117.4,52.3,47.3,45.7,41.7,32.2,31.1,21.5.

[0191] Example 22 Synthesis of N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-S4)

[0192] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-fluoro-3-methylaniline to obtain a white solid, namely FS-S4, with a yield of 0.24 g and a yield of 35.78%. mp 279~282℃. 1 H NMR (400MHz, DMSO-d6) δ8.26(s,1H),7.87(d,J=8.2Hz,2H),7.46(d,J=8.1Hz,2H),7. 41(d,J=8.4Hz,1H),7.26(dd,J=6.9,2.2Hz,1H),7.21-7.12(m,1H),6.97(t,J=9.2Hz, 1H),6.02(d,J=6.5Hz,1H),3.87-3.82(m,1H),3.46(s,1H),2.40(s,3H),2.17(s,3H) ,1.90(d,J=8.0Hz,4H), 1.49(dd,J=22.4,11.4Hz,2H), 1.25(dd,J=22.4,11.3Hz,2H). 13C NMR (100MHz, DMSO-d6) δ188.1,180.6,172.5,170.6,159.9,157.1,155.1,154.8,144.8,137.2,137. 0,130.5,127.6,124.5,124.3,121.0,117.1,115.3,115.1,52.8,47.4,32.4,31.6,21.5,14.9,14.8.

[0193] Example 23 Synthesis of N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-T4)

[0194] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-chloro-3-methylaniline to obtain a white solid, namely FS-T4, with a yield of 0.25 g and a yield of 35.89%. mp 280~285℃. 1 H NMR(400MHz,DMSO-d6)δ8.39(s,1H),7.87(d,J=8.2Hz,2H),7.46(d,J=8.2Hz ,2H),7.41(d,J=8.2Hz,1H),7.35(s,1H),7.23(d,J=3.9Hz,2H),6.09(d,J=6 .5Hz,1H),3.86-3.82(m,1H),3.46(s,1H),2.40(s,3H),2.26(s,3H),1.90(d ,J=7.9Hz,4H),1.49(dd,J=22.2,11.5Hz,2H),1.25(dd,J=22.3,11.3Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ188.1,180.5,170.5,159.8,154.9,144.9,139.9,137.2 ,135.8,130.5,129.3,125.3,120.4,117.2,52.8,47.5,32.4,31.5,21.5,20.3.

[0195] Example 24 Synthesis of N-(2-(((1r,4r)-4-(3-(1,2,3,5,6,7-hexahydro-s-indol-4-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide (FS-U4)

[0196] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 1,2,3,5,6,7-hexahydro-s-indan-4-amine to obtain a white solid, namely FS-U4, with a yield of 0.26 g and a yield of 36.21%. mp 271~274℃. 1 HNMR (400MHz, DMSO-d6) δ7.79(d,J=8.0Hz,2H),7.52(s,1H),7.38(dd,J=14.6,8.4Hz,3H),6.85(s,1H),5.95(d,J=7.5Hz,1H),3.83(d,J=8.3Hz, 1H),3.40(s,1H),2.78(t,J=7.3Hz,4H),2.68(t,J=7.2Hz,4H),2.38(s,3 H),1.97-1.88(m,8H),1.44(dd,J=22.2,11.5Hz,2H),1.27-1.22(m,2H).

[0197] Example 25 Synthesis of N-(3,4-dioxo-2-(((1r,4r)-4-(3-(p-tolyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-V4)

[0198] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by p-toluidine to obtain a white solid, namely FS-V4, with a yield of 0.17 g and a yield of 24.36%. mp 267~271℃. 1 HNMR(400MHz,DMSO-d6)δ8.19(s,1H),7.86(d,J=8.3Hz,2H),7.45(d,J=8.2Hz, 2H),7.41(d,J=8.3Hz,1H),7.24(d,J=8.4Hz,2H),7.01(d,J=8.3Hz,2H),5.98(d ,J=7.2Hz,1H),3.89-3.81(m,1H),3.45(s,1H),2.39(s,3H),2.20(s,3H),1.90 (d,J=9.9Hz,4H),1.48(dd,J=22.2,11.5Hz,2H),1.23(dd,J=21.2,10.5Hz,2H). 13 C NMR (100MHz, DMSO-d6) δ188.1,181.0,170.7,155.1,144.6,138.4,137.6,130.5,130.1,129.5,127.6,118.1,52.7,47.4,32.4,21.6,21.5,20.8.

[0199] Example 26 Synthesis of N-(2-(((1r,4r)-4-(3-benzhydrylureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-W4)

[0200] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by diphenyltoluidine to obtain a white solid, namely FS-W4, with a yield of 0.15 g and a yield of 23.15.0%. mp 290~294℃. 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),7.85(d,J=8.2Hz,2H),7.42(d,J=8.1Hz,2H),7.32-7.18(m,10H),6.99(d,J=8.6Hz,1H),6.08(s,1H),5.8 8(d,J=8.5Hz,1H),3.77(d,J=8.1Hz,1H),3.36(s,1H),2.38(s,3H),1.85(t,J=12.3Hz,4H),1.36(dd,J=21.9,10.8Hz,2H),1.20-1.15(m,2H). 13 C NMR (100MHz, DMSO-d6) δ188.2,170.7,157.1,144.4,130.3,128.8,127.6,127.4,127.1,57.2,52.5,47.4,32.3,31.5,21.5.

[0201] Example 27 Synthesis of N-(2-(((1r,4r)-4-(3-(4-fluorobenzyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-X4)

[0202] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-fluorobenzylamine to obtain a white solid, namely FS-X4, with a yield of 0.14 g and a yield of 23.36%. mp 263~266℃. 1HNMR (400MHz, DMSO-d6) δ8.31 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8. 2Hz,2H),7.28-7.25(m,3H),7.14-7.10(m,2H),6.26(s,1H),5.89(s,1H), 4.16(s,2H),3.79(d,J=8.0Hz,1H),3.37(s,1H),2.39(s,3H),1.86(t,J=1 3.2Hz, 4H), 1.40 (dd, J=22.8, 10.9Hz, 2H), 1.17 (dd, J=22.5, 10.8Hz, 2H). 13 C NMR (100MHz, DMSO-d6) δ170.8,162.7,137.7,130.3,129.4,129.3,127.6,115.4,115.2,47.6,42.5,32.5,31.6,21.5.

[0203] Example 28 Synthesis of N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)benzyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-Y4)

[0204] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-trifluoromethoxybenzylamine to obtain a white solid, namely FS-Y4, with a yield of 0.26 g and a yield of 36.56%. mp 288~291℃. 1 H NMR (400MHz, DMSO-d6) δ8.60(s,1H),7.87(d,J=8.3Hz,2H),7.66(d,J=8.6Hz,1H),7.43(dd,J=8.0,4.7Hz,3H),7.45--7.41(m,3H),6.43(s,1 H),6.07(s,1H),4.21(s,2H),3.76(d,J=8.5Hz,1H),3.36(s,1H),2.39(s,3H),1.86(t,J=12.7Hz,4H),1.41-1.33(m,2H),1.22-1.13(m,2H). 13 C NMR(100MHz,DMSO-d6)δ188.3,170.5,157.9,147.4,144.5,141.2,137.6,134.2,1 31.7,130.4,129.2,127.7,121.6,121.3,52.7,47.5,42.5,41.8,32.4,31.5,21.5.

[0205] Example 29 Synthesis of N-(2-(((1r,4r)-4-(3-(4-chlorobenzyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-Z4)

[0206] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-chlorobenzylamine to obtain a white solid, namely FS-Z4, with a yield of 0.22 g and a yield of 35.56%. mp 253~255℃. 1 HNMR(400MHz,DMSO-d6)δ7.85(d,J=8.3Hz,2H),7.45(d,J=8.1Hz,2H),7.38-7.35(m,3H),7.25(d,J=8.4Hz,2H),6.25(s,1H),5.8 7(s,1H),4.17(s,2H),3.82-3.78(m,1H),3.38(s,1H),2.39(s,3H),1.86(t,J=13.8Hz,4H),1.48-1.40(m,2H),1.24-1.16(m,2H). 13 C NMR (100MHz, DMSO-d6) δ188.1,180.9,170.7,157.8,144.7,140.6,137.5,131.5,130.5,129.3,128.6,127.6,52.8,47.6,42.6,32.5,31.8,21.5.

[0207] Example 30 Synthesis of N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethyl)benzyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-END4)

[0208] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-trifluoromethylbenzylamine to obtain a white solid, namely FS-END4, with a yield of 0.13 g and a yield of 16.32%. mp 266~268℃. 1HNMR (400MHz, DMSO-d6) δ7.85(d,J=8.2Hz,2H),7.67(d,J=8.1Hz,2H),7.45(d,J=8.1Hz,4H),7.39(d,J=8.3Hz,1H),6.35(s,1H),5. 94(s,1H),4.28(s,2H),3.83-3.78(m,1H),3.39(s,1H),2.39(s,3H),1.87(t,J=13.0Hz,4H),1.49-1.40(m,2H),1.23-1.15(m,2H). 13 C NMR (100MHz, DMSO-d6) δ188.1,170.7,157.9,146.6,144.7,137.5,130.5,128.0,127.6,125.5,52.8,47.7,42.9,32.5,31.8,21.5.

[0209] Example 31 Synthesis of tert-butyl ((1r,4r)-4-((2-((2-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate

[0210] The preparation method of this embodiment is the same as that of Example 2, except that p-toluenesulfonamide in Example 2 is replaced by o-toluenesulfonamide to obtain a white solid, namely, tert-butyl ((1r,4r)-4-((2-((2-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate, with a yield of 3.78 g and a yield of 92.13%.

[0211] Example 32 Synthesis of N-(2-(((1r,4r)-4-aminocyclohexyl)amino)-3,4-dioxetane-1-en-1-yl)-2-methylbenzenesulfonamide

[0212] The preparation method of this embodiment is the same as that of Example 3, except that tert-butyl ((1r, 4r)-4-((2-((4-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate in Example 3 is replaced with tert-butyl ((1r, 4r)-4-((2-((2-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate to obtain a white solid, namely N-(2-(((1r, 4r)-4-aminocyclohexyl)amino)-3,4-dioxetane-1-en-1-yl)-2-methylbenzenesulfonamide, with a yield of 3.96 g and a yield of 98.65%.

[0213] Example 33 Synthesis of N-(2-(((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-2-methylbenzenesulfonamide (MH-101)

[0214] The preparation method of this example is the same as that of Example 4, except that N-(2-(((1r,4r)-4-aminocyclohexyl)amino)-3,4-dioxet-1-en-1-yl)-4-methylbenzenesulfonamide in Example 4 is replaced by N-(2-(((1r,4r)-4-aminocyclohexyl)amino)-3,4-dioxet-1-en-1-yl)-2-methylbenzenesulfonamide to obtain a white solid, namely MH-101, with a yield of 0.13 g and a yield of 22.85%. mp 223~226℃. 1 HNMR(400MHz,DMSO-d6)δ8.99(s,1H),7.81(d,J=5.8Hz,1H),7.36(t,J=7.1Hz ,1H),7.26(d,J=7.1Hz,2H),7.16(d,J=7.2Hz,1H),5.53(d,J=7.7Hz,1H),5.41 (s,1H),3.81(s,1H),3.27(s,1H),2.56(s,3H),2.04(s,1H),1.81(t,J=14.0H z,4H),1.67(s,2H),1.50(s,4H),1.31-1.23(m,6H),1.07(s,4H),0.80(s,6H). 13 C NMR (100MHz, DMSO-d6): δ188.75,187.45,173.06,156.94,144.00,136.54,132.10,131.20,127.30,12 6.02,51.48,50.87,48.58,46.21,42.91,40.97,33.00,32.44,32.36,30.62,30.09,26.81,20.52,9.10

[0215] Example 34 Synthesis of N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-2-methylbenzenesulfonamide (MH-102)

[0216] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-fluoro-4-trifluoromethoxyaniline to obtain a white solid, namely MH-102, with a yield of 0.14 g and a yield of 23.25%. mp 231~235℃. 1 HNMR (400MHz, DMSO-d6) δ8.78 (s, 1H), 8.04 (d, J = 7.7Hz, 1H), 7.67 (dd, J = 13. 4,2.3Hz,1H),7.59(t,J=7.3Hz,1H),7.50-7.32(m,4H),7.10(d,J=8.9Hz,1H) ,6.24(d,J=7.5Hz,1H),3.83(d,J=7.9Hz,1H),3.49(d,J=6.9Hz,1H),2.61(s, 3H), 1.90 (d, J=9.7Hz, 4H), 1.48 (dd, J=22.5, 11.3Hz, 2H), 1.31-1.23 (m, 2H). 13 C NMR (100MHz, DMSO-d6): δ188.09,180.82,170.51,155.34,154.59,152.90,141.95,138.68,137.23,134. 13,133.01,129.83,127.00,124.69,119.40,114.02,106.18,105.95,52.65,47.50,32.39,31.38,20.25.

[0217] Example 35 Synthesis of N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-104)

[0218] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-chloro-3-fluoroaniline to obtain a white solid, namely MH-104, with a yield of 0.14 g and a yield of 25.34%. mp 256~258℃. 1H NMR(400MHz, DMSO-d6)δ8.72(s,1H),8.04(d,J=7.3Hz,1H),7.60(dd,J=22.6,9.8Hz,2H),7.53-7.27(m,4H),7.06(d,J=8.4Hz,1H), 6.22(d,J=6.4Hz,1H),3.82(s,1H),3.47(s,1H),2.61(s,3H),1.90(d,J=8.4Hz,4H),1.47(d,J=10.9Hz,2H),1.26(d,J=12.1Hz,2H). 13 CNMR (100MHz, DMSO-d6): δ188.07,170.59,158.79,156.38,154.61,141.80,138.89,137.22,134.01, 132.96,130.71,129.75,126.95,114.87,114.84,110.57,105.81,52.59,47.49,32.40,31.39,20.27.

[0219] Example 36 Synthesis of N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-105)

[0220] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-chloro-4-fluoroaniline to obtain a white solid, namely MH-105, with a yield of 0.17 g and a yield of 28.58%. mp 257~259℃. 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H),8.04(d,J=7.8Hz,1H),7.74(d,J=5.0Hz,1H),7. 59(t,J=7.4Hz,1H),7.43(t,J=7.7Hz,2H),7.36(d,J=8.1Hz,1H),7.26(t,J=9.0Hz,1H ),7.19(d,J=8.0Hz,1H),6.14(d,J=7.2Hz,1H),3.82(d,J=8.0Hz,1H),3.47(s,1H),2 .61(s,3H),1.90(d,J=11.3Hz,4H),1.48(dd,J=22.8,11.5Hz,2H),1.33-1.21(m,2H). 13CNMR (100MHz, DMSO-d6): δ188.09,180.82,170.51,154.80,153.45,151.07,138.27,137.28,134.14, 133.01,129.83,127.00,119.52,119.17,118.10,117.27,117.06,52.68,47.51,32.41,31.45,20.25.

[0221] Example 37 Synthesis of N-(3,4-dioxo-2-((4-(3-(p-tolyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-106)

[0222] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by p-toluidine to obtain a white solid, namely MH-106, with a yield of 0.13 g and a yield of 22.14%. mp 235~238℃. 1 HNMR(400MHz,DMSO-d6)δ8.18(s,1H),8.04(d,J=7.7Hz,1H),7.59(t,J=7.2Hz,1 H),7.43(t,J=7.6Hz,2H),7.36(d,J=8.2Hz,1H),7.25(d,J=8.3Hz,2H),7.01(d,J =8.2Hz,2H),5.98(s,1H),3.82(d,J=7.6Hz,1H),3.46(s,1H),2.61(s,3H),2.21( s,3H),1.90(d,J=10.3Hz,4H),1.47(dd,J=22.1,11.5Hz,2H),1.29-1.19(m,2H). 13 C NMR (100MHz, DMSO-d6): δ188.09,180.73,170.49,160.68,155.05,138.62,138.39,137.24,134. 14,133.02,130.10,129.86,129.49,127.02,118.12,52.72,47.35,32.44,31.61,20.75,20.25.

[0223] Example 38 Synthesis of N-(2-(((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-107)

[0224] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 2-chloro-4-cyanoaniline to obtain a white solid, namely MH-107, with a yield of 0.22 g and a yield of 31.11%. mp 242~246℃. 1 H NMR (400MHz, DMSO-d6) δ8.45(d,J=8.8Hz,1H),8.36(s,1H),8.06(d,J=7.8Hz,1H),7.98 (d,J=1.4Hz,1H),7.70(d,J=8.8Hz,1H),7.60(t,J=7.4Hz,1H),7.44(t,J=7.4Hz,2H),7 .38(d,J=8.2Hz,1H),7.31(d,J=7.3Hz,1H),3.86(d,J=7.9Hz,1H),3.51(d,J=6.9Hz,1H ),2.62(s,3H),1.94(d,J=9.2Hz,4H),1.51(dd,J=22.3,11.2Hz,2H),1.35-1.13(m,2H). 13 CNMR (100MHz, DMSO-d6): δ188.08,180.53,170.43,160.38,153.81,141.81,138.47,137.26,134.24, 133.04,132.38,129.93,127.04,120.85,119.70,118.53,103.99,52.59,47.65,32.22,31.24,20.24.

[0225] Example 39 Synthesis of N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-108)

[0226] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-fluoro-3-trifluoromethylaniline to obtain a white solid, namely MH-108, with a yield of 0.14 g and a yield of 26.54%. mp 268~271℃. 1H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.04(d,J=7.6Hz,1H),7.96(d,J=4.2Hz,1H),7.65-7.49(m,2H),7.50-7.27(m,4H),6.20(d,J=6.7 Hz,1H),3.83(d,J=7.4Hz,1H),3.49(s,1H),2.62(s,3H),1.91(d,J=8.4Hz,4H),1.48(d,J=11.2Hz,2H),1.28(dd,J=23.1,11.7Hz,2H). 13 C NMR (100MHz, DMSO-d6): δ188.10,180.81,170.53,160.80,154.87,138.68,137.86,137.24,134.12,133. 01,129.82,126.99,124.51,123.75,121.80,117.95,117.73,115.63,52.68,47.59,32.42,31.41,20.24.

[0227] Example 40 Synthesis of N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-109)

[0228] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-fluoro-4-methylaniline to obtain a white solid, namely MH-109, with a yield of 0.16 g and a yield of 25.13%. mp 251~254℃. 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),8.05(d,J=7.8Hz,1H),7.59(t,J=7.3Hz,1 H),7.50-7.31(m,4H),7.08(t,J=8.6Hz,1H),6.91(d,J=8.0Hz,1H),6.08(d,J=6 .5Hz,1H),3.83(d,J=8.1Hz,1H),3.47(s,1H),2.62(s,3H),2.13(s,3H),1.90( d, J=10.0Hz, 4H), 1.48 (dd, J=22.4, 11.3Hz, 2H), 1.25 (dd, J=22.6, 11.0Hz, 2H). 13C NMR (100MHz, DMSO-d6): δ188.10,170.42,162.16,159.78,154.83,140.38,138.49,137.26,134.23,133.04, 131.63,129.92,127.03,116.30,113.58,104.83,104.56,52.73,49.06,47.40,32.40,31.51,20.23,13.93.

[0229] Example 41 Synthesis of N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-110)

[0230] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-chloro-3-trifluoromethylaniline to obtain a white solid, namely MH-110, with a yield of 0.18 g and a yield of 28.69%. mp 235~239℃. 1 HNMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.88 (s, 1H), 8.07 (s, 1H), 7.83 (d, J = 5.8Hz, 1H), 7.53 (s, 2H), 7.36 (t, J = 7.1Hz, 1H), 7.26 (d, J = 6.1Hz, 2H),7.19(s,1H),6.29(d,J=7.6Hz,1H),3.86(s,1H),3.45(s,1H),2.5 7(s,3H),1.88(d,J=9.6Hz,4H),1.46-1.34(m,2H),1.34-1.24(m,2H). 13 C NMR (100MHz, DMSO-d6): δ187.43,173.81,173.13,154.68,144.08,140.63,136.54,132.27,132.07,131.15,127 .20,126.90,125.99,124.71,122.74,122.00,121.72,116.51,51.31,47.83,46.23,32.90,31.54,20.52,9.09.

[0231] Example 42 Synthesis of N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-111)

[0232] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-chloro-4-trifluoromethylaniline to obtain a white solid, namely MH-111, with a yield of 0.10 g and a yield of 20.13%. mp 236~238℃. 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),7.89(s,1H),7.84(d,J=6.1Hz,1H),7.67(d,J=8.7Hz,1H),7.37(t,J=8.1Hz,2H),7.33-7.12(m,3H ), 6.39 (d, J = 7.5Hz, 1H), 3.87 (s, 1H), 3.46 (s, 1H), 2.58 (s, 3H), 1.89 (d, J = 9.9Hz, 4H), 1.39 (d, J = 11.2Hz, 2H), 1.28 (d, J = 11.6Hz, 2H). 13 C NMR (100MHz, DMSO-d6): δ188.91,187.37,173 / 13,154.33,145.86,136.54,132.08,131.61,131.19,128.82, 127.31,126.01,125.11,122.41,119.28,118.82,118.51,115.89,51.33,47.86,46.28,32.88,31.48,20.52.

[0233] Example 43 Synthesis of N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-112)

[0234] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-fluoro-4-trifluoromethylaniline to obtain a white solid, namely MH-112, with a yield of 0.11 g and a yield of 20.14%. mp 239~242℃. 1H NMR(600MHz,DMSO-d6)δ9.05(s,1H),7.83(d,J=6.7Hz,1H),7.68(d,J=14.2Hz,1 H),7.58(t,J=8.7Hz,1H),7.36(d,J=6.9Hz,1H),7.27(d,J=4.9Hz,2H),7.20(d,J =8.5Hz,2H),6.40(d,J=7.6Hz,1H),3.86(s,1H),3.46(s,1H),2.57(s,3H),1.89 (d, J=10.2Hz, 4H), 1.39 (dd, J=22.4, 11.5Hz, 2H), 1.28 (dd, J=22.1, 11.4Hz, 2H). 13 C NMR (150MHz, DMSO-d6): δ188.89,187.39,173.79,173.11,161.14,158.67,154.33,146.97,144.04,136. 54,132.09,131.18,127.95,127.29,126.01,113.30,105.16,104.91,51.31,47.80,32.86,31.48,20.52.

[0235] Example 44 Synthesis of N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-113)

[0236] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-trifluoromethoxyaniline to obtain a white solid, namely MH-113, with a yield of 0.25 g and a yield of 38.23%. mp 249~251℃. 1 H NMR (400MHz, DMSO-d6) δ8.67(s,1H),7.83(d,J=5.5Hz,1H),7.48(d,J=8.7Hz,2H),7.36(d,J=6.7Hz,1H),7.30-7.13(m,5H),6 .23(d,J=7.3Hz,1H),3.86(s,1H),3.43(s,1H),2.57(s,3H),1.88(d,J=9.9Hz,4H),1.44-1.32(m,2H),1.24(d,J=10.5Hz,2H). 13CNMR (100MHz, DMSO-d6): δ187.39,173.15,154.89,144.03,142.40,140.36,136.55,132.09,13 1.19,127.30,126.01,122.01,119.42,119.02,51.34,47.65,46.12,32.88,31.65,20.53,9.02.

[0237] Example 45 Synthesis of N-(2-(((1r,4r)-4-(3-(4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-114)

[0238] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-fluoroaniline to obtain a white solid, namely MH-114, with a yield of 0.18 g and a yield of 29.12%. mp 241~245℃. 1 HNMR(400MHz, DMSO-d6)δ8.42(s,1H),7.99(d,J=7.7Hz,1H),7.66-7.46(m,2H),7.38(dd,J=7.9,3.8Hz,4H),7.05(t,J=8.8Hz,2H),6.09 (d,J=7.3Hz,1H),3.83(d,J=7.5Hz,1H),3.45(s,1H),2.61(s,3H),2.01-1.75(m,4H),1.44(dd,J=22.0,11.1Hz,2H),1.30-1.22(m,2H). 13 CNMR (100MHz, DMSO-d6): δ187.91,171.30,158.46,156.10,155.06,140.40,137.38,137.36,137.06,133.17 ,132.69,129.10,126.65,119.62,119.54,115.63,115.41,52.25,49.07,47.48,46.17,32.57,31.56,20.37.

[0239] Example 46 Synthesis of N-(2-(((1r,4r)-4-(3-(4-chlorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-115)

[0240] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-chloroaniline to obtain a white solid, namely MH-115, with a yield of 0.17 g and a yield of 28.56%. mp 237~240℃. 1 HNMR (400MHz, DMSO-d6) δ8.47(s,1H),8.04(d,J=7.7Hz,1H),7.59(t,J=7.3Hz,1H),7.40(td,J=15.3,8.0Hz,5H),7.25(d,J=8.7Hz,2H),6.09(d,J= 6.9Hz,1H),3.83(d,J=7.7Hz,1H),3.47(s,1H),2.61(s,3H),1.90(d,J=1 0.2Hz, 4H), 1.48 (dd, J=22.4, 11.2Hz, 2H), 1.25 (dd, J=22.7, 11.4Hz, 2H). 13 C NMR (100MHz, DMSO-d6): δ188.08,180.79,170.50,160.81,154.81,139.96,138.66,137.23,1 34.15,133.02,129.84,128.93,127.01,124.85,119.48,52.68,47.41,32.41,31.51,20.25.

[0241] Example 47 Synthesis of N-(2-(((1r,4r)-4-(3-(2-chloro-4-nitrophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-116)

[0242] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 2-chloro-4-nitroaniline to obtain a white solid, namely MH-116, with a yield of 0.22 g and a yield of 34.12%. mp 239~244℃. 1H NMR (600MHz, DMSO-d6) δ8.53(d,J=9.3Hz,2H),8.29(s,1H),8.16(d,J=9.2Hz,1H),8.05(d,J=7.8Hz,1H),7.59(t,J=7.3Hz,1H),7.50-7.33(m,4 H),3.96-3.74(m,1H),3.52(d,J=7.0Hz,1H),2.62(s,3H),1.94(t,J=11.4Hz,4H),1.51(dd,J=22.4,10.9Hz,2H),1.27(dd,J=22.5,11.0Hz,2H). 13 C NMR (150MHz, DMSO-d6): δ188.05,180.91,170.56,153.64,143.65,140.84,138.73,137.22,134. 10,133.00,129.80,126.99,125.27,124.09,120.39,118.76,52.52,47.75,32.22,31.19,20.25.

[0243] Example 48 Synthesis of N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-117)

[0244] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-trifluoromethylaniline to obtain a white solid, namely MH-117, with a yield of 0.15 g and a yield of 23.56%. mp 235~239℃. 1 H NMR (400MHz, DMSO-d6) δ8.79(s,1H),7.87(d,J=6.6Hz,1H),7.64-7.48(m,4H),7.39(d,J=6.8Hz,1H),7.30(d,J=6.0Hz,3H),6.26( d,J=7.5Hz,1H),3.85(s,1H),3.48(s,2H),2.58(s,3H),1.90(d,J=11.1Hz,4H),1.41(dd,J=22.4,11.3Hz,2H),1.32-1.22(m,2H). 13CNMR (100MHz, DMSO-d6): δ187.51,172.66,154.60,144.71,136.67,132.25,131.72,126.47, 126.42,126.38,126.19,123.78,121.48,121.17,117.61,51.56,46.21,32.80,31.56,20.48.

[0245] Example 49 Synthesis of N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-118)

[0246] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-fluoro-3-methylaniline to obtain a white solid, namely MH-118, with a yield of 0.12 g and a yield of 21.45%. mp 234~237℃. 1 H NMR (600MHz, DMSO-d6) δ8.26 (s, 1H), 8.05 (d, J = 7.7Hz, 1H), 7.59 (t, J = 7.3Hz, 1H), 7.44 (t,J=8.3Hz,2H),7.37(d,J=8.1Hz,1H),7.26(d,J=5.0Hz,1H),7.23-7.14(m,1H),6.97 (t,J=9.2Hz,1H),6.02(d,J=5.7Hz,1H),3.83(d,J=8.1Hz,1H),3.46(s,1H),2.61(s,3H ),2.17(s,3H),1.90(d,J=9.3Hz,4H),1.48(dd,J=22.3,11.3Hz,2H),1.29-1.22(m,2H). 13 CNMR (150MHz, DMSO-d6): δ188.09,170.47,155.04,154.76,138.57,137.24,136.95,134.19,133.03,129 .87,127.02,124.45,124.27,120.95,117.02,115.28,115.05,52.72,47.43,32.43,31.56,20.24,14.84.

[0247] Example 50 Synthesis of N-(2-(((1r,4r)-4-(3-(3-chloro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-119)

[0248] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-chloro-4-methylaniline to obtain a white solid, namely MH-119, with a yield of 0.16 g and a yield of 26.89%. mp 263~267℃. 1 H NMR (600MHz, DMSO-d6) δ8.43(s,1H),8.05(d,J=7.8Hz,1H),7.64(d,J=2.0Hz,1H),7.59(t,J =7.3Hz,1H),7.44(t,J=8.2Hz,2H),7.37(d,J=8.3Hz,1H),7.16(d,J=8.4Hz,1H),7.08(dd,J =8.3,1.7Hz,1H),6.09(d,J=7.2Hz,1H),3.91-3.76(m,1H),3.47(s,1H),2.61(s,3H),2.23( s, 3H), 1.90 (d, J = 9.4Hz, 4H), 1.48 (dd, J = 22.3, 11.4Hz, 2H), 1.25 (dd, J = 22.3, 11.1Hz, 2H). 13 C NMR (150MHz, DMSO-d6): δ188.05,170.71,154.82,140.17,139.10,137.18,133.91,133.46,132. 94,131.48,129.62,127.67,126.92,117.96,116.76,52.57,47.48,32.45,31.50,20.26,19.19.

[0249] Example 51 Synthesis of N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-120)

[0250] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-chloro-3-methylaniline) to obtain a white solid, namely MH-120, with a yield of 0.13 g and a yield of 23.26%. mp 235~239℃. 1H NMR(600MHz,DMSO-d6)δ8.38(s,1H),8.03(d,J=7.8Hz,1H),7.58(t,J=7.3Hz,1 H),7.51-7.40(m,2H),7.35(dd,J=12.9,5.0Hz,2H),7.29-7.19(m,2H),6.08(d, J=7.4Hz,1H),3.83(dd,J=8.0,4.2Hz,1H),3.46(d,J=6.8Hz,1H),2.61(s,3H), 2.26(s,3H),1.89(d,J=9.8Hz,4H),1.47(dd,J=22.2,11.6Hz,2H),1.23(s,2H). 13 C NMR (150MHz, DMSO-d6): δ188.06,170.64,154.84,139.91,138.93,137.20,135.79,134. 00,132.97,129.69,126.96,125.24,120.39,117.20,52.60,47.46,32.44,31.51,20.30.

[0251] Example 52 Synthesis of N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-121)

[0252] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-chloro-4-trifluoromethoxyaniline to obtain a white solid, namely MH-121, with a yield of 0.11 g and a yield of 21.56%. mp 232~237℃. 1 H NMR (600MHz, DMSO-d6) δ8.75(s,1H),8.05(d,J=7.8Hz,1H),7.84(d,J=2.5Hz,1H),7.59(t,J=7.3Hz,1H),7.48-7.36(m,4H),7.29(dd,J=9.0, 2.4Hz,1H),3.83(dd,J=7.9,3.9Hz,1H),3.58-3.42(m,1H),2.62(s,3H),2.01-1.85(m,4H),1.49(dd,J=22.1,11.7Hz,2H),1.33-1.23(m,2H). 13C NMR (150MHz, DMSO-d6): δ188.05,170.71,154.82,140.17,139.10,137.18,133.46,132.94, 131.48,129.62,127.67,126.92,117.96,116.76,52.57,47.48,32.45,31.50,20.26,19.19.

[0253] Example 53 Synthesis of N-(2-(((1r,4r)-4-(3-(1,2,3,5,6,7-hexahydro-s-indol-4-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-2-methylbenzenesulfonamide (MH-122)

[0254] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 1,2,3,5,6,7-hexahydro-s-indan-4-amine to obtain a white solid, namely MH-122, with a yield of 0.15 g and a yield of 24.16%. mp 278~281℃. 1 HNMR (400MHz, DMSO) δ8.03(d,J=7.8Hz,1H),7.58(t,J=7.3Hz,1H),7.53(s,1H),7.43(d,J=7.5Hz,2H),7.35(d,J=7.9Hz,1H),6.85(s,1H),5.95 (s,1H),3.80(s,1H),3.43(s,1H),2.78(t,J=7.0Hz,4H),2.68(t,J=7.0 Hz,4H),2.60(s,3H),1.98-1.88(m,8H),1.47-1.41(m,2H),1.24(s,2H).

[0255] Example 54 Synthesis of tert-butyl ((1r,4r)-4-((3,4-dioxo-2-((phenylmethyl)sulfonamido)cyclobut-1-en-1-yl)amino)cyclohexyl)carbamate

[0256] The preparation method of this embodiment is the same as that of Example 2, except that p-toluenesulfonamide in Example 2 is replaced by benzenesulfonamide to obtain a white solid, namely, tert-butyl ((1r,4r)-4-((3,4-dioxo-2-((phenylmethyl)sulfonamido)cyclobut-1-en-1-yl)amino)cyclohexyl)carbamate, with a yield of 4.56 g and a yield of 98.13%.

[0257] Example 55 Synthesis of N-(2-(((1r,4r)-4-aminocyclohexyl)amino)-3,4-dioxetane-1-en-1-yl)-1-phenylmethanesulfonamide

[0258] The preparation method of this embodiment is the same as that of Example 3, except that tert-butyl ((1r, 4r)-4-((2-((4-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate in Example 3 is replaced with tert-butyl ((1r, 4r)-4-((2-((2-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate to obtain a white solid, namely N-(2-(((1r, 4r)-4-aminocyclohexyl)amino)-3,4-dioxetane-1-en-1-yl)-1-phenylmethanesulfonamide, with a yield of 5.69 g and a yield of 99.18%.

[0259] Example 56 Synthesis of N-(2-((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)amino)-3,4-dioxetane-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-101)

[0260] The preparation method of this example is the same as that of Example 4, except that N-(2-(((1r, 4r)-4-aminocyclohexyl)amino)-3,4-dioxetane-1-ene-1-yl)-4-methylbenzenesulfonamide in Example 4 is replaced by N-(2-(((1r, 4r)-4-aminocyclohexyl)amino)-3,4-dioxetane-1-ene-1-yl)-1-phenylmethanesulfonamide to obtain a white solid, namely ZS-101, with a yield of 0.11 g and a yield of 22.58%. mp 248~251℃. 1 HNMR (400MHz, DMSO-d6) δ7.38(d,J=2.7Hz,3H),7.36(s,2H),7.01(d,J=8.2Hz,1H),5.53(s,1H),5.42(s,1H),4.83(s,2H),3.77-3.67(m,1 H),3.27(s,1H),2.04(s,1H),1.81(t,J=11.1Hz,4H),1.67(s,2H),1.49(s,4H),1.36-1.20(m,6H),1.10(s,1H),1.07(s,3H),0.80(s,6H). 13C NMR (100MHz, DMSO-d6): δ187.69,181.19,170.14,160.66,156.93,131.40,129.13,60.3 6,52.64,51.50,50.86,48.58,47.05,42.90,40.97,32.49,32.36,31.77,30.61,30.09.

[0261] Example 57 Synthesis of N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-102)

[0262] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-fluoro-4-trifluoromethoxyaniline to obtain a white solid, namely ZS-102, with a yield of 0.14 g and a yield of 23.89%. mp 234~239℃. 1 HNMR(400MHz, DMSO-d6)δ8.75(s,1H),7.67(dd,J=13.5,2.4Hz,1H),7.38(t,J=8.6Hz,1H),7.28(s,5H),7.12-7.10(m,1H ),7.03(s,1H),6.23(d,J=7.7Hz,1H),4.31(s,2H),3.73(s,1H),3.40(s,1H),1.84(t,J=10.8Hz,4H),1.35-1.24(m,4H). 13 C NMR (100MHz, DMSO-d6): δ188.57,186.82,174.66,173.18,155.34,154.58,152.89,141.99,141.89,131. 09,128.36,127.69,124.65,121.96,119.41,114.03,106.19,105.95,60.46,47.84,46.26,32.87,31.61.

[0263] Example 58 Synthesis of N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-103)

[0264] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-trifluoromethoxyaniline to obtain a white solid, namely ZS-102, with a yield of 0.22 g and a yield of 34.25%. mp 270~273℃. 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),7.47(d,J=9.0Hz,2H),7.39(d,J=2.3Hz,3H),7.37(s,2H),7.21(d,J=8.6Hz,2H),7.06(d,J=8.2Hz,1H), 6.11(d,J=7.5Hz,1H),4.84(s,2H),3.77(d,J=7.9Hz,1H),3.46(d,J=7.6Hz,1H),1.89(d,J=9.5Hz,4H),1.44-1.35(m,2H),1.30-1.21(m,2H). 13 C NMR (100MHz, DMSO-d6): δ206.89,187.70,181.28,170.20,154.84,142.46,140.28,131.40,129. 33,129.21,,129.12,122.03,121.95,119.41,119.08,60.38,52.57,47.43,32.41,31.42,31.14.

[0265] Example 59 Synthesis of N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-104)

[0266] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-chloro-3-fluoroaniline to obtain a white solid, namely ZS-104, with a yield of 0.17 g and a yield of 28.45%. mp 249~252℃. 1 H NMR (400MHz, DMSO-d6) δ8.69 (s, 1H), 7.63 (d, J = 12.5Hz, 1H), 7.38 (t, J = 8.7Hz, 1H), 7.28 (s, 5H), 7.14-6. 97(m,2H),6.21(d,J=7.5Hz,1H),4.31(s,2H),3.73(s,1H),3.39(s,1H),1.84(s,4H),1.33-1.23(m,4H). 13C NMR (100MHz, DMSO-d6): δ188.55,186.83,174.63,173.19,158.79,156.38,154.59,141.73,131.10,1 30.69,,128.37,127.70,114.88,110.71,110.53,106.08,105.82,60.46,51.39,47.81,32.88,31.64.

[0267] Example 60 Synthesis of N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-105)

[0268] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-chloro-4-fluoroaniline to obtain a white solid, namely ZS-105, with a yield of 0.14 g and a yield of 22.54%. mp 268~270℃. 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),7.96(dd,J=6.5,2.6Hz,1H),7.62-7.47(m,1H),7.38(dt,J=12.8,6.6Hz,6H),7.04(d,J=8.2Hz,1H),6.19(d, J=7.7Hz,1H),4.84(s,2H),3.77(d,J=8.3Hz,1H),3.46(d,J=7.5Hz,1H), 1.89(d,J=10.6Hz,4H), 1.39(dd,J=22.6,11.5Hz,2H), 1.29-1.21(m,2H). 13 C NMR (100MHz, DMSO-d6): δ187.72,181.13,170.13,154.86,137.85,137.82,131.41,1 29.25,129.14,123.75,117.97,117.76,115.56,60.36,52.59,47.55,32.41,31.33.

[0269] Example 61 Synthesis of N-(3,4-dioxo-2-(((1r,4r)-4-(3-(p-tolyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-106)

[0270] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by p-toluidine to obtain a white solid, namely ZS-106, with a yield of 0.16 g and a yield of 24.75%. mp 250~253℃. 1 HNMR(600MHz,DMSO-d6)δ8.20(s,1H),7.44-7.38(m,3H),7.36(d,J=3.3Hz,2H),7.25(d,J=8.3Hz,2H),7.05(d,J=8.3Hz,1H),7.01(d,J=8.3Hz,2H ),5.98(d,J=7.5Hz,1H),4.84(s,2H),3.87-3.67(m,1H),3.55-3.33(m,1 H),2.21(s,3H),1.93-1.83(m,4H),1.43-1.35(m,2H),1.32-1.23(m,2H). 13 C NMR (150MHz, DMSO-d6): δ187.70,181.20,170.16,160.70,155.05,138.39,131.40,130. 11,129.48,129.29,129.23,129.13,118.13,60.36,52.60,47.33,32.43,31.52,20.75.

[0271] Example 62 Synthesis of N-(2-(((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-107)

[0272] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 2-chloro-4-cyanoaniline to obtain a white solid, namely ZS-107, with a yield of 0.23 g and a yield of 32.59%. mp 249~252℃. 1 H NMR (400MHz, DMSO-d6) δ8.44(d,J=8.8Hz,1H),8.36(s,1H),7.98(d,J=1.8Hz,1H),7.69(dd,J=8.8,1.8Hz,1H) ,7.37-7.21(m,6H),7.03(s,1H),4.32(s,2H),3.75(s,1H),3.41(s,1H),1.94-1.79(m,4H),1.40-1.21(m,4H). 13C NMR (150MHz, DMSO-d6): δ153.79,141.85,133.30,132.37,131.09,128.37,127.70 ,120.83,119.72,118.58,103.92,60.45,51.25,47.98,46.23,32.71,31.46,9.10.

[0273] Example 63 Synthesis of N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-108)

[0274] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-fluoro-3-methylaniline to obtain a white solid, namely ZS-108, with a yield of 0.17 g and a yield of 26.88%. mp 254~259℃. 1 H NMR (600MHz, DMSO-d6) δ8.30 (s, 1H), 7.34-7.22 (m, 6H), 7.22-7.12 (m, 1H), 7.03 (d, J = 6.2Hz, 1H), 6.96 (t, J = 9.2Hz, 1H), 6 .05(d,J=7.4Hz,1H),4.31(s,2H),3.73(s,1H),3.38(s,1H),2.17(d,J=1.1Hz,3H),1.89-1.76(m,4H),1.35-1.21(m,4H). 13 C NMR (150MHz, DMSO-d6): δ188.57,186.82,157.07,155.06,154.72,137.01,131.09,128.36,127.68,124. 41,124.24,120.94,120.90,117.06,116.99,115.25,115.02,60.46,47.75,46.17,32.91,31.78,14.83.

[0275] Example 64 Synthesis of N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-109)

[0276] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-fluoro-4-methylaniline to obtain a white solid, namely ZS-109, with a yield of 0.14 g and a yield of 24.13%. mp 240~244℃. 1 HNMR(600MHz, DMSO-d6)δ8.49(s,1H),7.38(dd,J=12.7,1.9Hz,1H),7.32-7.22(m,5H),7.08(t,J=8.7Hz,1H),7.03(s,1H),6.90(dd, J=8.2,2.0Hz,1H),6.11(d,J=7.5Hz,1H),4.31(s,2H),3.72(s,1H),3.37(s,1H),2.13(s,3H),1.88-1.76(m,4H),1.35-1.21(m,4H). 13 C NMR (150MHz, DMSO-d6): δ188.50,186.82,162.15,159.77,154.84,140.56,140.45.131.68,131.61,131. 09,128.37,127.70,116.21,116.03,113.52,104.79,104.52,60.45,47.70,46.12,32.88,31.73,13.95.

[0277] Example 65 Synthesis of N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-110)

[0278] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-chloro-3-trifluoromethylaniline to obtain a white solid, namely ZS-110, with a yield of 0.15 g and a yield of 26.69%. mp 258~260℃. 1 H NMR (600MHz, DMSO-d6) δ8.85(s,1H),8.08(s,1H),7.54(s,2H),7.46-7.27(m,5H),7.05(d,J=8.3Hz,1H),6.26(d,J=7.7Hz,1 H),4.85(s,2H),3.82-3.72(m,1H),3.52-3.42(m,1H),1.92-1.82(m,4H),1.40(dd,J=22.2,11.5Hz,2H),1.33-1.21(m,2H). 13C NMR (150MHz, DMSO-d6): δ187.72,181.22,170.12,160.51,154.66,140.55,132.29,131. 41,129.24,129.13,122.75,121.79,116.57,116.52,60.36,52.58,47.57,32.39,31.28.

[0279] Example 66 Synthesis of N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-111)

[0280] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-chloro-4-trifluoromethylaniline to obtain a white solid, namely ZS-111, with a yield of 0.19 g and a yield of 33.15%. mp 273~277℃. 1 H NMR (600MHz, DMSO-d6) δ8.99(s,1H),7.87(s,1H),7.67(d,J=8.8Hz,1H),7.40(d,J=2.4Hz,3H),7.36(d,J=3.9Hz,3H),7.05(d,J=8.2Hz, 1H), 6.36 (d, J = 7.7Hz, 1H), 4.85 (s, 2H), 3.83-3.73 (m, 1H), 3.51-3.42 (m, 1H), 1.98-1.80 (m, 4H), 1.43-1.37 (m, 2H), 1.32-1.26 (m, 2H). 13 C NMR (150MHz, DMSO-d6): δ187.71,181.16,170.13,160.60,154.33,145.80,131.62,129.13,128. 85,128.80,125.09,122.39,119.26,118.86,118.55,115.88,60.36,52.55,47.58,32.36,31.22.

[0281] Example 67 Synthesis of N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-112)

[0282] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-fluoro-4-trifluoromethylaniline to obtain a white solid, namely ZS-112, with a yield of 0.15 g and a yield of 25.14%. mp 250~254℃. 1 H NMR (600MHz, DMSO-d6) δ9.06(s,1H),7.67(d,J=14.1Hz,1H),7.58(t,J=8.6Hz,1H),7.38(s,3H),7.36(d,J=3.2Hz,2H),7.19(d,J=8.1Hz ,1H),7.09(d,J=8.5Hz,1H),4.80(s,2H),3.80-3.75(m,1H),3.50-3.44(m,1H),1.94-1.83(m,4H),1.42-1.36(m,2H),1.31-1.25(m,2H). 13 C NMR (150MHz, DMSO-d6): δ187.63,181.85,170.42,154.34,147.05,146.93,131.37,129.58,1 29.06,127.98,124.89,122.21,113.30,105.17,104.91,60.37,52.43,47.56,32.38,31.24.

[0283] Example 68 Synthesis of N-(2-(((1r,4r)-4-(3-(3,5-difluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-113)

[0284] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3,5-difluoroaniline to obtain a white solid, namely ZS-113, with a yield of 0.24 g and a yield of 34.23%. mp 247~252℃. 1HNMR(600MHz, DMSO-d6)δ8.79(s,1H),7.42-7.28(m,5H),7.11(dd,J=10.0,2.1Hz,2H),7.07(d,J=8.2Hz,1H),6.68(tt,J=9.3,2.3Hz,1H),6.27(d,J =7.7Hz,1H),4.71(s,2H),3.86-3.65(m,1H),3.51-3.34(m,1H),1.87(d,J =8.7Hz, 4H), 1.37 (dd, J = 22.6, 11.1Hz, 2H), 1.26 (dd, J = 22.5, 10.9Hz, 2H). 13 C NMR (150MHz, DMSO-d6): δ187.48,183.15,170.94,164.34,154.50,143.72,131. 32,130.15,128.93,100.81,100.52,96.27,60.39,52.25,47.57,32.50,31.36.

[0285] Example 69 Synthesis of N-(2-(((1r,4r)-4-(3-(3-chloro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-114)

[0286] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-chloro-4-methylaniline to obtain a white solid, namely ZS-114, with a yield of 0.11 g and a yield of 19.83%. mp 262~267℃. 1 H NMR (400MHz, DMSO-d6) δ8.45(s,1H),7.64(d,J=2.1Hz,1H),7.27(d,J=9.0Hz,5H),7.16(d,J=8.4Hz,1H),7.08(dd,J=8.3,2.1Hz,1H),7.0 3(d,J=5.6Hz,1H),6.11(d,J=7.7Hz,1H),4.32(s,2H),3.73(s,1H),3.37(s,1H),2.22(s,3H),1.84(t,J=11.3Hz,4H),1.37-1.21(m,4H). 13C NMR (100MHz, DMSO-d6): δ188.38,186.84,173.14,172.46,154.83,140.22,133.45,131.10 ,128.39,127.61,117.94,116.74,60.46,51.42,47.77,46.20,32.89,31.71,19.20,9.08.

[0287] Example 70 Synthesis of N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-115)

[0288] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-chloro-3-methylaniline to obtain a white solid, namely ZS-115, with a yield of 0.18 g and a yield of 29.56%. mp 239~244℃. 1 H NMR (600MHz, DMSO-d6) δ8.45 (s, 1H), 7.36 (d, J = 2.1Hz, 1H), 7.31-7.26 (m, 5H), 7.22 (dd, J = 12.6, 5.5Hz, 2H), 7.04 (d, J = 5. 9Hz,1H),6.14(d,J=7.3Hz,1H),4.31(s,2H),3.73(s,1H),3.37(s,1H),2.25(s,3H),1.89-1.75(m,4H),1.35-1.19(m,4H). 13 C NMR (150MHz, DMSO-d6): δ187.72,181.14,170.13,160.57,154.61,141.37,137.87,131.41,1 29.26,129.13,126.53,124.03,119.40,119.00,117.71,60.37,52.58,47.53,32.38,31.29.

[0289] Example 71 Synthesis of N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-116)

[0290] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-chloro-4-trifluoromethoxyaniline to obtain a white solid, namely ZS-116, with a yield of 0.26 g and a yield of 33.58%. mp 247~252℃. 1 H NMR (400MHz, DMSO-d6) δ8.75(s,1H),7.84(d,J=2.0Hz,1H),7.38(d,J=7.8Hz,5H),7.29(dd,J=9.0,2.2Hz,1H),7.06(d,J=8.1Hz,1H) ,6.24(d,J=7.5Hz,1H),4.85(s,2H),3.78(d,J=7.9Hz,1H),3.46(s,1H),1.89(d,J=9.7Hz,4H),1.44-1.36(m,2H),1.32-1.23(m,2H). 13 C NMR (100MHz, DMSO-d6): δ187.72,181.14,170.13,160.57,154.61,141.37,137.87,131.41,129. 26,129.13,126.53,124.03,121.95,119.40,119.00,117.71,60.37,52.58,47.53,32.38,31.29.

[0291] Example 72 Synthesis of N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-117)

[0292] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-fluoro-3-trifluoromethylaniline to obtain a white solid, namely ZS-117, with a yield of 0.17 g and a yield of 26.56%. mp 273~277℃. 1 H NMR(400MHz, DMSO-d6)δ8.71(s,1H),7.96(dd,J=6.4,2.5Hz,1H),7.58-7.46(m,1H),7.38(dt,J=21.5,6.7Hz,6H),7.05(d,J=8.2Hz,1H), 6.20(d,J=7.7Hz,1H),4.84(s,2H),3.77(d,J=8.0Hz,1H),3.47(d,J=7.7Hz,1H),1.94-1.80(m,4H),1.43-1.35(m,2H),1.32-1.23(m,2H).13 C NMR (100MHz, DMSO-d6): δ187.72,181.20,170.15,160.68,154.86,152.30,137.82,131.41,129. 23,129.13,124.51,123.83,123.75,117.97,117.76,115.56,60.36,52.58,47.55,32.41,31.33.

[0293] Example 73 Synthesis of tert-butyl (1-(2-ethoxy-3,4-dioxetane-1-en-1-yl)piperidin-4-yl)carbamate (Compound f)

[0294] The preparation method of this embodiment is the same as that of Example 1, except that tert-butyl trans-(4-aminocyclohexyl)carbamate in Example 1 is replaced with 4-tert-butyloxycarbonylaminopiperidine to obtain a white solid, namely tert-butyl (1-(2-ethoxy-3,4-dioxocyclobutane-1-ene-1-yl)piperidin-4-yl)carbamate (compound f), with a yield of 4.56 g and a yield of 98.13%.

[0295] Example 74 Synthesis of tert-butyl (1-(2-((4-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)piperidin-4-yl)carbamate (Compound g)

[0296] The preparation method of this embodiment is the same as that of Example 2, except that tert-butyl ((1r, 4r)-4-((2-ethoxy-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate (compound b) in Example 2 is replaced with tert-butyl (1-(2-ethoxy-3,4-dioxetane-1-en-1-yl)piperidin-4-yl)carbamate (compound f) to obtain a white solid, namely tert-butyl (1-(2-((4-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)piperidin-4-yl)carbamate (compound g), with a yield of 4.56 g and a yield of 98.13%.

[0297] Example 75 Synthesis of N-(2-(4-aminopiperidin-1-yl)-3,4-dioxetane-1-en-1-yl)-4-methylbenzenesulfonamide (Compound h)

[0298] The preparation method of this embodiment is the same as that of Example 3, except that tert-butyl ((1r, 4r)-4-((2-((4-methylphenyl)sulfonamido)-3,4-dioxetane-1-ene-1-yl)amino)cyclohexyl)carbamate (compound e) in Example 3 is replaced by tert-butyl (1-(2-((4-methylphenyl)sulfonamido)-3,4-dioxetane-1-ene-1-yl)piperidin-4-yl)carbamate (compound g) to obtain a white solid, namely N-(2-(4-aminopiperidin-1-yl)-3,4-dioxetane-1-ene-1-yl)-4-methylbenzenesulfonamide (compound h), with a yield of 5.69 g and a yield of 99.18%.

[0299] Example 76 Synthesis of N-(2-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (WG-101)

[0300] The preparation method of this example is the same as that of Example 4, except that N-(2-(((1r, 4r)-4-aminocyclohexyl)amino)-3,4-dioxetane-1-en-1-yl)-4-methylbenzenesulfonamide in Example 4 is replaced by 4-chloro-3-trifluoromethylaniline to obtain a white solid, namely WG-101, with a yield of 0.13 g and a yield of 23.45%. mp 181-184°C. 1 H NMR (400MHz, DMSO) δ8.89(s,1H),8.07(s,1H),7.89(d,J=8.2Hz,2H),7.55(s,2H),7.39(d,J=8.1Hz,2H),6.43(d,J=7.6Hz,1 H),4.36(s,1H),4.02(s,1H),3.78-3.75(m,1H),3.32(t,J=11.8Hz,2H),2.38(s,3H),1.93-1.90(m,2H),1.55-1.46(m,2H).

[0301] Example 77 Synthesis of N-(2-(4-(3-(3-chloro-4-methylphenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (WG-103)

[0302] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-chloro-4-methylaniline to obtain a white solid, namely WG-103, with a yield of 0.15 g and a yield of 26.53%. mp 225~227℃. 1HNMR (400MHz, DMSO) δ8.47(s,1H),7.90(d,J=8.2Hz,2H),7.64(d,J=1.9Hz,1H),7.40(d,J=8.2Hz,2H),7.26-7.04(m,2H),6.27(d,J=7.3Hz,1H),4.3 7(s,1H),3.96(s,1H),3.75(d,J=6.3Hz,1H),3.33(t,J=11.2Hz,2H),2.39 (s,3H),2.23(s,3H),1.91(d,J=10.0Hz,2H),1.49(td,J=14.5,3.8Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ190.4,182.1,171.9,154.7,143.8,140.0,138.8,13 3.5,131.5,130.0,127.8,127.7,118.0,116.9,55.4,45.6,32.3,21.5,19.2.

[0303] Example 78 Synthesis of N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (WG-105)

[0304] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-trifluoromethoxyaniline to obtain a white solid, namely WG-105, with a yield of 0.17 g and a yield of 26.78%. mp 199~203℃. 1 HNMR (400MHz, DMSO) δ8.66(s,1H),7.89(d,J=8.2Hz,2H),7.48(d,J=9.0Hz,2H),7.37(d,J=8.1Hz,2H),7.22(d,J=8.6Hz,2H),6.35( d,J=7.4Hz,1H),4.33(s,1H),4.07(s,1H),3.77(s,1H),3.33(t,J=11.6Hz,2H),2.38(s,3H),1.93-1.90(m,2H),1.43-1.44(m,2H). 13 C NMR (100MHz, DMSO-d6) δ190.0,171.9,154.8,143.3,142.5,140.2,129.8,127.7,122.1,119.1,46.1,45.6,34.8,32.4,21.5.

[0305] Example 79 Synthesis of N-(2-(4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (WG-106)

[0306] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-fluoro-4-trifluoromethoxyaniline to obtain a white solid, namely WG-106, with a yield of 0.13 g and a yield of 23.46%. mp 227~228℃. 1 H NMR (400MHz, DMSO) δ8.81(s,1H),7.89(d,J=8.2Hz,2H),7.68(dd,J=13.4,2.4Hz,1H),7.40(t,J=7.6Hz,3H),7.12(d,J=9.3Hz,1H),6.40( d,J=7.6Hz,1H),4.36(s,1H),4.01(s,1H),3.78-3.76(m,1H),3.33(t,J=11.7Hz,2H),2.39(s,3H),1.93-1.90(m,2H),1.55-1.45(m,2H). 13 C NMR(100MHz,DMSO-d6)δ190.3,182.3,171.9,155.3,154.5,152.9,143.7,141.8,141 .7,139.0,129.9,127.7,124.7,122.0,119.4,114.1,106.3,106.1,45.7,32.3,21.5.

[0307] Example 80 Synthesis of N-(2-(4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (WG-108)

[0308] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-fluoro-3-trifluoromethylaniline to obtain a white solid, namely WG-108, with a yield of 0.15 g and a yield of 27.35%. mp 170~175℃. 1HNMR (400MHz, DMSO) δ8.89(s,1H),7.96(dd,J=6.4,2.4Hz,1H),7.85(d,J=7.1Hz,2H),7.56-7.54(m,1H),7.37(t,J=9.8Hz,1H),7.31(d ,J=7.7Hz,2H),6.46(d,J=7.6Hz,1H),4.30(s,2H),3.74(s,1H),3.33-3.25(m,2H),2.36(s,3H),1.95-1.85(m,2H),1.54-1.47(m,2H). 13 C NMR(100MHz,DMSO-d6)δ189.2,184.2,171.9,165.8,154.8,137.8,2,137.79,129.5,127.6, 127.6,124.5,123.9,123.8,118.0,117.8,115.63,115.6,53.9,48.4,46.1,32.4,21.4,9.0.

[0309] Example 81 Synthesis of tert-butyl (1-(2-((2-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)piperidin-4-yl)carbamate

[0310] The preparation method of this embodiment is the same as that of Example 2, except that the p-toluenesulfonamide of tert-butyl ((1r, 4r)-4-((2-ethoxy-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate in Example 2 is replaced by o-methylbenzenesulfonamide to obtain a white solid, i.e., tert-butyl (1-(2-((2-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)piperidin-4-yl)carbamate, with a yield of 6.98 g and a yield of 94.32%.

[0311] Example 82 Synthesis of N-(2-(4-aminopiperidin-1-yl)-3,4-dioxetane-1-en-1-yl)-2-methylbenzenesulfonamide The preparation method of this example is the same as that of Example 3, except that tert-butyl ((1r, 4r)-4-((2-((4-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)amino)cyclohexyl)carbamate in Example 3 is replaced by tert-butyl (1-(2-((2-methylphenyl)sulfonamido)-3,4-dioxetane-1-en-1-yl)piperidin-4-yl)carbamate to give a white solid, namely N-(2-(4-aminopiperidin-1-yl)-3,4-dioxetane-1-en-1-yl)-2-methylbenzenesulfonamide, with a yield of 7.26 g and a yield of 98.85%.

[0312] Example 83 Synthesis of N-(2-(4-(3-(4-chloro-3-fluorophenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-A104)

[0313] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-chloro-3-fluoroaniline to obtain a white solid, namely MH-A104, with a yield of 0.14 g and a yield of 24.65%. mp 239~242℃. 1 H NMR (400MHz, DMSO-d6) δ9.04(s,1H),7.98(d,J=7.6Hz,1H),7.70-7.66(m,1H),7.39(t,J=8.9Hz,1H),7.30(t,J=7.2Hz,1H),7.26-7.17(m,2H),7.13 (d,J=9.0Hz,1H),6.58(d,J=7.6Hz,1H),4.48(s,2H),3.83-3.61(m,1H),3 .22(t,J=11.2Hz,2H),2.56(s,3H),1.87-1.84(m,2H),1.46-1.37(m,2H). 13 C NMR (100MHz, DMSO-d6): δ187.59,186.65,175.77,171.63,155.33,154.58,152.88,144.89,142.00,136.2 9,131.41,130.69,128.74,125.48,124.65,121.96,119.41,114.08,106.22,46.09,44.84,32.66,20.61.

[0314] Example 84 Synthesis of N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-A117)

[0315] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-trifluoromethylaniline to obtain a white solid, namely MH-A117, with a yield of 0.11 g and a yield of 23.89%. mp 243~246℃. 1H NMR(400MHz, DMSO-d6)δ8.83(s,1H),7.99(d,J=7.5Hz,1H),7.61-7.58(m,4H),7.51(t,J=7.4Hz,1H),7.39-7.34(m,2H),6.40(d, J=7.4Hz,1H),4.31(s,2H),3.79(d,J=6.4Hz,1H),3.35(t,J=11.3Hz,2H),2.62(s,3H),1.94(d,J=10.0Hz,2H),1.56-1.48(m,2H). 13 C NMR (100MHz, DMSO-d6): δ190.00,182.56,171.64,161.97,154.53,144.56,140.44,136.88,1 33.11,132.53,129.50,126.43,123.75,121.67,121.35,117.73,46.26,45.68,32.32,20.37.

[0316] Example 85 Synthesis of tert-butyl (1-(3,4-dioxo-2-((phenylmethyl)sulfonamido)cyclobut-1-en-1-yl)piperidin-4-yl)carbamate

[0317] The preparation method of this embodiment is the same as that of Example 2, except that the memantine in Example 2 is replaced by benzenesulfonamide to obtain a white solid, i.e., tert-butyl (1-(3,4-dioxo-2-((phenylmethyl)sulfonamido)cyclobut-1-ene-1-yl)piperidin-4-yl)carbamate, with a yield of 5.48 g and a yield of 97.64%.

[0318] Example 86 Synthesis of N-(2-(4-aminopiperidin-1-yl)-3,4-dioxetane-1-en-1-yl)-1-phenylmethanesulfonamide

[0319] The preparation method of this embodiment is the same as that of Example 3, except that the memantine in Example 3 is replaced by tert-butyl (1-(3,4-dioxo-2-((phenylmethyl)sulfonamido)cyclobut-1-ene-1-yl)piperidin-4-yl)carbamate to obtain a white solid, namely N-(2-(4-aminopiperidin-1-yl)-3,4-dioxocyclobut-1-ene-1-yl)-1-phenylmethanesulfonamide, with a yield of 4.56 g and a yield of 99.85%.

[0320] Example 87 Synthesis of N-(2-(4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-A102)

[0321] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 3-fluoro-4-trifluoromethoxyaniline to obtain a white solid, namely ZS-A102, with a yield of 0.13 g and a yield of 22.31%. mp 271~274℃. 1 HNMR(400MHz, DMSO-d6)δ9.03(s,1H),7.69(d,J=13.5Hz,1H),7.39(t,J=8.8Hz,1H),7.33-7.26(m,5H),7.13(d,J=8.9Hz, 1H),6.58(d,J=7.0Hz,1H),4.54(s,2H),4.45(d,J=12.2Hz,2H),3.71(s,1H),3.21(s,2H),1.81(s,2H),1.40-1.37(m,2H). 13 CNMR (100MHz, DMSO-d6): δ187.91,186.70,175.64,171.93,155.32,154.58,152.88,141.99,141. 89,133.31,131.07,128.33,127.41,124.64,114.11,106.23,106.00,60.48,46.06,44.86,32.66.

[0322] Example 88 Synthesis of N-(2-(4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-A112)

[0323] The preparation method of this example is the same as that of Example 4, except that ** in Example 4 is replaced by 3-fluoro-4-trifluoromethylaniline to obtain a white solid, namely ZS-A112, with a yield of 0.14 g and a yield of 27.36%. mp 242~246℃. 1 H NMR (400MHz, DMSO-d6) δ9.11(s,1H),7.67(d,J=14.0Hz,1H),7.59(t,J=8.3Hz,1H),7.39(s,5H),7.21(d,J=8.4Hz,1H ),6.55(d,J=7.2Hz,1H),4.94(s,2H),4.43(s,1H),3.94(s,1H),3.77(s,1H),3.34(s,2H),1.91(s,2H),1.52(s,2H). 13C NMR (100MHz, DMSO-d6): δ189.16,183.69,171.41,161.14,158.65,154.29,146.95,146.83,131.40,1 30.41,128.97,128.69,128.01,124.87,122.19,113.39,105.26,105.01,60.87,46.22,45.70,32.21.

[0324] Example 89 Synthesis of N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-A113)

[0325] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-trifluoromethoxyaniline to obtain a white solid, namely ZS-A113, with a yield of 0.15 g and a yield of 26.54%. mp 250~255℃. 1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),7.48(d,J=8.9Hz,2H),7.33-7.26(m,5H),7.22(t,J=8.7Hz,2H),6.30(d,J=7.7Hz,1 H),4.54(s,2H),4.45(d,J=12.1Hz,2H),3.72-3.70(m,1H),3.26-3.21(m,2H),1.88-1.84(m,2H),1.40(d,J=8.1Hz,2H). 13 C NMR (100MHz, DMSO-d6): δ187.91,186.76,175.68,171.92,165.87,154.76,142.48,140. 24,133.34,131.07,128.33,127.41,122.04,119.15,48.35,46.02,32.78,32.18,28.69.

[0326] Example 90 Synthesis of N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-A117)

[0327] The preparation method of this example is the same as that of Example 4, except that the memantine in Example 4 is replaced by 4-trifluoromethylaniline to obtain a white solid, namely ZS-A117, with a yield of 0.18 g and a yield of 30.56%. mp 259~264℃. 1 H NMR (400MHz, DMSO-d6) δ9.05 (s, 1H), 7.57 (q, J = 8.9Hz, 4H), 7.33-7.26 (m, 5H), 6.60 (d, J = 7.6Hz, 1H), 4.54(s,2H),4.43(d,J=12.4Hz,2H),3.74-3.72(m,1H),3.23(s,2H),1.84(s,2H),1.42-1.37(m,2H). 13 C NMR (100MHz, DMSO-d6): δ187.91,186.71,175.64,171.93,154.60,144.72,133.31,131.99,131.07,1 29.13,128.34,127.42,126.41,126.37,123.79,121.49,121.18,117.65,60.48,45.97,44.81,32.70.

[0328] Test Example 1

[0329] 1. Inhibitory activity test

[0330] Detection principle: The specific substrate (3-phenyl-oxy)-acetic acid cyano-(6-methoxy-naphthalen-2-yl) methyl ester, PHOME, itself has no fluorescence, but is hydrolyzed under the action of sEH enzyme to generate the product 6-methoxy-2-naphthaldehyde. 6-methoxy-2-naphthaldehyde can emit fluorescence with a wavelength of 465nm under 330nm light wave excitation. The intensity of the detected fluorescence signal is inversely proportional to the inhibitory effect on sEH enzyme. Based on the above principle, the inhibition rate of samples with different concentrations was calculated compared with the positive control group. The IC value of the compound was calculated using SPSS20 software based on the inhibition rate and concentration. 50 value.

[0331] 2. Preparation of reagents and drugs

[0332] 25 mM Tris-HCl buffer (pH = 7.4, containing 0.1 mg / mL BSA): Take 12.5 mL of 1 M Tris-HCl buffer, add 5 mg BAS, dilute with purified water and adjust the pH to 7.4 with hydrochloric acid, and make up to 500 mL.

[0333] PHOME solution: Dissolve 0.79 mg of PHOME in 106 μL DMSO to obtain a 20 mM PHOME solution, which was diluted to 1 / 3 mM with Tris-HCl buffer before use.

[0334] sEH solution: sEH (5 mg / mL) stock solution was stored in a -80°C refrigerator and diluted to 4 μg / mL with 25 mM Tris-HCl buffer before use.

[0335] The sample powder to be tested was dissolved in DMSO to a 20 mM solution, stored in a -20°C refrigerator for later use, and diluted with Tris-HCl buffer to the corresponding concentration when used.

[0336] 3. Experimental Grouping

[0337] Experimental design: solvent group, 100% activity group (A), inhibitor group (B), positive control group (C), as shown in Table 1.

[0338] Table 1 Experimental grouping

[0339] hole Buffer DMSO Inhibitors HkDJ Substrate Solvent Group 168μL 2μL — — 30μL 100% Vitality Group (A) 148μL 2μL — 20μL 30μL Inhibitor group (B) 148μL — 2μL 20μL 30μL Positive control group (C) 148μL — 2μL 20μL 30μL

[0340] 4. Experimental steps

[0341] (a) Add 148 μL / well Tris-HCl buffer to a 96-well black-bottom microplate;

[0342] (b) 2 μL of the sample solution to be tested was added, the solvent group and the 100% activity group were replaced with an equal volume of DMSO, and the positive control group was added with the lead compound t-TUCB, the structural formula of which is:

[0343]

[0344] (c) The inhibitor group had a total of 5 concentrations, with final concentrations of 10 nM, 5 nM, 2.5 nM, 1.25 nM, and 0.625 nM, respectively;

[0345] (d) 20 μL of s-EH solution (final concentration 400 ng / mL) was added, and the solvent group was replaced with an equal volume of Tris-HCl buffer;

[0346] (e) Add 30 μL of PHOME substrate to start the reaction (final concentration 50 μM) and incubate in a 37°C incubator for 10 min;

[0347] (f) The fluorescence signal data was detected by an enzyme-labeled instrument with an excitation wavelength of 330 nm and an emission wavelength of 465 nm.

[0348] 5. Data Analysis

[0349] Three replicate wells were set for each sample, and the mean of the three replicate wells was the fluorescence value (F) of the compound to be tested. The inhibition rate % = [(AF-BF) / AF] × 100, where AF is the fluorescence value of the 100% activity group and BF is the fluorescence value of the inhibitor group. The IC value of the compound was calculated using SPSS20 software based on the inhibition rate and concentration. 50 value.

[0350] The inhibitory activities of FS, MH, ZS, WG, MH-A and ZS-A series compounds against human sEH (HsEH) and mouse sEH (MsEH) are shown in Table 1.

[0351] Table 1 Inhibitory activity of the urea derivatives of the present invention on human sEH (HsEH) and mouse sEH (MsEH)

[0352]

[0353] According to Table 1, the compounds provided by the present invention contain trans-cyclohexane fragments, FS, MH and ZS series compounds, and the IC 50 The value is between 0.1nM and 3.0nM, which has a high inhibitory effect. The WG, MH-A and ZS-A series compounds containing piperidine fragments have an IC 50 The value is between 0.4nM and 7.1nM, which has a good inhibitory effect. The compounds provided by the present invention contain trans-cyclohexane fragments of FS, MH and ZS series compounds on MsEH IC 50The value is between 0.1nM and 27.8nM, which has a good inhibitory effect. The experimental results showed that the inhibitory activity of FS-A4, FS-E4, FS-G4, FS-H4, FS-I4, FS-S4, FS-T4, FS-110, MH-102, MH-103, MH-104, MH-105, MH-106, MH-108, MH-109, MH-110, MH-111, MH-112, MH-114, MH-115, MH-118, MH-119, MH-120, MH-121, ZS-101, ZS-102, ZS-103, ZS-104, ZS-105, ZS-110, ZS-111, ZS-112, ZS-116, and ZS-117 against HsEH was better than that of the lead compound t-TUCB. The experimental results showed that the inhibitory activity of FS series, MH series (except MH-107 and MH-116), ZS series, and WG-103 against MsEH was better than that of the lead compound t-TUCB. Finally, compounds FS-A4, FS-E4, FS-G4, FS-H4, FS-I4, FS-S4, FS-T4, FS-110, MH-102, MH-103, MH-104, MH-105, and MH- 106, MH-108, MH-109, MH-110, MH-111, MH-112, MH-114, MH-115, MH-118, MH-119, MH-120, MH- 121. ZS-101, ZS-102, ZS-103, ZS-104, ZS-105, ZS-110, ZS-111, ZS-112, ZS-116, ZS-117 on HsEH IC 50 and MsEH IC 50 The value is better than that of the lead compound t-TUCB.

[0354] It can be seen from the above examples that the urea derivatives containing an aromatic sulfonamide structure provided by the present invention have high inhibitory activity against human sEH and mouse sEH, with few side effects, and can be used as sEH inhibitors for preparing drugs for treating soluble cyclooxygenase-mediated diseases.

[0355] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A urea derivative containing an aromatic sulfonamide structure, the structure of which is shown in Formula A or Formula B: In formula A or formula B, R1 is independently alkyl, substituted alkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heterocyclic group or substituted heterocyclic group; R2 is independently -H, alkyl, substituted alkyl, alkoxy or substituted alkoxy; Z is independently -NH-, -O- or -S-; n is independently 0, 1, 2 or 3.

2. The urea derivative containing an aromatic sulfonamide structure according to claim 1, characterized in that: The alkyl group in R1 includes a straight chain alkyl group, adamantyl group or a branched chain alkyl group; The substituted alkyl group includes a substituted straight-chain alkyl group, a substituted adamantyl group or a substituted branched-chain alkyl group; The heterocyclic group includes pyridine, pyrimidine, pyran, pyrazole, piperidine, thiazole or thiophene; The substituted heterocyclic group includes substituted pyridine, substituted pyrimidine, substituted pyran, substituted pyrazole, substituted piperidine, substituted thiazole or substituted thiophene.

3. The urea derivative containing an aromatic sulfonamide structure according to claim 1 or 2, characterized in that: The substituents of the substituted alkyl group in R1 independently include halogen groups, hydroxyl groups, amino groups, cyano groups, nitro groups, trifluoromethyl groups, trifluoromethoxy groups, methylamino groups, dimethylamino groups, alkyl groups, aromatic groups, heterocyclic groups, heteroaryl groups, -OR, -SR, -NRR', -C(O)R, -C02R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S02R, -CONRR', -SO2NRR', -OCOR, -NRCOR' or -NRNRR'; In the OR, -SR, -NRR', -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -SO2R, -CONRR', -SO2NRR', -OCOR, -NRCOR' and -NRNRR', R or R' is independently an alkyl group; The type of the substituent of the substituted phenyl group described in R1 is the same as the type of the substituent of the substituted alkyl group described in R1; The type of substituents of the substituted naphthyl group described in R1 is the same as the type of substituents of the substituted alkyl group described in R1; The types of substituents for the substituted heterocyclic group described in R1 are the same as the types of substituents for the substituted alkyl group described in R1.

4. The urea derivative containing an aromatic sulfonamide structure according to claim 1 or 2, characterized in that: The alkyl group in R2 is a C1-C6 alkyl group; The substituted alkyl group is a substituted C1-C6 alkyl group; The alkoxy group is a C1 to C6 alkoxy group; The substituted alkoxy group is a substituted C1-C6 alkoxy group.

5. The urea derivative containing an aromatic sulfonamide structure according to claim 1, characterized in that: The substituent of the substituted alkyl group in R2 includes a halogen group, a hydroxyl group, an amino group, a methylamino group, a dimethylamino group or an alkyl group; The types of substituents for the substituted alkoxy group described in R2 are the same as the types of substituents for the substituted alkyl group described in R2.

6. The urea derivative containing an aromatic sulfonamide structure according to claim 1, characterized in that: The urea derivatives containing an aromatic sulfonamide structure include N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)cyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3,5-difluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-ene-1-yl)-4-methylbenzenesulfonamide, -4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl) 4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide Toluenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide,4r)-4-(3-(4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chlorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(2-chloro-4-nitrophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en -1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(1,2,3,5,6,7-hexahydro-s-indol-4-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(3,4- Dioxo-2-(((1r,4r)-4-(3-(p-tolyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-benzhydrylureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluorobenzyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)benzyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl )-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chlorobenzyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethyl)benzyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, 3-(3-chloro-4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(3,4-dioxo-2-((4-(3-(p-tolyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide 1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, ,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chlorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(2-chloro-4-nitrophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1 r,4r)-4-(3-(3-chloro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(1,2,3,5,6,7-hexahydro-s-indole -4-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, 1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(p-tolyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureido)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide,4r)-4-(3-(2-chloro-4-cyanophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-( -1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3,5-difluorophenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide 1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, 1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(4-(3-(3-chloro-4-methylphenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide,4-dioxo-2-(4-(3-(4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(4-(3-(4-fluoro-3- (trifluoromethyl)phenyl)ureidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(4-(3-(4-chloro-3-fluorophenyl)ureidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethyl)phenyl)ureidin-1-yl) piperidin-1-yl)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, 1-en-1-yl)-1-phenylmethanesulfonamide, N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethoxy)phenyl)ureido)piperidin-1-yl)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide or N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethyl)phenyl)ureido)piperidin-1-yl)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide.

7. The method for preparing the urea derivative containing an aromatic sulfonamide structure according to any one of claims 1 to 6, characterized in that: The preparation method of the urea derivative containing an aromatic sulfonamide structure shown in formula A comprises the following steps: (1) subjecting compound a to a first nucleophilic substitution reaction with trans-(4-aminocyclohexyl)carbamic acid tert-butyl ester to obtain compound b; (2) subjecting the compound b to a second nucleophilic substitution reaction with the compound I to obtain a compound c; (3) subjecting the compound c to a first deprotection reaction to obtain a compound d; (4) subjecting the compound d to a first acylation reaction with (trichloromethyl) carbonate to obtain a first intermediate compound; subjecting the first intermediate compound to a third nucleophilic substitution reaction with compound II to obtain a urea derivative containing an aromatic sulfonamide structure as shown in formula A; The structural formula of the compound I is The structural formula of the compound II is The structural formulas of the compound a, compound b, compound c, compound d and the first intermediate compound are: In the structural formula of compound I, compound II, compound c, compound d or the first intermediate compound, R1, R2 and n are defined the same as in formula A or formula B; The preparation method of the urea derivative containing an aromatic sulfonamide structure shown in formula B comprises the following steps: (A) subjecting compound a to a fourth nucleophilic substitution reaction with 4-tert-butyloxycarbonylaminopiperidine to obtain compound f; (B) subjecting the compound f to a fifth nucleophilic substitution reaction with the compound I to obtain a compound g; (C) deprotecting the compound g to obtain compound h; (D) subjecting the compound H to a second acylation reaction with (trichloromethyl) carbonate to obtain a second intermediate compound; subjecting the second intermediate compound to a sixth nucleophilic substitution reaction with compound II to obtain a urea derivative containing an aromatic sulfonamide structure as shown in formula B; The structural formula of the compound I is The structural formula of the compound II is The structural formulas of the compound f, compound g, compound h and the second intermediate compound are: In the structural formula of compound I, compound II, compound g, compound h or the second intermediate compound, the definitions of R1, R2 and n are the same as those of formula A or formula B.

8. The preparation method according to claim 7, characterized in that: The first acylation reaction is carried out in triethylamine and dichloromethane; the temperature of the first acylation reaction is -78 to -30°C, and the insulation time is 30 to 60 minutes.

9. The preparation method according to claim 7, characterized in that: The second acylation reaction is carried out in triethylamine and dichloromethane; the molar ratio of triethylamine to dichloromethane is 1-1.2:1-100; the molar ratio of compound h to triethylamine is 1-1.2:1-10.

10. Use of the urea derivative containing an aromatic sulfonamide structure according to any one of claims 1 to 6 or the urea derivative containing an aromatic sulfonamide structure obtained by the preparation method according to any one of claims 7 to 9 in the preparation of drugs for treating diseases mediated by soluble epoxides.

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