A urea derivative containing an arylsulfonamide structure, its preparation method and application

Abstract

This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a urea derivative containing an arylsulfonamide structure, its preparation method, and its applications. The urea derivative provided by this invention possesses 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 triplet of the sEH protein, and the arylsulfonamide structure, as a hydrophilic fragment, facilitates polar interactions with the receptor. Therefore, the urea derivative containing an arylsulfonamide structure provided by this invention exhibits high inhibitory activity against human sEH (HsEH) and murine sEH (MsEH), with few side effects, and can be used as an sEH inhibitor in the preparation of drugs for treating soluble epoxide enzyme-mediated diseases.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a urea derivative containing an aryl sulfonamide structure, its preparation method, and its application. Background Technology

[0002] Epoxide hydrolases are widely distributed enzymes responsible for the rapid hydrolysis of epoxides into their corresponding vicinal diols (Arch. Toxicol, 2014, 88(11): 2013-2032). In mammals, soluble epoxide hydrolases (sEH) are α / β hydrolases expressed in the cytoplasm and sometimes in peroxisomes, including the liver, kidneys, lungs, heart, brain, spleen, adrenal glands, and intestines (Prog LipidRes, 2005, 44(1): 1-51). sEH is present in all vertebrates except mammals, but only mammalian sEH possesses phosphatase activity.

[0003] Mammalian sEH is a bifunctional enzyme composed of two 62.5 kDa monomers, possessing a 25 kDa N-terminal phosphatase domain and a 35 kDa C-terminal hydrolase domain (Annu. Rev Pharmacol. Toxicol, 2005, 45: 311-333.). The C-terminal hydrolase catalyzes the hydrolysis of epoxidized fatty acids (EpFAs), such as epoxidized eicosatetrienoic acid (EET), which is 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. In the catalytic triple Asp333-Asp495-His523, the nucleophilic carboxylic acid Asp333 is located on the opposite side of Tyr381 and Tyr465. It is directionally activated by His523 and Asp495, attacking the epoxide carbon skeleton and forming an ester bond with the opened epoxide. The ester is then hydrolyzed to generate the corresponding diol.

[0004] Pain is a complex signal transduction process originating from damage caused by harmful substances and the release of inflammatory mediators, such as cytokines, ions, bradykinin, prostaglandins, and leukotrienes. These mediators act directly on pain receptors and drive action potentials to produce the sensation of pain (Neuron, 2007, 55(3):353-364). While many methods can currently alleviate pain, most have dose-dependent or limited-use side effects. Therefore, we need new therapies to treat pain. Inflammatory pain is caused by biological or chemical inflammation. The study of sEH activity to alleviate inflammatory pain stems from research on the anti-inflammatory effects of sEH inhibitors. In a study of a lipopolysaccharide-induced sepsis model, inhibition of sEH was found to alter not only the levels of epoxidized eicosatrienoic acid (EET) and diol metabolites, but also the levels of several other metabolites in the arachidonic acid cascade cyclooxygenase (COX) and lipoxygenase (LOX) metabolic pathways (Proc Natl Acad Sci USA, 2005, 102(28):9772-9777). Notably, inhibition of sEH activity with small molecules reduced prostaglandin 2 (PGE2) levels, an inflammatory mediator and pain-inducing substance. This finding is groundbreaking because it demonstrates that stabilizing endogenous bioactive lipids is a novel strategy for limiting inflammation. Because previous studies have found that sEH inhibitors inhibit cyclooxygenase 2 (COX-2), the synergistic effect of sEH inhibitors and COX-2 selective inhibitors (NSAIDs) was first investigated in an inflammatory pain model (Proc Natl Acad Sci USA, 2006, 103(37):13646-13651). The results showed that sEH inhibitors and NSAIDs together reduced the expression levels of PGE2 and COX-2 in mice and increased the latency of heat retraction. Notably, these improvements occurred without a significant change in the prostacyclin-thromboxane ratio. The adverse side effect of COX-2 selective inhibitors (NSAIDs) inducing thrombosis is suspected to be caused by changes in COX metabolite homeostasis (N Engl J Med, 2004, 351:1709-1711). In later studies, sEH inhibitors were administered alone to determine whether they could alleviate hyperalgesia. Inceoglu et al. (Life Sciences, 2006, 79(24):2311-2319) found that local administration of two different sEH inhibitors effectively increased the thermal withdrawal latency and pain threshold in a lipopolysaccharide (LPS)-induced rat model of inflammatory pain. This study also revealed that EpFA metabolites counteract hyperalgesia by increasing the thermal withdrawal latency against LPS-induced pain. Therefore, it can be inferred that inhibiting sEH activity may be an effective method for treating inflammatory pain.

[0005] In 2011, the official IASP academic journal PAIN published a new definition of neuropathic pain (NPP): pain directly caused by damage or disease of the somatic sensory nervous system, which can be secondary to various diseases or injuries, such as stroke and diabetes. Preliminary studies on the effects of sEH inhibitors in neuropathy aimed 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 could block diabetic neuropathy in a chronic pain model, and therefore it was proposed as a negative control experimental model. This is exciting because most COX-blocking NSAIDs have little effect on neuropathic pain (European Journal of Pharmacology, 2013, 700(1-3): 93-101). Inceoglu et al. (Proc Natl Acad Sci USA, 2012, 109(28): 11390-11395) explored the effects of sEH inhibitors on diabetic neuropathy in preclinical models, revealing a dose-dependent improvement in the mechanical pain threshold by sEH inhibitors, and that sEH inhibitors were superior to standard gabapentin treatment. This anti-hyperalgesia effect was independent of changes in glucose tolerance, insulin tolerance, and glucose-stimulated insulin secretion. Wagner et al. (Behavioural Brain Research, 2017, 326: 69-76) further demonstrated the effect of sEH inhibitors in a congenital Akita mouse model of type 1 diabetes. In studies using Akita mice as a model, sEH inhibitors were found to be effective against diabetic neuropathy in mice, and sEH activity was correlated with the severity of the disease. Guedes A et al. (Equine Veterinary Journal, 2017, 49(3):345-351) found in their study on the treatment of severe esophageal lamina that sEH inhibitors were more effective than previous standard treatments, and that sEH inhibitors have continued to be successful as a treatment for this disease. Therefore, 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 EpFAs 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 levels of EpFAs in the body, such as EETs, thereby exerting analgesic, anti-inflammatory, and multi-organ protective effects. However, the inhibitory activity of existing sEH inhibitors is insufficient. Summary of the Invention

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

[0008] To achieve the above objectives, the present invention provides the following technical solution:

[0009] This invention provides a urea derivative containing an arylsulfonamide structure, the structure of which is shown in Formula A or Formula B:

[0010]

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

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

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

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

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

[0016] Preferably, 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, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -SO2R, -CONRR', -SO2NRR', -OCOR, -NRCOR', or -NRNRR'; wherein 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 substituent for the substituted phenyl group in R1 is the same as the type of substituent for the substituted alkyl group in R1; the type of substituent for the substituted naphthyl group in R1 is the same as the type of substituent for the substituted alkyl group in R1; the type of substituent for the substituted heterocyclic group in R1 is the same as the type of substituent for the substituted alkyl group 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 substituents of the substituted alkoxy group in R2 are of the same type as the substituents of the substituted alkyl group in R2.

[0019] Preferably, the urea derivatives containing the arylsulfonamide structure include N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3,5-difluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r, 4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4- -Methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro ...4r)-4-(3-(4-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chlorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(2-chloro-4-nitrophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)cyclobut-1-ene -1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureo)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-indole-4-yl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(3,4- Dioxo-2-(((1r,4r)-4-(3-(p-tolyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-diphenylmethylureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluorobenzyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)benzyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl) )-4-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chlorobenzyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethyl)benzyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantane-1-yl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantane-1-yl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantane-1-yl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-( 3-(3-chloro-4-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(3,4-dioxo-2-((4-(3-(p-tolyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl) N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r) ,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chlorophenyl)ureo)cyclohexyl)amino)-3,4-Dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(2-chloro-4-nitrophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, (r,4r)-4-(3-(3-chloro-4-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureo)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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantane-1-yl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl) N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(3,4-dioxo-2-(((1r,4r)-4-(3-(p-tolyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(p-tolyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(p-tolyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide,4r)-4-(3-(2-chloro-4-cyanophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-( Trifluoromethyl)phenyl)ureoyl)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureoyl)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureoyl)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureoyl)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3,5-difluorophenyl)ureoyl)cyclohex ...cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclohexyl)cyclo N-(2-(((1r,4r)-4-(3-(3-chloro-4-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy) ...phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(3- Oxycyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureo)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(4-(3-(3-chloro-4-methylphenyl)ureo)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(3,4-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)ureo)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide, N-(2-(4-(3-(4-chloro-3-fluorophenyl)ureo)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethyl)phenyl)ureo) Piperidin-1-yl)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide, N-(2-(4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, N-(2-(4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureo)piperidin-1-yl)-3,4-dioxocyclobut- 1-En-1-yl)-1-phenylmethanesulfonamide, N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethoxy)phenyl)ureo)piperidin-1-yl)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, or N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethyl)phenyl)ureo)piperidin-1-yl)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide.

[0020] This invention also provides a method for preparing urea derivatives containing an arylsulfonamide structure as described in the above-described scheme. The method for preparing urea derivatives containing an arylsulfonamide structure as shown in Formula A includes the following steps:

[0021] (1) Compound a was subjected to a first nucleophilic substitution reaction with trans-(4-aminocyclohexyl)carbamate tert-butyl ester to obtain compound b;

[0022] (2) Compound b was subjected to a second nucleophilic substitution reaction with compound I to obtain compound c;

[0023] (3) Compound c is subjected to a first deprotection reaction to obtain compound d;

[0024] (4) The compound d and (trichloromethyl) carbonate are subjected to a first acylation reaction to obtain a first intermediate compound; the first intermediate compound and compound II are subjected to a third nucleophilic substitution reaction to obtain a urea derivative containing an aryl sulfonamide structure as shown in Formula A;

[0025] The structural formula of compound I is as follows: The structural formula of compound II is as follows:

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

[0027]

[0028] In the structural formulas of compounds I, II, c, d, or the first intermediate compound, the definitions of R1, R2, and n are the same as those in formula A or B.

[0029] The preparation method of the urea derivative containing the aryl sulfonamide structure shown in Formula B includes the following steps:

[0030] (A) Compound a was subjected to a fourth nucleophilic substitution reaction with 4-tert-butoxycarbonylaminopiperidine to give compound f;

[0031] (B) Compound f is reacted with compound I in a fifth nucleophilic substitution reaction to obtain compound g;

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

[0033] (D) The compound h and (trichloromethyl) carbonate are subjected to a second acylation reaction to obtain a second intermediate compound; the second intermediate compound and compound II are subjected to a sixth nucleophilic substitution reaction to obtain a urea derivative containing an arylsulfonamide structure as shown in formula B;

[0034] The structural formula of compound I is as follows: The structural formula of compound II is as follows:

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

[0036]

[0037] In the structural formulas of compounds I, II, g, h, or the second intermediate compound, the definitions of R1, R2, and n are the same as those in formula A or 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 holding 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; and the molar ratio of compound h to triethylamine is 1-1.2:1-10.

[0040] The present invention also provides the application of urea derivatives containing arylsulfonamide structures as described in the above-described schemes or urea derivatives containing arylsulfonamide structures obtained by the preparation methods described in the above-described schemes in the preparation of medicaments for treating soluble epoxide enzyme-mediated diseases.

[0041] This invention provides a urea derivative containing an arylsulfonamide structure. The urea derivative provided by this invention possesses 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 triplet of the sEH protein, and the arylsulfonamide structure, as a hydrophilic fragment, facilitates polar interaction with the receptor. Therefore, the urea derivative containing the arylsulfonamide structure provided by this invention exhibits high inhibitory activity against human sEH (HsEH) and murine sEH (MsEH), with few side effects, and can be used as an sEH inhibitor in the preparation of drugs for treating soluble epoxide enzyme-mediated diseases.

[0042] This invention also provides a method for preparing urea derivatives containing arylsulfonamide structures as described in the above-described scheme. The preparation method provided by this invention is simple in steps, convenient to operate, highly feasible, and has the prospect of large-scale application.

[0043] This invention also provides the application of urea derivatives containing arylsulfonamide structures as described in the above-described schemes, or urea derivatives containing arylsulfonamide structures obtained by the preparation methods described in the above-described schemes, in the preparation of medicaments for treating soluble epoxide-mediated diseases. The urea derivatives containing arylsulfonamide structures provided by this invention, when prepared into medicaments, have a positive effect on treating soluble epoxide-mediated diseases. Attached Figure Description

[0044] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0045] Figure 1 This is a synthetic route diagram of the urea derivative containing an aryl sulfonamide structure as shown in Formula A of the present invention;

[0046] Figure 2 This is a synthetic route diagram for the urea derivatives containing an aryl sulfonamide structure as shown in Formula B of the present invention. Detailed Implementation

[0047] This invention provides a urea derivative containing an arylsulfonamide structure, the structure of which is shown in Formula A or Formula B:

[0048]

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

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

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

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

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

[0054] In this invention, the substituted alkyl group in R1 preferably includes a substituted linear alkyl group, a substituted adamantyl group, or a substituted branched alkyl group; the substituted linear 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 medamantyl group, a substituted 1,3-dihydroxyadamantyl group, a substituted 5-hydroxy-2-adamantyl ketone group, or a substituted 4-hydroxy-2-adamantyl ketone group; the substituted branched alkyl group preferably includes a substituted isopropyl group, a substituted isobutyl group, or a substituted isopentyl group.

[0055] In this invention, the substituents of the substituted alkyl group preferably include halogen groups, hydroxyl groups (-OH), amino groups (-NH2), cyano groups (-CN), nitro groups (-NO2), trifluoromethyl groups (-CF3), trifluoromethoxy groups (-OCF3), methylamino groups (-NHCH3), dimethylamino groups (-N(CH3)2), 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 halogen group is preferably -F, -Cl, or -Br; the alkyl group is preferably straight-chain. Alkyl or cycloalkyl; 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 hexahydropyrran; the heteroaryl group is preferably pyridine, pyrimidine, furan, or pyran; in 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 preferably an alkyl group; the alkyl group preferably includes methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

[0056] In this invention, the structure of the substituent of the substituted alkyl group is specifically as follows (wherein, the solid pentagram represents the linking site):

[0057]

[0058] In this invention, the type of substituent for the substituted phenyl group in R1 is preferably the same as the type of substituent for the substituted alkyl group in R1, and will not be repeated here.

[0059] In this invention, the type of substituent of the naphthyl group described in R1 is preferably the same as the type of substituent of the alkyl group described in R1, and will not be repeated here.

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

[0061] In this 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 this invention, the type of substituent in the heterocyclic group described in R1 is preferably the same as the type of substituent in the alkyl group described in R1, and will not be repeated here.

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

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

[0065] In this invention, the substituents of the substituted alkyl group in R2 preferably include halogen groups, hydroxyl (-OH), amino (-NH2), methylamino (-NHCH3), dimethylamino (-N(CH3)2), or alkyl groups; the halogen groups are preferably -F, -Cl, or -Br; the alkyl groups are preferably C1 to C6 alkyl groups; the C1 to C6 alkyl groups preferably include methyl, ethyl, propyl, butyl, pentyl, or hexyl.

[0066] In this 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, pentoxy, isopentoxy, or hexoxy.

[0067] In this invention, the substituted alkoxy group in R2 is preferably a substituted C1-C6 alkoxy group; the substituted C1-C6 alkoxy group preferably includes substituted methoxy, substituted ethoxy, substituted propoxy, substituted isopropoxy, substituted butoxy, substituted isobutoxy, substituted pentoxy, substituted isopentoxy, or substituted hexoxy.

[0068] In this invention, the type of substituent for the alkoxy group in R2 is preferably the same as the type of substituent for the alkyl group in R2, and will not be repeated here.

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

[0070] In this invention, the urea derivatives containing the arylsulfonamide structure preferably include N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-A4), N-(2-(((1r,4r)-4-(3-(3,5-difluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-B4), N-(2-(((1r,4r)-4-(3-(4-chloro-3- ... N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-D4), N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-E4), N-(2-(((1r,4r)-4-(3-(2-chloro-4-cyano ... -1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-F4), N-(2-(((1r,4r)-4-(3-(4-fluoro-3-(trifluoromethyl)phenyl)ureo)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)ureo)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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide Butyl-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-I4), N-(2-(((1r,4r)-4-(3-(3-chloro-4-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobutyl-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-J4), N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobutyl-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-L4), N-(2-(((1r,4r)-4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-Dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-M4), N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-N4), N-(2-(((1r,4r)-4-(3-(4-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-O4), N-(2-(((1r,4r)-4-(3-(4-chlorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide N-(2-(((1r,4r)-4-(3-(2-chloro-4-nitrophenyl)ureo)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)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-R4), N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide Amide (denoted as FS-S4), N-(2-(((1r,4r)-4-(3-(4-chloro-3-methylphenyl)ureo)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)ureo)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)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-V4), N-(2-(((1r,4r)-4-(3-diphenylmethylurea)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-W4), N-(2-(((1r,4r)-4-(3-(4-fluorobenzyl)urea)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)urea)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-Y4), N-(2-(((1r,4r)-4-(3-(4-(trifluoromethoxy)benzyl)urea)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as FS-Y4), N-(2-(((1r,4r)-4-(3-diphenylmethylurea)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide4r)-4-(3-(4-chlorobenzyl)ureo)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)ureo)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-dimethyladamantane-1-yl)ureo)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-dimethyladamantane-1-yl)ureo)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)ureo)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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide ( The following are listed as MH-104, N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-105), N-(3,4-dioxo-2-((4-(3-(p-tolyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-106), N-(2-(((1r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-107 ...3-chloro-4-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-107), N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-107), N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1 N-(2-(((1r,4r)-4-(3-(3-fluoro-3-(trifluoromethyl)phenyl)ureo)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)ureo)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)ureo)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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-110), N-(2-(((1r,4r)-4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureo)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)ureo)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)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-113), N-(2-( ((1r,4r)-4-(3-(4-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-114), N-(2-(((1r,4r)-4-(3-(4-chlorophenyl)ureo)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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-116), N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-116), N-(3,4-dioxo-2-(((1r,4r)-4-(3-(4-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide N-(2-(((1r,4r)-4-(3-(4-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-117), N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureo)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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-119), N-(2-(((1r,4r)-4-(3-(4-chloro-4-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (denoted as MH-119), N-(2-(((1r,4r)-4-(3-(4-chloro-4-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (-3-methylphenyl)ureo)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)ureo)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-indole-4-yl)ureo)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-dimethyladamantane-1-yl)ureo)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)ureo)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)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS) -103), N-(2-(((1r,4r)-4-(3-(4-chloro-3-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (designated ZS-104), N-(2-(((1r,4r)-4-(3-(3-chloro-4-fluorophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (designated ZS-105), N-(3,4-dioxo-2-(((1r,4r)-4-(3-(p-tolyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (designated ZS-106), N-(2-(((1r,4r)-4-(3-(p-tolyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (designated ZS-106), N-(2-(((1r,4r)-4-(3-(p-tolyl)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (r,4r)-4-(3-(2-chloro-4-cyanophenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-107), (N-(2-(((1r,4r)-4-(3-(4-fluoro-3-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-108), (N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-109 ... -(3-(4-chloro-3-(trifluoromethyl)phenyl)ureo)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)ureo)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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-112), N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-112), N-(2-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethyl)phenyl)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-112), N-(2-(((1r,4r)-4-(3-(3,5-difluorophenyl)ureo)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)ureo)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)ureo)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)ureo)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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-117), N-(2-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureo)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (denoted as WG-101), N-( 2-(4-(3-(3-chloro-4-methylphenyl)ureo)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (WG-103), N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethoxy)phenyl)ureo)piperidin-1-yl)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (WG-105), N-(2-(4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (WG-106), N-(2-(4-(3-(4-fluoro-3-(trifluoro)methoxy)phenyl)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (Methyl)phenyl)ureo)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (WG-108), N-(2-(4-(3-(4-chloro-3-fluorophenyl)ureo)piperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-A104), N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethyl)phenyl)ureo)piperidin-1-yl)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-A117), N-(2-(4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)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)ureo)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)ureo)piperidin-1-yl)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-A113) or N-(3,4-dioxo-2-(4-(3-(4-(trifluoromethyl)phenyl)ureo)piperidin-1-yl)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (denoted as ZS-A117), the specific structural formulas are shown below:

[0071]

[0072]

[0073] The present invention also provides a method for preparing urea derivatives containing an arylsulfonamide structure as described in the above-described scheme, wherein the method for preparing urea derivatives containing an arylsulfonamide structure as shown in Formula A includes the following steps:

[0074] (1) Compound a was subjected to a first nucleophilic substitution reaction with trans-(4-aminocyclohexyl)carbamate tert-butyl ester to obtain compound b;

[0075] (2) Compound b was subjected to a second nucleophilic substitution reaction with compound I to obtain compound c;

[0076] (3) Compound c is subjected to a first deprotection reaction to obtain compound d;

[0077] (4) The compound d and (trichloromethyl) carbonate are subjected to a first acylation reaction to obtain a first intermediate compound; the first intermediate compound and compound II are subjected to a third nucleophilic substitution reaction to obtain a urea derivative containing an aryl sulfonamide structure as shown in Formula A;

[0078] The structural formula of compound I is as follows: The structural formula of compound II is as follows:

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

[0080]

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

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

[0083] In this 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 compound a to the acid-binding agent is preferably 1:(1-4), more preferably 1:1.2.

[0084] In this 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 compound a to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:1-10.

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

[0086] In this invention, the first nucleophilic substitution reaction preferably further includes adding water, extracting with ethyl acetate, drying, filtering, and concentrating the resulting reaction system in sequence.

[0087] In this invention, the concentration is preferably carried out until the product is dried.

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

[0089] In this 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 compound b to the acid-binding agent is preferably 1:(1-6), more preferably 1:6.

[0090] In this 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 compound b to the organic solvent is preferably 1-1.2:1-100, more preferably 1-1.2:1-10.

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

[0092] In this invention, the second nucleophilic substitution reaction preferably further includes adding water, extracting with ethyl acetate, drying, filtering, and concentrating the resulting reaction system in sequence.

[0093] In this invention, the concentration is preferably carried out until the product is dried.

[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 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 compound c to the acidic reagent is preferably 1:(3-10), more preferably 1:5.

[0095] In this 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 this invention, the temperature of the first deprotection reaction is preferably -20 to 50°C, more preferably 30°C, and the holding time is preferably 2 to 8 hours, more preferably 3 hours.

[0097] In this invention, the first deprotection reaction preferably further includes concentrating the resulting reaction solution; the concentration is preferably vacuum concentration; the concentration is preferably until it becomes dry.

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

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

[0100] In this 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 this invention, the temperature of the first acylation reaction is preferably -78 to -30°C, more preferably -78°C, and the holding time is preferably 30 to 60 minutes, more preferably 30 minutes.

[0102] In this invention, the first acylation reaction preferably includes concentrating the resulting reaction solution; the concentration is preferably vacuum concentration; the concentration temperature is preferably 25-60°C, more preferably 40°C, until it dries.

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

[0104] In this 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 compound II to the acid-binding agent is preferably 1:(4-6), more preferably 1:6.

[0105] In this 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 this invention, the temperature of the third nucleophilic substitution reaction is preferably -10 to -30°C, more preferably -25°C, and the holding time is preferably 30 to 60 minutes, more preferably 30 minutes.

[0107] In this invention, the third nucleophilic substitution reaction preferably further includes sequentially adding water, adding ethyl acetate for extraction, washing, drying, filtration, concentration, and column chromatography to the resulting reaction system.

[0108] In this invention, the extraction is preferably performed once or more, and more preferably three times or more.

[0109] In this invention, the washing process preferably involves sequentially performing an HCl wash, a water wash, and a saturated saline wash; the HCl wash is preferably performed at least once, more preferably at least twice; the water wash is preferably performed at least once, more preferably at least twice; and the saturated saline wash is preferably performed at least once.

[0110] In this invention, the drying is preferably performed using anhydrous sodium sulfate.

[0111] In this invention, the concentration is preferably carried out until the product is dried.

[0112] In this invention, the preferred parameters for column chromatography are: 5x silica gel packing, 1.2x silica gel for sample mixing, and MeOH and DCM as eluents in a volume ratio of 1:50. The synthetic route for the urea derivatives containing the aryl sulfonamide structure shown in Formula A provided by this invention is as follows: Figure 1 As shown.

[0113] In this invention, the preparation method of the urea derivative containing the aryl sulfonamide structure shown in Formula B includes the following steps:

[0114] (A) Compound a was subjected to a fourth nucleophilic substitution reaction with 4-tert-butoxycarbonylaminopiperidine to give compound f;

[0115] (B) Compound f is reacted with compound I in a fifth nucleophilic substitution reaction to obtain compound g;

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

[0117] (D) The compound h and (trichloromethyl) carbonate are subjected to a second acylation reaction to obtain a second intermediate compound; the second intermediate compound and compound II are subjected to a sixth nucleophilic substitution reaction to obtain a urea derivative containing an arylsulfonamide structure as shown in formula B;

[0118] The structural formula of compound I is as follows: The structural formula of compound II is as follows:

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

[0120]

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

[0122] In this invention, compound a is subjected to a fourth nucleophilic substitution reaction with 4-tert-butoxycarbonylaminopiperidine to obtain compound f. In this invention, the molar ratio of compound a to 4-tert-butoxycarbonylaminopiperidine is preferably 1:(1.0–2), more preferably 1:1.0.

[0123] In this 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 compound a to the acid-binding agent is preferably 1:(1-4), more preferably 1:1.2.

[0124] In this 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, more preferably ethanol.

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

[0126] In this invention, the fourth nucleophilic substitution reaction preferably further includes adding water, extracting with ethyl acetate, drying, filtering, and concentrating the resulting reaction system in sequence; the concentration is preferably carried out until the system is completely dry.

[0127] After obtaining compound f, the present invention performs 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 this 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 compound f to the acid-binding agent is preferably 1:(1-6), more preferably 1:6.

[0129] In this 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 this invention, the temperature of the fifth nucleophilic substitution reaction is preferably 40-80°C, more preferably 80°C, and the holding time is preferably 3-8 hours, more preferably 4 hours.

[0131] In this invention, the second nucleophilic substitution reaction preferably further includes adding water, extracting with ethyl acetate, drying, filtering, and concentrating the resulting reaction system in sequence; the concentration is preferably carried out until the system is completely dry.

[0132] After obtaining compound g, the present invention deprotects 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 compound g to the acidic reagent is preferably 1:(3-10), more preferably 1:5.

[0133] In this 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 this invention, the temperature for removing the protection is preferably -20 to 50°C, more preferably 30°C, and the heat preservation time is preferably 2 to 8 hours, more preferably 3 hours.

[0135] In this invention, the process of deprotection preferably further includes concentrating the resulting reaction solution; the concentration is preferably vacuum concentration; the concentration is preferably until the solution is dried.

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

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

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

[0139] In this invention, the second acylation reaction preferably further includes concentrating the resulting reaction solution; the concentration is preferably vacuum concentration; the concentration temperature is preferably 25-60°C, more preferably 40°C, until it dries.

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

[0141] In this 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 compound II to the acid-binding agent is preferably 1:(4-6), more preferably 1:6.

[0142] In this 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 this invention, the temperature of the sixth nucleophilic substitution reaction is preferably -10 to -30°C, more preferably -25°C, and the holding time is preferably 30 to 60 minutes, more preferably 30 minutes.

[0144] In this invention, the sixth nucleophilic substitution reaction preferably further includes sequentially adding water, extracting with ethyl acetate, drying, filtering, concentrating, and performing column chromatography on the resulting reaction system; the extraction, drying, filtering, concentration, and column chromatography are preferably the same as those for the urea derivatives containing the aryl sulfonamide structure shown in Formula A, and will not be described again here. The specific synthetic route for the urea derivatives containing the aryl sulfonamide structure shown in Formula B of this invention is as follows: Figure 2 As shown.

[0145] The present invention also provides the application of urea derivatives containing arylsulfonamide structures as described in the above-described schemes or urea derivatives containing arylsulfonamide structures obtained by the preparation methods described in the above-described schemes in the preparation of medicaments for treating soluble epoxide enzyme-mediated diseases.

[0146] In this 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] To further illustrate the present invention, the following detailed description of the invention's solutions, in conjunction with the accompanying drawings and embodiments, is provided, but should not be construed as limiting the scope of protection of the present invention.

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

[0149] To a 100 mL three-necked flask, add tert-butyl trans-(4-aminocyclohexyl)carbamate (4.04 g, 18.86 mmol), diethyl squaric acid (compound a) (2.92 g, 17.15 mmol), TEA (2.08 g, 20.58 mmol), and EtOH (30 mL). React at 40 °C for 3 h. TLC was used to confirm complete reaction, and the reaction was stopped. The reaction solution was concentrated to dryness, dissolved in DCM (30 mL), washed with H₂O (25 mL × 1), and washed with saturated brine (30 mL × 1). After drying with anhydrous magnesium sulfate, after 4 h, the solution was filtered and concentrated under reduced pressure to obtain tert-butyl trans-((1r,4r)-4-((2-ethoxy-3,4-dioxane-1-en-1-yl)amino)cyclohexyl)carbamate (compound b) (5.8 g pale yellow solid, yield 100.0%).

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

[0151] To a 100 mL single-necked flask, add ((1r,4r)-4-((2-ethoxy-3,4-dioxane-1-en-1-yl)amino)cyclohexyl)tert-butyl 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). Heat to reflux. After 4 h, a solid precipitates. The reaction is complete by TLC, and the reaction is stopped. Cool the reaction solution to room temperature, filter, and wash the filter cake with EtOH to give ((1r,4r)-4-((2-((4-methylphenyl)sulfonamido)-3,4-dioxane-1-en-1-yl)amino)cyclohexyl)tert-butyl 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-dioxanebut-1-en-1-yl)-4-methylbenzenesulfonamide (compound d)

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

[0154] Example 4: Synthesis of N-(2-((1R,4r)-4-(3-((1r,3R,5S,7R)-3,5-dimethyladamantane-1-yl)ureo)cyclohexyl)amino)-3,4-dioxane-1-en-1-yl)-4-methylbenzenesulfonamide (FS-110)

[0155] Add solid phosgene (0.15 g, 0.51 mmol) and dry DCM (30 mL) to a three-necked flask. Cool the flask to below -78 °C and add dropwise N-(2-(((1r,4r)-4-aminocyclohexyl)amino)-3,4-dioxane-1-en-1-yl)-4-methylbenzenesulfonamide (compound d) (0.3 g, 0.82 mmol) and triethylamine (0.31 g, 3.54 mmol) in dry dichloromethane (20 mL). After the addition is complete, move the flask to room temperature and stir for 0.5 h. Then stop the reaction. Concentrate the resulting reaction solution to dryness under reduced pressure. Add dry DCM (10 mL) to the residue to dissolve it and obtain an isocyanate solution for later use.

[0156] Add memantine (0.18 g, 1.03 mmol), triethylamine (0.63 g, 7.08 mmol), and dry dichloromethane (15 mL) to a three-necked flask. Add the above isocyanate solution dropwise and react at room temperature for 0.5 h. TLC showed the reaction was complete. Pour the reaction solution into water (20 mL), extract with EA (20 mL × 3), then wash successively with 1 mol / L HCl (40 mL × 2), water (40 mL × 2), saturated brine (40 mL), and dry with anhydrous sodium sulfate. Filter and concentrate the filtrate under reduced pressure. Concentrate the organic phase under reduced pressure to obtain 0.48 g of a pale yellow oily substance. Pack a 5x silica gel column, add 1.2x silica gel as a sample, and use MeOH:DCM = 1:50 as eluent. Column chromatography yielded a white solid, FS-110, with a yield of 0.11 g, or 21.58%. mp 235–238℃. 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)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-A4)

[0158] The preparation method in this embodiment is the same as that in Example 4, except that 4-trifluoromethoxyaniline is replaced with methimazole in Example 4, resulting in a white solid, namely FS-A4, with a yield of 0.21 g and a recovery rate of 35.0%. The temperature range is 245–248 °C. 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-en-1-yl)-4-methylbenzenesulfonamide (FS-B4)

[0160] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with 3,5-difluoroaniline, resulting in a white solid, namely FS-B4, with a yield of 0.23 g and a recovery rate of 36.12%. The temperature range is 243–245 °C. 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 in this embodiment is the same as that in Example 4, except that the quasi-grandiol in Example 4 is replaced with 4-chloro-3-fluoroaniline, resulting in a white solid, namely FS-C4, with a yield of 0.23 g and a recovery rate of 36.55%. The temperature range is 269–271 °C. 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-en-1-yl)-4-methylbenzenesulfonamide (FS-D4)

[0164] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with 4-chloro-3-trifluoromethylaniline, resulting in 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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-E4)

[0166] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with 3-fluoro-4-trifluoromethoxyaniline, resulting in a white solid, namely FS-E4, with a yield of 0.27 g and a recovery rate of 36.89%. The temperature range is 297–299 °C. 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 in this embodiment is the same as that in Example 4, except that 2-chloro-4-cyanoaniline is replaced with methimazole in Example 4, resulting in a white solid, namely FS-F4, with a yield of 0.25 g and a recovery rate of 36.35%. The temperature range is 289–294 °C. 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-en-1-yl)-4-methylbenzenesulfonamide (FS-G4)

[0170] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with 4-fluoro-3-trifluoromethylaniline, resulting in a white solid, namely FS-G4, with a yield of 0.16 g and a recovery rate of 22.56%. The temperature range is 296–298 °C. 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 1: Synthesis of 2N-(2-(((1r,4r)-4-(3-(3-fluoro-4-methylphenyl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-H4)

[0172] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with 3-fluoro-4-methylaniline, resulting in a white solid, namely FS-H4, with a yield of 0.21 g and a recovery rate of 33.12%. The temperature range is 271–274 °C. 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-en-1-yl)-4-methylbenzenesulfonamide (FS-I4)

[0174] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with 3-chloro-4-fluoroaniline, resulting in a white solid, namely FS-I4, with a yield of 0.22 g and a recovery rate of 35.21%. The temperature range is 280–282 °C. 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-en-1-yl)-4-methylbenzenesulfonamide (FS-J4)

[0176] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with 3-chloro-4-methylaniline, resulting in a white solid, namely FS-J4, with a yield of 0.23 g and a recovery rate of 35.66%. The temperature range is 286–288 °C. 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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-L4)

[0178] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with 3-chloro-4-trifluoromethoxyaniline, resulting in a white solid, namely FS-L4, with a yield of 0.14 g and a recovery rate of 19.89%. The temperature range is 248–251 °C. 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-en-1-yl)-4-methylbenzenesulfonamide (FS-M4)

[0180] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with 4-chloro-3-trifluoromethylaniline, resulting in a white solid, namely FS-M4, with a yield of 0.15 g and a recovery rate of 20.06%. The temperature range is 289–251 °C. 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-en-1-yl)-4-methylbenzenesulfonamide (FS-N4)

[0182] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with 3-fluoro-4-trifluoromethylaniline, resulting in a white solid, namely FS-N4, with a yield of 0.26 g and a recovery rate of 36.22%. The temperature range is 265–271 °C. 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-en-1-yl)-4-methylbenzenesulfonamide (FS-O4)

[0184] The preparation method in this embodiment is the same as that in Example 4, except that 4-fluoroaniline is replaced with quasi-manganese in Example 4, resulting in a white solid, namely FS-O4, with a yield of 0.24 g and a recovery rate of 35.69%. The temperature range is 292–297 °C. 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-en-1-yl)-4-methylbenzenesulfonamide (FS-P4)

[0186] The preparation method in this embodiment is the same as that in Example 4, except that 4-chloroaniline is replaced with quasi-manganese in Example 4, resulting in a white solid, namely FS-P4, with a yield of 0.19 g and a recovery rate of 26.11%. The temperature range is 284–287 °C. 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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-Q4)

[0188] The preparation method in this embodiment is the same as that in Example 4, except that 2-chloro-4-nitroaniline is replaced with methimazole in Example 4, resulting in a white solid, namely FS-Q4, with a yield of 0.19 g and a recovery rate of 25.87%. The temperature range is 289–292 °C. 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)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-R4)

[0190] The preparation method in this embodiment is the same as that in Example 4, except that 4-trifluoromethylaniline is replaced with methimazole in Example 4, resulting in a white solid, namely FS-R4, with a yield of 0.11 g and a recovery rate of 14.23%. The temperature range is 295–299 °C. 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 2N-(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 in this embodiment is the same as that in Example 4, except that the quasi-grandiol in Example 4 is replaced with 4-fluoro-3-methylaniline, resulting in a white solid, namely FS-S4, with a yield of 0.24 g and a recovery rate of 35.78%. The temperature range is 279–282 °C. 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-en-1-yl)-4-methylbenzenesulfonamide (FS-T4)

[0194] The preparation method in this embodiment is the same as that in Example 4, except that 4-chloro-3-methylaniline is replaced with methimazole in Example 4, resulting in a white solid, namely FS-T4, with a yield of 0.25 g and a recovery rate of 35.89%. The temperature range is 280–285 °C. 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-indole-4-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-U4)

[0196] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with 1,2,3,5,6,7-hexahydro-s-indan-4-amine, resulting in a white solid, namely FS-U4, with a yield of 0.26 g and a recovery rate of 36.21%. The temperature range is 271–274 °C. 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)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-V4)

[0198] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with p-toluidine, resulting in a white solid, namely FS-V4, with a yield of 0.17 g and a recovery rate of 24.36%. The temperature range is 267–271 °C. 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-diphenylmethylureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-4-methylbenzenesulfonamide (FS-W4)

[0200] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with diphenyltoluidine, resulting in a white solid, namely FS-W4, with a yield of 0.15 g and a yield of 23.15%. The temperature range is 290–294 °C. 1 HNMR (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. 88(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 in this embodiment is the same as that in Example 4, except that 4-fluorobenzylamine is replaced with quasi-fluorobenzylamine in Example 4, resulting in a white solid, namely FS-X4, with a yield of 0.14 g and a recovery rate of 23.36%. The temperature range is 263–266 °C. 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 in this embodiment is the same as that in Example 4, except that 4-trifluoromethoxybenzylamine is replaced with methimazole in Example 4, resulting in a white solid, namely FS-Y4, with a yield of 0.26 g and a recovery rate of 36.56%. The temperature range is 288–291 °C. 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 in this embodiment is the same as that in Example 4, except that 4-chlorobenzylamine is replaced with quasi-dimethicone in Example 4, resulting in a white solid, namely FS-Z4, with a yield of 0.22 g and a recovery rate of 35.56%. The temperature range is 253–255 °C. 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 in this embodiment is the same as that in Example 4, except that 4-trifluoromethylbenzylamine is replaced with methimazole in Example 4, resulting in a white solid, namely FS-END4, with a yield of 0.13 g and a recovery rate of 16.32%. The temperature range is 266–268 °C. 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 carbamate (1r,4r)-4-((2-((2-methylphenyl)sulfonamido)-3,4-dioxane-1-en-1-yl)amino)cyclohexyl)carbamate

[0210] The preparation method in this embodiment is the same as in Example 2, except that p-methylbenzenesulfonamide in Example 2 is replaced with o-methylbenzenesulfonamide, resulting in a white solid, namely ((1r,4r)-4-((2-((2-methylphenyl)sulfonamido)-3,4-dioxanebut-1-en-1-yl)amino)cyclohexyl)tert-butyl 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-dioxanebut-1-en-1-yl)-2-methylbenzenesulfonamide

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

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

[0214] The preparation method in this embodiment is the same as that in Example 4, except that N-(2-(((1r,4r)-4-aminocyclohexyl)amino)-3,4-dioxanebut-1-en-1-yl)-4-methylbenzenesulfonamide in Example 4 is replaced with N-(2-(((1r,4r)-4-aminocyclohexyl)amino)-3,4-dioxanebut-1-en-1-yl)-2-methylbenzenesulfonamide, yielding a white solid, namely MH-101, with a yield of 0.13 g and a yield of 22.85%. The temperature range is 223–226 °C. 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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-102)

[0216] The preparation method in this embodiment is the same as that in Example 4, except that the methyl dimethylamine in Example 4 is replaced with 3-fluoro-4-trifluoromethoxyaniline, resulting in a white solid, namely MH-102, with a yield of 0.14 g and a recovery rate of 23.25%. The temperature range is 231–235 °C. 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 5N-(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 in this embodiment is the same as in Example 4, except that 4-chloro-3-fluoroaniline is replaced with quasi-mono-manganese in Example 4, resulting in a white solid, namely MH-104, with a yield of 0.14 g and a recovery rate of 25.34%. The temperature range is 256–258 °C. 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 in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with 3-chloro-4-fluoroaniline, resulting in a white solid, namely MH-105, with a yield of 0.17 g and a recovery rate of 28.58%. The temperature range is 257–259 °C. 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)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-106)

[0222] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with p-toluidine, resulting in a white solid, namely MH-106, with a yield of 0.13 g and a recovery rate of 22.14%. The temperature range is 235–238 °C. 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 in this embodiment is the same as that in Example 4, except that 2-chloro-4-cyanoaniline is replaced with methimazole in Example 4, resulting in a white solid, namely MH-107, with a yield of 0.22 g and a recovery rate of 31.11%. The temperature range is 242–246 °C. 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 in this embodiment is the same as that in Example 4, except that the quasi-golden is replaced with 4-fluoro-3-trifluoromethylaniline in Example 4, resulting in a white solid, namely MH-108, with a yield of 0.14 g and a recovery rate of 26.54%. The temperature range is 268–271 °C. 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 in this embodiment is the same as that in Example 4, except that the methylphenidate in Example 4 is replaced with 3-fluoro-4-methylaniline, resulting in a white solid, namely MH-109, with a yield of 0.16 g and a recovery rate of 25.13%. The temperature range is 251–254 °C. 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 in this embodiment is the same as that in Example 4, except that the methylphenidate in Example 4 is replaced with 4-chloro-3-trifluoromethylaniline, resulting in a white solid, namely MH-110, with a yield of 0.18 g and a recovery rate of 28.69%. The temperature range is 235–239 ​​°C. 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 in this embodiment is the same as that in Example 4, except that the methylphenidate in Example 4 is replaced with 3-chloro-4-trifluoromethylaniline, resulting in a white solid, namely MH-111, with a yield of 0.10 g and a recovery rate of 20.13%. The temperature range is 236–238 °C. 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 in this embodiment is the same as that in Example 4, except that the methylphenidate in Example 4 is replaced with 3-fluoro-4-trifluoromethylaniline, resulting in a white solid, namely MH-112, with a yield of 0.11 g and a recovery rate 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)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-113)

[0236] The preparation method in this embodiment is the same as that in Example 4, except that 4-trifluoromethoxyaniline is replaced with methyl methoxyaniline in Example 4, resulting in a white solid, namely MH-113, with a yield of 0.25 g and a recovery rate of 38.23%. The temperature range is 249–251 °C. 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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-114)

[0238] The preparation method in this embodiment is the same as that in Example 4, except that 4-fluoroaniline is replaced with quasi-manganese in Example 4, resulting in a white solid, namely MH-114, with a yield of 0.18 g and a recovery rate of 29.12%. The temperature range is 241–245 °C. 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 in this embodiment is the same as that in Example 4, except that 4-chloroaniline is replaced with quasi-manganese in Example 4, resulting in a white solid, namely MH-115, with a yield of 0.17 g and a recovery rate of 28.56%. The temperature range is 237–240 °C. 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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-116)

[0242] The preparation method in this embodiment is the same as that in Example 4, except that 2-chloro-4-nitroaniline is replaced with methimazole in Example 4, resulting in a white solid, namely MH-116, with a yield of 0.22 g and a recovery rate of 34.12%. The temperature range is 239–244 °C. 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)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-117)

[0244] The preparation method in this embodiment is the same as that in Example 4, except that 4-trifluoromethylaniline is replaced with methimazole in Example 4, resulting in a white solid, namely MH-117, with a yield of 0.15 g and a recovery rate of 23.56%. The temperature range is 235–239 ​​°C. 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 in this embodiment is the same as that in Example 4, except that the quasi-grandiol in Example 4 is replaced with 4-fluoro-3-methylaniline, resulting in a white solid, namely MH-118, with a yield of 0.12 g and a recovery rate of 21.45%. The temperature range is 234–237 °C. 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 in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with 3-chloro-4-methylaniline, resulting in a white solid, namely MH-119, with a yield of 0.16 g and a recovery rate of 26.89%. The temperature range is 263–267 °C. 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 in this embodiment is the same as that in Example 4, except that the methylphenidate in Example 4 is replaced with 4-chloro-3-methylaniline, resulting in a white solid, namely MH-120, with a yield of 0.13 g and a recovery rate of 23.26%. The temperature range is 235–239 ​​°C. 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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-121)

[0252] The preparation method in this embodiment is the same as that in Example 4, except that the methyl dimethoxyaniline in Example 4 is replaced with 3-chloro-4-trifluoromethoxyaniline, resulting in a white solid, namely MH-121, with a yield of 0.11 g and a recovery rate of 21.56%. The temperature range is 232–237 °C. 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-indole-4-yl)ureido)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-2-methylbenzenesulfonamide (MH-122)

[0254] The preparation method in this embodiment is the same as that in Example 4, except that the methimazole in Example 4 is replaced with 1,2,3,5,6,7-hexahydro-s-indan-4-amine, resulting in a white solid, namely MH-122, with a yield of 0.15 g and a recovery rate of 24.16%. The temperature range is mp 278–281 °C. 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 carbamate ((1r,4r)-4-((3,4-dioxo-2-((phenylmethyl)sulfonamide)cyclobut-1-en-1-yl)amino)cyclohexyl)carbamate

[0256] The preparation method in this embodiment is the same as in Example 2, except that p-toluenesulfonamide in Example 2 is replaced with benzylsulfonamide, resulting in a white solid, namely ((1r,4r)-4-((3,4-dioxo-2-((phenylmethyl)sulfonamide)cyclobut-1-en-1-yl)amino)cyclohexyl)tert-butyl 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-dioxanebut-1-en-1-yl)-1-phenylmethanesulfonamide

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

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

[0260] The preparation method in this embodiment is the same as that in Example 4, except that N-(2-(((1r,4r)-4-aminocyclohexyl)amino)-3,4-dioxanebut-1-en-1-yl)-4-methylbenzenesulfonamide in Example 4 is replaced with N-(2-(((1r,4r)-4-aminocyclohexyl)amino)-3,4-dioxanebut-1-en-1-yl)-1-phenylmethanesulfonamide, yielding a white solid, namely ZS-101, with a yield of 0.11 g and a yield of 22.58%. The temperature range is mp 248–251 °C. 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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-102)

[0262] The preparation method in this embodiment is the same as that in Example 4, except that the methyl dimethylamine in Example 4 is replaced with 3-fluoro-4-trifluoromethoxyaniline, resulting in a white solid, namely ZS-102, with a yield of 0.14 g and a recovery rate of 23.89%. The temperature range is 234–239 °C. 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)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-103)

[0264] The preparation method in this embodiment is the same as that in Example 4, except that 4-trifluoromethoxyaniline is replaced with quasi-trifluoromethoxyaniline in Example 4, resulting in a white solid, namely ZS-102, with a yield of 0.22 g and a recovery rate of 34.25%. The temperature range is 270–273 °C. 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 in this embodiment is the same as that in Example 4, except that the quasi-grandiol in Example 4 is replaced with 4-chloro-3-fluoroaniline, resulting in a white solid, namely ZS-104, with a yield of 0.17 g and a recovery rate of 28.45%. The temperature range is 249–252 °C. 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 in this embodiment is the same as that in Example 4, except that the methyl dimethicone in Example 4 is replaced with 3-chloro-4-fluoroaniline, resulting in a white solid, namely ZS-105, with a yield of 0.14 g and a recovery rate of 22.54%. The temperature range is 268–270 °C. 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)ureo)cyclohexyl)amino)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-106)

[0270] The preparation method in this embodiment is the same as that in Example 4, except that the quasi-grandiol in Example 4 is replaced with p-toluidine, resulting in a white solid, namely ZS-106, with a yield of 0.16 g and a recovery rate of 24.75%. The temperature range is 250–253 °C. 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 in this embodiment is the same as that in Example 4, except that 2-chloro-4-cyanoaniline is replaced with methimazole in Example 4, resulting in a white solid, namely ZS-107, with a yield of 0.23 g and a recovery rate of 32.59%. The temperature range is 249–252 °C. 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 in this embodiment is the same as that in Example 4, except that 4-fluoro-3-methylaniline is replaced with quasi-mono-aniline in Example 4, resulting in a white solid, namely ZS-108, with a yield of 0.17 g and a recovery rate of 26.88%. The temperature range is 254–259 °C. 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 in this embodiment is the same as that in Example 4, except that the methylphenidate in Example 4 is replaced with 3-fluoro-4-methylaniline, resulting in a white solid, namely ZS-109, with a yield of 0.14 g and a recovery rate of 24.13%. The temperature range is 240–244 °C. 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 in this embodiment is the same as that in Example 4, except that the quasi-golden is replaced with 4-chloro-3-trifluoromethylaniline in Example 4, resulting in a white solid, namely ZS-110, with a yield of 0.15 g and a recovery rate of 26.69%. The temperature range is 258–260 °C. 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 in this embodiment is the same as that in Example 4, except that the methylphenidate in Example 4 is replaced with 3-chloro-4-trifluoromethylaniline, resulting in a white solid, namely ZS-111, with a yield of 0.19 g and a recovery rate of 33.15%. The temperature range is 273–277 °C. 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 in this embodiment is the same as that in Example 4, except that the methylphenidate in Example 4 is replaced with 3-fluoro-4-trifluoromethylaniline, resulting in a white solid, namely ZS-112, with a yield of 0.15 g and a recovery rate of 25.14%. The temperature range is 250–254 °C. 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 in this embodiment is the same as that in Example 4, except that the methyl dimethicone in Example 4 is replaced with 3,5-difluoroaniline, resulting in a white solid, namely ZS-113, with a yield of 0.24 g and a recovery rate of 34.23%. The temperature range is 247–252 °C. 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 in this embodiment is the same as that in Example 4, except that the methylphenidate in Example 4 is replaced with 3-chloro-4-methylaniline, resulting in a white solid, namely ZS-114, with a yield of 0.11 g and a recovery rate of 19.83%. The temperature range is 262–267 °C. 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 in this embodiment is the same as that in Example 4, except that the quasi-golden is replaced with 4-chloro-3-methylaniline in Example 4, resulting in a white solid, namely ZS-115, with a yield of 0.18 g and a recovery rate of 29.56%. The temperature range is 239–244 °C. 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)ureo)cyclohexyl)amino)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-116)

[0290] The preparation method in this embodiment is the same as that in Example 4, except that the methyl dimethylamine in Example 4 is replaced with 3-chloro-4-trifluoromethoxyaniline, resulting in a white solid, namely ZS-116, with a yield of 0.26 g and a recovery rate of 33.58%. The temperature range is 247–252 °C. 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 in this embodiment is the same as that in Example 4, except that the quasi-golden is replaced with 4-fluoro-3-trifluoromethylaniline in Example 4, resulting in a white solid, namely ZS-117, with a yield of 0.17 g and a recovery rate of 26.56%. The temperature range is 273–277 °C. 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 carbamate (compound f)

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

[0295] Example 74 Synthesis of tert-butyl carbamate (compound g)

[0296] The preparation method in this embodiment is the same as that in Example 2, except that ((1r,4r)-4-((2-ethoxy-3,4-dioxane-1-en-1-yl)amino)cyclohexyl)tert-butyl carbamate (compound b) in Example 2 is replaced with (1-(2-ethoxy-3,4-dioxane-1-en-1-yl)piperidin-4-yl)tert-butyl carbamate (compound f), yielding a white solid, namely (1-(2-((4-methylphenyl)sulfonamido)-3,4-dioxane-1-en-1-yl)piperidin-4-yl)tert-butyl 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-dioxane-1-en-1-yl)-4-methylbenzenesulfonamide (compound h)

[0298] The preparation method in this embodiment is the same as that in Example 3, except that ((1r,4r)-4-((2-((4-methylphenyl)sulfonamido)-3,4-dioxane-1-en-1-yl)amino)cyclohexyl)tert-butyl carbamate (compound e) in Example 3 is replaced with (1-(2-((4-methylphenyl)sulfonamido)-3,4-dioxane-1-en-1-yl)piperidin-4-yl)tert-butyl carbamate (compound g), yielding a white solid, namely N-(2-(4-aminopiperidin-1-yl)-3,4-dioxane-1-en-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 in this embodiment is the same as that in Example 4, except that N-(2-(((1r,4r)-4-aminocyclohexyl)amino)-3,4-dioxanebut-1-en-1-yl)-4-methylbenzenesulfonamide in Example 4 is replaced with 4-chloro-3-trifluoromethylaniline, resulting in a white solid, namely WG-101, with a yield of 0.13 g and a recovery rate of 23.45%. The temperature range is 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 in this embodiment is the same as in Example 4, except that 3-chloro-4-methylaniline is replaced with methimazole in Example 4, resulting in a white solid, namely WG-103, with a yield of 0.15 g and a recovery rate of 26.53%. The temperature range is 225–227 °C. 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 in this embodiment is the same as that in Example 4, except that 4-trifluoromethoxyaniline is replaced with methyl methoxyaniline in Example 4, resulting in a white solid, namely WG-105, with a yield of 0.17 g and a recovery rate of 26.78%. The temperature range is 199–203 °C. 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 in this embodiment is the same as that in Example 4, except that 3-fluoro-4-trifluoromethoxyaniline is replaced with methyl methoxyaniline in Example 4, resulting in a white solid, namely WG-106, with a yield of 0.13 g and a recovery rate of 23.46%. The temperature range is 227–228 °C. 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 in this embodiment is the same as that in Example 4, except that 4-fluoro-3-trifluoromethylaniline is replaced with methylaniline in Example 4 to obtain a white solid, namely WG-108, with a yield of 0.15 g and a recovery rate of 27.35%. The temperature range is 170–175 °C. 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-(1-(2-((2-methylphenyl)sulfonamido)-3,4-dioxane-1-en-1-yl)piperidin-4-yl)carbamate

[0310] The preparation method in this embodiment is the same as in Example 2, except that the p-toluenesulfonamide of ((1r,4r)-4-((2-ethoxy-3,4-dioxane-1-en-1-yl)amino)cyclohexyl)carbamate tert-butyl ester in Example 2 is replaced with o-methylbenzenesulfonamide, resulting in a white solid, namely (1-(2-((2-methylphenyl)sulfonamido)-3,4-dioxane-1-en-1-yl)piperidin-4-yl)carbamate tert-butyl ester, 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-dioxane-1-en-1-yl)-2-methylbenzenesulfonamide. The preparation method of this example is the same as that of Example 3, except that the tert-butyl carbamate ((1r,4r)-4-((2-((4-methylphenyl)sulfonamido)-3,4-dioxane-1-en-1-yl)amino)cyclohexyl)carbamate in Example 3 is replaced with tert-butyl carbamate (1-(2-((2-methylphenyl)sulfonamido)-3,4-dioxane-1-en-1-yl)piperidin-4-yl)carbamate, yielding a white solid, namely N-(2-(4-aminopiperidin-1-yl)-3,4-dioxane-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 in this embodiment is the same as that in Example 4, except that the quasi-grandiol in Example 4 is replaced with 4-chloro-3-fluoroaniline, resulting in a white solid, namely MH-A104, with a yield of 0.14 g and a recovery rate of 24.65%. The temperature range is 239–242 °C. 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 in this embodiment is the same as that in Example 4, except that 4-trifluoromethylaniline is replaced with methimazole in Example 4, resulting in a white solid, namely MH-A117, with a yield of 0.11 g and a recovery rate of 23.89%. The temperature range is 243–246 °C. 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 in this embodiment is the same as in Example 2, except that the methyl methacrylate in Example 2 is replaced with benzyl sulfonamide, and a white solid is obtained, namely (1-(3,4-dioxo-2-((phenylmethyl)sulfonamide)cyclobut-1-en-1-yl)piperidin-4-yl)tert-butyl 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-dioxane-1-en-1-yl)-1-phenylmethanesulfonamide

[0319] The preparation method in this embodiment is the same as in Example 3, except that the methimazole in Example 3 is replaced with (1-(3,4-dioxo-2-((phenylmethyl)sulfonamido)cyclobut-1-en-1-yl)piperidin-4-yl)tert-butyl carbamate, yielding a white solid, namely N-(2-(4-aminopiperidin-1-yl)-3,4-dioxocyclobut-1-en-1-yl)-1-phenylmethanesulfonamide, with a yield of 4.56 g and a recovery rate 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 in this embodiment is the same as that in Example 4, except that the methyl dimethylamine in Example 4 is replaced with 3-fluoro-4-trifluoromethoxyaniline, resulting in a white solid, namely ZS-A102, with a yield of 0.13 g and a recovery rate of 22.31%. The temperature range is 271–274 °C. 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 in this embodiment is the same as that in Example 4, except that ** in Example 4 is replaced with 3-fluoro-4-trifluoromethylaniline, resulting in a white solid, namely ZS-A112, with a yield of 0.14 g and a recovery rate of 27.36%. The temperature range is 242–246 °C. 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)ureo)piperidin-1-yl)cyclobut-1-en-1-yl)-1-phenylmethanesulfonamide (ZS-A113)

[0325] The preparation method in this embodiment is the same as that in Example 4, except that 4-trifluoromethoxyaniline is replaced with quasi-trifluoromethoxyaniline in Example 4, resulting in a white solid, namely ZS-A113, with a yield of 0.15 g and a recovery rate of 26.54%. The temperature range is 250–255 °C. 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 in this embodiment is the same as that in Example 4, except that 4-trifluoromethylaniline is replaced with quasi-trifluoromethylaniline in Example 4, resulting in a white solid, namely ZS-A117, with a yield of 0.18 g and a recovery rate of 30.56%. The temperature range is 259–264 °C. 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)-cyanoacetate-(6-methoxy-naphth-2-yl)methyl ester, i.e., PHOME, is itself non-fluorescent. However, under the action of sEH enzyme, it is hydrolyzed to produce the product 6-methoxy-2-naphthaldehyde. 6-methoxy-2-naphthaldehyde can emit fluorescence at a wavelength of 465 nm when excited by light at 330 nm. The intensity of the detected fluorescence signal is inversely proportional to the strength of the inhibitory effect on sEH enzyme. Based on the above principle, the inhibition rate of samples at different concentrations was calculated compared with the positive control group. The IC50 of the compound was calculated using SPSS 20 software based on the inhibition rate and concentration. 50 value.

[0331] 2. Preparation of reagents and drugs

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

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

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

[0335] The sample powder to be tested is dissolved in DMSO to prepare a 20mM solution, stored at -20℃ for later use, and diluted with Tris-HCl buffer to the corresponding concentration before use.

[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 solution DMSO Inhibitors sEH 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 Procedure

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

[0342] (b) Add 2 μL of the test sample solution. Replace the solvent group and the 100% activity group with an equal volume of DMSO. Add the lead compound t-TUCB (structural formula:) to the positive control group.

[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) Add 20 μL of s-EH solution (final concentration of 400 ng / mL), and replace the solvent group 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 at 37 °C for 10 min;

[0347] (f) ELISA reader detects fluorescence signal data, with an excitation wavelength of 330 nm and an emission wavelength of 465 nm.

[0348] 5. Data Analysis

[0349] Each sample was prepared in triplicate, and the mean value of the three replicates was the fluorescence value (F) of the analyte. The inhibition rate % was calculated as [(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 IC50 of the compound was calculated using SPSS 20 software based on the inhibition rate and concentration. 50 value.

[0350] The inhibitory activities of the 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 against human sEH (HsEH) and mouse sEH (MsEH).

[0352]

[0353] As shown in Table 1, the compounds provided by this invention, including the FS, MH, and ZS series compounds containing the trans-cyclohexane fragment, are effective against HsEH IC. 50 With values ​​between 0.1 nM and 3.0 nM, they exhibit high inhibitory activity. The WG, MH-A, and ZS-A series compounds containing piperidine fragments show strong inhibitory activity against HsEH IC. 50 The values ​​range from 0.4 nM to 7.1 nM, exhibiting good inhibitory effects. The compounds provided by this invention, including the FS, MH, and ZS series compounds containing the trans-cyclohexane fragment, exhibit good inhibitory effects on MsEH IC. 50The values ​​range from 0.1 nM to 27.8 nM, exhibiting excellent inhibitory effects. Experimental results showed that 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 exhibited superior inhibitory activity against HsEH compared to the lead compound t-TUCB. Experimental results showed that the FS series, MH series (except MH-107 and MH-116), ZS series, and WG-103 exhibited superior inhibitory activity against MsEH compared to the lead compound t-TUCB. Ultimately, 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- were also found to be effective against MsEH. 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 superior to that of the lead compound t-TUCB.

[0354] As can be seen from the above embodiments, the urea derivatives containing arylsulfonamide structures 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 to prepare drugs for treating soluble cyclooxide enzyme-mediated diseases.

[0355] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. Other embodiments can be obtained based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A urea derivative containing an arylsulfonamide structure, with a structure as shown in Formula A or Formula B: In formula A or formula B, R1 is independently an alkyl, substituted alkyl, phenyl, substituted phenyl, naphthyl or substituted naphthyl; The alkyl group in R1 is methyl, ethyl, propyl, butyl, memantyl, 1,3-dihydroxyadamantyl, 5-hydroxy-2-adamantyl, 4-hydroxy-2-adamantyl, isopropyl, isobutyl, or isopentyl. The substituted alkyl group in R1 is a substituted methyl group, a substituted ethyl group, a substituted propyl group, a substituted isopropyl group, a substituted memantyl group, a substituted 1,3-dihydroxyadamantyl group, a substituted 5-hydroxy-2-adamantyl group, a substituted 4-hydroxy-2-adamantyl group, a substituted isobutyl group, or a substituted isopentyl group. The substituents of the alkyl group in R1 are independently selected from halogen groups, hydroxyl groups, amino groups, cyano groups, nitro groups, trifluoromethyl groups, trifluoromethoxy groups, methylamino groups, dimethylamino groups, alkyl groups, or aromatic groups; the alkyl group in the substituents of R1 is selected from methyl, ethyl, propyl, butyl, or isopropyl groups; the aromatic group in the substituents of R1 is selected from phenyl or naphthyl groups. The types of substituents for the substituted phenyl groups described in R1 are the same as the types of substituents for the substituted alkyl groups described in R1; The types of substituents for the naphthyl group described in R1 are the same as the types of substituents for the alkyl group described in R1; R2 is independently -H, alkyl, substituted alkyl, alkoxy, or substituted alkoxy; the alkyl group in R2 is a C1 to C6 alkyl group; The substituted alkyl group in R2 is a substituted C1 to C6 alkyl group; The alkoxy group in R2 is a C1-C6 alkoxy group; The substituted alkoxy group in R2 is a substituted C1 to C6 alkoxy group; The substituent of the alkyl group in R2 is selected from halogen groups, hydroxyl groups, amino groups, methylamino groups, dimethylamino groups, or alkyl groups, and the alkyl group in the substituent of R2 is a C1 to C6 alkyl group. The types of substituents for the substituted alkoxy groups described in R2 are the same as the types of substituents for the substituted alkyl groups described in R2. Z is independently -O-; n can be 0, 1, 2, or 3 independently.

2. A urea derivative containing an arylsulfonamide structure, characterized in that, The specific structural formulas of the urea derivatives containing arylsulfonamide structures are shown below:

3. The method for preparing the urea derivative containing the arylsulfonamide structure according to claim 1, characterized in that, The method for preparing the urea derivative containing the aryl sulfonamide structure shown in Formula A includes the following steps: (1) Compound a was subjected to a first nucleophilic substitution reaction with trans-(4-aminocyclohexyl)carbamate tert-butyl ester to obtain compound b; (2) Compound b was subjected to a second nucleophilic substitution reaction with compound I to obtain compound c; (3) Compound c is subjected to a first deprotection reaction to obtain compound d; (4) The compound d and bis(trichloromethyl) carbonate were subjected to a first acylation reaction to obtain a first intermediate compound; the first intermediate compound and compound II were subjected to a third nucleophilic substitution reaction to obtain a urea derivative containing an aryl sulfonamide structure as shown in Formula A; The structural formula of compound I is as follows: The structural formula of compound II is as follows: The structural formulas of compounds a, b, c, d, and the first intermediate compound are as follows: In the structural formulas of compounds I, II, c, d, or the first intermediate compound, the definitions of R1, R2, and n are the same as in formula A; The preparation method of the urea derivative containing the aryl sulfonamide structure shown in Formula B includes the following steps: (A) Compound a was subjected to a fourth nucleophilic substitution reaction with 4-tert-butoxycarbonylaminopiperidine to give compound f; (B) Compound f is reacted with compound I in a fifth nucleophilic substitution reaction to obtain compound g; (C) Deprotecting compound g to obtain compound h; (D) The compound h and bis(trichloromethyl) carbonate are subjected to a second acylation reaction to obtain a second intermediate compound; the second intermediate compound and compound II are subjected to a sixth nucleophilic substitution reaction to obtain a urea derivative containing an arylsulfonamide structure as shown in formula B; The structural formula of compound I is as follows: The structural formula of compound II is as follows: The structural formulas of compounds f, g, h, and the second intermediate compound are as follows: In the structural formulas of compounds I, II, g, h, or the second intermediate compound, the definitions of R1, R2, and n are the same as in formula B.

4. The preparation method according to claim 3, 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 holding time is 30 to 60 min.

5. The preparation method according to claim 4, 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.

6. The use of the urea derivative containing an arylsulfonamide structure as described in claim 1 or claim 2, or the urea derivative containing an arylsulfonamide structure obtained by the preparation method described in any one of claims 3 to 5, in the preparation of a medicament for treating soluble epoxide enzyme-mediated diseases.

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