Compounds and methods for their preparation, and their use in the preparation of sEH inhibitors and PPARs agonists - Patent Application 20070122997

Abstract

The present application belongs to the field of pharmaceutical technology, and specifically relates to compounds and their preparation methods, as well as their use in the preparation of sEH inhibitors and PPAR agonists. The present application provides compounds having the structures shown in Formula I, II, III, IV, V, or VI. The compounds provided herein have a typical urea structure as the primary pharmacophore for soluble epoxide hydrolase (sEH) and a thiazolidinedione moiety as the primary pharmacophore for peroxisome proliferator-activated receptors (PPARs). The sEH inhibitor and PPAR agonist compounds provided herein have high inhibitory activity against human HsEH and high agonistic activity against PPARs, and can be used as sEH inhibitor and PPAR agonist compounds for the preparation of drugs for the treatment of soluble epoxidase- and peroxisome proliferator-activated receptor-mediated diseases.

Description

[Technical Field]

[0001] Related Applications This application claims priority from a Chinese patent application filed with the China Patent Office on March 22, 2023, with application number CN202310282598.7 and titled "Dual-target compound and method for preparing same and use thereof in preparing sEH inhibitors and PPARs agonists," the entire contents of which are incorporated herein by reference.

[0002] The present application is in the field of pharmaceutical technology, and specifically relates to compounds and methods for their preparation and use in the preparation of sEH inhibitors and PPARs agonists. [Background technology]

[0003] Pain sensation is mediated by the action of specialized subsets of sensory afferent neurons (nociceptors), which are activated in response to thermal, mechanical, and chemical stimuli through a variety of mechanisms. Studies have shown that modulation of ion channels includes transient receptor potential (TRP) channels, activation of G protein-coupled receptors (GPCRs), and changes in the cell membrane, all of which represent mechanisms of lipid mediator signaling in nociceptors (Nature, 2001, 413(6852):203-210).

[0004] Studies have shown that prostaglandins and leukotrienes, metabolites of cyclooxygenase and lipoxygenase, can induce pain and inflammation, demonstrating the role of lipid mediators in pain signaling. Certain long-chain polyunsaturated fatty acids (PUFAs) are metabolized by cytochrome P450 enzymes (CYP450) to form epoxide metabolites, or epoxy fatty acids (EpFAs). Researchers have discovered that these metabolites mediate analgesic effects in several types of pain pathologies, including acute pain, chronic pain, cancer pain, and intractable pain.

[0005] Arachidonic acid (ARA), a PUFA containing 20 carbon atoms and four unsaturated double bonds, is metabolized by CYP450 enzymes to one or more of four epoxy metabolites (EETs), including 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET. EpFAs containing EETs limit pain and inflammation through multiple direct and indirect mechanisms, including nuclear receptor agonism, limiting endoplasmic reticulum stress, and blocking mitochondrial dysfunction. Small molecule inhibitors of soluble epoxide hydrolase exhibit potent analgesic effects in animal models of inflammatory pain and diabetic neuropathic pain (Neurotherapeutics, 2020, 17, 900-916). EETs are easily metabolized by soluble epoxide hydrolase (sEH) in the body, leading to their inactivation. Dihydroxy metabolites (DHETs), which are metabolites of EETs, have pro-inflammatory effects. Small molecule inhibitors of soluble epoxide hydrolase can stabilize EpFAs in the body. Therefore, inhibiting sEH activity and increasing the amount of EETs in the body has become a new approach for treating EETs-related diseases.

[0006] EpFAs exert their analgesic effects through multiple mechanisms, including reducing endoplasmic reticulum (ER) stress, preventing or reversing endothelial cell dysfunction (ECD), and stabilizing mitochondrial function (Cell Physiol Biochem, 2015, 36, 474-486). EpFAs can regulate cellular stress caused by reactive oxygen species and redirect the ER stress response toward maintaining homeostasis rather than activating inflammatory pathways that lead to cellular senescence and cell death. EpFAs can indirectly maintain the stability of mitochondrial function by reducing the ER stress response and limiting reactive oxygen species (ROS). EpFAs can also directly block mitochondrial dysfunction. Inhibiting sEH activity stabilizes EpFAs and also limits the production of some pro-inflammatory diol metabolites. Therefore, EpFAs mediate beneficial effects in all of these processes, shifting the ER stress response toward homeostasis and reducing pain.

[0007] Because there is substantial evidence that the role of EpFA in nociception includes blocking inflammatory and neuropathic pain, sEH inhibitors and EpFA mimetics hold great potential for alleviating pain in humans.

[0008] Epidemiological studies have confirmed that inflammatory biomarkers are associated with the development of type 2 diabetes mellitus (T2DM) and its complications. The mechanisms underlying T2DM inflammation remain unclear. Inflammatory responses may contribute to the development of T2DM by causing insulin resistance, and an obese environment induces adipose tissue dysfunction, macrophage infiltration, and the massive release of cytokines such as IL-6 and TNF-α. Long-term elevations in these molecules promote insulin resistance in skeletal muscle and endothelial dysfunction in the vasculature, facilitating the release of acute-phase proteins from the liver. Chronic elevations of specific inflammatory markers, such as IL-6 and TNF-α, appear to be associated with metabolic disorders and may alter insulin sensitivity by triggering various key steps in the insulin signaling pathway. Hyperglycemia can also induce the production of IL-6 by endothelial cells and macrophages. Furthermore, hyperglycemia enhances the effects of suppressors of cytokine signaling (SOCS), impairing insulin release and signaling and promoting the long-term complications of diabetes. Targeting inflammatory pathways may be an essential part of strategies for the prevention and control of diabetes and its associated complications.

[0009] PPAR agonists have been shown to inhibit the expression of cytokines such as resistin, tumor necrosis factor alpha (TNFα), and interleukin-6, which promote insulin resistance. PPAR agonists induce an increase in the plasma concentration of adiponectin, a hormone secreted by adipose tissue and found at low levels in the plasma of patients with T2DM. Adiponectin increases fatty acid oxidation in the liver and skeletal muscle. Overall, adiponectin enhances insulin sensitivity in skeletal muscle and liver, reduces hepatic glucose production, thereby reducing circulating FFA, TG, and glucose levels. Macrophage infiltration into obese adipose tissue contributes to local inflammation that enhances insulin resistance. PPARs within macrophages have recently been shown to partially mediate the antidiabetic effects of TZDs. Inactivation of PPARs in macrophages leads to impaired alternative macrophage activation, impaired glucose tolerance, and insulin resistance in skeletal muscle and liver.

[0010] The analgesics currently in clinical use mainly include opioid analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs), both of which have certain side effects. For example, traditional opioid analgesics are relatively effective, but they are also highly addictive and can cause side effects such as respiratory depression, hypotension, nausea, vomiting, constipation, and difficulty urinating. NSAIDs can be divided into nonselective NSAIDs and selective cyclooxygenase-2 (COX-2) inhibitors. While nonselective NSAIDs have good analgesic effects, they often cause severe gastrointestinal irritation, easily lead to gastric ulcers, and have adverse reactions to the coagulation and hematopoietic systems. Selective COX-2 inhibitors do not have the adverse reactions of gastrointestinal irritation, but are prone to cause prostacyclin and thromboxane imbalances, which can lead to cardiovascular diseases. They are generally ineffective for treating neuropathic pain.

[0011] The blood glucose-lowering drugs currently in clinical use mainly include insulin, insulin secretagogues, insulin sensitizers, α-glycosidase inhibitors, GLP-1 agonists, dipeptidyl peptidase-4 inhibitors, etc. For example, insulin α-glucosidase inhibitors cannot be used alone to treat diabetes and usually need to be combined with other drugs to control blood glucose levels. Insulin secretagogues may cause gastrointestinal symptoms (e.g., nausea and upper abdominal bloating) and headaches, and require insulin injections for treatment, which leads to poor patient compliance. Other drugs have certain drawbacks, such as difficulty in dealing with inflammatory complications of diabetes and concomitant neuropathic pain.

[0012] The previously reported dual-target compound RB394, an sEH IC, is an sEH inhibitor and PPARs agonist. 50 = 0.3 μM, PPARγEC 50 Although a dose of 0.3 μM has shown some efficacy in the fields of diabetic nephropathy and steatohepatitis, further development and exploration are still needed. Considering that dual-targeting compounds of sEH inhibitors and PPAR agonists are effective not only in lowering blood glucose levels but also in diabetic inflammatory complications, non-alcoholic fatty liver disease, and neuropathic pain, this reduces the drug-drug interactions that previously required patients to take multiple doses. Therefore, the development of new and more efficient dual-targeting compounds of sEH inhibitors and PPAR agonists for the treatment of diabetes, non-alcoholic fatty liver disease, pain, and depression is urgent and necessary. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Nature,2001,413(6852):203-210 [Non-patent document 2] Neurotherapeutics,2020,17,900-916 [Non-patent document 3] Cell Physiol Biochem,2015,36,474-486 Summary of the Invention [Problem to be solved by the invention]

[0014] The present application aims to provide a compound, a method for producing the compound, and its use in producing an sEH inhibitor and a PPARs agonist. The compound provided by the present application has high activity against human sEH (HsEH) and PPARs, has minimal side effects, and as a dual-target compound acting as an sEH inhibitor and a PPARs agonist, can be used to treat diabetes and its inflammatory complications, neuropathic pain, and depression. [Means for solving the problem]

[0015] The present application provides compounds having the structure shown in Formula I, II, III, IV, V or VI. [ka] JPEG2025527059000002.jpg72128

[0016] wherein R1 is a memanthyl group, an aryl group, an alkyl-substituted aryl group, a haloaryl group, a haloalkyl-substituted aryl group, a haloalkoxy-substituted aryl group, or a haloaryloxy-substituted aryl group; R2 is a hydrogen atom, a hydroxyl group, an alcoholic hydroxyl group, an amine group, a carboxyl group, an acyl group, an amide group, or an ester group; R3 is a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group, a cyano group, or a carboxyl group; R4 is a hydrogen atom or an alkyl group; R5 is a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group, a cyano group, or a carboxyl group; R6 is a hydrogen atom, a hydroxyl group, an alkyl group, an ester group, or an amine group; A is a cycloalkyl group, a heterocyclyl group, or an aryl group; B is a single bond, a cycloalkyl group, a heterocyclyl group, or an aryl group; W is a single bond, -CH2-, -O-, -S-, -NH- or TIFF2025527059000003.tif1214, Y is a single bond, -CH2-, -O-, -S- or -NH-; Z is =CH2, =O, =S or =NH; and n is an integer of 0-12. [Effects of the Invention]

[0017] The present application provides compounds having the structure shown in Formula I, II, III, IV, or V. The compounds provided in the present application have a typical urea structure as the primary pharmacophore for soluble epoxide hydrolase (sEH) and a thiazolidinedione moiety as the primary pharmacophore for peroxisome proliferator-activated receptors (PPARs). The sEH inhibitor and PPARs agonist compounds provided by the present application have high inhibitory activity against human HsEH and high agonistic activity against PPARs, and can be used as sEH inhibitor and PPARs agonist compounds for the manufacture of drugs for treating soluble epoxidase- and peroxisome proliferator-activated receptor-mediated diseases. [Brief explanation of the drawings]

[0018] [Figure 1] 1 is a schematic diagram of a reaction pathway for preparing sEH inhibitor and PPARs agonist compounds having the structure shown in Formula I of the present application. [Figure 2] FIG. 1 is a reaction pathway diagram of sEH inhibitor and PPARs agonist compounds having the structure shown in Formula II. [Figure 3] FIG. 1 is a reaction pathway diagram of sEH inhibitor and PPARs agonist compounds having the structure shown in Formula III of the present application. [Figure 4] 1 is a reaction pathway diagram of an sEH inhibitor having the structure shown in formula IV in the present application and a PPARs agonist compound when R3 is a halogen group. [Figure 5] FIG. 1 is a reaction pathway diagram of sEH inhibitor and PPARs agonist compounds having the structure shown in Formula V of the present application. [Figure 6]FIG. 1 shows the effect of compound SP-B07, prepared in an example, on the body weight of KM mice. [Figure 7] FIG. 1 shows the effect of compound SP-C01, prepared in an example, on the body weight of KM mice. [Figure 8] FIG. 1 shows the effect of compound SP-C01 prepared in an example on the visceral index of KM mice. [Figure 9] 1 shows representative H&E stained sections showing the effect of compound SP-C01 produced in an example on the organs of KM mice. [Figure 10] 1 is an evaluation of the compound SP-B07 prepared in the examples in the treatment of (CFA)-induced arthritis in a mouse model (AIA). [Figure 11] 1 is an evaluation of the compound SP-C01 prepared in the examples in the treatment of (CFA)-induced arthritis by intraperitoneal injection in a mouse model (AIA). [Figure 12] 1 shows an evaluation of compound SP-C01 prepared in an example in the treatment of (CFA)-induced arthritis by intragastric administration in a mouse model (AIA). [Figure 13] FIG. 1 shows the survival rate of C57B1 / 6 mice in LPS-induced inflammation after treatment with compound SP-B07 prepared in the Examples. [Figure 14] FIG. 1 shows Western blot detection of COX-2, sEH, NOS2 and VCAM expression in mouse plasma after treatment with compound SP-B07 prepared in the Examples. [Figure 15] FIG. 1 shows the measurement of IL-6, MCP-5, and TNF-α inflammatory factors in mouse plasma by ELISA after treatment with compound SP-B07 prepared in the Examples. [Figure 16] FIG. 1 shows that SP-C01 blocks pain measured by the von Frey test (mechanical withdrawal threshold) in a chronic constriction injury model of nerve pathology in male SD rats. [Figure 17]1 shows the results of histological analysis of the pancreas of mice treated with control, Mod, celecoxib, urinastatin, and compound SP-C01. Representative H&E-stained sections of pancreas obtained from an in vivo efficacy study are shown. [Figure 18] FIG. 1 shows the results of histological analysis of the pancreas of mice treated with control, Mod, celecoxib, urinastatin, and compound SP-C01. [Figure 19] 1 shows representative H&E stained sections showing the effect of compound SP-B07 prepared in an example on the organs of KM mice. [Figure 20] 1 shows blood glucose analysis results for control, Mod, pioglitazone, compound SP-B07 and compound SP-C01 treated mice. [Figure 21] 1 shows the results of an analysis of diabetic neuralgia in control, Mod, pioglitazone, compound SP-B07, and compound SP-C01-treated mice. [Figure 22] FIG. 1 is a reaction pathway diagram of sEH inhibitor and PPARs agonist compounds having the structure shown in Formula VI of the present application. [Figure 23] FIG. 1 is a reaction pathway diagram of an sEH inhibitor having a structure shown in Formula V and a PPARs agonist compound in the present application, where Y is —NH—. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present application provides compounds having the structure shown in Formula I, II, III, IV, V or VI. [ka] JPEG2025527059000005.jpg72128

[0020] wherein R1 is an adamantyl group, an aryl group, an alkyl-substituted aryl group, a haloaryl group, a haloalkyl-substituted aryl group, a haloalkoxy-substituted aryl group, or a haloaryloxy-substituted aryl group; R2 is a hydrogen atom, a hydroxyl group, an alcoholic hydroxyl group, an amine group, a carboxyl group, an acyl group, an amide group, or an ester group; R3 is a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group, a cyano group, or a carboxyl group; R4 is a hydrogen atom or an alkyl group; R5 is a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyl group, a cyano group, or a carboxyl group; R6 is a hydrogen atom, a hydroxyl group, an alkyl group, an ester group, or an amine group; A is a cycloalkyl group, a heterocyclyl group, or an aryl group; B is a single bond, a cycloalkyl group, a heterocyclyl group, or an aryl group; W is a single bond, -CH2-, -O-, -S-, -NH- or TIFF2025527059000006.tif1214, Y is a single bond, -CH2-, -O-, -S- or -NH-; Z is independently =CH2, =O, =S or =NH; and n is an integer of 0-12.

[0021] In the present application, the alkyl groups in the alkyl-substituted aryl group and the haloalkyl-substituted aryl group are preferably independently a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, an isobutyl group, an isopropyl group, an isopentyl group, or a tertbutyl group; the alkoxy group in the haloalkoxy-substituted aryl group is preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a phenoxy group, or a benzyloxy group; and the halogens in the haloaryl group, the haloalkyl-substituted aryl group, and the haloalkoxy-substituted aryl group are preferably independently -F, -Cl, or -Br.

[0022] In the present application, the cycloalkyl group is an unsubstituted or substituted C3-C8 cycloalkyl group, and the substituents of the substituted C3-C8 cycloalkyl group are preferably independently -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2 or a C1-C6 alkyl group, and the heterocyclyl group is independently an unsubstituted or substituted 3- to 10-membered heterocyclyl group, and the substituents of the substituted 3- to 10-membered heterocyclyl group are preferably The aryl groups are preferably, independently, -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2, or a C1-C6 alkyl group, and the aryl groups are, independently, a substituted or unsubstituted phenyl group, pyridyl group, or naphthyl group, and the substituents of the substituted phenyl group, pyridyl group, or naphthyl group are, independently, preferably, -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2, or a C1-C6 alkyl group.

[0023] In the present application, R1 is preferably a memanthyl group, a haloaryl group, a haloalkyl-substituted aryl group, or a haloalkoxy-substituted aryl group, R2 is preferably hydrogen or an ester group, R3 is preferably hydrogen or an alkyl group, R4 is preferably hydrogen, a methyl group, or an ethyl group, R5 is preferably hydrogen or an alkyl group, R6 is preferably a hydroxyl group, an amino group, an alkyl group, or an ester group, A is preferably a cyclohexyl group or a phenyl group, B is preferably a single bond or a phenyl group, W is preferably a single bond or -O-, Y is preferably a single bond, -O-, or -NH-, Z is ═O, and n is preferably an integer of 0 to 2.

[0024] In the present application, R1 is preferably JPEG2025527059000007.jpg18128 R2 is preferably hydrogen or -CH2-C(O)-CH3, R3 is preferably hydrogen or a methyl group, R4 is preferably hydrogen, R5 is preferably hydrogen or a methyl group, and R6 is preferably a hydroxyl group, -NH2, a methyl group, -C(O)-O-CH2-CH3, or a sec-butyl group.

[0025] In the present application, the formula 1 and the formula 3 JPEG2025527059000008.jpg23128 In the present application, the compound preferably has any of the following structures: [ka]

[0026] In this application, the chemical names of compounds having the above specific structures are as follows: 1-[(1r,3R,5S,7R)-3,5-dimethyladamant-1-yl]-3-((1r,4R)-4-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxy}cyclohexyl)urea, 1-[(1r,3R,5S,7R)-3,5-dimethyladamant-1-yl]-3-((1r,4R)-4-(4-{[(E)-(2,4-dioxythiazolinyl-5-ylidene)methyl]phenoxy}cyclohexyl)urea, N-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-4-{4-[(Z)-(2, 4-dioxothiazolidin-5-ylidene)methyl]phenoxy}piperidine-1-formamide, N-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-4-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxy}piperidine-1-formamide, N-[(1r,3R,5S,7r)-3,5-dimethyladamant-1-yl]-4-{4-[(Z)-(2,5-dioxoimidazolin-4-ylidene)methyl]phenoxy}piperidine-1-formamide, (Z)-4-[4-(2,5-dioxoimi (Z)-4-{4-[(2,4-dioxythiazolidin-5-ylidene)methyl]phenoxy}-N-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide, (Z)-4-{4-[(2,4-dioxythiazolidin-5-ylidene)methyl]phenoxy}-N-[4-(trifluoromethoxy)phenyl]piperidine-1-formamide, 4-[4-(2,4-dioxythiazolidin-5-yl)methyl]phenoxy-N-[4-(trifluoromethoxy)phenyl]piperidine-1-formamide, (Z)-4-4-{[2,4-dioxythiazolidin-5-ylidene)methyl] phenoxy}-N-[3-fluoro-4-(trifluoromethoxy)phenyl]piperidine-1-formamide, 4-{4-[(2,4-dioxythiazolidin-5-yl)methyl]phenoxy}-N-[3-fluoro-4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide, 1-((1r,4r)-4-(4-{(E)-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)-3-[3-fluoro-4-(trifluoromethoxy)phenyl]urea, 1-((1r,4r)-4-{4-[(2,4-dioxothiazolidin-5-yl)methyl]phenoxy}cyclohexyl)-3-[3-fluoro-4-(trifluoromethoxy)phenyl]urea, 2-(4-{(1r,4r)-4-[3-(3-fluoro-4-trifluoromethoxyphenyl)ureido]cyclohexyl}oxy)phenoxyacetic acid, 2-(4-{(1r,4r)-4-[3-(3-fluoro-4-trifluoromethoxyphenyl)ureido]cyclohexyl}oxy)phenoxy)acetic acid methyl ester, 2-(4-{(1r,4r)-4-[3-(3-fluoro-4-trifluoromethoxyphenyl)ureido]cyclohexyl}oxy)phenoxy)acetic acid methyl ester, 2-(4-{(1r,4r)-4-[3-(3-fluoro-4-trifluoromethoxyphenyl)ureido]cyclohexyl}oxy)phenoxy)acetic acid ethyl ester, 2-(4-{(1r,4r)-4-[3-(3-fluoro-4-trifluoromethoxyphenyl)ureido]cyclohexyl}oxy)phenoxy)-2-methylpropionic acid, 2-(4-{(1r,4r)-4-[3-(3-fluoro-4-trifluoromethoxyphenyl)ureido]cyclohexyl}oxy)phenoxy)-2-methylpropionic acid methyl ester, 2-(4-{(1r,4r)-4-[3-(4-trifluoromethoxyphenyl)ureido ]cyclohexyl)oxy}phenoxy)acetic acid, 2-(4-{(1r,4r)-4-[3-(4-trifluoromethoxyphenyl)ureido]cyclohexyl}oxy)phenoxy)acetic acid methyl ester, 2-(4-{(1r,4r)-4-[3-(4-trifluoromethoxyphenyl)ureido]cyclohexyl}oxy)phenoxy)acetic acid ethyl ester, 2-methyl-2-(4-((1r,4r)-4{[3-(4-trifluoromethoxyphenylureido)cyclohexyl]oxy}phenoxy)propionic acid, 2-methyl-2-(4-{(1r, 4r)-4-[3-(4-trifluoromethoxyphenyl)ureido]cyclohexyl}oxy)phenoxy)methyl propionate, 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy)acetic acid, 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy)acetic acid methyl ester, 2-[4-((1R,4r)-4{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy)acetic acid ethyl ester, 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy)-2-methylpropionic acid, methyl 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy)-2-propionic acid methyl ester, 2-(2,4-dioxo-5-((E)-4-(((1r,4r)-4-)3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzylidene)thiazolidin-3-yl)acetic acid methyl ester, 2-(5-((E)-4-(((1R,4r)-4-)(3-((1R,3R,5S,7R))-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)benzylidene)-2,4-dioxothiazolidin-3-yl)acetic acid methyl ester, 4-(((1r,4r )-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)acetic acid phenyl ester, 4-(4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenoxy)butyric acid methyl ester, 4-(4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenoxy)butyric acid, 4-(4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenoxy)butyric acid, r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)phenoxy)butyric acid methyl ester, 4-(4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)phenoxy)butyric acid, 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(4-((Z)-(2,4-dioxothiazolidin-5)-ylidene)methyl)phenyl)urea, (Z)-1-(4-((2,4-Dioxothiazolidin-5-ylidene)methyl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, 1-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-((1r,4r)-4-(4-hydroxyphenoxy)cyclohexyl)urea, 4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid, 4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl cyclohexyl)oxy)acetic acid phenyl ester, N-(4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzene)acetamide, N-(4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenyl)acetamide, N-(4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzene 4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzene)-2-methylbutyramide, 4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzamide, N-(4-(((1R,4r)-4-(3-((1R,3R,5S,7R))-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenyl)propionamide, N- (4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzene)propionamide, N-(4-((3-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenyl)propionamide, N-(4-((3-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenyl)-2-methylbutanamide, 3-((4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzene)amino)-3-oxopropionic acid ethyl ester, 3-((4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzene)amino)-3-oxopropionic acid.,

[0027] The present application provides a method for preparing the compounds described in the above technical solutions, (1) A compound having the structure shown in Formula I is prepared, the preparation method comprising: performing a first substitution reaction between compound a and compound b to obtain compound c; performing a first condensation reaction between the compound c and the compound d to obtain a compound e; performing a first hydrolysis reaction on compound e to obtain compound f; performing a first nucleophilic substitution reaction on the compound f, the compound w, and the compound af to obtain a compound g; the compound g is a compound having a structure represented by formula I in which a thiazolidinedione group is bonded to a double bond; and performing a first reduction reaction on compound g to obtain a compound having the structure shown in Formula I, in which the thiazolidinedione group is bonded to a single bond; The structural formulae of Compound a, Compound b, Compound c, Compound d, Compound e, Compound f, Compound g, Compound w, and Compound af are as follows: [ka]

[0028] Among them, Q of chemical substance a is H, hydroxyl group, amino group, mercapto group, carboxyl group, or acyl chloride, and X of compound b is H, hydroxyl group, halogen, and haloalkyl group.

[0029] As shown in the reaction pathway diagram in Figure 1, in the present application, compound c is obtained by subjecting compound a and compound b to a nucleophilic substitution reaction. In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of triphenylphosphine and DIAD. In the present application, the nucleophilic substitution reaction is preferably carried out under ice-salt bath conditions at -10°C, and the nucleophilic substitution reaction time is preferably 8 to 12 hours. In the present application, the molar ratio of compound a, compound b, triphenylphosphine, and DIAD is preferably 1:1:1.5:1.5. The solvent for the nucleophilic substitution reaction is preferably tetrahydrofuran, and after the nucleophilic substitution reaction, the product is purified by column chromatography.

[0030] In the present application, compound c and compound d are subjected to a Claisen-Schmidt condensation reaction to obtain compound e. In the present application, the condensation reaction is preferably carried out in the presence of pyridine or piperidine and acetic acid or benzoic acid. In the present application, the molar ratio of compound c, compound d, base, and acid is preferably 1:1:0.5:0.5. In the present application, the nucleophilic substitution reaction is preferably carried out at 110°C, the solvent for the condensation reaction is preferably toluene, and the time for the condensation reaction is preferably 4 to 8 hours. After the condensation reaction, the mixture is cooled to room temperature and filtered by suction.

[0031] After obtaining compound e, compound e is deprotected under acidic conditions to obtain compound f. In the present application, the reagent providing the acidic conditions is preferably trifluoroacetic acid or hydrogen chloride in ethyl acetate, and the deprotection reaction is preferably carried out under dichloromethane conditions. In the present application, the temperature of the deprotection reaction is preferably room temperature, and the time is preferably 1.5 to 2.5 hours. After the deprotection reaction, in the present application, the resulting reaction solution is preferably distilled under reduced pressure, and water and dichloromethane are added to the resulting residue. The pH of the system is adjusted to 10 using solid sodium hydroxide under ice-water bath conditions, the organic layer is separated and removed, and the aqueous layer is extracted with dichloromethane (100 mL x 2), followed by washing with water and saturated brine, drying over anhydrous sodium sulfate, and suction filtration. The resulting filtrate is concentrated under reduced pressure to obtain compound f.

[0032] In the present application, after obtaining compound f, compound f is subjected to a nucleophilic substitution reaction with compound af to obtain compound g. In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of triethylamine. In the present application, the molar ratio of compound f, solid phosgene, and base is preferably 1:(0.33-0.6):3, more preferably 1:(0.4-0.5):3. In the present application, the nucleophilic substitution reaction is preferably carried out under ice bath conditions, and the nucleophilic substitution reaction time is preferably 10-50 minutes, more preferably 30 minutes. After the nucleophilic substitution reaction, the product is purified by column chromatography to obtain compound g.

[0033] In the present application, after obtaining compound g, compound g is subjected to a first reduction reaction to obtain a compound having the structure shown in Formula I in which the thiazolidinedione group in the structure is bonded via a single bond. In the present application, the first reduction reaction is preferably carried out in the presence of hydrogen and palladium on carbon. In the present application, the molar ratio of compound g to palladium on carbon is preferably 1:0.1. In the present application, the catalytic hydrogenation reaction is preferably carried out at room temperature for a period of preferably 240 minutes to obtain an sEH inhibitor and PPARs agonist compound having the structure shown in Formula I.

[0034] (2) preparing a compound having the structure shown in formula II, the preparation method comprising: performing a first substitution reaction between compound a and compound h to obtain compound i; subjecting compound i to a first hydrolysis reaction to obtain compound j; performing a second substitution reaction between compound j and compound aa to obtain compound k; performing a second hydrolysis reaction on compound k to obtain compound l; and performing a nucleophilic substitution reaction on compound l, compound w, and compound af to obtain a compound having the structure shown in formula II, The structural formulae of the compounds h, i, j, k, l and aa are as follows: [ka]

[0035] In the present application, X in compound h represents H, a hydroxyl group, a halogen, or a haloalkyl group. As shown in the reaction pathway diagram in Figure 2, in the present application, compound i is obtained by subjecting compound a and compound h to a nucleophilic substitution reaction. In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of triphenylphosphine and DIAD. In the present application, the molar ratio of compound a, compound h, triphenylphosphine, and DIAD is preferably 1:1:1.5:1.5. In the present application, the nucleophilic substitution reaction is preferably carried out under ice-salt bath conditions, and the nucleophilic substitution reaction time is preferably 8 to 12 hours. The solvent for the nucleophilic substitution reaction is preferably tetrahydrofuran, and the reaction product is purified by column chromatography after the reaction.

[0036] In the present application, compound i is subjected to ester hydrolysis under alkaline conditions to obtain compound j. In the present application, the reagent providing the alkaline conditions is preferably LiOH, and the ester hydrolysis reaction is preferably carried out under THF / HO conditions. In the present application, the temperature of the ester hydrolysis reaction is preferably room temperature, and the time is preferably 1.5 to 2.5 hours. After the ester hydrolysis reaction, in the present application, the resulting reaction solution is preferably distilled under reduced pressure, and water and dichloromethane are added to the resulting residue. The pH of the system is adjusted to 2 using 6N HCl under ice-water bath conditions, and the mixture is extracted with dichloromethane (40 mL x 3), followed by washing with water and saturated brine, drying over anhydrous sodium sulfate, and suction filtering. The resulting filtrate is concentrated under reduced pressure to obtain compound j.

[0037] In the present application, compound j and compound aa are subjected to a nucleophilic substitution reaction to obtain compound k. In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of K2CO3. In the present application, the molar ratio of compound j, nucleophile, and base in the nucleophilic substitution reaction is preferably 1:1:3. In the present application, the nucleophilic substitution reaction is preferably carried out at 80°C, the time for the nucleophilic substitution reaction is preferably 5 to 6 hours, and the solvent is preferably acetonitrile. After the nucleophilic substitution reaction, the product is purified by column chromatography.

[0038] After obtaining compound k, compound k is subjected to a second hydrolysis reaction to obtain compound l. In the second hydrolysis reaction, a deprotection reaction is carried out under acidic conditions. In the present application, the reagent providing the acidic conditions is preferably trifluoroacetic acid or hydrogen chloride in EA, and the deprotection reaction is preferably carried out under dichloromethane conditions. In the present application, the deprotection reaction is preferably carried out at room temperature for 1.5 to 2.5 hours. After the deprotection reaction, in the present application, the resulting reaction solution is preferably distilled under reduced pressure, and water and dichloromethane are added to the resulting residue. The pH of the system is adjusted to 7 using solid sodium hydroxide under ice-water bath conditions. The organic layer is separated and removed, and the aqueous layer is extracted with dichloromethane (100 mL x 2), followed by washing with water and saturated brine, drying over anhydrous sodium sulfate, and suction filtration. The resulting filtrate is concentrated under reduced pressure to obtain compound l.

[0039] After obtaining compound l, in the present application, compound l and compound af are subjected to a nucleophilic substitution reaction to obtain an sEH inhibitor and PPARs agonist compound having the structure shown in Formula II. In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of triethylamine. In the present application, the molar ratio of compound l, compound af, and base is preferably 1:(0.33-0.6):3, more preferably 1:(0.4-0.5):3. In the present application, the nucleophilic substitution reaction is preferably carried out under ice-bath conditions, the nucleophilic substitution reaction time is preferably 10-50 minutes, more preferably 30 minutes, and the solvent is preferably DCM. After the nucleophilic substitution reaction, the product is purified by column chromatography.

[0040] (3) preparing a compound having the structure shown in formula III, the preparation method comprising: performing a first substitution reaction between compound m and compound b to obtain compound n; performing a first condensation reaction between the compound n and the compound d to obtain a compound o; performing a first hydrolysis reaction on compound o to obtain compound p; a step of performing a first nucleophilic substitution reaction on the compound p, the compound w, and the compound af to obtain a compound q, the compound q being a compound having a structure represented by formula III in which a thiazolidinedione group is bonded to a double bond; and performing a first reduction reaction on compound q to obtain a compound having a structure shown in formula III, in which the thiazolidinedione group is bonded to a single bond; The structural formulae of the compounds m, n, o, p and q are as follows: [ka]

[0041] Among them, Q of chemical substance m is H, a hydroxyl group, an amino group, a mercapto group, a carboxyl group, or an acyl chloride.

[0042] As shown in the reaction pathway diagram in Figure 3, in the present application, compound n is obtained by subjecting compound m and compound b to a nucleophilic substitution reaction. In the present application, the molar ratio of compound m to compound b is preferably 1:1. In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of triphenylphosphine and DIAD. In the present application, the molar ratio of compound m, compound b, triphenylphosphine, and DIAD is preferably 1:1:1.5:1.5. In the present application, the solvent for the nucleophilic substitution reaction is preferably tetrahydrofuran, the nucleophilic substitution reaction is preferably carried out under ice-salt bath conditions, and the nucleophilic substitution reaction time is preferably 8 to 12 hours. After the nucleophilic substitution reaction, the product is purified by column chromatography.

[0043] In the present application, compound n and compound d are subjected to a Claisen-Schmidt condensation reaction to obtain compound o. In the present application, the condensation reaction is preferably carried out in the presence of pyridine or piperidine and acetic acid or benzoic acid. In the present application, the molar ratio of compound n, compound d, base, and acid is preferably 1:1:0.5:0.5. In the present application, the nucleophilic substitution reaction is preferably carried out at 110°C, the solvent for the condensation reaction is preferably toluene, and the time for the condensation reaction is preferably 4 to 8 hours. After the condensation reaction, the mixture is cooled to room temperature and filtered by suction.

[0044] After obtaining compound o, compound o is subjected to a first hydrolysis reaction to obtain compound p. The first hydrolysis reaction is a deprotection reaction under acidic conditions. In the present application, the reagent providing the acidic conditions is preferably trifluoroacetic acid, and the deprotection reaction is preferably performed under dichloromethane conditions. In the present application, the temperature of the deprotection reaction is preferably room temperature, and the time is preferably 1.5 to 2.5 hours. After the deprotection reaction, in the present application, the resulting reaction solution is preferably distilled under reduced pressure, and water and dichloromethane are added to the resulting residue. The pH of the system is adjusted to 12 using solid sodium hydroxide under ice-water bath conditions. The organic layer is separated and removed, and the aqueous layer is extracted with dichloromethane (100 mL x 2), followed by washing with water and saturated brine, drying over anhydrous sodium sulfate, and suction filtration. The resulting filtrate is concentrated under reduced pressure to obtain compound p.

[0045] After obtaining compound p, in the present application, compound p and compound af are subjected to a nucleophilic substitution reaction to obtain compound q. Compound q is a compound having a structure represented by formula III in which a thiazolidinedione group is bonded to a double bond. Compound q is subjected to a first reduction reaction to obtain a compound having a structure represented by formula III in which a thiazolidinedione group is bonded to a single bond. In the present application, the molar ratio of compound p, solid phosgene, and base is preferably 1:(0.33-0.6):3, more preferably 1:(0.4-0.5):3. In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of triethylamine, using DCM as a solvent. In the present application, the nucleophilic substitution reaction is preferably carried out under ice-bath conditions, and the nucleophilic substitution reaction time is preferably 10-50 minutes, more preferably 30 minutes. After the nucleophilic substitution reaction, the product is purified by column chromatography.

[0046] When R4 is H, the compound is subjected to ester hydrolysis under alkaline conditions. In the present application, the reagent providing the alkaline conditions is preferably LiOH, and the ester hydrolysis is preferably carried out under THF / HO conditions. In the present application, the temperature of the ester hydrolysis is preferably room temperature, and the time is preferably 1.5 to 2.5 hours. After the ester hydrolysis, the present application preferably distills the resulting reaction solution under reduced pressure, adds water and dichloromethane to the resulting residue, adjusts the pH of the system to 2 using 6N HCl under ice-water bath conditions, extracts with dichloromethane (40 mL x 3), sequentially washes with water and saturated brine, dries over anhydrous sodium sulfate, and suction-filters, and the resulting filtrate is concentrated under reduced pressure.

[0047] (4) Producing a compound having the structure shown in formula IV, the method comprising: performing a first substitution reaction between compound m and compound h to obtain compound r; performing a first hydrolysis reaction on the compound r to obtain a compound s; performing a second substitution reaction on compound s to obtain compound t; performing a second hydrolysis reaction on compound t to obtain compound u; and subjecting compound u, compound w, and compound af to a first nucleophilic substitution reaction to form a urea to obtain a compound having the structure shown in Formula IV, The structural formulae of the compounds r, s, t, and u are as follows: [ka]

[0048] As shown in the reaction pathway diagram in Figure 4, in the present application, compound m and compound h are subjected to a first substitution reaction to obtain compound r. In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of triphenylphosphine and DIAD. The molar ratio of compound m, compound h, triphenylphosphine, and DIAD is preferably 1:1:1.5:1.5. In the present application, the nucleophilic substitution reaction solvent is preferably tetrahydrofuran, the nucleophilic substitution reaction is preferably carried out under ice-salt bath conditions, and the nucleophilic substitution reaction time is preferably 8 to 12 hours. After the nucleophilic substitution reaction, the product is purified by column chromatography.

[0049] In the present application, compound r is subjected to ester hydrolysis under alkaline conditions to obtain compound s. In the present application, the reagent providing the alkaline conditions is preferably LiOH, and the ester hydrolysis reaction is preferably carried out under THF / HO conditions. In the present application, the temperature of the ester hydrolysis reaction is preferably room temperature, and the time is preferably 1.5 to 2.5 hours. After the ester hydrolysis reaction, the present application preferably distills the resulting reaction solution under reduced pressure, adds water and dichloromethane to the resulting residue, and adjusts the pH of the system to 2 using 6N HCl under ice-water bath conditions. The mixture is extracted with dichloromethane (40 mL x 3), washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and filtered under suction. The resulting filtrate is concentrated under reduced pressure to obtain compound s.

[0050] In the present application, compound t is obtained by subjecting compound s to a nucleophilic substitution reaction. In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of K2CO3. In the present application, the molar ratio of compound j, nucleophile, and base in the nucleophilic substitution reaction is preferably 1:1:3. In the present application, the nucleophilic substitution reaction is preferably carried out at 80°C, the time for the nucleophilic substitution reaction is preferably 5 to 6 hours, and the solvent is preferably acetonitrile. After the nucleophilic substitution reaction, the product is purified by column chromatography.

[0051] After obtaining compound t, compound t is deprotected under acidic conditions to obtain compound u. In the present application, the reagent providing the acidic conditions is preferably trifluoroacetic acid, and the deprotection reaction is preferably carried out under dichloromethane conditions. In the present application, the temperature of the deprotection reaction is preferably room temperature, and the time is preferably 1.5 to 2.5 hours. After the deprotection reaction, in the present application, the resulting reaction solution is preferably distilled under reduced pressure, and water and dichloromethane are added to the resulting residue. The pH of the system is adjusted to 14 using solid sodium hydroxide under ice-water bath conditions, the organic layer is separated and removed, and the aqueous layer is extracted with dichloromethane (100 mL x 2), followed by washing with water and saturated brine, drying over anhydrous sodium sulfate, and suction filtering. The resulting filtrate is concentrated under reduced pressure to obtain compound u.

[0052] After obtaining compound u, in the present application, compound u and compound af are subjected to a nucleophilic substitution reaction to obtain an sEH inhibitor and PPARs agonist compound having the structure shown in Formula I. In the present application, the molar ratio of compound l to compound af is preferably 1:(0.33-0.6), more preferably 1:(0.4-0.5). In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of triethylamine. In the present application, the nucleophilic substitution reaction is preferably carried out under ice bath conditions, and the nucleophilic substitution reaction time is preferably 10-50 minutes, more preferably 30 minutes. After the nucleophilic substitution reaction, the product is purified by column chromatography.

[0053] When R4 is H, the compound is subjected to ester hydrolysis under alkaline conditions. In the present application, the reagent providing the alkaline conditions is preferably LiOH, and the ester hydrolysis is preferably carried out under THF / HO conditions. In the present application, the temperature of the ester hydrolysis is preferably room temperature, and the time is preferably 1.5 to 2.5 hours. After the ester hydrolysis, the present application preferably distills the resulting reaction solution under reduced pressure, adds water and dichloromethane to the resulting residue, adjusts the pH of the system to 2 using 6N HCl under ice-water bath conditions, extracts with dichloromethane (40 mL x 3), sequentially washes with water and saturated brine, dries over anhydrous sodium sulfate, and suction-filters, and the resulting filtrate is concentrated under reduced pressure.

[0054] (5) A compound having the structure shown in formula V is prepared by the method comprising: performing a first substitution reaction between compound a and compound h to obtain compound i; subjecting compound i to a first hydrolysis reaction to obtain compound v; and performing a first nucleophilic substitution reaction on compound v, compound w, and compound af to obtain a compound having a structure shown in formula V or formula VI, The structural formulae of the compounds a, h, i and v are as follows: [ka] .

[0055] As shown in the reaction pathway diagram in Figure 5, in the present application, compound i is obtained by subjecting compound a and compound h to a nucleophilic substitution reaction. In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of triphenylphosphine and DIAD. In the present application, the molar ratio of compound a, compound h, triphenylphosphine, and DIAD is preferably 1:1:1.5:1.5. In the present application, the nucleophilic substitution reaction solvent is preferably tetrahydrofuran, the nucleophilic substitution reaction is preferably carried out under ice-salt bath conditions, and the nucleophilic substitution reaction time is preferably 8 to 12 hours. After the nucleophilic substitution reaction, the product is purified by column chromatography.

[0056] After obtaining compound i, compound i is deprotected under acidic conditions to obtain v. In the present application, the reagent providing the acidic conditions is preferably trifluoroacetic acid, and the deprotection reaction is preferably carried out under dichloromethane conditions. In the present application, the temperature of the deprotection reaction is preferably room temperature, and the time is preferably 1.5 to 2.5 hours. After the deprotection reaction, in the present application, the resulting reaction solution is preferably distilled under reduced pressure, and water and dichloromethane are added to the resulting residue. The pH of the system is adjusted to 14 using solid sodium hydroxide under ice-water bath conditions, the organic layer is separated and removed, and the aqueous layer is extracted with dichloromethane (100 mL x 2), followed by washing with water and saturated brine, drying over anhydrous sodium sulfate, and suction filtering. The resulting filtrate is concentrated under reduced pressure to obtain compound v.

[0057] After obtaining compound v, in the present application, compound v, compound w, and compound af are subjected to a first nucleophilic substitution reaction to obtain an sEH inhibitor and PPARs agonist compound having the structure shown in Formula V. In the present application, the molar ratio of compound v to compound af is preferably 1:(0.33-0.6), more preferably 1:(0.4-0.5). In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of triethylamine. In the present application, the nucleophilic substitution reaction is preferably carried out under ice bath conditions, and the nucleophilic substitution reaction time is preferably 10-50 minutes, more preferably 30 minutes. After the nucleophilic substitution reaction, the product is purified by column chromatography.

[0058] (6) A compound having the structure shown in formula VI is prepared by the method comprising: performing a first substitution reaction between compound a and compound x to obtain compound y; performing a first hydrolysis reaction on compound y to obtain compound z; and performing a first nucleophilic substitution reaction on compound z, compound w, and compound af to obtain a compound having the structure shown in formula V, The structural formulae of the compounds a, x, y and z are as follows: [ka]

[0059] X in compound x is H, a hydroxyl group, a halogen, or a haloalkyl group; As shown in the reaction pathway diagram in Figure 22, in the present application, compound a and compound x are subjected to a nucleophilic substitution reaction to obtain compound y. In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of triphenylphosphine and DIAD. In the present application, the molar ratio of compound a, compound x, triphenylphosphine, and DIAD is preferably 1:1:1.5:1.5. In the present application, the nucleophilic substitution reaction solvent is preferably tetrahydrofuran, the nucleophilic substitution reaction is preferably carried out under ice-salt bath conditions, and the nucleophilic substitution reaction time is preferably 8 to 12 hours. After the nucleophilic substitution reaction, the product is purified by column chromatography.

[0060] After obtaining compound y, compound y is deprotected under acidic conditions to obtain z. In the present application, the reagent providing the acidic conditions is preferably trifluoroacetic acid, and the deprotection reaction is preferably carried out under dichloromethane conditions. In the present application, the temperature of the deprotection reaction is preferably room temperature, and the time is preferably 1.5 to 2.5 hours. After the deprotection reaction, in the present application, the resulting reaction solution is preferably distilled under reduced pressure, and water and dichloromethane are added to the resulting residue. The pH of the system is adjusted to 14 using solid sodium hydroxide under ice-water bath conditions, the organic layer is separated and removed, and the aqueous layer is extracted with dichloromethane (100 mL x 2), followed by washing with water and saturated brine, drying over anhydrous sodium sulfate, and suction filtering. The resulting filtrate is concentrated under reduced pressure to obtain compound z.

[0061] After obtaining compound z, in the present application, compound z, compound w, and compound af are subjected to a first nucleophilic substitution reaction to obtain an sEH inhibitor and PPARs agonist compound having the structure shown in Formula VI. In the present application, the molar ratio of compound z to compound af is preferably 1:(0.33-0.6), more preferably 1:(0.4-0.5).

[0062] In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of triethylamine. In the present application, the nucleophilic substitution reaction is preferably carried out under ice bath conditions, and the nucleophilic substitution reaction time is preferably 10 to 50 minutes, more preferably 30 minutes. After the nucleophilic substitution reaction, the product is purified by column chromatography.

[0063] (7) When Y of the compound having the structure represented by formula V or VI is —NH—, the method for producing the compound having the structure represented by formula V or VI is performing a first substitution reaction between compound a and compound ab to obtain compound ac; performing a first hydrolysis reaction on the compound ac to obtain a compound ad; performing a nucleophilic substitution reaction on the compound ad, the compound w, and the compound af to obtain a compound ae; subjecting compound ae to a first reduction reaction to obtain a compound having the structure shown in formula VI; and condensing the compound having the structure of formula VI with compound ag to obtain a compound having the structure of formula V, [ka] X in compound ab is H, a hydroxyl group, a halogen, or a haloalkyl group.

[0064] As shown in the reaction pathway diagram in Figure 23, in the present application, compound a and compound ab are subjected to a first nucleophilic substitution reaction to obtain compound ac. In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of triphenylphosphine and DIAD. In the present application, the molar ratio of compound a, compound ab, triphenylphosphine, and DIAD is preferably 1:1:1.5:1.5. In the present application, the nucleophilic substitution reaction solvent is preferably tetrahydrofuran, the nucleophilic substitution reaction is preferably carried out under ice-salt bath conditions, and the nucleophilic substitution reaction time is preferably 8 to 12 hours. After the nucleophilic substitution reaction, the product is purified by column chromatography.

[0065] After obtaining compound ac, compound ac is subjected to a first hydrolysis reaction to obtain compound ad. In the first hydrolysis reaction, a deprotection reaction is carried out under acidic conditions to obtain compound ad. In the present application, the reagent providing the acidic conditions is preferably trifluoroacetic acid, and the deprotection reaction is preferably carried out under dichloromethane conditions. In the present application, the temperature of the deprotection reaction is preferably room temperature, and the time is preferably 1.5 to 2.5 hours. After the deprotection reaction, in the present application, the resulting reaction solution is preferably distilled under reduced pressure, and water and dichloromethane are added to the resulting residue. The pH of the system is adjusted to 14 using solid sodium hydroxide under ice-water bath conditions. The organic layer is separated and removed, and the aqueous layer is extracted with dichloromethane (100 mL x 2), followed by washing with water and saturated brine, drying over anhydrous sodium sulfate, and suction filtration. The resulting filtrate is concentrated under reduced pressure to obtain compound ad.

[0066] After obtaining compound ad, in the present application, compound ad, compound w, and compound af are subjected to a nucleophilic substitution reaction to obtain compound ae. In the present application, the molar ratio of compound ad to compound af is preferably 1:(0.33-0.6), more preferably 1:(0.4-0.5). In the present application, the nucleophilic substitution reaction is preferably carried out in the presence of triethylamine. In the present application, the nucleophilic substitution reaction is preferably carried out under ice bath conditions, and the nucleophilic substitution reaction time is preferably 10-50 minutes, more preferably 30 minutes. After the nucleophilic substitution reaction, the product is purified by column chromatography.

[0067] After obtaining compound ae, in the present application, compound ae is subjected to a first reduction reaction to obtain a compound having a structure represented by formula VI. In the present application, the reducing agent in the first reduction reaction is preferably hydrogen, the catalyst is Pb—C, and the solvent is methanol. In the present application, the mass ratio of compound ae to Pd—C is 1:0.1. The reduction reaction is preferably carried out under reflux conditions, and the reduction reaction time is preferably 4 to 8 hours. After the reduction reaction, the reaction solution is suction filtered and evaporated to dryness.

[0068] After obtaining the compound having the structure shown in Formula VI, the present application provides a method for condensing the compound having the structure shown in Formula VI with Compound ag to obtain a compound having the structure shown in Formula V. The condensing agent used in the present application is preferably HATU, the base is preferably DIEA, and the solvent used is preferably THF. In the present application, the condensation reaction temperature is preferably room temperature, and the reaction time is preferably 4 to 8 hours. The molar ratio of the compound of Formula VI to HATU and DIEA is preferably 1:1.5:3. In the present application, after the condensation reaction, the obtained reaction solution is preferably distilled under reduced pressure, and the obtained residue is extracted with water and dichloromethane, washed with 1N HCl, and the organic layer is dried over anhydrous sodium sulfate. The resulting mixture is then suction filtered, and the filtrate is concentrated to dryness under reduced pressure and purified by column chromatography to obtain a compound having the structure shown in Formula V. In this application, unless otherwise stated, all manufacturing materials / compositions are commercially available products well known by those skilled in the art.

[0069] The present application provides the use of said compounds and their pharmaceutically acceptable deuterated products, salts or hydrates, or compounds prepared by the preparation methods described in the above technical solutions, in the manufacture of peroxisome proliferator-activated receptor agonists and / or soluble epoxide hydrolase inhibitors.

[0070] In the present application, the peroxisome proliferator-activated receptor agonists and soluble epoxide hydrolase inhibitors are used for the treatment of soluble epoxidase and peroxisome proliferator-activated receptor-mediated diseases, and the diseases mediated by the soluble epoxidase and peroxisome proliferator-activated receptors preferably include inflammatory diseases, pain, sepsis, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications and depression, liver fibrosis, renal failure, chronic obstructive pulmonary disease, or pulmonary hypertension.

[0071] In the present application, the inflammatory diseases preferably include non-alcoholic steatohepatitis and chronic nephritis, and the pain preferably includes neuropathic pain.

[0072] The present application provides sEH inhibitor and PPARs agonist compounds, which have a typical urea structure as the primary pharmacophore for sEH and a thiazolidinedione moiety as the primary pharmacophore for PPARs. The sEH inhibitor and PPARs agonist compounds provided by the present application have high inhibitory activity against human HsEH and high agonistic activity against PPARs, and can be used as sEH inhibitor and PPARs agonist compounds for the manufacture of drugs for the treatment of soluble epoxidase- and peroxisome proliferator-activated receptor-mediated diseases.

[0073] The present application provides sEH inhibitor and PPARs agonist compounds or pharmaceutically acceptable compositions thereof, as well as methods for producing and using the same, which belong to the field of pharmaceutical technology. The sEH inhibitor and PPARs agonist compounds provided by the present application have the structures shown in Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI. The sEH inhibitor moiety provided by the present application can stabilize epoxy fatty acids, an endogenous substance with a wide range of physiological activities. It has strong inhibitory effects on human recombinant sEH and has multiple mechanisms of action, including regulating the production of various pro-inflammatory cytokines, reducing endoplasmic reticulum stress, preventing or reversing endothelial dysfunction, and stabilizing mitochondrial function. PPAR agonists, in synergy with the action of sEH inhibitors, can inhibit the expression of cytokines such as resistin, tumor necrosis factor alpha (TNFα), and interleukin-6, which promote insulin resistance. PPAR agonists induce an increase in plasma adiponectin, a hormone secreted by adipose tissue that is found at low levels in the plasma of patients with type 2 diabetes. Adiponectin increases fatty acid oxidation in the liver and skeletal muscle. Therefore, the compounds of the present application can be used for diseases mediated by soluble epoxidase and peroxisome proliferator-activated receptors, such as inflammatory diseases, pain, sepsis, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications, depression, non-alcoholic steatohepatitis, liver fibrosis, chronic nephritis, renal failure, chronic obstructive pulmonary disease or pulmonary hypertension.

[0074] To further explain the present application, the technical solutions provided by the present application are described in detail below in conjunction with figures and examples, which should not be understood as limiting the protection scope of the present application.

[0075] Example 1 Synthesis of ((1r,4r)-4-hydroxycyclohexyl)carbamic acid tert-butyl ester A 100 mL three-neck flask was charged with trans-4-aminocyclohexanol hydrochloride (5.00 g, 32.98 mmol), sodium carbonate (10.49 g, 98.98 mmol), and water (25 mL) in that order. The mixture was cooled to 0 °C in an ice bath, and a DCM solution (5 mL) of BocO (7.92 g, 36.28 mmol) was added dropwise. The addition was completed within 3 min, and the mixture was allowed to warm to room temperature. After 4 h, the reaction was monitored by TLC (EA:PE = 1:3, phosphomolybdic acid coloring). The reaction was stopped when the reaction was complete. The reaction mixture was poured into 50 mL of water, extracted with DCM (30 mL x 3), and EA (30 mL x 3). The combined organic layers were washed with water (30 mL), saturated NaCl (30 mL), and dried over anhydrous magnesium sulfate. It was filtered with suction, leached with EA, and the filtrate was concentrated to dryness under reduced pressure to give 8.0 g of a crude white powdery solid, which was used directly in the next step without purification.

[0076] Example 2 Synthesis of 4-aminophenyl-4-nitrobenzoate A 100 mL three-neck flask was charged with cis-4-Boc-aminocyclohexanol (7.10 g, 32.98 mmol), p-nitrobenzoic acid (5.51 g, 98.98 mmol), triphenylphosphine (12.98 g, 49.47 mol), and THF (20 mL). The flask was cooled to below -10 °C in an ice-salt bath, and a THF solution (20 mL) of DIAD (10 g, 49.47 mol) was added dropwise. After 2 h, the reaction was monitored by TLC and completion was confirmed. The solvent was evaporated under reduced pressure to give 35.6 g of crude product. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 volumes of silica gel and the column was filled 5 times with EA:PE (1:10) as the eluent, yielding 5.53 g of a white solid.

[0077] Example 3 tert-butyl(4-hydroxyphenyl)carbamate In a 100 mL three-neck flask, 4-aminophenyl-4-nitrobenzoate (5.53 g, 14.88 mmol), NaOH (1.79 g, 44.65 mmol), THF (20 mL), and HO (20 mL) were added in that order and reacted at room temperature. After 4 hours, the reaction was monitored by TLC and the mixture was concentrated to dryness under reduced pressure. EA (30 mL) was added and extracted with saturated sodium carbonate (20 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, suction filtered, and concentrated to dryness under reduced pressure to give 3.01 g of a white solid, with a yield of 94.08%.

[0078] Example 4 tert-butyl ((1r,4r)-4-(4-formylphenoxy)cyclohexyl)carbamate A 500 mL three-neck flask was charged with cis-N-BOC-4-aminocyclohexanol (2.50 g, 11.61 mmol, 1 eq), p-hydroxybenzaldehyde (1.42 g, 11.61 mmol, 1 eq), triphenylphosphine (4.57 g, 17.42 mmol, 1.5 eq), and THF (10 mL) in that order. The mixture was cooled to below -10 °C in an ice-salt bath, and a THF solution (5 mL) of DIAD (3.52 g, 17.42 mmol, 1.5 eq) was added dropwise at a rate of 1 drop every 2 seconds. After 72 h, the reaction was monitored by TLC. The EA:PE ratio was 1:1, and the reaction was almost complete. The reaction was then stopped. The THF was removed by concentration under reduced pressure to give 12.21 g of a brownish-yellow oil. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 volumes of the crude oil and the column was filled with 10 volumes of silica gel. The eluent was EA:PE=1:30. 2.85 g of a white solid was obtained, with a yield of 76.82%.

[0079] Example 5 Synthesis of tert-butyl ((1r,4r)-4-{4-[(Z)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)carbamate A 100 mL round-bottom flask was charged sequentially with tert-butyl [(1r,4r)-4-(4-formylphenoxy)cyclohexyl]carbamate (2.85 g, 8.93 mmol, 1 eq), 2,4-thiazolidinedione (1.05 g, 8.93 mmol, 1 eq), pyridine (0.35 g, 4.46 mmol, 0.5 eq), glacial acetic acid (0.27 g, 4.46 mmol, 0.5 eq), and toluene (10 mL). The mixture was heated to reflux. As the reaction proceeded, a solid precipitated. After 8 h, the reaction was monitored by TLC and stopped upon completion. The reaction was cooled to room temperature, suction filtered, and the filter cake was leached with a small amount of toluene to yield 2.03 g of a white solid. ESI-MS (m / z): 424.1 [M+H] +

[0080] Example 6 Synthesis of 5-{(Z)-4-[(1r,4r)-4-aminocyclohexyl]oxybenzylidene}thiazolidine-2,4-dione In a 500 mL three-neck flask, tert-butyl ((1r,4r)-4-{4-[(Z)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)carbamate (2.03 g, 4.85 mmol) and DCM (15 mL) were added in that order, cooled to 0 °C in an ice bath, and TFA (4 mL) was added dropwise. After 0.5 hours, the reaction was monitored by TLC. When the reaction was complete, it was stopped. The TFA in the reaction solution was removed by distillation under reduced pressure. Water (30 mL) was added, and the mixture was extracted with DCM (30 mL × 3). The combined organic layer was concentrated to dryness under reduced pressure. 1.17 g of a brown solid was obtained as a crude product. The crude product was used directly in the next step without purification.

[0081] Example 7 Synthesis of 1-[(1r,3R,5S,7R)-3,5-dimethyladamant-1-yl]-3-((1r,4R)-4-{4-[(E)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)urea (SP-B01) A 50 mL single-bottle mixture was charged with memantine, dry dichloromethane, and a dichloromethane solution of BTC (2 mL). The mixture was cooled to below -10°C in an ice-salt bath, and a DCM solution of triethyl ether (TEA) was slowly added dropwise. The solution was evaporated to dryness, and 20 mL of DCM was added. 5-{(Z)-4-[(1r,4r)-4-aminocyclohexyl]oxybenzylidene}thiazolidine-2,4-dione was then added and the mixture was refluxed. After 3 hours, the reaction was monitored by TLC. Upon completion, the reaction was stopped. The mixture was poured into 30 mL of water and suction filtered to obtain a small amount of non-fluorescent white solid. The filtrate was extracted three times with 30 mL of DCM, washed once with water and once with saturated brine, dried over anhydrous magnesium sulfate, and evaporated to dryness to obtain 1.2 g of a white solid. The sample was mixed with 1.2 g of silica gel, and a column was filled with 10 g of silica gel. The eluent was EA:PE = 1:7. 0.15 g of a yellow solid was obtained. ESI-MS (m / z): 522.0 [M−H] - .

[0082] Example 8 Synthesis of 1-[(1r,3R,5S,7R)-3,5-dimethyladamant-1-yl]-3-((1r,4R)-4-{4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)urea (SP-A01) A 50 mL bottle was charged with 1-[(1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl]-3-((1r,4R)-4-{4-[(E)-(2,4-dioxythiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)urea) and 10% Pd / C. The atmosphere was purged with hydrogen three times and with Ar three times. The reaction was allowed to proceed at 30°C. After 3.5 hours, the reaction was complete. The reaction was stopped, suction filtered, and the filter cake was washed with a small amount of water and dried to give 0.15 g of a white solid. ESI-MS (m / z): 524.1 [MH] - . 1H NMR(400MHz,DMSO-d6)δ11.98(s,1H),7.13(d,J=8.4Hz,2H),6.90-6.83(m,2H),5.58(d,J=7.6Hz,1H),5.41(s,1 H),4.85(dd,J=9.1,4.3Hz,1H),4.25(tt,J=9.3,3.8Hz,1H),3.28(d,J=4.4Hz,1H),3.04(dd,J=14.2,9.1Hz,1H), 2.04(p,J=3.1Hz,1H),1.98(dd,J=12.9,4.1Hz,2H),1.87-1.78(m,2H),1.67(d,J=3.2Hz,2H),1.50(s,3H),1.36( ddd,J=12.8,9.8,3.2Hz,2H),1.32-1.24(m,2H),1.26-1.19(m,3H),1.19-1.12(m,1H),1.07(s,2H),0.80(s,6H).

[0083] Example 9 Synthesis of 1-((1r,4r)-4-{4-[(E)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)-3-[3-fluoro-4-(trifluoromethoxy)phenyl]urea (SP-B07) A 100 mL three-neck flask was charged with 3-fluoro-4-trifluoromethoxyaniline (1.21 g, 4.72 mmol, 1.5 eq), EtN (0.95 g, 18.70 mmol, 3 eq), and dry DCM (10 mL) in that order. The mixture was cooled to -15 °C using a cold trap, and a DCM solution (15 mL) of BTC (0.48 g, 1.60 mmol, 0.51 eq) was added dropwise. The addition was completed within 3 min, and the mixture was allowed to warm to room temperature. After 2 h, the reaction was monitored by TLC and stopped when complete.

[0084] A 100 mL three-neck flask was charged with 5-{(Z)-4-[(1r,4r)-4-aminocyclohexyl]oxybenzylidene}thiazolidine-2,4-dione (1.17 g, 3.68 mmol, 1 eq), EtN (0.95 g, 18.7 mmol, 3 eq), DCM (6 mL), and a solution of 3-fluoro-4-trifluoromethoxyaniline isocyanate in DCM (20 mL) in that order. The reaction was allowed to proceed at room temperature for 6 h. The reaction was monitored by TLC and stopped when complete. The mixture was concentrated under reduced pressure to remove DCM, and 30 mL of 1 N HCl was added. The mixture was stirred for 5 min, suction filtered, and the filter cake was leached with 20 mL of water to give 1.46 g of a crude white solid. The crude product was purified by silica gel column chromatography, the sample was mixed with 1.5 times, and the column was filled with 10 times silica gel, the eluent was EA:PE=1:7, and 0.34 g of a white solid was obtained. 1 H NMR(400MHz,DMSO-d6):δ(ppm)12.49(s,1H),8.71(s,1H),7.75(s,1H),7.69(d,J=2.4Hz,1H),7.54(d,J=8.8Hz,2H),7.55-7.36(m,1H), 7.13-7.08(m,3H),6.31(d,J=7.6Hz,1H),4.50-4.44(m,1H),3.58-3.51(m,1H),2.08-2.05(m,2H),1.96-1.91(m,2H),1.54-1.34(m,4H). 13 C NMR(100MHz,DMSO-d6):δ(ppm)168.4,167.9,159.7,155.4,154.6,152.9,141.8,1 32.6,125.7,124.7,120.6,116.7,114.0,106.2,106.0,74.9,47.7,30.3,30.1.ESI MS:m / z 540.0[M+H] + .

[0085] Example 10 Synthesis of 1-((1r,4r)-4-{4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)-3-[3-fluoro-4-(trifluoromethoxy)phenyl]urea (SP-A07) To a 100 mL single-mouth bottle, 1-((1r,4r)-4-{4-[(E)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)-3-[3-fluoro-4-(trifluoromethoxy)phenyl]urea (1.65 g, 3.06 mmol, 1 eq), 10% Pd / C (0.17 g), and anhydrous methanol (10 mL) were added in that order and stirred at 30°C. After 3 h, the reaction was monitored by TLC and stopped when complete. The mixture was filtered with suction and concentrated under reduced pressure to give 40 mg of a white solid. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 12.01 (s, 1H), 8.73(s, 1H), 7.68 (d, J = 2.4 Hz, 1H),7.65-7.40 (m, 1H), 7.38-7.09 (m, 3H), 6.88 (d, J = 8.6 Hz, 2H), 6.30 (d, J = 7.6 Hz, 1H),4.88-4.84 (m, 1H), 4.32-4.27 (m, 1H), 3.56-3.49 (m, 1H), 3.28 (s, 1H), 3.07-3.02 (m, 1H), 2.50-2.01 (m, 4H), 1.93-1.41 (m, 4H). 13 C NMR (100 MHz, DMSO-d6): δ (ppm)168.4, 167.9, 159.7, 155.4, 154.6, 152.9, 141.8, 132.6, 125.7, 124.7, 120.6, 116.7, 114.0, 106.0, 74.9, 47.7, 30.3, 30.1. ESI MS: m / z 542.1 [M + H] + .

[0086] Example 11 Synthesis of tert-butyl 4-(4-formylphenoxy)piperidine-1-carboxylate N-Boc-4-hydroxypiperidine (5.00 g, 0.25 mol), p-hydroxybenzaldehyde (15.18 g, 0.25 mol), triphenylphosphine (48.92 g, 0.37 mol), and THF (75 mL) were added sequentially to a 500 mL three-neck flask. The mixture was cooled to below -10 °C in an ice-salt bath, and a THF solution (80 mL) of DIAD (37.74 mg, 0.37 mol) was added dropwise at a rate of 1 drop per 2 seconds. The reaction was monitored by TLC for 5 h and stopped when complete. The THF was removed by concentration under reduced pressure to give 127.01 g of a tan oil, which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ (ppm) 9.88 (s, 1H), 7.82 (d, J = 2.0 Hz, 2H), 7.01 (d, J = 2.0 Hz, 2H), 4.64-4.59 (m, 1H), 3.73-3.67 (m, 2H), 3.42-3.35 (m, 2H), 1.99-1.92 (m, 2H), 1.82-1.74 (m, 2H), 1.77 (s, 9H).

[0087] Example 12 Synthesis of 4-(piperidin-4-oxy)benzaldehyde 4-(4-Formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (127.01 g) and DCM (180 mL) were added sequentially to a 500 mL three-neck flask, cooled to 0 °C in an ice bath, and TFA (119.04 g, 1.04 mol) was added dropwise. After 37 hours, the reaction was monitored by TLC and stopped when complete. TFA in the reaction solution was removed by distillation under reduced pressure. DCM (50 mL) was added, and the mixture was extracted with 1 N HCl (200 mL × 6). The aqueous layers were combined, adjusted to pH 10 with solid NaOH, and extracted with n-butanol (200 mL × 12). The combined organic layers were concentrated to dryness under reduced pressure, triturated with acetone (12 mL), and suction filtered. The filter cake was washed with acetone (2 mL) and dried to give 17.45 g of a crude reddish-brown solid. The combined yield for the two steps was 34%. The crude product was used directly in the next step without purification.

[0088] Example 13 Synthesis of (Z)-5-[4-(piperidin-4-oxy)benzylidene]thiazolidine-2,4-dione A 250 mL round-bottom flask was charged with 4-(piperidin-4-oxy)benzaldehyde (4.00 g, 19.50 mmol), 2,4-thiazolidinedione (2.28 g, 19.50 mmol), pyridine (0.77 g, 9.75 mmol), glacial acetic acid (0.59 g, 9.75 mmol), and toluene (15 mL), in that order, and the temperature was raised to reflux. As the reaction progressed, a solid precipitated. After 8 hours, the reaction was monitored by TLC and stopped when complete. The reaction was cooled to room temperature, suction filtered, and the filter cake was leached with a small amount of toluene to give 3 g of a pale yellow solid. ESI MS: m / z 304.10 [M + H] + .

[0089] Example 14 Synthesis of N-[(1r,3R,5S,7r)-3,5-dimethyladamant-1-yl[-4-{4-[(Z)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}piperidine-1-formamide (SP-B02) Memantine (16.51 g, 0.031 mol), EtN (10.71 g, 0.11 mol), and dry DCM (50 mL) were added in this order to a 250 mL three-neck flask, cooled to -10 °C in an ice-salt bath, and a DCM solution (50 mL) of BTC (8.01 g, 0.027 mol) was added dropwise. The addition was completed within 30 minutes. After the addition was completed, the temperature naturally rose to room temperature. The reaction was continued for 4 hours, after which the reaction was stopped, and the solvent was concentrated under reduced pressure and evaporated to dryness.

[0090] A 250 mL three-neck flask was charged with (Z)-5-[4-(piperidin-4-oxy)benzylidene]thiazolidine-2,4-dione (6.33 g, 0.021 mol), EtN (6.33 g, 0.062 mol), and DCM (30 mL) in that order. The above DCM solution of memantine isocyanate (30 mL) was added dropwise at room temperature. The addition was completed within 30 minutes and monitored by TLC. The reaction solution was poured into water (30 mL) and extracted with DCM (30 mL × 3). The combined organic layer was washed with water (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to give 12.5 g of a yellow oily liquid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 times, and the column was filled with 5 times silica gel. The eluent was EA:PE=1:3. 6.11 g of a pale yellow solid was obtained with a melting point of 83-84°C. 1 H NMR (400 MHz, CDCl3): δ (ppm) 9.07 (s, 1H), 7.80 (s,1H), 7.45 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 4.57 (s, 1H), 3.57 (d, J = 8.3 Hz, 2H), 3.30-3.29 (m, 2H), 2.16 (d, J = 10.0 Hz, 2H),1.98(d, J = 4.2 Hz, 4H), 1.83 (s,5H), 1.38 (d, J = 12.1 Hz, 2H), 1.28 (d, J = 12.0Hz, 2H), 1.20-1.11(m, 2H), 0.85 (s, 6H). ESI MS: m / z 510.3 [M + H] + .

[0091] Example 15 Synthesis of N-[(1r,3R,5S,7r)-3,5-dimethyladamant-1-yl[-4-{4-[(2,4-dioxothiazolidin-5-ylidene)methane]phenoxy}piperidine-1-formamide (SP-A02) N-[(1r,3R,5S,7r)-3,5-dimethyladamant-1-yl[-4-{4-[(Z)-(2,4-dioxythiazolidin-5-ylidene)methyl]phenoxy}piperidine-1-formamide (0.2 g, 0.39 mmol), 10% Pd / C (0.02 g), and anhydrous methanol (10 mL) were added to a 50 mL single-mouth bottle in this order and stirred at 30 °C. After 3 h, the reaction was monitored by TLC and stopped when complete. The mixture was filtered and concentrated under reduced pressure to give 0.18 g of a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.38 (s, 1H), 7.14 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.3 Hz, 2H), 4.46 (ddt, J = 17.9, 7.2, 3.7 Hz, 2H), 4.26 (s, 1H), 3.57 (ddd, J = 12.5, 7.7, 3.7 Hz, 2H), 3.44 (dd, J = 14.2, 4.0 Hz, 1H), 3.24 (ddd, J = 13.0, 7.8, 4.1 Hz, 2H), 3.11 (dd, J = 14.2, 9.4 Hz, 1H), 2.14 (p, J = 3.3 Hz, 1H), 1.92 (ddd, J = 11.9, 8.0, 3.7 Hz, 2H), 1.85 - 1.71 (m, 3H), 1.77 (s, 1H), 1.38 (d, J = 12.4 Hz, 2H), 1.27 (dd, J = 15.7, 9.6 Hz, 4H), 1.14 (t, J = 10.4 Hz, 2H), 0.85 (s, 6H).

[0092] Example 16 Synthesis of (Z)-4-{4-[(2,4-dioxythiazolidin-5-ylidene)methyl]phenoxy}-N-[4-(trifluoromethoxy)phenyl]piperidine-1-formamide (SP-B05) A 100 mL three-neck flask was charged with p-trifluoromethoxyaniline (0.58 g, 3.28 mmol), EtN (0.66 g, 6.56 mmol), and dry DCM (10 mL) in that order. The flask was cooled to -10 °C in an ice-salt bath, and a DCM solution (10 mL) of BTC (0.34 g, 1.12 mmol) was added dropwise. The addition was completed within 3 min, and the mixture was allowed to warm to room temperature. After 2 h, the reaction was monitored by TLC and stopped when complete.

[0093] A 100 mL three-neck flask was charged with 5-{(Z)-4-[(1r,4r)-4-aminocyclohexyl]oxybenzylidene}thiazolidine-2,4-dione (1.00 g, 3.28 mmol), EtN (0.66 g, 6.56 mmol), DCM (6 mL), and a solution of p-trifluoromethoxyaniline isocyanate in DCM (20 mL) in sequence. The reaction was allowed to react at room temperature for 30 min. DMSO (6 mL) was added, and the reaction was heated to reflux. After 6 h, the reaction was monitored by TLC and stopped when complete. The mixture was concentrated under reduced pressure to remove DCM, and 30 mL of 1 N HCl was added. The mixture was stirred for 5 min, suction filtered, and the filter cake was leached with 20 mL of water to give 1.46 g of a crude white solid. The crude product was purified by silica gel column chromatography, the sample was mixed 1.5 times, and the column was filled with 5 times silica gel, and the eluent was EA:PE=1:5, to obtain 0.46 g of a white solid. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 12.48 (s, 1H), 8.75 (s, 1H), 7.73 (s, 1H), 7.56 (s, 4H), 7.23-7.15 (m, 4H), 4.73 (s, 1H), 3.82 (s, 2H), 3.30 (s, 2H), 2.00 (s, 2H), 1.62 (s, 2H). 13 C NMR (100 MHz, DMSO-d6): δ (ppm) 168.8, 159.2, 155.2, 143.0, 140.4, 132.6, 131.8, 126.1, 121.6, 121.1, 119.8, 116.9, 72.8, 30.9.

[0094] Example 17 Synthesis of 4-{4-[(2,4-dioxythiazolidin-5-ylidene)methyl]phenoxy}-N-[4-(trifluoromethoxy)phenyl]piperidine-1-formamide (SP-A05) To a 50 mL single-mouth bottle, (Z)-4-{4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}-N-[4-(trifluoromethoxy)phenyl]piperidine-1-formamide (1.65 g, 3.06 mmol, 1 eq), 10% Pd / C (0.20 g), and anhydrous methanol (10 mL) were added in that order and stirred at 30 °C. After 3 h, the reaction was monitored by TLC and stopped when complete. The mixture was filtered and concentrated under reduced pressure to give 0.18 g of a white solid. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 12.01 (s, 1H), 8.73(s, 1H), 7.68 (d, J = 2.4 Hz, 1H),7.65-7.40 (m, 1H), 7.38-7.09 (m, 3H), 6.88 (d, J = 8.6 Hz, 2H), 6.30 (d, J = 7.6 Hz, 1H),4.88-4.84 (m, 1H), 4.32-4.27 (m, 1H), 3.56-3.49 (m, 1H), 3.28 (s, 1H), 3.07-3.02 (m, 1H), 2.50-2.01 (m, 4H), 1.93-1.41 (m, 4H). 13 C NMR (100 MHz, DMSO-d6): δ (ppm)168.4, 167.9, 159.7, 155.4, 154.6, 152.9, 141.8, 132.6, 125.7, 124.7, 120.6, 116.7, 114.0, 106.0, 74.9, 47.7, 30.3, 30.1. ESI MS: m / z 542.1 [M + H] + .

[0095] Example 18 Synthesis of (Z)-4-{4-[(2,4-dioxythiazolidin-5-ylidene)methyl]phenoxy}-N-[3-fluoro-4-(trifluoromethoxy)phenyl]piperidine-1-formamide (SP-B06) A 100 mL three-neck flask was charged with 3-fluoro-4-trifluoromethoxyaniline (1.21 g, 4.72 mmol, 1.5 eq), EtN (0.95 g, 18.70 mmol, 3 eq), and dry DCM (10 mL) in that order. The mixture was cooled to -15 °C using a cold trap, and a DCM solution (15 mL) of BTC (0.48 g, 1.60 mmol, 0.51 eq) was added dropwise. The addition was complete within 3 min, and the mixture was allowed to warm to room temperature. After 2 h, the reaction was monitored by TLC for completeness and then stopped.

[0096] A 100 mL three-neck flask was charged with 5-{(Z)-4-[(1r,4r)-4-aminocyclohexyl]oxybenzylidene}thiazolidine-2,4-dione (1.17 g, 3.68 mmol, 1 eq), EtN (0.95 g, 18.7 mmol, 3 eq), DCM (6 mL), and a solution of 3-fluoro-4-trifluoromethoxyaniline isocyanate in DCM (20 mL) in that order. The reaction was allowed to proceed at room temperature for 6 h. The reaction was monitored by TLC and stopped when complete. The mixture was concentrated under reduced pressure to remove DCM, and 30 mL of 1 N HCl was added. The mixture was stirred for 5 min, suction filtered, and the filter cake was leached with 20 mL of water to give 1.46 g of a crude white solid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 times and the column was filled with 10 times silica gel. The eluent was EA:PE=1:7. 0.34 g of white solid was obtained, with a yield of 39.48%. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 12.49 (s, 1H), 8.71 (s, 1H),7.75 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H),7.55-7.36 (m, 1H), 7.13-7.08 (m, 3H), 6.31 (d, J = 7.6 Hz, 1H), 4.50-4.44 (m, 1H), 3.58-3.51 (m, 1H), 2.08-2.05 (m, 2H), 1.96-1.91 (m, 2H), 1.54-1.34 (m, 4H). 13 C NMR (100 MHz, DMSO-d6): δ (ppm) 168.4, 167.9, 159.7, 155.4, 154.6, 152.9, 141.8, 132.6, 125.7, 124.7, 120.6, 116.7, 114.0, 106.2, 106.0, 74.9, 47.7, 30.3, 30.1. ESI MS: m / z 540.0 [M + H] + .

[0097] Example 19 Synthesis of 4-{4-[(2,4-dioxythiazolidin-5-ylidene)methyl]phenoxy}-N-[3-fluoro-4-(trifluoromethoxy)phenyl]piperidine-1-formamide (SP-A06) To a 50 mL single-mouth bottle, (Z)-4-{4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}-N-[3-fluoro-4-(trifluoromethoxy)phenyl]piperidine-1-formamide (1.65 g, 3.06 mmol, 1 eq), 10% Pd / C (0.20 g), and anhydrous methanol (10 mL) were added in that order and stirred at 30 °C. After 3 h, the reaction was monitored by TLC and stopped when complete. The mixture was filtered and concentrated under reduced pressure to give 1.04 g of a white solid. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 12.01 (s, 1H), 8.73(s, 1H), 7.68 (d, J = 2.4 Hz, 1H),7.65-7.40 (m, 1H), 7.38-7.09 (m, 3H), 6.88 (d, J = 8.6 Hz, 2H), 6.30 (d, J = 7.6 Hz, 1H),4.88-4.84 (m, 1H), 4.32-4.27 (m, 1H), 3.56-3.49 (m, 1H), 3.28 (s, 1H), 3.07-3.02 (m, 1H), 2.50-2.01 (m, 4H), 1.93-1.41 (m, 4H). 13 C NMR (100 MHz, DMSO-d6): δ (ppm)168.4, 167.9, 159.7, 155.4, 154.6, 152.9, 141.8, 132.6, 125.7, 124.7, 120.6, 116.7, 114.0, 106.0, 74.9, 47.7, 30.3, 30.1. ESI MS: m / z 542.1 [M + H] + .

[0098] Example 20 Synthesis of (Z)-5-[4-(piperidin-4-oxy)benzylidene]imidazoline-2,4-dione A 100 mL round-bottom flask was charged with 2,4-imidazolidinedione (1.95 g, 19.50 mmol) and water (5 mL), heated to 70 °C, and the pH was adjusted to 7 with saturated aqueous sodium bicarbonate. Ethanolamine (2.38 g, 19.50 mmol) was added to the mixture, the temperature was raised to 100 °C, and a solution of 4-(piperidin-4-oxy)benzaldehyde (4 g, 19.50 mmol) in EtOH (15 mL) was added dropwise. As the reaction progressed, a solid precipitated. It was monitored by TLC after 16 h. Upon completion, the reaction was stopped. The reaction mixture was cooled to room temperature, filtered under suction, and the filter cake was leached with a small amount of water to give 1.8 g of a white solid. ESI MS: m / z 287.13 [M + H] + .

[0099] Example 21 Synthesis of N-[(1r,3R,5S,7r)-3,5-dimethyladamant-1-yl]-4-{4-[(Z)-(2,5-dioximidazolin-4-ylidene)methyl]phenoxy}piperidine-1-formamide (SP-B03) Memantine (1.10 g, 3.46 mmol), EtN (0.70 g, 6.92 mmol), and dry DCM (5 mL) were added in this order to a 100 mL three-neck flask, and the mixture was cooled to -10 °C in an ice-salt bath. A DCM solution (4 mL) of BTC (0.51 g, 1.73 mmol) was added dropwise, and the addition was completed within 3 minutes. After the addition was completed, the temperature naturally rose to room temperature, and the reaction was continued for 4 hours. The reaction was then stopped, and the solvent was concentrated under reduced pressure and evaporated to dryness.

[0100] To a 100 mL three-neck flask, (Z)-5-[4-(piperidin-4-oxy)benzylidene]imidazoline-2,4-dione (0.89 g, 3.08 mmol), EtN (0.70 g, 6.92 mmol), and DCM (10 mL) were added, in that order. The above solution of memantine isocyanate in DCM (10 mL) was added dropwise at room temperature. The addition was complete within 20 minutes, and the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to give 3.14 g of a white solid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 volumes of ethyl acetate and the column was filled 5 times with silica gel. The eluent was EA:PE = 1:3, and 1.02 g of a white solid was obtained. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 11.11 (s, 1H), 10.40 (s, 1H),7.56 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H),6.38 (s, 1H), 5.70 (s, 1H), 4.62-4.58 (m, 1H),3.64-3.61 (m, 2H), 3.09-3.02 (m, 2H), 2.06-2.05 (m, 1H), 1.91-1.80 (m, 2H),1.76 (s, 1H), 1.76 (s, 1H), 1.59-1.43 (m, 6H), 1.31-1.16 (m, 4H), 1.06 (s, 2H), 0.81 (s, 6H).

[0101] Example 22 Synthesis of (Z)-4-[4-(2,5-dioxoimidazolin-4-ylidene)methyl]phenoxy)-N-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide (SP-B04) A 100 mL three-neck flask was charged with p-trifluoromethoxyaniline (0.41 g, 3.50 mmol), EtN (0.70 g, 7.00 mmol), and dry DCM (10 mL) in that order. The mixture was cooled to -10 °C in an ice-salt bath, and a DCM solution (10 mL) of BTC (0.33 g, 1.13 mmol) was added dropwise. The addition was completed within 3 min, and the mixture was allowed to warm to room temperature. After 2 h, the reaction was monitored by TLC (EA:PE = 1:1, 2 drops of glacial acetic acid). When the reaction was complete, it was stopped.

[0102] A 100 mL three-neck flask was charged with (Z)-5-[4-(piperidin-4-oxy)benzylidene]imidazoline-2,4-dione (0.50 g, 1.75 mmol), EtN (0.71 g, 7.00 mmol), DCM (5 mL), and a solution of p-trifluoromethoxyaniline isocyanate in DCM (20 mL) in sequence. The mixture was allowed to react at room temperature for 30 min. DMSO (6 mL) was added, and the reaction was heated to reflux. After 12 h, the reaction was stopped by TLC. The mixture was concentrated under reduced pressure to remove DCM, and 30 mL of 1 N hydrochloric acid was added. The mixture was stirred for 5 min and suction filtered. The filter cake was leached with 20 mL of water to give 0.65 g of a crude white solid.

[0103] The crude product was purified by silica gel column chromatography, the sample was mixed 1.5 times, and the column was filled with 5 times silica gel, and the eluent was EA:PE=1:5, to obtain 0.42 g of a white solid. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 11.25 (s, 1H), 10.42 (s, 1H),7.59 (d, J = 8.8 Hz, 2H), 7.41-7.39 (m, 2H), 7.37-7.13 (m, 1H), 7.13-7.12 (m, 2H), 7.03 (d, J = 8.8 Hz, 2H),6.39 (s, 1H), 5.75 (s, 1H), 3.81 (d, J = 49 Hz, 2H),3.44 (d, J = 49 Hz, 2H), 2.01 (s, 2H), 1.69 (s, 2H). 13 C NMR (100 MHz, DMSO-d6): δ (ppm) 166.1, 157.6, 156.1, 153.4, 151.7, 131.7, 129.7, 126.7, 126.2, 125.6, 122.4, 116.6, 109.1, 72.0, 55.4, 30.6.

[0104] Example 23 Synthesis of 4-{(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl}oxy)phenyl acetate A 500 mL three-neck flask was charged with trans-4-Boc-aminocyclohexanol (9.27 g, 43.08 mmol, 1 eq), 4-hydroxyphenylacetate (6.55 g, 43.08 mmol, 1 eq), triphenylphosphine (16.94 g, 64.62 mmol, 1.5 eq), and THF (25 mL) in that order. The mixture was cooled to below -10 °C in an ice-salt bath, and a THF solution (12.5 mL) of DIAD (13.07 g, 64.62 mmol, 1.5 eq) was added dropwise at a rate of 1 drop every 2 seconds. The reaction was monitored by TLC for 72 h and stopped upon completion. The THF was removed by concentration under reduced pressure to give 35.57 g of a yellow-brown oil, and the crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 times the amount of the sample, and the column was filled with 10 times the amount of silica gel. The eluent was EA:PE=1:30, and 2.33 g of a white solid was obtained.

[0105] Example 24 Synthesis of tert-butyl [(1r,4r)-4-(4-hydroxyphenoxy)cyclohexyl]carbamate To a 25 mL one-mouth bottle, 4-{(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl}oxy)phenyl acetate (0.16 g, 0.46 mmol, 1 eq), THF (5 mL), HO (0.5 mL), and LiOH (0.03 g, 1.37 mmol, 3 eq) were added in that order and stirred at room temperature. After 50 min of TLC monitoring, the reaction was stopped, concentrated under reduced pressure to remove THF, extracted with EA (30 mL), adjusted to pH 4 with 1N HCl, and then diluted with DCM (30 mL x 3). The organic layer was dried over anhydrous magnesium sulfate, suction filtered, and concentrated to dryness under reduced pressure to give 0.10 g of a pale yellow solid as crude product. ESI MS: m / z 330.2 [M + H] + .

[0106] Example 25 Synthesis of 2-(4-{(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl)oxy}phenoxy)acetic acid methyl ester To a 25 mL one-mouth bottle, tert-butyl [(1r,4r)-4-(4-hydroxyphenoxy)cyclohexyl]carbamate (0.43 g, 1.40 mmol, 1 eq) and MeCN (15 mL) were added in that order, followed by KCO (0.58 g, 4.20 mmol, 3 eq), KI (0.023 g, 0.14 mmol, 0.1 eq), and methyl bromoacetate (0.32 g, 2.10 mmol, 1.5 eq) dropwise. The mixture was purged with Ar three times and heated to reflux. After 16 hours, the reaction was monitored by TLC, stopped, concentrated to dryness under reduced pressure, and extracted with water (30 mL) and DCM (30 mL x 3). The combined organic layers were washed with water (30 mL), saturated brine (30 mL), dried over anhydrous magnesium sulfate, suction filtered, and concentrated under reduced pressure to give 0.78 g of a brown-black oily liquid. The crude product was purified by silica gel column chromatography. The sample was mixed 1.5 times and the column was filled 3 times with silica gel. The eluent was EA:PE = 1:5. 0.40 g of a white solid was obtained in 75.35% yield. ESI MS: m / z 402.1 [M + H]+.

[0107] Example 26 Synthesis of 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetic acid methyl ester To a 25 mL one-mouth bottle, 2-(4-{(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl)oxy}phenoxy)acetic acid methyl ester (0.30 g, 0.79 mmol) and DCM (10 mL) were added in that order, and the mixture was cooled to 0°C in an ice bath, followed by dropwise addition of TFA (3 mL). After 2 hours, the reaction was monitored by TLC, and when it reached completion, the reaction was stopped. The TFA in the reaction mixture was removed by distillation under reduced pressure, yielding 0.21 g of a crude brown oil.

[0108] Example 27 Synthesis of 2-[4-((1r,4r)-4-{3-[3-fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)acetic acid methyl ester (SP-C03) BTC (0.08 g, 0.27 mmol, 0.34 eq), EtN (0.16 g, 1.58 mmol, 3 eq), and dry DCM (5 mL) were added sequentially to a 25 mL single-mouth bottle. The mixture was cooled to -80 °C using a cold trap, and a DCM solution (5 mL) of 3-fluoro-4-trifluoromethoxyaniline (0.21 g, 0.79 mmol, 1 eq) was added dropwise. The addition was completed within 3 min. After the addition was complete, the mixture was allowed to warm to room temperature. After 10 min, the reaction was monitored by TLC and stopped when complete.

[0109] A 25 mL three-neck flask was charged with a solution of 3-fluoro-4-trifluoromethoxyaniline isocyanate in DCM (10 mL) and EtN (0.16 g, 1.58 mmol, 3 eq). The mixture was then cooled to 0 °C in an ice bath and a solution of 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetic acid methyl ester (0.22 g, 0.79 mmol, 1 eq) in DCM (10 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. The reaction was monitored by TLC and stopped when complete. The mixture was concentrated under reduced pressure to remove the DCM, yielding 0.44 g of a crude white solid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 volumes of silica gel and the column was filled 10 times with EA:PE (1:5). 0.10 g of a white solid was obtained in 25.6% yield. ESI MS: m / z 523.0 [M + Na] + .

[0110] Example 28 Synthesis of 2-[4-((1r,4r)-4-{3-[3-fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)acetic acid (SP-C02) To a 25 mL single-mouth bottle, 2-[4-((1r,4r)-4-{3-[3-fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)acetic acid methyl ester (70 mg, 0.14 mmol, 1 eq), THF (2 mL), HO (0.5 mL), and LiOH (10 mg, 0.42 mmol, 3 eq) were added in that order and stirred at room temperature. After 50 min, the reaction was monitored by TLC, stopped, concentrated under reduced pressure to remove THF, and extracted with EA (30 mL) and water (20 mL × 2). The aqueous layer was adjusted to pH = 2 with 1 N HCl and suction filtered to give 20.02 mg of a white solid. The yield was 29.06%. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 13.04 (s, 1H), 9.02 (s, 1H), 7.68 (dd, J = 13.4Hz, 2.2 Hz, 1H), 7.38 (t, J = 8.8Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), 6.55 (d, J = 7.6 Hz, 1H), 4.49 (s, 2H), 3.51-3.49 (m, 2H), 1.99 (d, J = 9.6 Hz, 2H), 1.89 (d, J = 9.6 Hz, 2H), 1.46-1.23 (m, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 171.46, 155.36, 154.74, 152.91, 152.60, 151.84, 142.12, 142.02, 128.75, 128.62, 124.65, 124.52, 121.97, 119.42, 117.47, 115.78, 113.93, 106.06, 105.83, 75.32, 66.10, 47.72, 30.34, 30.26. ESI MS: m / z 484.8 [M - H] - .

[0111] Example 29 Synthesis of 2-(4-{(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl}oxy)phenoxy)acetic acid ethyl ester To a 25 mL one-mouth bottle was added 2-(4-{(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl)oxy}phenoxy)acetic acid methyl ester (4.00 g, 13.02 mmol, 1 eq), MeCN (20 mL), KCO (5.40 g, 39.06 mmol, 3 eq), and KI (0.22 g, 1.30 mmol, 0.1 eq) in that order. Ethyl chloroacetate (2.39 g, 19.53 mmol, 1.5 eq) was added dropwise, and the mixture was purged with Ar three times and heated to reflux. After 16 hours, the reaction was monitored by TLC, stopped, concentrated to dryness under reduced pressure, extracted with water (30 mL) and DCM (30 mL × 3), the organic layers were combined, washed with water (30 mL), washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, suction filtered, and concentrated under reduced pressure to give 0.78 g of a brown-black oily liquid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 volumes of EA and PE, and the column was filled with 3 volumes of silica gel. The eluent was EA:PE = 1:5, to give 4.06 g of a white solid.

[0112] Example 30 Synthesis of 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetic acid ethyl ester To a 100 mL single-mouth bottle, ethyl 2-(4-{(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl}oxy)phenoxy)acetate (4.06 g, 10.33 mmol) and DCM (20 mL) were added sequentially, cooled to 0 °C in an ice bath, and TFA (6 mL) was added dropwise. After 6 h, the reaction was monitored by TLC and stopped when complete. DCM and TFA were removed from the reaction solution by distillation under reduced pressure to give 4.40 g of a brown oil as a crude product, which was used directly in the next step without further purification.

[0113] Example 31 Synthesis of ethyl 2-[4-((1r,4r)-4-{3-[3-fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)acetate (SP-C04) BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) were added sequentially to a 25 mL single-mouth bottle, cooled to -80 °C in a cold trap, and a DCM solution (15 mL) of 3-fluoro-4-trifluoromethoxyaniline (0.21 g, 0.79 mmol, 1 eq) and EtN (0.24 g, 2.37 mmol, 3 eq) was added dropwise. The addition was complete within 30 min, after which the temperature was allowed to rise to room temperature. After 10 min, the reaction was monitored by TLC and stopped when complete.

[0114] A 100 mL three-neck flask was charged with a solution of 3-fluoro-4-trifluoromethoxyaniline isocyanate in DCM (25 mL) and EtN (0.24 g, 2.37 mmol, 3 eq). The mixture was then cooled to 0 °C in an ice bath and a solution of 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetic acid ethyl ester (0.23 g, 0.79 mmol, 1 eq) in DCM (10 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. The reaction was monitored by TLC and stopped when complete. The mixture was concentrated under reduced pressure to remove the DCM, yielding 0.62 g of a white solid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 volumes of silica gel and the column was filled 12 times with silica gel. The eluent was EA:PE = 1:10. 0.27 g of a white solid was obtained in 69.23% yield. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.68 (dd, J = 13.4, 2.5 Hz, 1H), 7.44 - 7.34 (m, 1H), 7.09 (ddd, J = 9.0, 2.6, 1.3 Hz, 1H), 6.92 - 6.79 (m, 4H), 6.31 (d, J = 7.6 Hz, 1H), 4.69 (s, 2H), 4.16 (q, J = 7.1 Hz, 3H), 3.55 - 3.45 (m, 1H), 2.05 - 1.97 (m, 2H), 1.95 - 1.87 (m, 2H), 1.50 - 1.25 (m, 4H), 1.21 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 169.44, 154.63, 152.93, 152.18, 141.95, 141.84, 128.85, 124.73, 121.97, 117.48, 115.98, 114.01, 106.15, 105.92, 75.29, 65.72, 61.00, 47.78, 30.38, 30.27, 14.52. ESI MS: m / z 537.1 [M + Na] + .

[0115] Example 32 Synthesis of 2-[4-((1r,4r)-4-{3-[3-fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)-2-methylpropionic acid methyl ester (SP-C06) A 25 mL three-neck flask was charged with a solution of 3-fluoro-4-trifluoromethoxyaniline isocyanate in DCM (10 mL) and EtN (0.24 g, 2.37 mmol, 3 eq). The temperature was then cooled to 0 °C in an ice bath, and a solution of 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)-2-methylpropionic acid methyl ester (0.24 g, 0.79 mmol, 1 eq) in DCM (10 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. After completion of the reaction, the reaction was monitored by TLC and stopped. The DCM was removed by concentration under reduced pressure to give 0.47 g of a crude white solid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 times and the column was filled with 10 times silica gel. The eluent was EA:PE=1:5. 0.32 g of white solid was obtained, with a yield of 76.19%. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.68 (dd, J = 13.5, 2.5 Hz, 1H), 7.39 (t, J = 8.9 Hz, 1H), 7.09 (dt, J = 9.3, 1.9 Hz, 1H), 6.89 - 6.81 (m, 2H), 6.79 - 6.71 (m, 2H), 6.30 (d, J = 7.6 Hz, 1H), 4.21 (dt, J = 9.9, 5.6 Hz, 1H), 3.70 (s, 3H), 3.50 (s, 1H), 3.43 - 3.36 (m, 2H), 2.01 (d, J = 15.5 Hz, 2H), 1.95 - 1.87 (m, 2H), 1.45 (s, 10H). 13 C NMR (101 MHz, DMSO-d6) δ 174.26, 154.63, 153.28, 148.83, 141.94, 141.84, 128.85, 124.72, 121.97, 121.76, 119.42, 116.85, 114.01, 106.16, 105.92, 79.60, 75.05, 52.69, 47.79, 30.42, 30.31, 25.37, 15.62. ESI MS: m / z 551.2 [M + Na] + .

[0116] Example 33 Synthesis of 2-[4-((1r,4r)-4-{3-[3-fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)-2-methylpropionic acid (SP-C05) To a 25 mL single-mouth bottle, 2-[4-((1r,4r)-4-{3-[3-fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)-2-methylpropionic acid methyl ester (0.20 g, 0.38 mmol, 1 eq), THF (5 mL), HO (0.5 mL), and LiOH (30 mg, 1.20 mmol, 3 eq) were added in that order and stirred at room temperature. After 3 h, the reaction was monitored by TLC, stopped, concentrated under reduced pressure to remove THF, and extracted with DCM (30 mL) and water (20 mL × 2). The aqueous layer was adjusted to pH = 2 with 1 N HCl and suction filtered to give 0.15 g of a white solid. The yield was 76.92 g. 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.78 (s, 1H), 7.68 (dd, J = 13.5, 2.5 Hz, 1H), 7.44 - 7.35 (m, 1H), 7.09 (ddd, J = 9.1, 2.6, 1.3 Hz, 1H), 6.90 - 6.82 (m, 2H), 6.82 - 6.75 (m, 2H), 6.34 (d, J = 7.6 Hz, 1H), 4.21 (dq, J = 9.6, 5.6, 4.7 Hz, 1H), 3.57 - 3.46 (m, 1H), 2.05 - 1.97 (m, 2H), 1.91 (dd, J = 12.8, 4.2 Hz, 2H), 1.50 - 1.26 (m, 10H). 13 C NMR (101 MHz, DMSO-d6) δ 175.60, 155.37, 154.64, 152.93, 149.26, 141.96, 141.86, 124.71, 121.97, 121.32, 116.88, 114.00, 106.14, 105.90, 79.27, 75.08, 47.77, 30.40, 30.29, 25.46. ESI MS: m / z 512.8 [M - H] - .

[0117] Example 34 Synthesis of 2-[4-((1r,4r)-4-{3-[4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)acetic acid methyl ester (SP-C09) BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) were added sequentially to a 25 mL one-mouth bottle, cooled to -80 °C in a cold trap, and a DCM solution (20 mL) of p-trifluoromethoxyaniline (0.14 g, 0.79 mmol, 1 eq) and EtN (0.24 g, 2.37 mmol, 3 eq) was added dropwise. The addition was completed within 30 min, after which the temperature was allowed to rise to room temperature. After 10 min, the reaction was monitored by TLC and stopped when complete.

[0118] A 25 mL three-neck flask was charged with a solution of p-trifluoromethoxyaniline isocyanate in DCM (10 mL) and EtN (0.24 g, 2.37 mmol, 3 eq). The mixture was then cooled to 0 °C in an ice bath and a solution of 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetic acid methyl ester (0.22 g, 0.79 mmol, 1 eq) in DCM (10 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. The reaction was monitored by TLC and stopped when complete. The mixture was concentrated under reduced pressure to remove the DCM, yielding 0.50 g of a crude white solid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 volumes of silica gel and the column was filled 10 times with EA:PE (1:10) as the eluent, yielding 0.31 g of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.51 - 7.43 (m, 2H), 7.21 (d, J = 8.2 Hz, 2H), 6.91 - 6.80 (m, 4H), 6.18 (d, J = 7.6 Hz, 1H), 4.71 (s, 2H), 4.19 (dt, J = 9.8, 5.7 Hz, 1H), 3.69 (s, 3H), 3.57 - 3.46 (m, 1H), 2.00 (dd, J = 11.5, 4.1 Hz, 2H), 1.96 - 1.87 (m, 2H), 1.49 - 1.26 (m, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 169.93, 154.87, 152.21, 152.17, 142.43, 140.29, 122.09, 119.01, 117.50, 115.95, 75.34, 65.62, 52.19, 47.71, 30.48, 30.29. ESI MS: m / z 505.0 [M + Na] + .

[0119] Example 35 Synthesis of 2-[4-((1r,4r)-4-{3-[4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)acetic acid (SP-C08) To a 25 mL single-mouth bottle, 2-[4-((1r,4r)-4-{3-[4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)acetic acid methyl ester (0.20 g, 0.41 mmol, 1 eq), THF (5 mL), HO (0.5 mL), and LiOH (30 mg, 1.20 mmol, 3 eq) were added in that order and stirred at room temperature. After 3 h, the reaction was monitored by TLC, stopped, concentrated under reduced pressure to remove THF, and extracted with DCM (30 mL) and water (10 mL × 2). The aqueous layer was adjusted to pH = 2 with 1 N HCl and suction filtered to give 0.15 g of a white solid. The yield was 78.94%. 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 7.51 - 7.44 (m, 2H), 7.21 (d, J = 8.6 Hz, 2H), 6.91 - 6.76 (m, 4H), 6.40 (d, J = 7.6 Hz, 1H), 4.52 (s, 2H), 4.17 (tt, J = 9.7, 4.0 Hz, 1H), 3.55 - 3.45 (m, 1H), 2.04 - 1.95 (m, 2H), 1.94 - 1.86 (m, 2H), 1.36 (dddd, J = 40.3, 20.2, 16.5, 10.0 Hz, 5H). 13 C NMR (101 MHz, DMSO-d6) δ 171.14, 154.96, 152.56, 151.89, 142.35, 140.44, 122.04, 118.97, 117.49, 115.79, 75.39, 66.00, 47.67, 30.45, 30.29. ESI MS: m / z 466.8 [M - H] - .

[0120] Example 36 Synthesis of 2-[4-((1r,4r)-4-{3-[4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)acetic acid ethyl ester (SP-C10) BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) were added sequentially to a 25 mL single-mouth bottle, cooled to -80 °C in a cold trap, and a DCM solution (15 mL) of p-trifluoromethoxyaniline (0.14 g, 0.79 mmol, 1 eq) and EtN (0.24 g, 2.37 mmol, 3 eq) was added dropwise. The addition was completed within 30 min, and the mixture was allowed to warm to room temperature. After 10 min, the reaction was monitored by TLC (EA:PE = 1:3). When the reaction was complete, it was stopped.

[0121] A 25 mL three-neck flask was charged with a solution of p-trifluoromethoxyaniline isocyanate in DCM (10 mL) and EtN (0.24 g, 2.37 mmol, 3 eq). The mixture was then cooled to 0 °C in an ice bath and a solution of 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetic acid ethyl ester (0.23 g, 0.79 mmol, 1 eq) in DCM (10 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. The reaction was monitored by TLC and stopped when complete. The mixture was concentrated under reduced pressure to remove the DCM, yielding 0.93 g of a crude white solid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 volumes of silica gel and the column was filled 12 times with silica gel. The eluent was EA:PE = 1:10, yielding 0.24 g of a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.50 - 7.43 (m, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.92 - 6.80 (m, 4H), 6.18 (d, J = 7.6 Hz, 1H), 4.69 (s, 2H), 4.19 - 4.09 (m, 2H), 3.60 - 3.42 (m, 1H), 2.04 - 1.96 (m, 2H), 1.92 (d, J = 13.7 Hz, 2H), 1.48 - 1.24 (m, 5H), 1.21 (t, J = 7.1 Hz, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 169.43, 154.87, 152.20, 142.43, 140.28, 122.08, 119.02, 117.49, 115.98, 75.34, 65.74, 61.00, 47.70, 30.48, 30.29, 14.51. ESI MS: m / z 519.1 [M + Na] + .

[0122] Example 37 Synthesis of 2-methyl-2-[4-((1,4r)-4-{3-[4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)-2-methylpropionic acid methyl ester (SP-C12) A 25 mL three-neck flask was charged with a solution of p-trifluoromethoxyaniline isocyanate in DCM (10 mL) and EtN (0.24 g, 2.37 mmol, 3 eq). The mixture was then cooled to 0 °C in an ice bath and a solution of 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)-2-methylpropionic acid methyl ester (0.24 g, 0.79 mmol, 1 eq) in DCM (10 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. The reaction was monitored by TLC and stopped upon completion. The mixture was concentrated under reduced pressure to remove the DCM, yielding 0.47 g of a crude white solid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 volumes of silica gel and the column was filled 10 times with EA:PE (1:5). 0.33 g of a white solid was obtained in 76.19% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.50 - 7.42 (m, 2H), 7.21 (d, J = 8.5 Hz, 2H), 6.88 - 6.81 (m, 2H), 6.79 - 6.72 (m, 2H), 6.18 (d, J = 7.6 Hz, 1H), 4.21 (tt, J = 9.7, 3.7 Hz, 1H), 3.70 (s, 3H), 3.51 (dtd, J = 10.9, 7.3, 4.2 Hz, 1H), 2.01 (dd, J = 12.6, 4.6 Hz, 2H), 1.92 (dd, J = 13.0, 4.3 Hz, 2H), 1.51 - 1.25 (m, 11H). 13 C NMR (101 MHz, DMSO-d6) δ 174.25, 154.88, 153.32, 148.84, 142.45, 140.29, 122.07, 121.78, 119.03, 116.88, 79.62, 75.12, 52.68, 47.72, 30.52, 30.33, 25.38. ESI MS: m / z 533.0 [M + Na] + .

[0123] Example 38 Synthesis of 2-methyl-2-[4-((1,4r)-4-{3-[4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)-2-methylpropionic acid (SP-C11) To a 25 mL single-mouth bottle, 2-methyl-2-[4-((1,4r)-4-{3-[4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)-2-methylpropionic acid (0.20 g, 0.39 mmol, 1 eq), THF (5 mL), HO (0.5 mL), and LiOH (30 mg, 1.20 mmol, 3 eq) were added in that order and stirred at room temperature. After 3 h, the reaction was monitored by TLC, stopped, concentrated under reduced pressure to remove THF, and extracted with DCM (30 mL) and water (10 mL × 2). The aqueous layer was adjusted to pH = 2 with 1 N HCl and suction filtered to give 0.14 g of a white solid. The yield was 73.68%. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.51 - 7.43 (m, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.90 - 6.72 (m, 4H), 6.20 (d, J = 7.6 Hz, 1H), 4.21 (td, J = 9.6, 4.8 Hz, 1H), 3.57 - 3.45 (m, 1H), 2.08 - 1.97 (m, 2H), 1.91 (dd, J = 12.0, 4.6 Hz, 2H), 1.50 - 1.23 (m, 11H). 13 C NMR (101 MHz, DMSO-d6) δ 175.60, 154.88, 152.94, 149.26, 142.42, 140.30, 122.08, 121.31, 119.01, 116.88, 79.27, 75.13, 47.70, 30.51, 30.32, 25.46. ESI MS: m / z 494.9 [M - H] - .

[0124] Example 39 Synthesis of 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy}acetic acid methyl ester (SP-C15) BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) were added sequentially to a 25 mL single-mouth bottle, cooled to -80 °C in a cold trap, and a DCM solution (20 mL) of memantine (0.14 g, 0.79 mmol, 1 eq) and EtN (0.24 g, 2.37 mmol, 3 eq) was added dropwise. The addition was completed within 30 min, after which the temperature was allowed to rise to room temperature. After 10 min, the reaction was monitored by TLC and stopped when complete.

[0125] A 25 mL three-neck flask was charged with a solution of p-memantine isocyanate in DCM (10 mL) and EtN (0.24 g, 2.37 mmol, 3 eq). The mixture was then cooled to 0 °C in an ice bath and a solution of 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetic acid methyl ester (0.22 g, 0.79 mmol, 1 eq) in DCM (10 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. The reaction was monitored by TLC and stopped upon completion. The mixture was concentrated under reduced pressure to remove the DCM, yielding 0.50 g of a crude white solid. The crude product was purified by silica gel column chromatography. The sample was mixed 1.5 times and the column was loaded 10 times with silica gel. The eluent was EA:PE = 1:10, yielding 0.33 g of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 6.89 - 6.79 (m, 4H), 5.58 (d, J = 7.6 Hz, 1H), 5.41 (s, 1H), 4.70 (s, 2H), 4.15 (tt, J = 10.0, 4.0 Hz, 1H), 3.69 (s, 3H), 3.35 (dt, J = 7.3, 3.6 Hz, 1H), 2.04 (p, J = 3.2 Hz, 1H), 1.96 (dt, J = 13.4, 3.9 Hz, 2H), 1.86 - 1.77 (m, 2H), 1.67 (d, J = 3.1 Hz, 2H), 1.49 (s, 4H), 1.40 - 1.11 (m, 9H), 1.07 (s, 2H), 0.79 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 169.92, 157.00, 152.25, 152.17, 117.56, 115.96, 75.50, 65.66, 52.18, 51.49, 50.87, 48.61, 47.37, 42.91, 41.00, 32.36, 30.83, 30.61, 30.40, 30.10. ESI MS: m / z 507.1 [M + Na] + .

[0126] Example 40 Synthesis of 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy}acetic acid (SP-C14) To a 25 mL bottle, 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido)}cyclohexyl)oxy]phenoxy}acetic acid methyl ester (0.20 g, 0.41 mmol, 1 eq), THF (5 mL), HO (0.5 mL), and LiOH (30 mg, 1.24 mmol, 3 eq) were added in that order and stirred at room temperature. After 3 h, the reaction was monitored by TLC, stopped, concentrated under reduced pressure to remove THF, and extracted with DCM (30 mL) and water (10 mL × 2). The aqueous layer was adjusted to pH = 2 with 1 N HCl and filtered under vacuum to give 0.15 g of a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.85 - 6.78 (m, 2H), 6.78 - 6.70 (m, 2H), 5.77 (d, J = 7.6 Hz, 1H), 5.59 (s, 1H), 4.24 (s, 2H), 4.11 (tt, J = 9.5, 4.0 Hz, 1H), 3.33 (ddd, J = 11.1, 7.1, 3.7 Hz, 1H), 2.04 (p, J = 3.2 Hz, 1H), 2.00 - 1.90 (m, 2H), 1.81 (dq, J = 11.8, 3.8 Hz, 2H), 1.67 (d, J = 3.1 Hz, 2H), 1.55 - 1.43 (m, 4H), 1.42 - 1.25 (m, 4H), 1.25 - 1.09 (m, 5H), 1.07 (s, 2H), 0.79 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 171.28, 157.12, 153.18, 151.45, 117.53, 115.68, 75.61, 67.74, 51.46, 50.89, 48.61, 47.33, 42.93, 40.99, 32.36, 30.79, 30.62, 30.40, 30.10.

[0127] Example 41 Synthesis of 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy}acetic acid ethyl ester (SP-C16) To a 25 mL single-mouth bottle, BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) were added in that order, cooled to -80 °C in a cold trap, and a DCM solution (15 mL) of memantine (0.14 g, 0.79 mmol, 1 eq) and EtN (0.24 g, 2.37 mmol, 3 eq) was added dropwise. The addition was completed within 30 min, after which the mixture was allowed to warm to room temperature. After 10 min, the reaction was monitored by TLC and stopped when complete.

[0128] A 25 mL three-neck flask was charged with a solution of memantine isocyanate in DCM (10 mL) and EtN (0.24 g, 2.37 mmol, 3 eq). The mixture was then placed in an ice bath at 0 °C and a solution of 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetic acid ethyl ester (0.23 g, 0.79 mmol, 1 eq) in DCM (10 mL) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 30 min. The reaction was monitored by TLC and stopped when complete. The mixture was concentrated under reduced pressure to remove the DCM, yielding 0.93 g of a crude white solid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 volumes of ethyl acetate and the column was loaded 15 times over silica gel (excluding the non-fluorescent urea form of memantine, which is not detected with iodine). The eluent was EA:PE = 1:10, yielding 0.20 g of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 6.89 - 6.79 (m, 4H), 5.58 (d, J = 7.6 Hz, 1H), 5.41 (s, 1H), 4.68 (s, 2H), 4.16 (q, J = 7.1 Hz, 3H), 3.35 (dd, J = 7.1, 3.6 Hz, 1H), 2.04 (p, J = 3.2 Hz, 1H), 2.01 - 1.90 (m, 2H), 1.86 - 1.76 (m, 2H), 1.67 (d, J = 3.2 Hz, 2H), 1.49 (s, 4H), 1.40 - 1.11 (m, 11H), 1.07 (s, 2H), 0.79 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 169.43, 156.99, 152.21, 152.17, 117.51, 115.97, 75.46, 65.73, 61.00, 51.47, 50.85, 48.60, 47.36, 42.90, 40.99, 32.36, 30.84, 30.61, 30.40, 30.09, 14.52.

[0129] Example 42 Synthesis of 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy}-2-methylpropionic acid methyl ester (SP-C18) BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) were added sequentially to a 25 mL single-mouth bottle, cooled to -80 °C in a cold trap, and a DCM solution (15 mL) of memantine (0.14 g, 0.79 mmol, 1 eq) and EtN (0.24 g, 2.37 mmol, 3 eq) was added dropwise. The addition was completed within 30 min, after which the temperature was allowed to rise to room temperature. After 10 min, the reaction was monitored by TLC and stopped when complete.

[0130] A 25 mL three-neck flask was charged with a solution of memantine isocyanate in DCM (10 mL) and EtN (0.24 g, 2.37 mmol, 3 eq). The mixture was then cooled to 0 °C in an ice bath and a solution of 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)-2-methylpropionic acid methyl ester (0.24 g, 0.79 mmol, 1 eq) in DCM (10 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. The reaction was monitored by TLC and stopped upon completion. The mixture was concentrated under reduced pressure to remove the DCM, yielding 0.93 g of a crude white solid. The crude product was purified by silica gel column chromatography. The sample was mixed 1.5 times and the column was loaded 15 times with silica gel. The eluent was EA:PE = 1:10, yielding 0.32 g of a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.87 - 6.78 (m, 2H), 6.78 - 6.69 (m, 2H), 5.58 (d, J = 7.6 Hz, 1H), 5.41 (s, 1H), 4.22 - 4.11 (m, 1H), 3.69 (s, 3H), 2.04 (p, J = 3.1 Hz, 1H), 2.01 - 1.92 (m, 2H), 1.86 - 1.77 (m, 2H), 1.67 (d, J = 3.2 Hz, 2H), 1.50 - 1.13 (m, 18H), 1.07 (s, 2H), 0.79 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 174.25, 156.99, 153.32, 148.80, 121.77, 116.88, 79.61, 75.21, 52.68, 51.48, 50.86, 48.60, 47.37, 42.91, 40.99, 32.36, 30.88, 30.61, 30.44, 30.09, 25.38.

[0131] Example 43 Synthesis of 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy}-2-methylpropionic acid (SP-C17) To a 25 mL single-mouth bottle, 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy}-2-methylpropionic acid methyl ester (0.20 g, 0.39 mmol, 1 eq), THF (5 mL), HO (0.5 mL), and LiOH (30 mg, 1.24 mmol, 3 eq) were added in that order and stirred at room temperature. After 3 h, the reaction was monitored by TLC, stopped, concentrated under reduced pressure to remove THF, and extracted with DCM (30 mL) and water (10 mL × 2). The aqueous layer was adjusted to pH = 2 with 1 N HCl and filtered under suction to give 0.10 g of a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.79 (s, 4H), 5.73 (d, J = 7.7 Hz, 1H), 5.54 (s, 1H), 4.14 (td, J = 9.6, 4.8 Hz, 1H), 3.33 (ddd, J = 10.8, 7.0, 3.6 Hz, 1H), 2.04 (p, J = 3.2 Hz, 1H), 2.01 - 1.91 (m, 2H), 1.85 - 1.76 (m, 2H), 1.67 (d, J = 3.2 Hz, 2H), 1.55 - 1.43 (m, 4H), 1.43 - 1.10 (m, 14H), 1.07 (s, 2H), 0.79 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 175.96, 157.08, 152.49, 149.72, 121.01, 116.83, 79.75, 75.30, 51.46, 50.88, 48.60, 47.34, 42.92, 40.98, 32.36, 30.84, 30.62, 30.43, 30.09, 25.78.

[0132] Example 44 Synthesis of 4-(((1r,4r)-4-aminocyclohexyl)oxy)acetic acid phenyl ester To a 100 mL single-mouth bottle, 4-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)acetic acid phenyl ester (1.69 g, 4.84 mmol) and DCM (12 mL) were added in that order, and TFA (6 mL) was added dropwise at room temperature. After 3 hours, the reaction was monitored by TLC. When the reaction was complete with EA:PE=1:1, the reaction was stopped. The TFA in the reaction solution was removed by distillation under reduced pressure. 2.06 g of a brown oil was obtained as a crude product. The crude product was dried in an oven at 60 °C for 12 hours and directly used in the next step without purification.

[0133] Example 45 Synthesis of 4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)acetic acid phenyl ester (SP-C01) BTC (0.51 g, 1.17 mmol, 0.34 eq) and dry DCM (10 mL) were added to a 100 mL bottle in that order, cooled to -78 °C using a cold trap, and 3-fluoro-4-trifluoromethoxyaniline (1 g, 5.13 mmol, 1 eq), EtN (1.65 g, 15.39 mmol, 3 eq), and DCM solution (10 mL) were added dropwise. The addition was completed within 30 minutes. After the addition was complete, the mixture was returned to room temperature and stirred for 4 hours. After 4 hours, the reaction was monitored by TLC. One drop of the reaction mixture was taken into an EP tube, and memantine was added. The mixture was stirred with EA:PE = 1:3 and iodine was added to complete the reaction.

[0134] A mixture of 4-(((1r,4r)-4-aminocyclohexyl)oxy)acetic acid phenyl ester·TFA (1.86 g, 5.13 mmol, 1 eq), EtN (1.65 g, 15.39 mmol, 3 eq), and DCM (5 mL) was added to a 100 mL bottle. The reaction mixture was added dropwise at room temperature and monitored by TLC for 2 h. Upon completion, the reaction was stopped with 2 mL of EA:PE (1:3, AcOH 2d). The mixture was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, suction filtered, and concentrated to dryness under reduced pressure to give 0.23 g of a yellow oil as crude product. A column was loaded 5 times with silica gel, and the sample was mixed 1.2 times with the silica gel. The eluent was EA:PE (1:10). 0.42 g of a white solid was obtained in 17.3% yield. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 8.72 7.69 (d, J = 2.5 Hz, 1H), 7.65-7.38 (m, 1H), 7.36-7.35 (m, 1H), 7.11-6.94 (m, 4H), 6.30 (d, J = 8.0 Hz, 1H), 4.29 (d, J = 4.0 Hz, 1H), 3.51 (s, 1H), 2.23 (s, 3H), 2.05 (d, J = 3.0 Hz, 2H), 2.02-1.91 (m, 2H), 1.48-1.34 (m, 4H). 13 C NMR (100 MHz, DMSO-d6): δ (ppm)169.9, 155.3, 154.6, 152.9, 144.3, 141.9, 124.7, 123.1, 116.8, 114.0, 114.0, 106.2, 105.9, 75.0, 47.8, 30.4, 30,2, 21.1. ESI MS: m / z 471.1 [M + H] + .

[0135] Example 46 Synthesis of 4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)phenol (SP-C01b) In a 100 mL single-mouth bottle, 4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)acetic acid phenyl ester (0.24 g, 0.51 mmol, 1 eq), LiOH (2.1 g, 17.20 mmol, 34 eq), and HO (7 mL) were added in that order and reacted at room temperature. After 1.5 h, the reaction was monitored by TLC and stopped when complete. DCM (30 mL × 3) was added for extraction, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. 0.21 g of a brown solid was obtained as a crude product. The yield was 96.33%.

[0136] Example 47 Synthesis of 4-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)benzoic acid methyl ester A 100 mL single-mouth bottle was charged with cis-4-Boc-aminocyclohexanol (1.00 g, 4.64 mmol), parahydroxybenzoic acid methyl ester (0.7 g, 4.64 mmol), triphenylphosphine (1.8 g, 6.96 mmol), A4 molecular sieves (dried in a 120 °C oven for 4 h), and THF (10 mL) in that order. The mixture was purged with argon gas three times and cooled to below -10 °C in an ice-salt bath. A THF solution (5 mL) of dihydrodibenzofuran (1.4 g, 6.96 mmol) was added dropwise at a rate of 1 drop per 2 seconds. After 12 h, the reaction was monitored by TLC. The EA:PE ratio was 1:1. The temperature was raised to 30 °C, 4A molecular sieves were added, and after 6 h, the reaction was monitored by TLC. The EA:PE ratio was 1:1. The reaction was almost complete, so the reaction was stopped. The THF was removed by concentration under reduced pressure to obtain 5.2 g of a yellow-brown oil. No solid precipitated during beating. The column was filled with 4 times the amount of silica gel, and the sample was mixed 1.2 times with the silica gel. As the eluent (EA:PE=1:10), 0.73 g of a white solid was obtained as the product, with a yield of 45.1%.

[0137] Example 48 Synthesis of 4-(((1r,4r)-4-aminocyclohexyl)oxy)benzoic acid methyl ester To a 100 mL one-mouth bottle, (((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)benzoic acid methyl ester (0.60 g, 2.09 mmol) and DCM (5 mL) were added in this order, and TFA (4 mL) was added dropwise at room temperature. After 3 hours, the reaction was monitored by TLC. When the reaction was complete with EA:PE=1:1, the reaction was stopped. The TFA in the reaction solution was removed by distillation under reduced pressure. 0.62 g of a brown oil was obtained as a crude product. The crude product was dried in an oven at 60 °C for 12 hours and directly used in the next step without purification.

[0138] Example 49 Synthesis of 4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid methyl ester BTC (0.23 g, 0.79 mmol) and dry DCM (15 mL) were added to a 100 mL bottle in that order, cooled to -78 °C using a cold trap, and free 3-fluoro-4-trifluoromethoxyaniline (0.41 g, 2.32 mmol), EtN (1.41 g, 13.92 mmol), and DCM solution (10 mL) were added dropwise. The addition was completed within 30 min. After the addition was completed, the mixture was returned to room temperature and stirred for 4 h. After 4 h, the reaction mixture was monitored by TLC. One drop of the reaction mixture was taken into an EP tube, and 4-(((1r,4r)-4-aminocyclohexyl)oxy)benzoic acid methyl ester was added in an EA:PE ratio of 1:3.

[0139] A mixture of 4-(((1r,4r)-4-aminocyclohexyl)oxy)benzoic acid methyl ester·TFA (0.58 g, 1.59 mmol), EtN (1.41 g, 13.92 mmol), and DCM (10 mL) was added to a 100 mL bottle and allowed to react at room temperature. After 2 hours, the reaction was monitored by TLC (EA:PE = 1:3). The mixture was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give 0.93 g of crude yellow oil. The column was loaded 7 times with silica gel, and the sample was mixed 1.2 times with the silica gel as the eluent (EA:PE = 1:5). 0.40 g of white solid was obtained as product in 40.0% yield. ESI-MS: m / z 453.2 [M+H] +

[0140] Example 50 Synthesis of 4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid In a 100 mL bottle, 4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid methyl ester (2.59 g, 5.50 mmol, 1 eq), THF (20 mL), HO (2 mL), and LiOH (0.40 g, 16.50 mmol, 3 eq) were added in that order and stirred at room temperature. After 3 h, the reaction was monitored by TLC (EA:PE = 1:1), quenched, concentrated under reduced pressure to remove THF, extracted with DCM (50 mL) and water (15 mL × 2), and the aqueous layer was adjusted to pH = 2 with 1 N HCl. The solvent was concentrated under reduced pressure to a small amount, filtered, and leached with 5 mL of water to give 0.53 g of a pale yellow solid. The combined yield of the three steps was 21.13%. 1H NMR (600 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.88 (s, 1H), 8.35 (s, 3H), 7.86 (d, J = 8.6 Hz, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 8.6 Hz, 5H), 6.85 (d, J = 8.3 Hz, 4H), 4.39 (tt, J = 10.0, 4.3 Hz, 1H), 3.04 (dt, J = 10.8, 5.5 Hz, 1H), 2.15 - 2.09 (m, 2H), 2.06 - 2.01 (m, 2H), 1.61 - 1.50 (m, 2H), 1.50 - 1.38 (m, 2H).

[0141] Example 51 Synthesis of 4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)acetic acid phenyl ester BTC (0.02 g, 0.07 mmol, 0.34 eq) and dry DCM (5 mL) were added to a 100 mL bottle in that order, cooled to -78 °C using a cold trap, and memantine (0.04 g, 0.22 mmol, 1 eq), EtN (0.07 g, 0.66 mmol, 3 eq), and DCM solution (10 mL) were added dropwise. The addition was completed within 30 min. After the addition was complete, the mixture was returned to room temperature and stirred for 4 h. After 4 h, the mixture was monitored by TLC (a drop of the reaction mixture was taken into an EP tube, and 4-trifluoromethoxyaniline was added (EA:PE = 1:3). The mixture was then irrigated with iodine until the reaction was complete.

[0142] A mixture of 4-(((1r,4r)-4-aminocyclohexyl)oxy)acetic acid phenyl ester·TFA (0.08 g, 0.22 mmol, 1 eq), EtN (0.07 g, 0.66 mmol, 3 eq), and DCM (5 mL) was added to a 25 mL single-mouth bottle. The reaction mixture was added dropwise at room temperature and monitored by TLC for 2 h. Upon completion, the reaction was stopped. The mixture was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, suction filtered, and concentrated to dryness under reduced pressure to give 0.10 g of crude yellow oil. A column was loaded 5 times with silica gel, and the sample was mixed 1.2 times with the silica gel. The eluent was (EA:PE = 1:10). 32 mg of a white solid was obtained in 32.0% yield. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 7.04 - 6.97 (d, 2H), 6.97 - 6.89 (d, 2H), 5.58 (d, J = 7.9 Hz, 1H), 5.41 (d, J = 3.2 Hz, 1H), 4.25 (tt, J = 9.9, 3.9 Hz, 1H), 3.35 (dd, J = 7.3, 3.7 Hz, 1H), 2.23 (s, 3H), 2.02 (ddt, J = 24.4, 8.4, 3.5 Hz, 3H), 1.87 - 1.80 (m, 2H), 1.67 (d, J = 3.1 Hz, 2H), 1.50 (s, 4H), 1.37 (ddd, J = 15.2, 9.1, 4.3 Hz, 2H), 1.31 - 1.22 (m, 4H), 1.22 - 1.16 (m, 2H), 1.16 - 1.10 (m, 1H), 1.07 (s, 2H), 0.80 (s, 6H). 13 C NMR (100 MHz, DMSO-d6): δ (ppm) 169.94, 157.00, 155.37, 144.29, 123.06, 116.77, 75.17, 51.49, 50.87, 48.61, 47.33, 42.91, 41.00, 32.36, 30.89, 30.82, 30.61, 30.31, 30.10, 21.26. ESI MS: m / z 455.2 [M + H]+ .

[0143] Example 52 Synthesis of tert-butyl ((1r,4r)-4-(4-acetylphenoxy)cyclohexyl)carbamate A 250 mL single-bottle solution of cis-4-Boc-aminocyclohexanol (1 g, 4.64 mmol, 1 eq), p-acetaminophen (0.70 g, 4.64 mmol, 1 eq), and PPh3 (1.83 g, 6.96 mmol, 1.5 eq), 4A-type molecular sieves (dried in an oven at 120 °C for 4 h), and THF (20 mL) were added in that order. The mixture was purged with argon gas three times and cooled to -10 °C in an ice-salt bath. A THF solution (10 mL) of dihydrodibenzofuran (DIAD) (1.21 g, 6.96 mmol, 1.5 eq) was added dropwise at a rate of 1 drop every 2 seconds. After 12 h, the reaction was monitored by TLC. The EA:PE ratio was 1:2, and the reaction was almost complete. The reaction was then stopped. The THF was removed by concentration under reduced pressure to give 5.62 g of a yellow-brown oil, which was stirred with 10 mL of ethanol and 5 mL of petroleum ether for 2 hours, triturated, and filtered with suction to give 0.90 g of a pale yellow solid, a yield of 55.9%.

[0144] Example 53 Synthesis of N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)acetamide To a 100 mL single-mouth bottle, tert-butyl ((1r,4r)-4-(4-acetylphenoxy)cyclohexyl)carbamate (0.90 g, 2.58 mmol) and DCM (6 mL) were added in this order, and TFA (4 mL) was added dropwise at room temperature. After 3 hours, the reaction was monitored by TLC. When the reaction was complete with EA:PE=1:1, the reaction was stopped. The TFA in the reaction solution was removed by distillation under reduced pressure. 1.06 g of a brown oil was obtained as a crude product. The crude product was dried in an oven at 60 °C for 12 hours and used directly in the next step without further purification.

[0145] Example 54 Synthesis of N-(4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzene)acetamide (SP-C01e) BTC (0.08 g, 0.26 mmol, 0.34 eq) and dry DCM (10 mL) were added sequentially to a 50 mL single-mouth bottle. The bottle was cooled to -78 °C using a cold trap. A DCM solution (5 mL) of 3-fluoro-4-trifluoromethoxyaniline (0.15 g, 0.77 mmol, 1 eq) and EtN (0.47 g, 4.61 mmol, 3 eq) was added dropwise within 15 min. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 0.5 h. After 0.5 h, the reaction mixture was monitored by TLC. One drop of the reaction mixture was transferred to an EP tube and N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)acetamide·TFA was added in a 1:1 EA:PE ratio.

[0146] A mixture of N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)acetamide·TFA (0.30 g, 0.77 mmol), EtN (0.47 g, 4.61 mmol), and DCM (5 mL) was added to a 100 mL bottle and allowed to react at room temperature. After 0.5 h, the reaction was monitored by TLC (EA:PE = 1:1). The mixture was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give 0.52 g of a yellow oil as crude product. A column was loaded 4 times with silica gel, and the sample was mixed 1.2 times with the silica gel. 0.11 g of a white solid was obtained in 33.4% yield. ESI-MS: m / z 470.2 [M+H] + ,492.1 [M+Na] + 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 9.75 (s, 1H), 8.74 (s, 1H),7.67 (dd, J= 13.4, 2.4 Hz, 1H), 7.44 (d, J= 8.9 Hz, 2H), 7.38 (t, J= 8.7 Hz, 1H), 7.09 (d, J= 8.8 Hz, 1H), 6.86 (d, J= 8.9 Hz, 2H), 6.29 (d, J= 7.6 Hz, 1H), 4.26-4.21 (m, 1H), 3.53-3.48 (m, 1H), 2.03-2.20 (m, 2H), 2.20 (s, 3H),1.93-1.90 (m, 2H), 1.46-1.38 (m, 2H), 1.38-1.32 (m, 2H).

[0147] Example 55 Synthesis of N-(4-hydroxyphenyl)-2-methylbutanamide 2-Methylbutyric acid (3.0 g, 27.51 mmol, 1 eq) and dry tetrahydrofuran (15 mL) were added to a 100 mL bottle, cooled to 0 °C in an ice bath, and SOCl (3.93 g, 33.01 mmol, 1.2 eq) was added dropwise and stirred for 30 min. 1.5 mL was transferred to an EP tube, anhydrous methanol was added, and the reaction was monitored for completion by TLC and concentrated to dryness under reduced pressure.

[0148] A 100 mL round-bottom flask was charged with para-aminophenol (3.0 g, 27.51 mmol, 1 eq) and THF (5 mL). The above 2-methylbutyryl chloride solution in THF (10 mL) was added dropwise. After the addition was complete, the reaction was monitored for completion by TLC and then terminated. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, and dichloromethane (20 mL) was added. The mixture was extracted twice with water (20 mL), washed once with saturated brine (25 mL), dried over anhydrous magnesium sulfate, and suction filtered. The organic phase was concentrated under reduced pressure to give 16.5 g of a yellow oil. A column was loaded 4 times with silica gel, and the sample was mixed 1.2 times with the silica gel. Column chromatography using an eluent (EA:PE = 1:5) afforded 4.85 g of a white solid. The yield was 91.3%. ESI-MS: m / z 194.1 [M+H]+ ,216.1 [M+Na] +

[0149] Example 56 Synthesis of tert-butyl ((1r,4r)-4-(4-(2-methylbutyramido)phenoxy)cyclohexyl)carbamate A 100 mL single-mouth bottle was charged with cis-4-Boc-aminocyclohexanol (2.00 g, 9.29 mmol, 1 eq), N-(4-hydroxyphenyl)-2-methylbutanamide (1.79 g, 9.29 mmol, 1 eq), triphenylphosphine (3.65 g, 13.9 mmol, 1.5 eq), A4 molecular sieves (dried in an oven at 120 °C for 4 h), and THF (15 mL) in that order. The atmosphere was flushed with argon gas three times, cooled to below -10 °C in an ice-salt bath, and a THF solution (5 mL) of dihydrodibenzofuran (DIAD) (2.43 g, 13.9 mmol, 1.5 eq) was added dropwise at a rate of 1 drop per 2 seconds. After the addition was complete, the mixture was transferred to room temperature and monitored by TLC for 12 h. The reaction was almost complete, and the reaction was stopped. The mixture was concentrated under reduced pressure to remove a portion of the THF, and then 15 mL of absolute ethanol and 15 mL of ethyl ether were added and triturated, followed by suction filtration to obtain 2.24 g of a pale pink solid. The resulting solid was monitored by TLC, dissolved in 20 mL of DCM, and washed with saturated Na2CO3 (16 mL). The organic layer was dried over anhydrous magnesium sulfate, suction filtration, and concentrated to dryness under reduced pressure to obtain 1.94 g of a pure white solid, with a yield of 53.6%.

[0150] Example 57 Synthesis of N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)-2-methylbutanamide To a 100 mL single-mouth bottle, tert-butyl ((1r,4r)-4-(4-(2-methylbutyramido)phenoxy)cyclohexyl)carbamate (1.94 g, 4.97 mmol) and DCM (5 mL) were added sequentially, followed by dropwise addition of TFA (6 mL) at room temperature. After 3 h, the reaction was monitored by TLC. When the reaction was complete with EA:PE (1:1), the reaction was stopped. The reaction mixture was concentrated under reduced pressure to remove TFA. 1.92 g of crude N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)-2-methylbutanamide·TFA was obtained as a brown oil. The crude product was dried in an oven at 60 °C for 12 h and used directly in the next step without further purification.

[0151] Example 58 Synthesis of N-(4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenyl)acetamide (SP-C01f) BTC (0.14 g, 0.47 mmol) and dry DCM (10 mL) were added in this order to a 100 mL single-mouth bottle, and the bottle was cooled to -78 °C using a cold trap. Free memantine (0.25 g, 1.41 mmol), EtN (0.85 g, 8.46 mmol), and a DCM solution (10 mL) were added dropwise. The addition was completed within 30 minutes. After the addition was completed, the bottle was returned to room temperature and stirred for 4 hours.

[0152] A 100 mL bottle was charged with a mixture of A4 (0.35 g, 1.41 mmol), EtN (0.28 g, 2.82 mmol), and DCM (5 mL). The mixture was allowed to react at room temperature for 2 h. The reaction was monitored by TLC and quenched. The mixture was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give 0.52 g of crude yellow oil. The column was loaded 4 times with silica gel, and the sample was mixed 1.2 times with silica gel. The eluent (EA:PE = 1:5) gave 0.21 g of product in 36.7% yield. 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 9.73 (s, 1H), 7.43 (d, J= 8.96 Hz, 2H), 6.84 (d, J= 8.96 Hz, 2H), 5.54 (d, J= 7.60 Hz, 1H), 5.41 (s, 1H), 4.22-4.17 (m, 1H), 3.37-3.34 (m, 1H), 2.05-2.03 (m, 1H), 1.99 (s, 3H), 1.97-1.94 (m, 1H), 1.84-1.81 (m, 2H), 1.67-1.66 (m, 2H), 1.52-1.46 (m, 4H), 1.40-1.34 (m, 2H), 1.30 (s, 1H), 1.27-1.24 (m, 4H), 1.19-1.14 (m, 2H), 1.07 (s, 2H), 0.79 (s, 6H).

[0153] Example 59 Synthesis of N-(4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzene)-2-methylbutanamide (SP-C01g) BTC (0.10 g, 0.35 mmol, 1 eq) and dry DCM (10 mL) were added sequentially to a 50 mL single-mouth bottle, cooled to -78 °C using a cold trap, and a DCM solution (10 mL) of 3-fluoro-4-trifluoromethoxyaniline (0.2 g, 1.02 mmol, 1 eq) and EtN (0.93 g, 9.22 mmol, 3 eq) was added dropwise. The addition was completed within 30 min. After completion of the addition, the mixture was allowed to return to room temperature and stirred for 0.5 h. The reaction mixture was monitored by TLC, and a drop of the reaction mixture was taken in an EP tube and memantine was added.

[0154] A mixture of N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)-2-methylbutanamide·TFA (0.41 g, 1.02 mmol, 1 eq), EtN (0.93 g, 9.22 mmol, 3 eq), and DCM (10 mL) was added to a 100 mL single-mouth bottle and the reaction was allowed to proceed at room temperature. After 0.5 h, the reaction was monitored by TLC (EA:PE = 1:2, AcOH 1 d) and quenched. The mixture was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and concentrated to dryness to obtain 0.74 g of a yellow oily crude product. The column was loaded 7 times with silica gel, and the sample was mixed 1.2 times with the silica gel. The eluent (EA:PE = 1:5, EA:PE = 1:2) gave 0.13 g of a yellow solid, the purity of which was insufficient. The product was placed in a 25 mL one-mouth bottle, and 0.5 mL of DCM was added to dissolve the product. After adding 4 mL of petroleum ether, a white solid precipitated. The product was filtered under reduced pressure to obtain 62 mg of product. The filtrate was collected for a yield of 11.9%. ESI-MS: m / z 512.3 [M+H] + 1 H-NMR (400 MHz, DMSO-d6): δ (ppm) 9.64 (s, 1H), 8.17 (s, 1H),7.67 (dd, J= 13.4, 2.1 Hz, 1H), 7.48 (d, J= 8.8 Hz, 2H), 7.38 (t, J= 8.9 Hz, 1H), 7.10-7.08 (m, 1H), 6.87 (d, J= 8.8 Hz, 2H), 6.27 (d, J= 7.4 Hz, 1H), 4.26-4.22 (m, 1H), 3.53-3.52 (m, 1H), 2.36-2.31 (m, 1H), 2.03-2.00 (m, 2H), 1.93-1.90 (m, 2H), 1.63-1.56 (m, 1H), 1.48-1.30 (m, 5H), 1.06 (d, J= 6.7 Hz, 3H), 0.85 (t, J= 7.4 Hz, 3H).

[0155] Example 60 Synthesis of ((1r,4r)-4-(4-nitrophenoxy)cyclohexyl)carbamic acid tert-butyl ester A 100 mL three-neck flask was charged with cis-4-Boc-aminocyclohexanol (10.00 g, 0.046 mol, 1 eq), 4-nitrophenol (6.47 g, 0.046 mol, 1 eq), PPh3 (13.95 g, 0.069 mmol, 1.5 eq), and THF (10 mL). The mixture was cooled to below -10 °C in an ice-salt bath. A THF solution (20 mL) of dihydrodibenzofuran (18.10 g, 0.069 mol, 1.5 eq) was added dropwise at a rate of 1 drop per 2 seconds. After 8 h, the reaction was monitored by TLC. The EA:PE ratio was 1:2, and the reaction was stopped upon completion. Concentration under reduced pressure to remove THF gave 12.21 g of a tan oil, which was stirred with 50 mL of ethanol for 2 hours, triturated, and suction filtered to give 12.46 g of a yellow solid, a yield of 80.58%.

[0156] Example 61 Synthesis of (1r,4r)-4-(4-nitrophenoxy)cyclohexan-1-amine To a 100 mL single-mouth bottle, ((1r,4r)-4-(4-nitrophenoxy)cyclohexyl)carbamic acid tert-butyl ester (0.60 g, 2.09 mmol) and DCM (5 mL) were added in this order, and TFA (4 mL) was added dropwise at room temperature. After 3 hours, the reaction was monitored by TLC. When the reaction was complete with EA:PE=1:1, the reaction was stopped. The TFA in the reaction solution was removed by distillation under reduced pressure. 0.62 g of a brown oil was obtained as a crude product. The crude product was dried in an oven at 60 °C for 12 hours and used directly in the next step without further purification.

[0157] Example 62 Synthesis of 1-((1r,3R,5S,7R)-3,5-dimethyladamant-1-yl)-3-((1r,4R)-4-(4-nitrophenoxy)cyclohexyl)urea BTC (5.50 g, 18.53 mmol, 0.5 eq) and dry DCM (50 mL) were added sequentially to a 250 mL single-mouth bottle, cooled to -80 °C in a cold trap, and a DCM solution (50 mL) of memantine (6.56 g, 37.06 mmol, 1 eq) and EtN (30.00 g, 296.48 mmol, 8 eq) was added dropwise. The addition was completed within 4 h and the mixture was allowed to warm to room temperature. After 30 min, the reaction was monitored by TLC and stopped when complete. The reaction mixture was evaporated to dryness, and DCM (50 mL) and EtN (30.00 g, 296.48 mmol, 8 eq) were added. The mixture was placed in an ice bath at 0 °C, and a DCM solution (50 mL) of I9 (8.89 g, 37.06 mmol, 1 eq) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature. After 30 min, the reaction was monitored by TLC. Upon completion, the reaction was stopped. The DCM was removed by concentration under reduced pressure to give 17.82 g of a reddish-brown oil, which was used directly in the next step without further purification.

[0158] Example 63 Synthesis of 1-((1r,4R)-4-(4-aminophenoxy)cyclohexyl)-3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)urea (SP-C01h) A 25 mL bottle was charged with 2-methylbutyric acid (3.0 g, 27.51 mmol, 1 eq), dry tetrahydrofuran (10 mL), HATU (0.034 g, 0.29 mmol, 1.2 eq), and DIEA (0.18 g, 1.74 mmol, 16 eq) and stirred for 30 min. A solution of 1-((1r,4R)-4-(4-aminophenoxy)cyclohexyl)-3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)urea (0.1 g, 0.24 mmol, 1 eq) in THF (5 mL) was added and monitored by TLC. Upon completion, the reaction was stopped and suction filtered to give 72 mg of a white solid. The yield was 60.56%. 1H NMR (400 MHz, Chloroform-d) δ 7.37(d, J = 8.8 Hz, 2H), 7.21 (s, 1H), 6.82 (d, J = 8.8 Hz, 2H), 4.14 - 4.06 (m, 1H), 3.56 - 3.51 (m, 1H), 2.38 (q, J = 7.6 Hz, 2H), 2.17 - 1.99 (m, 6H), 1.78 (d, J = 3.1 Hz, 2H), 1.56 - 1.41 (m, 3H), 1.39 - 1.08 (m, 12H), 0.84 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 156.72, 154.42, 131.17, 121.86, 116.60, 75.57, 50.64, 48.46, 42.72, 41.02, 32.48, 31.04, 30.59, 30.23, 30.21, 30.10, 9.81.

[0159] Example 64 Synthesis of 4-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)benzoic acid methyl ester A 100 mL bottle was charged with cis-4-Boc-aminocyclohexanol (1.00 g, 4.64 mmol), parahydroxybenzoic acid methyl ester (0.7 g, 4.64 mmol), triphenylphosphine (1.8 g, 6.96 mmol), A4 molecular sieves (dried in an oven at 120 °C for 4 hours), and THF (10 mL) in that order. The mixture was purged with argon gas three times, cooled to below -10 °C in an ice-salt bath, and a THF solution (5 mL) of DIAD (1.4 g, 6.96 mmol) was added dropwise at a rate of one drop every 2 seconds. After 12 hours, the reaction was monitored by TLC. The temperature was raised to 30 °C, 4A molecular sieves were added, and the reaction was monitored by TLC for 6 hours. The reaction was almost complete, so the reaction was stopped. The THF was removed by concentration under reduced pressure to obtain 5.2 g of a yellow-brown oil. No solid precipitated during beating. The column was filled with 4 times the amount of silica gel, and the sample was mixed 1.2 times with the silica gel. Using an eluent (EA:PE=1:10), 0.73 g of a white solid was obtained as the product, with a yield of 45.1%.

[0160] Example 65 Synthesis of 4-(((1r,4r)-4-aminocyclohexyl)oxy)benzoic acid methyl ester To a 100 mL single-mouth bottle, 4-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)benzoic acid methyl ester (0.60 g, 2.09 mmol) and DCM (5 mL) were added in that order, and TFA (4 mL) was added dropwise at room temperature. After 3 hours, the reaction was monitored by TLC. When the reaction was complete, the reaction was stopped. The TFA in the reaction solution was removed by distillation under reduced pressure. 0.62 g of a brown oil was obtained as a crude product. The crude product was dried in an oven at 60 °C for 12 hours and directly used in the next step without purification.

[0161] Example 66 Synthesis of 4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid methyl ester BTC (0.23 g, 0.79 mmol) and dry DCM (15 mL) were added in this order to a 100 mL one-mouth bottle, and the mixture was cooled to -78 °C using a cold trap. Free p-trifluoromethoxyaniline (0.41 g, 2.32 mmol), EtN (1.41 g, 13.92 mmol), and a DCM solution (10 mL) were added dropwise. The addition was completed within 30 minutes. After the addition was completed, the mixture was returned to room temperature and stirred for 4 hours.

[0162] A mixture of I15·TFA (0.58 g, 1.59 mmol), Et3N (1.41 g, 13.92 mmol), and DCM (10 mL) was added to a 100 mL bottle and allowed to react at room temperature. After 2 h, the reaction was monitored by TLC and quenched. The mixture was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give 0.93 g of crude yellow oil. A column was loaded 7 times with silica gel, and the sample was mixed 1.2 times with silica gel. The eluent (EA:PE = 1:5) gave 0.40 g of white solid product in 40.0% yield. ESI-MS: m / z 453.2 [M+H] +

[0163] Example 67 Synthesis of 4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid In a 25 mL single-mouth bottle, 4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid methyl ester (0.15 g, 0.33 mmol), THF (3 mL), HO (2 mL), and LiOH (39.8 mg, 0.99 mmol) were added in that order, stirred at room temperature, and monitored by TLC after 3 hours. A small amount was reacted, the temperature was raised to 30 °C, 0.1 g of lithium hydroxide was added, and the reaction mixture was monitored by TLC after 2 hours. A small amount was reacted, the temperature was raised to 50 °C, and 0.2 g of lithium hydroxide was added, and the reaction mixture was monitored by TLC after 2 hours. The reaction was quenched, adjusted to pH 2 with 3 N HCl, concentrated under reduced pressure until the solvent was reduced to a small amount, suction filtered, and leached with 5 mL of water to obtain 70 mg of a pale yellow solid in a yield of 48.6%.

[0164] Example 68 Synthesis of 4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzamide (SP-C01i) 4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid (0.17 g, 0.39 mmol) and dry tetrahydrofuran (10 mL) were added to a 25 mL bottle at room temperature. HATU (0.18 g, 0.46 mmol) was added thereto, and the mixture was stirred for 15 minutes. DIEA (0.12 g, 0.97 mmol) was added dropwise and stirred for 0.5 h. NH₃·H₂O (0.3 mL) was added. After 0.5 h, the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran, dichloromethane (12 mL) was added, extracted twice with water (10 mL), washed once with saturated brine (25 mL), dried over anhydrous magnesium sulfate, and suction filtered. The organic phase was concentrated under reduced pressure to give 0.20 g of a yellow oil. A column was loaded 4 times with silica gel, and the sample was mixed 1.2 times with the silica gel. Column chromatography using an eluent of EA:PE (1:3) afforded 0.12 g of a pale yellow solid. The yield was 70.5%. 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.82 (dd, J = 9.4, 2.7 Hz, 3H), 7.54 - 7.45 (m, 2H), 7.21 (d, J = 8.5 Hz, 2H), 7.14 (s, 1H), 7.02 - 6.94 (m, 2H), 6.48 (d, J = 7.6 Hz, 1H), 4.43 (tt, J = 9.8, 4.0 Hz, 1H), 3.54 (ddt, J = 14.2, 10.6, 5.3 Hz, 1H), 2.06 (dd, J = 12.6, 4.3 Hz, 2H), 2.01 - 1.89 (m, 2H), 1.55 - 1.30 (m, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 167.89, 160.26, 155.02, 142.36, 140.48, 129.85, 126.78, 122.03, 121.97, 119.43, 118.99, 115.28, 74.64, 47.64, 30.44, 30.15.

[0165] Example 69 Synthesis of N-(4-(((1R,4r)-4-(3-((1R,3R,5S,7R))-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenyl)propionamide (SP-C01j) Propionic acid (0.02 g, 0.24 mmol, 1 eq.), dry tetrahydrofuran (10 mL), HATU (0.034 g, 0.29 mmol, 1.2 eq.), and DIEA (0.18 g, 1.74 mmol, 6 eq.) were added to a 25 mL bottle and stirred for 30 min. A solution of 1-((1r,4R)-4-(4-aminophenoxy)cyclohexyl)-3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)urea (0.1 g, 0.24 mmol, 1 eq.) in THF (5 mL) was added. The reaction was monitored by TLC (EA:PE = 1:2). Upon completion, the reaction was stopped and filtered under vacuum to give 80 mg of a white solid. The yield was 71.32%. 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.48(d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.58 (d, J = 7.5 Hz, 1H), 5.42 (s, 1H), 4.22 - 4.18 (m, 1H), 2.38 - 2.31 (m, 1H), 2.05 (s, 1H), 1.97(d, J = 10.5 Hz, 2H), 1.82(d, J = 10.5 Hz, 2H), 1.68 (s, 2H), 1.62 - 1.55 (m, 2H), 1.07 - 1.05 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H) 0.80 (s, 6H).

[0166] Example 70 Synthesis of N-(4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzene)acetamide (SP-C01k) BTC (0.08 g, 0.26 mmol) and dry DCM (10 mL) were added to a 50 mL bottle in this order, cooled to -78 °C in a cold trap, and a DCM solution (5 mL) of 3-fluoro-4-trifluoromethoxyaniline (0.15 g, 0.77 mmol) and EtN (0.47 g, 4.61 mmol) was added dropwise. The addition was completed within 15 min. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 0.5 h. After 0.5 h, the mixture was monitored by TLC, revealing a 1:1 EA:PE ratio.

[0167] A mixture of N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)acetamide·TFA (0.30 g, 0.77 mmol), EtN (0.47 g, 4.61 mmol), and DCM (5 mL) was added to a 100 mL bottle and allowed to react at room temperature. After 0.5 h, the reaction was monitored by TLC and quenched. The mixture was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give 0.52 g of crude yellow oil. A column was loaded 4 times with silica gel, and the sample was mixed 1.2 times with the silica gel. The resulting mixture was mixed with EA:PE (1:5, EA:PE (1:3)) to give 0.21 g of a white solid in 36.7% yield.

[0168] Example 71 Synthesis of 3-((4-((((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzene)amino)-3-oxopropionic acid ethyl ester (SP-C01s) Monoethyl malonate (0.16 g, 0.12 mmol, 1 eq.), dry tetrahydrofuran (5 mL), HATU (0.017 g, 0.29 mmol, 1.2 eq.), and DIEA (0.09 g, 0.87 mmol, 6 eq.) were added to a 25 mL bottle and stirred for 30 min. A solution of 1-((1r,4r)-4-(4-aminophenoxy)cyclohexyl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)urea (0.05 g, 0.12 mmol, 1 eq.) in THF (5 mL) was added and monitored by TLC (EA:PE = 1:1, AcOH 1 d). Upon completion, the reaction was stopped and suction filtered to give 42 mg of a white solid. The yield was 64.67%. 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.73 (s, 1H), 7.68 (dd, J = 13.4, 2.5 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.39 (t, J = 8.9 Hz, 1H), 7.10 (dt, J = 9.1, 1.8 Hz, 1H), 6.92 - 6.83 (m, 2H), 6.30 (d, J = 7.6 Hz, 1H), 4.24 (tt, J = 9.6, 4.0 Hz, 1H), 3.63 - 3.46 (m, 1H), 2.27 (q, J = 7.5 Hz, 2H), 2.02 (dd, J = 12.7, 4.4 Hz, 2H), 1.92 (dd, J = 12.9, 4.0 Hz, 2H), 1.51 - 1.27 (m, 4H), 1.07 (t, J = 7.5 Hz, 3H).

[0169] Example 72 Synthesis of 4-(4-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)phenoxy)butyric acid methyl ester In a 25 mL one-mouth bottle, tert-butyl ((1r,4r)-4-(4-hydroxyphenoxy)cyclohexyl)carbamate (0.30 g, 0.98 mmol, 1 eq), KCO (0.40 g, 2.92 mmol, 3 eq), KI (0.02 g, 0.10 mmol, 0.1 eq), and TBAB (0.03 g, 0.10 mmol, 0.1 eq) were sequentially added, followed by MeCN (15 mL). 4-Bromobutyric acid methyl ester (0.26 g, 1.46 mmol, 1.5 eq) was added dropwise, and the mixture was purged with Ar three times and heated to reflux. After 3 hours, the reaction mixture was monitored by TLC. The mixture was quenched with EA:PE=1:3, concentrated to dryness under reduced pressure, and extracted with water (20 mL) and DCM (20 mL x 2). The combined organic layers were washed with water (10 mL), saturated brine (10 mL), dried over anhydrous magnesium sulfate, filtered under suction, and concentrated under reduced pressure to give 0.46 g of a brown-black oil. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 volumes of silica gel and the column was filled 7 times with silica gel. The eluent was EA:PE=1:15. 0.12 g of a white solid was obtained in a 30.07% yield.

[0170] Example 73 Synthesis of 4-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenoxy)butyric acid methyl ester 4-(4-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)phenoxy)butyric acid methyl ester (0.12 g, 0.29 mmol, 1 eq) and DCM (8 mL) were added in this order to a 100 mL single-mouth bottle, cooled to 0°C in an ice bath, and TFA (0.5 mL) was added dropwise. After 2 hours, the reaction was monitored by TLC. When the reaction was complete with EA:PE = 1:3, the reaction was stopped. DCM and TFA in the reaction solution were removed by distillation under reduced pressure to give 0.11 g of a pale yellow solid as a crude product, which was used directly in the next step without purification. ESI MS: m / z 308.1 [M + H] + .

[0171] Example 74 Synthesis of methyl 4-(4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenoxy)butyrate (SP-C20) BTC (0.97 g, 3.26 mmol, 0.5 eq) and dry DCM (10 mL) were added sequentially to a 250 mL single-mouth bottle, cooled to -80 °C in a cold trap, and a DCM solution (15 mL) of memantine (1.15 g, 6.51 mmol, 1 eq) and EtN (5.27 g, 52.08 mmol, 8 eq) was added dropwise. The addition was completed within 30 min, and the mixture was allowed to warm to room temperature. After 30 min, the reaction was monitored by TLC. The EA:PE ratio was 1:3, and when the reaction was complete, it was stopped. The reaction mixture was evaporated to dryness, and DCM (15 mL) and EtN (5.27 g, 52.08 mmol, 8 eq) were added. The mixture was then cooled to 0 °C in an ice bath, and a DCM solution (10 mL) of 4-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenoxy)butyric acid methyl ester (2.00 g, 6.51 mmol, 1 eq) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature. After 30 min, the reaction was monitored by TLC. The EA:PE ratio was 1:2. When the reaction was complete, the reaction was stopped. The mixture was concentrated under reduced pressure to remove DCM, giving 4.05 g of a yellow oil. The sample was mixed 1.5 times with silica gel, and a column was loaded 4 times with silica gel (EA:PE = 1:7). 1.05 g of a white solid was obtained. The yield was 31.48%. 1 H NMR (400 MHz, DMSO-d6) δ 6.94 - 6.82 (m, 4H), 5.65 (d, J = 7.6 Hz, 1H), 5.49 (s, 1H), 4.19 (tt, J = 10.0, 3.9 Hz, 1H), 3.96 (t, J = 6.3 Hz, 2H), 3.66 (s, 3H), 2.51 (t, J = 7.3 Hz, 3H), 2.10 (p, J = 3.2 Hz, 1H), 2.03 - 1.93 (m, 4H), 1.92 - 1.83 (m, 2H), 1.73 (d, J = 3.1 Hz, 2H), 1.55 (s, 4H), 1.49 - 1.15 (m, 9H), 1.13 (s, 2H), 0.85 (s, 6H).13 C NMR (101 MHz, DMSO-d6) δ 173.54, 157.00, 153.02, 151.71, 117.66, 115.77, 75.52, 67.31, 51.79, 51.47, 50.86, 48.60, 47.37, 42.90, 40.99, 32.36, 30.85, 30.61, 30.43, 30.09, 24.77.

[0172] Example 75 Synthesis of 4-(4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenoxy)butyric acid (SP-C21) SP-C20 (0.50 g, 0.98 mmol, 1 eq), THF (15 mL), HO (5 mL), and LiOH (0.10 g, 2.93 mmol, 3 eq) were added to a 25 mL bottle in this order and stirred at room temperature. After 1.5 h, the reaction was monitored by TLC. The EA:PE ratio was 1:3, and the mixture was quenched. The mixture was concentrated under reduced pressure to remove THF, extracted with EA (20 mL), and the aqueous layer was adjusted to pH 2 with 1 N HCl. The mixture was then suction filtered and 0.42 g of a pale yellow solid was obtained after decompression. The yield was 86.01%. 1 H NMR (400 MHz, DMSO-d6) δ 6.94 - 6.74 (m, 4H), 4.16 - 4.10 (m, 1H), 3.90 (t, J = 6.4 Hz, 4H), 3.90 (t, J = 6.4 Hz, 2H),3.33 (tt, J = 10.4, 3.8 Hz, 1H), 2.37 (t, J = 7.3 Hz, 2H), 2.04 (dt, J = 6.8, 3.3 Hz, 1H), 1.97 (d, J = 4.1 Hz, 1H), 1.92 (dt, J = 14.1, 6.1 Hz, 3H), 1.82 (dd, J = 13.5, 3.6 Hz, 2H), 1.68 - 1.67 (m, 2H), 1.52 - 1.44 (m, 4H), 1.41 - 1.11 (m, 9H), 1.09 - 1.04 (m, 2H), 0.80 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 174.60, 157.05, 153.08, 151.68, 117.66, 115.79, 75.50, 67.42, 51.47, 51.39, 50.86, 48.59, 48.55, 47.35, 42.94, 42.90, 40.98, 32.46, 32.36, 30.82, 30.62, 30.39, 30.09, 24.80.

[0173] Example 76 Synthesis of 4-(4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)phenoxy)butyric acid methyl ester (SP-C23) BTC (0.03 g, 0.10 mmol, 0.34 eq) and dry DCM (5 mL) were added sequentially to a 25 mL single-mouth bottle, cooled to -80 °C in a cold trap, and a DCM solution (10 mL) of 4-trifluoromethoxyaniline (0.05 g, 0.29 mmol, 1 eq) and EtN (0.09 g, 0.87 mmol, 3 eq) was added dropwise. The addition was complete within 5 min, and the mixture was allowed to warm to room temperature. After 10 min, the reaction was monitored by TLC. The reaction was stopped when complete with EA:PE = 1:3. The reaction mixture was evaporated to dryness, and DCM (10 mL) and EtN (0.09 g, 0.87 mmol, 3 eq) were added. The mixture was then cooled to 0 °C in an ice bath, and a DCM solution (5 mL) of 4-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenoxy)butyric acid methyl ester (0.09 g, 0.29 mmol, 1 eq) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature. After 30 min, the mixture was monitored by TLC. The reaction was stopped when the reaction was complete with EA:PE = 1:2. The mixture was concentrated under reduced pressure to remove DCM, yielding 0.15 g of a white solid as a crude product. The sample was mixed 1.5 times with silica gel, and a column was filled 4 times with silica gel (EA:PE = 1:7), yielding 0.10 g of a white solid. The yield was 65.28%. 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.69 (dd, J = 13.5, 2.5 Hz, 1H), 7.37 (td, J = 9.0, 1.2 Hz, 1H), 7.12 (ddd, J = 9.0, 2.6, 1.4 Hz, 1H), 6.91 - 6.79 (m, 4H), 6.77 (d, J = 7.6 Hz, 1H), 4.17 (tt, J = 9.3, 3.8 Hz, 1H), 3.91 (t, J = 6.3 Hz, 2H), 3.61 (s, 4H), 3.57 - 3.45 (m, 1H), 2.46 (t, J = 7.3 Hz, 2H), 2.01 - 1.99 (m, 2H), 1.97 - 1.89 (m, 4H), 1.44 - 1.31 (m, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 173.53, 154.85, 153.01, 152.89, 151.67, 142.26, 142.15, 124.63, 117.61, 115.77, 113.94, 106.02, 105.78, 75.36, 51.78, 47.73, 30.43, 30.36, 30.29, 24.77.

[0174] Example 77 Synthesis of 4-(4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)phenoxy)butyric acid (SP-C24) SP-C23 (0.50 g, 0.95 mmol, 1 eq), THF (15 mL), HO (5 mL), and LiOH (0.10 g, 4.18 mmol, 4.4 eq) were added to a 25 mL single-mouth bottle in this order and stirred at room temperature. After 1.5 h, the reaction was monitored by TLC. The EA:PE ratio was 1:3. The reaction was stopped, concentrated under reduced pressure to remove THF, and extracted with EA (20 mL). The aqueous layer was adjusted to pH 2 with 1N HCl, filtered under suction, and 0.47 g of a pale yellow solid was obtained after vacuum filtration. The yield was 96.21%. 1H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 9.19 (s, 1H), 7.68 (dd, J = 13.5, 2.6 Hz, 1H), 7.38 (td, J = 8.9, 1.2 Hz, 1H), 7.10 (ddd, J = 9.0, 2.6, 1.3 Hz, 1H), 6.91 - 6.79 (m, 4H), 6.57 (s, 1H), 4.19 (tt, J = 9.3, 3.8 Hz, 1H), 3.90 (t, J = 6.4 Hz, 2H), 3.54 (ddt, J = 11.1, 7.4, 3.9Hz, 1H), 2.37 (t, J = 7.3 Hz, 2H), 2.05 - 1.97 (m, 2H), 1.96 - 1.85 (m, 4H), 1.50 - 1.21 (m, 5H). 13 C NMR (101 MHz, DMSO-d6) δ 174.62, 155.37, 154.80, 153.10, 152.92, 151.65, 142.11, 142.01, 124.70, 117.63, 115.81, 113.86, 105.95, 105.71, 75.25, 67.44, 47.62, 30.64, 30.27, 30.13, 24.82.

[0175] Example 78 Synthesis of 2-(5-((Z)-4-(((1r,4r)-4-(tert-butoxycarbonyl)amino)cyclohexyl)oxy)benzylidene)-2,4-dioxythiazolidin-3-yl)acetic acid methyl ester A 100 mL round-bottom flask was charged with tert-butyl ((1r,4r)-4-(4-formylphenoxy)cyclohexyl)carbamate (4.00 g, 12.53 mmol, 1 eq), 2-(2,4-dioxythiazolin-3-yl)acetic acid methyl ester (2.37 g, 12.53 mmol, 1 eq), piperidine (0.50 g, 6.27 mmol, 0.5 eq), acetic acid (0.38 g, 6.27 mmol, 0.5 eq), and toluene (20 mL) in that order, and the temperature was raised to reflux. As the reaction proceeded, a solid precipitated. The reaction was monitored by TLC after 8 h. The reaction was stopped when complete, using EA:PE (1:1). The reaction mixture was cooled to room temperature, filtered under suction, and the filter cake was leached with a small amount of n-hexane to give 3.89 g of a white solid. The filtrate showed no product spots on TLC, and the yield was 63.36%.

[0176] Example 79 Synthesis of 2-(5-((Z)-4-(((1r,4r)-4-aminocyclohexyl)oxy)benzylidene)-2,4-dioxythiazolidin-3-yl)acetic acid methyl ester 2-(5-((Z)-4-(((1r,4r)-4-(tert-butoxycarbonyl)amino)cyclohexyl)oxy)benzylidene)-2,4-dioxythiazolidin-3-yl)acetic acid methyl ester (3.89 g, 7.94 mmol, 1 eq) and DCM (8 mL) were added sequentially to a 100 mL single-mouth bottle, cooled to 0 °C in an ice bath, and TFA (2 mL) was added dropwise. After 4 hours, the reaction was monitored by TLC. When the reaction was complete with EA:PE = 1:3, the reaction was stopped. DCM and TFA in the reaction solution were removed by distillation under reduced pressure to obtain 3.87 g of a pale yellow solid as a crude product, which was used directly in the next step without purification. ESI MS: m / z 390.1 [M + H] + .

[0177] Example 80 Synthesis of 2-(2,4-dioxo-5-((Z)-4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzylidene)thiazolidin-3-yl)acetic acid methyl ester (SP-D01) BTC (0.03 g, 0.10 mmol, 0.34 eq) and dry DCM (5 mL) were added sequentially to a 25 mL single-mouth bottle, cooled to -80 °C in a cold trap, and a DCM solution (10 mL) of 4-trifluoromethoxyaniline (0.05 g, 0.29 mmol, 1 eq) and EtN (0.13 g, 1.30 mmol, 5 eq) was added dropwise. The addition was complete within 5 min, and the mixture was allowed to warm to room temperature. After 10 min, the reaction was monitored by TLC. The reaction was stopped when complete with EA:PE = 1:3. The reaction mixture was evaporated to dryness, and DCM (10 mL) and EtN (0.13 g, 1.30 mmol, 5 eq) were added. The mixture was cooled to 0 °C in an ice bath, and a DCM solution (5 mL) of 2-(5-((Z)-4-(((1r,4r)-4-aminocyclohexyl)oxy)benzylidene)-2,4-dioxythiazolidin-3-yl)acetic acid methyl ester (0.10 g, 0.26 mmol, 1 eq) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. After 30 min, the reaction was monitored by TLC and quenched with 2 mL of AcOH in a 1:1 mixture of EA:PE. The DCM was removed by concentration under reduced pressure to give 0.23 g of a crude white solid. The crude product was purified by silica gel column chromatography. The sample was mixed 1.5 times and the column was filled with 5 times silica gel. The eluent was EA:PE = 1:10. 0.10 g of a white solid was obtained in a 66.67% yield. ESI MS: m / z 616.0 [M + Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 7.96 (s, 1H), 7.65 - 7.57 (m, 2H), 7.54 - 7.45 (m, 2H), 7.22 (d, J = 8.6 Hz, 2H), 7.18 - 7.12 (m, 2H), 6.44 (d, J = 7.6 Hz, 1H), 4.51 (s, 2H), 3.72 (s, 3H), 3.57 - 3.53 (m, 1H), 3.28 - 3.25 (m, 1H), 2.12 - 2.03 (m, 2H), 1.98 - 1.90 (m, 2H), 1.58 - 1.32 (m, 6H).

[0178] Example 81 Synthesis of 2-(2,4-dioxo-5-((Z)-4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzylidene)thiazolidin-3-yl)acetic acid SP-D01 (0.08 g, 0.13 mmol, 1 eq), THF (5 mL), HO (1 mL), and LiOH (0.01 g, 0.40 mmol, 3 eq) were added to a 25 mL one-mouth bottle in this order and stirred at room temperature. After 1.5 h, the reaction was monitored by TLC. The reaction mixture was quenched with EA:PE (1:3), concentrated under reduced pressure to remove THF, adjusted to pH 4 with 1N HCl, extracted with EA (10 mL) and HO (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered with suction, and concentrated to dryness under reduced pressure to give 70 mg of a white solid. The yield was 92.98%. ESI MS: m / z 578.3 [M - H] - .

[0179] Example 82 Synthesis of 2-(5-((Z)-4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)benzylidene)-2,4-dioxythiazolin-3-yl)acetic acid methyl ester BTC (0.03 g, 0.10 mmol, 0.34 eq) and dry DCM (5 mL) were added sequentially to a 25 mL single-mouth bottle, cooled to -80 °C in a cold trap, and a DCM solution (10 mL) of memantine (0.05 g, 0.28 mmol, 1 eq) and EtN (0.28 g, 2.80 mmol, 10 eq) was added dropwise. The addition was completed within 5 min, and the mixture was allowed to warm to room temperature. After 10 min, the reaction was monitored by TLC. The EA:PE ratio was 1:3, and the reaction was stopped when it reached completion. The reaction mixture was evaporated to dryness, and DCM (10 mL) and EtN (0.28 g, 2.80 mmol, 10 eq) were added. The mixture was cooled to 0 °C in an ice bath. A DCM solution (5 mL) of N (0.10 g, 0.28 mmol, 1 eq) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 30 min. After 30 min, the mixture was monitored by TLC. The reaction was stopped by adding 2 mL of AcOH in a 1:1 EA:PE mixture. The DCM was removed by concentration under reduced pressure, yielding 0.31 g of a crude white solid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 volumes of silica gel, and the column was filled 5 times with silica gel. The eluent was 1:10 EA:PE. 0.08 g of a white solid was obtained in a 48.20% yield. ESI MS: m / z 594.66 [M - H] - . 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.65 - 7.56 (m, 2H), 7.18 - 7.09 (m, 2H), 5.62 (d, J = 7.6 Hz, 1H), 5.43 (s, 1H), 4.51 (s, 2H), 4.45 (dd, J = 8.9, 4.7 Hz, 1H), 3.72 (s, 3H), 2.09 - 1.99 (m, 3H), 1.89 - 1.81 (m, 2H), 1.68 (d, J = 3.1 Hz, 2H), 1.50 (s, 4H), 1.48 - 1.37 (m, 2H), 1.33 - 1.14 (m, 7H), 1.08 (s, 2H), 0.80 (s, 6H).

[0180] Example 83 Synthesis of (Z) 5-(4-nitrobenzylidene)thiazolidine-2,4-dione To a 100 mL round-bottom flask, p-nitrobenzaldehyde (5.00 g, 33.09 mmol, 1 eq), 2,4-thiazolidinedione (3.88 g, 33.09 mmol, 1 eq), piperidine (1.41 g, 16.55 mmol, 0.5 eq), acetic acid (1.00 g, 16.55 mmol, 0.5 eq), and toluene (40 mL) were added sequentially and the temperature was raised to reflux. As the reaction progressed, a solid precipitated. After 8 h, the reaction was monitored by TLC and quenched with 1 d of AcOH in a 1:1 EA:PE mixture. The reaction mixture was cooled to room temperature, filtered under suction, and the filter cake was leached with a small amount of n-hexane to give 5.06 g of a reddish-brown solid. The filtrate was evaporated to dryness, concentrated, and triturated with DCM (10 mL) and MeOH (1 mL) to give 3.06 g of a yellow solid, with a yield of 98.19%. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 1 H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.31 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.81 (s, 1H). ESI MS: m / z 249.1 [M - H] - .

[0181] Example 84 Synthesis of (Z)-5-(4-aminobenzylidene)thiazolidine-2,4-dione A 500 mL three-neck flask was charged with (Z)5-(4-nitrobenzylidene)thiazolidine-2,4-dione (8.27 g, 33.09 mmol, 1 eq), Fe (11.12 g, 198.54 mmol, 6 eq), EtOH (250 mL), HO (70 mL), and NHCl (17.70 g, 330.90 mmol, 10 eq) in that order. The mixture was heated to reflux and, after 1.5 h of TLC monitoring, the reaction was quenched with 1 d of AcOH in a 1:1 EA:PE mixture until complete. The reaction mixture was cooled to room temperature, filtered under suction, and the filter cake was leached with a small amount of DCM. The filtrate was evaporated to dryness and concentrated to remove some of the EtOH and HO. The mixture was extracted with DCM:MeOH = 10:1 (60 mL × 4), dried over anhydrous magnesium sulfate, filtered under suction, and the filtrate was concentrated under reduced pressure to give 2.06 g of a reddish-brown solid in a 72.38% yield. ESI MS: m / z 199.3 [M - H] - .

[0182] Example 85 Synthesis of 1-((1r,3R,5S,7r)-3,5-dimethyladamant-1-yl)-3-(4-((E)-(2,4-dioxythiazolinyl-5-ylidene)methyl)phenyl)urea (SP-E01) BTC (0.05 g, 0.15 mmol, 0.34 eq) and dry DCM (5 mL) were added sequentially to a 25 mL single-mouth bottle, cooled to -80 °C in a cold trap, and a DCM solution (10 mL) of memantine (0.08 g, 0.45 mmol, 1 eq) and EtN (0.46 g, 4.50 mmol, 10 eq) was added dropwise. The addition was completed within 5 min, and the mixture was allowed to warm to room temperature. After 30 min, the reaction was monitored by TLC. The EA:PE ratio was 1:3, and when the reaction was complete, it was stopped. The reaction mixture was evaporated to dryness, and then DCM (10 mL) and EtN (0.46 g, 4.50 mmol, 10 eq) were added. The mixture was cooled to 0 °C in an ice bath, and a DCM solution (5 mL) of (Z)-5-(4-aminobenzylidene)thiazolidine-2,4-dione (0.10 g, 0.45 mmol, 1 eq) was added dropwise. After the addition was complete, the reaction mixture was allowed to react at room temperature for 30 min. The reaction mixture was monitored by TLC (EA:PE = 1:1, AcOH 2d). Upon completion, the reaction mixture was stopped. The organic layers were extracted with 1 N HCl (30 mL) and DCM (30 mL × 3). The combined organic layers were washed with water (30 mL), saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered under suction, and concentrated under reduced pressure. The crude product was obtained as a yellow oil (0.37 g). The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 volumes of silica gel and the column was filled with 7 volumes of silica gel. The eluent was EA:PE = 1:10. 0.11 g of a white solid was obtained (57.49% yield). ESI MS: m / z 423.9 [M - H] - .

[0183] Example 86 Synthesis of (E)-1-(4-((2,4-dioxythiazolinyl-5-ylidene)methyl)phenyl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)urea (SP-E03) BTC (0.05 g, 0.15 mmol, 0.34 eq) and dry DCM (5 mL) were added sequentially to a 25 mL single-mouth bottle, cooled to -80 °C in a cold trap, and a DCM solution (10 mL) of 4-trifluoromethoxyaniline (0.08 g, 0.45 mmol, 1 eq) and EtN (0.46 g, 4.50 mmol, 10 eq) was added dropwise. The addition was completed within 5 min. After completion of the addition, the temperature was allowed to rise to room temperature. After 30 min, the reaction was monitored by TLC. The reaction was stopped when complete with EA:PE = 1:3. The reaction mixture was evaporated to dryness to remove excess phosgene. DCM (10 mL) and EtN (0.46 g, 4.50 mmol, 10 eq) were added, and the mixture was cooled to 0 °C in an ice bath. A DCM solution (5 mL) of (Z)-5-(4-aminobenzylidene)thiazolidine-2,4-dione (0.10 g, 0.45 mmol, 1 eq) was added dropwise. After the addition was complete, the reaction mixture was allowed to react at room temperature for 15 min. After 15 min, the reaction mixture was monitored by TLC. Upon completion, the reaction was quenched with 2 mL of AcOH in a 1:1 EA:PE mixture. The mixture was extracted with 1 N HCl (30 mL) and DCM (30 mL × 3). The combined organic layer was washed with water (30 mL), washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered under suction, and concentrated under reduced pressure to give the desired product. The crude product was obtained as a yellow oil (0.31 g). The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 volumes of silica gel and the column was filled with 7 volumes of silica gel. The eluent was EA:PE = 1:10. 0.09 g of a white solid was obtained (47.37% yield). ESI MS: m / z 421.8 [M - H] - .

[0184] Test Example 1 1. sEH inhibitory activity test The detection principle is as follows: The specific substrate cyano-(6-methoxy-naphthyl-2-yl)methyl(3-phenyl-oxy)acetate, or PHOME, itself is non-fluorescent, but is hydrolyzed by the sEH enzyme to produce the product 6-methoxy-2-naphthalaldehyde. 6-Methoxy-2-naphthalaldehyde emits fluorescence at a wavelength of 465 nm when excited with 330 nm light. The intensity of the detected fluorescent signal is inversely proportional to the strength of the inhibitory effect on the sEH enzyme. Based on the above principle, the inhibition rates of samples at different concentrations were calculated compared with the positive control group. The IC values of the compounds were calculated using SPSS20 software based on the inhibition rates and concentrations. 50 values were calculated. 2. Preparation of reagents and drugs 25 mM Tris-HCl buffer (pH = 7.4, containing 0.1 mg / mL BSA): 12.5 mL of 1 M Tris-HCl buffer was taken, 5 mg of BSA was added, diluted with purified water, the pH was adjusted to 7.4 with hydrochloric acid, and the volume was adjusted to 500 mL. PHOME solution: 0.79 mg PHOME was dissolved in 106 μL DMSO to obtain a PHOME solution with a concentration of 20 mM, which was diluted to 1 / 3 mM with Tris-HCl buffer before use. sEH solution: sEH (5 mg / mL) mother solution was stored in a refrigerator at −80° C. and diluted to 4 μg / mL with 25 mM Tris-HCl buffer before use. The test sample powder was dissolved in DMSO to a 20 mM solution, stored in a refrigerator at -20°C for later use, and diluted to the corresponding concentration with Tris-HCl buffer when used. 3. Experimental grouping Experimental design: Vehicle group, 100% active group (A), inhibitor group (B), and positive control group (C) are shown in detail in Table 1.

[0185] Table 1. Experimental grouping [Table 1]

[0186] 4. Experimental steps (a) 148 μL / well of Tris-HCl buffer was added to a 96-black bottom microwell plate. (b) 2 μL of the test sample solution was added, and the solvent group and 100% active group were replaced with the same volume of DMSO. The lead compound GL-B401 was added to the positive control group, and the structural formula is The file was TIFF2025527059000018.tif1443. (c) The inhibitor group had five concentrations, with final concentrations of 10 nM, 5 nM, 2.5 nM, 1.25 nM, and 0.625 nM, respectively. (d) 20 μL of s-EH solution (final concentration: 400 ng / mL) was added, and the solvent group was replaced with an equal volume of Tris-HCl buffer. (e) The reaction was initiated by adding 30 μL of PHOME substrate (final concentration: 50 μM) and incubated in a 37°C incubator for 10 minutes. (f) Fluorescence signal data were detected by a microplate reader with an excitation wavelength of 330 nm and an emission wavelength of 465 nm. 5. Data analysis Three wells were set up for each sample, and the average value of the three wells was the fluorescence value (F) of the test compound. The inhibition rate (%) was calculated as [(AF-BF) / AF] × 100, where AF is the fluorescence value of the 100% active group and BF is the fluorescence value of the inhibitor group. The IC of the compound was calculated using SPSS20 software based on the inhibition rate and concentration. 50 values were calculated. Using biochemical methods, the activity of the compounds was evaluated using recombinant human sEH (HsEH) and mouse sEH (MsEH) using cyano(6-methoxynaphthalen-2-yl)2-(3-phenyloxiran-2-yl)acetic acid methyl ester (PHOME) as a substrate, and the results are shown in Table 2.

[0187] Table 2 Human (HsEH) and Murine (MsEH) sEH IC of compounds 50 [Table 2] JPEG2025527059000020.jpg56128

[0188] Test Example 2 1. PPARγ agonist activity test The detection principle is as follows: when pM-hPPAR binds to an appropriate ligand, it is activated and binds to the GAL4 DNA binding site of the plasmid pB4-RES-tk-luc, thereby initiating the expression of the downstream luciferase reporter gene. The amount of luciferase is detected to determine whether the test compound is a PPAR agonist. 2. Test results: SP-C01 is PPARγEC 50 = 4.2 μM, SP-A01 is PPARγEC 50 = 6.77 μM, SP-A07 is PPARγEC 50 = 7.75 μM, SP-B07 is PPARγEC 50 =1.43 μM.

[0189] Table 3. PPARγ of Example Compounds [Table 3] JPEG2025527059000022.jpg187133JPEG2025527059000023.jpg87133

[0190] Test Example 3 Acute Toxicity Test 3.1 Experimental animals Healthy KM mice, half male and half female, SPF grade, weighing 18–22 g, were housed at a temperature of 24 ± 2°C, a relative humidity of 60 ± 10%, and an alternating 12-hour light and 12-hour dark period with free access to food and water. 3.2 Laboratory Reagents and Chemicals

[0191] Table 4 Experimental supplies [Table 4]

[0192] 3.3 Experimental method (1) Drug composition SP-B07 and SP-C01 were accurately weighed and first dissolved in a mixed solvent of DMSO and Tween 80 (1:1). After complete dissolution, the mixed solvent was diluted with 9 times the volume of saline, resulting in a drug solution with a final dosage of 1 mg / mL. (2) Grouping, rearing, and administration After one week of adaptive feeding, the KM mice were randomly divided into five groups (n=8) according to their body weight: a normal control group (Vehicle), a SP-B07 1g / kg group, and a SP-C01 1g / kg group. Each group received intragastric administration at a dose volume of 10 mL / kg for 14 consecutive days. The other two groups received a single dose of SP-C01 1g / kg and SP-C01 5g / kg, respectively, and were then observed for 14 consecutive days. (3) Physiological status and weight changes of mice The mice were observed for 30 minutes immediately after administration to monitor whether they had any adverse reactions or died, and at the same time, they were observed once every 1, 2, 4, and 8 hours to monitor whether they had any adverse reactions or died. Thereafter, the mice's daily activities and mental state were monitored and recorded daily, and the body weight of each group of mice was measured and recorded weekly. (4) Detection of mouse organ indices After 2 weeks of administration, the mice in each group were macroscopically dissected, and the heart, liver, spleen, lungs, and kidneys of each mouse were removed and simultaneously rinsed with saline, absorbed with medical gauze, placed in EP tubes, and stored for analysis. The organ index was calculated according to the following formula: Organ index (%) = organ weight / body weight × 10% 3.4 Data Statistics The experimental data were expressed as the mean ± standard error (Mean ± SEM), statistics were performed using GraphPad Prism 8.4 software, comparisons between multiple groups were analyzed using one-way ANOVA method, homogeneity of variance was analyzed using LSD method, and P < 0.05 was considered as a significant difference. 3.5 Experimental results The effects of the compounds on organ indices in male and female mice are shown in Figures 6-8. There was no significant difference in the visceral indices of the treated mice compared to the blank group. Figure 6 shows the effect of compound SP-B07 on the body weight of KM mice. SP-B07 prepared in 0.5% CMC Na solution was intragastrically administered at a dose of 1.0 g / kg. The control group was given 0.5% CMC Na. In Figure 6(A), SP-B07 and 0.5% CMC Na were administered intragastrically for 14 consecutive days, and body weight was monitored. In Figure 6(B), the visceral indices were calculated after 2 weeks of administration. Figure 7 shows the effect of compound SP-C01 on the body weight of KM mice. SP-C01 prepared in 0.5% CMC Na solution was intragastrically administered at doses of 1.0 g / kg and 5.0 g / kg, respectively. The control group was given 0.5% CMC Na. In Figure 7(A), mice were administered a single dose of (op)SP-C01 at 1.0 g / kg or 5.0 g / kg with 0.5% CMC Na, and their body weights were monitored for 14 days. In Figure 7(B), mice were administered a single dose of (op)SP-C01 at 1.0 g / kg or 0.5% CMC Na for 14 consecutive days, and their body weights were monitored. Figure 8 shows the effect of compound SP-C01 on the visceral index of KM mice. SP-C01 prepared in a 0.5% CMC Na solution was intragastrically administered at doses of 1.0 g / kg and 5.0 g / kg, respectively. The control group was given 0.5% CMC Na. In Figure 8(A), mice were administered a single dose of (op)SP-C01 at 1.0 g / kg, 5.0 g / kg, or 0.5% CMC Na, and their visceral index was calculated on day 14. In FIG. 8(B), (op) SP-C01 1.0 g / kg and 0.5% CMC Na were administered continuously for 14 days, and the visceral index was calculated on the 14th day.

[0193] Figure 9 shows representative H&E-stained sections showing the effect of compound SP-C01 on the organs of KM mice. SP-C01 prepared in 0.5% CMC Na solution was orally administered at a dose of 1.0 g / kg for 14 consecutive days. The control group was given 0.5% CMC sodium. No obvious abnormalities were found. Figure 19 shows representative H&E-stained sections showing the effect of compound SP-B07 on the organs of KM mice. SP-B07 prepared in 0.5% CMC Na solution was orally administered at a dose of 1.0 g / kg for 14 consecutive days. The control group was given 0.5% CMC sodium.

[0194] After 14 days, no significant differences were observed between treated and blank group mice, and further pathological section examination of heart, liver, spleen, lung, kidney, and stomach tissues showed no significant differences compared to the blank control.

[0195] Test Example 4 Stability of liver microsomes The microsomal stability of compounds SP-B07 and SP-C01 was evaluated in SD rat liver microsomes, and the tested compounds showed satisfactory stability in terms of in vitro microsomal stability. Compound SP-B07 showed a half-life (t 1 / 2 Compound SP-C01 had a half-life (t 1 / 2 Preliminary results indicate that compounds SP-B07 and SP-C01 are metabolically stable and worthy of continued development.

[0196] Table 5. Mean concentrations (ng / mL) of SP-B07 in microsome buffer at different time points [Table 5]

[0197] Table 6. Mean concentrations of SP-C01 in microsome buffer at different time points (ng / mL). [Table 6]

[0198] Test Example 5 Plasma protein binding rate (%PPB) Plasma protein binding (%PPB) was measured in SD rats using a typical equilibrium dialysis apparatus. Compound SP-B07 showed a moderate %PPB (95.29%). Compound SP-C01 showed a moderate %PPB (83.9%). Because the therapeutic effect of a drug depends on the concentration of free drug, a moderate concentration of %PPB is beneficial for the drug's effect in the body and may result in analgesic and anti-inflammatory effects.

[0199] Test Example 6 Pharmacokinetics To determine the metabolic stability of compounds SP-B07 and SP-C01 in vivo, pharmacokinetic characteristics were measured in 6-8 week-old Sprague-Dawley (SD) rats, half male and half female, by oral administration (ig) at a single dose of 50 mg / kg and by intravenous injection (iv) at a single dose of 10 mg / kg. Pharmacokinetic parameters are shown in Table 7. After oral administration, blood concentrations were examined within 8 hours. The maximum concentration reached at 0.5 hours (1.14 μM) and the area under the curve (AUC 0-8h ) was 13.80 (μM·h), and the plasma t 1 / 2 The maximum concentration of compound SP-B07 (3.29 μM) was reached 2 minutes after intravenous injection, and the area under the curve (AUC 0-8h ) was 14.12 μM·h, and the plasma t 1 / 2 The bioavailability of SP-B07 was 19.54%, which was moderate, and provided a good basis for further in vivo studies. SP-C01 reached a maximum concentration of 20.71 μM after 0.5 hours, and the area under the curve (AUC 0-8h ) was 38.88 (μM·h), and the plasma t 1 / 2 The maximum concentration of compound SP-C01 (5.71 μM) was reached 2 minutes after intravenous injection, and the area under the curve (AUC 0-8h ) was 10.72 μM·h, and the plasma t 1 / 2The mean bioavailability was 1.91 hours. SP-C01 had a higher bioavailability of 72.54% (see Table 8), laying a good foundation for further in vivo studies.

[0200] Table 7. Pharmacokinetics of SP-B07 after intravenous and oral administration in rats (n=3). [Table 7]

[0201] Table 8. Pharmacokinetics of SP-C01 after intravenous and oral administration in rats (n=3). [Table 8]

[0202] Test Example 7 Complete Freund's Adjuvant (CFA)-Induced Arthritis in Mice (AIA) The complete Freund's adjuvant (CFA)-induced arthritis (AIA) mouse model shares similar characteristics with human rheumatoid arthritis (RA) in terms of pathogenesis, joint pain, bone destruction, and synovial hyperplasia. It has been widely used to study the pathogenesis and treatment mechanisms of human rheumatoid arthritis. To determine whether compound SP-B07 is effective in treating AIA in female KM mice (20-22 g), five groups were designed for intraperitoneal injection comparison: the model group (CFA), the SP-B07 group (SP-B07-10 mg / kg), the SP-B07 group (SP-B07-20 mg / kg), and the celecoxib group (celecoxib-10 mg / kg). First, we tested the pain threshold of AIA mice using the hot plate method and the percentage increase in pain threshold at 10, 45, 120, and 240 minutes after drug treatment (Figure 10A). The time course curves for the increase in pain threshold were plotted (Figure 10B), and the area under the curve (AUC) for the percentage increase in pain threshold was obtained (Figure 10C). Compound SP-C01 began to exert its effect 10 minutes after administration, increasing the pain threshold and maintaining a high level for up to 4 hours. The effect of celecoxib began to decrease at 4 hours. The curves for the percentage increase in pain threshold showed that the analgesic effect of compound SP-B07 was superior to that of celecoxib, demonstrating a clear dose-response relationship. Finally, we evaluated the paw thickness of the AIA mouse model at various time points after compound injection and calculated the reduction in paw swelling compared to the paw thickness before the model. Figures 10D-F show that compound SP-B07 significantly reduced swelling in the mouse paws, and was superior to celecoxib. In summary, compound SP-B07 exhibited significant analgesic and anti-inflammatory effects (reducing swelling in the mouse paws) against CFA-induced AIA, and was superior to celecoxib.

[0203] Figure 10 shows the evaluation of compound SP-B07 in the treatment of CFA-induced arthritis in a mouse model (AIA). 24 hours after CFA induction in an AAI (25 μL / 25 g, ip), Figure 10 (A) shows the percentage increase in pain threshold in the CFA group, the CFA + SP-B07 group, and the CFA + celecoxib group. Figure 10 (B) shows a schematic diagram illustrating the time-dependent change in pain threshold percentage within 240 minutes in the CFA group, the CFA + SP-B07 group, and the CFA + celecoxib group. Figure 10 (C) shows the area under the curve for the percentage increase in pain threshold in the CFA group, the CFA + SP-B07 group, and the CFA + celecoxib group. Figure 10 (D) shows the swelling reduction rate in the CFA group, the CFA + SP-B07 group, and the CFA + celecoxib group. Figure 10 (E) is a schematic diagram showing the time course of the swelling reduction rate within 12 hours in the CFA group, the CFA + SP-B07 group, and the CFA + celecoxib group. Figure 10 (F) shows the area under the curve for the swelling reduction rate within 12 hours in the CFA group, the CFA + SP-B07 group, and the CFA + celecoxib group. Significance: Compared to the Mod group, ***P<0.0001, ***P<0.001, **P<0.01, *P<0.05.

[0204] To determine whether compound SP-C01 is effective against AIA in female KM mice (20-22 g), five intraperitoneal injection groups were designed for comparison: a model group (CFA), an SP-C01 group (5 mg / kg), an SP-C01 group (10 mg / kg), an SP-C01 group (20 mg / kg), and a celecoxib group (10 mg / kg). First, the pain thresholds of AIA mice were detected using the hot plate method. The percentage increase in pain threshold was detected at 10, 45, 120, and 240 minutes after drug treatment (Figure 11A). The time-dependent increase curves of pain threshold were plotted (Figure 11B), and the area under the curve (AUC) of the percentage increase in pain threshold was obtained (Figure 11C). Compound SP-C01 began to elevate pain thresholds 10 minutes after administration, maintaining a high level even after 4 hours. Celecoxib increased pain thresholds within 2 hours, but this effect began to decrease by 4 hours. The pain threshold increase percentage curves showed that the analgesic effect of compound SP-C01 (5 mg / kg) was superior to that of celecoxib (10 mg / kg) after 60 minutes, demonstrating a clear dose-effect relationship. Finally, paw thickness was assessed in the AIA mouse model at various time points after compound injection, and the reduction in paw swelling was calculated compared to the paw thickness before the model. Figures 11D–F show that compound SP-C01 significantly reduced paw swelling, superior to celecoxib. In summary, compound SP-C01 had obvious effects on (CFA)-induced AIA in analgesia and anti-inflammatory (reducing swelling of mouse paws) and was significantly superior to celecoxib-10 mg / kg.

[0205] Figure 11 shows the evaluation of compound SP-C01 in the treatment of CFA-induced arthritis in a mouse model (AIA). 24 hours after CFA induction in an AAI (25 μL / 25 g, ip), Figure 11 (A) shows the percentage increase in pain threshold in the CFA group, the CFA + SP-C01 group, and the CFA + celecoxib group. Figure 11 (B) shows a schematic diagram illustrating the time-dependent change in pain threshold percentage within 240 minutes in the CFA group, the CFA + SP-C01 group, and the CFA + celecoxib group. Figure 11 (C) shows the area under the curve for the percentage increase in pain threshold in the CFA group, the CFA + SP-C01 group, and the CFA + celecoxib group. Figure 11 (D) shows the swelling reduction rate in the CFA group, the CFA + SP-C01 group, and the CFA + celecoxib group. Figure 11 (E) is a schematic diagram showing the time course of the swelling reduction rate within 12 hours in the CFA group, CFA + SP-C01 group, and CFA + celecoxib group. Figure 11 (F) shows the area under the curve for the swelling reduction rate within 12 hours in the CFA group, CFA + SP-C01 group, and CFA + celecoxib group. Significance: Compared to the Mod group, ****P<0.0001, ***P<0.001, **P<0.01, *P<0.05; compared to the celecoxib group, ##P<0.01, #P<0.05.

[0206] Next, six groups were designed for comparison by intragastric administration: model group (CFA), SP-C01 low-dose group (SP-C01-30mg / kg), and SP-C01 high-dose group (SP-C01-60mg / kg), SP-C01h low-dose group (SP-C01h-30mg / kg), SP-C01h high-dose group (SP-C01h-60mg / kg), and celecoxib group (celecoxib-30mg / kg). Complete Freund's adjuvant (CFA) (25 μL / 25 g) was injected intraplantarly into the right hind paw of female C57BL / 6 mice (20-22 g). 24 hours after administration, the hot plate method was used to measure the pain threshold of mice with AIA. The percentage increase in pain threshold was measured at 10, 30, 45, 60, 120, and 240 minutes after drug treatment (Figure 12A). The time course curves for the increase in pain threshold were plotted (Figure 12B), and the area under the curve (AUC) for the percentage increase in pain threshold was obtained (Figure 12C). Compound SP-C01 began to elevate pain thresholds 10 minutes after administration and maintained a high level for 4 hours. Celecoxib increased pain thresholds at 30 minutes after administration, slightly later than SP-C01, and the effect began to decrease by 4 hours. The percentage increase in pain threshold curves show that the analgesic effect of compound SP-C01 at 30 mg / kg was superior to that of celecoxib at 30 mg / kg. Finally, the paw thickness of the AIA mouse model was evaluated at various time points after compound injection, and the reduction in paw swelling was calculated by comparing the thickness of the mouse paws before the model. Figures 12D-F show that compound SP-C01 significantly reduced paw swelling, superior to celecoxib. In summary, compound SP-C01, whether administered intraperitoneally or intragastrically, had clear analgesic and anti-inflammatory (reducing paw swelling) effects on CFA-induced AIA, significantly superior to celecoxib.

[0207] Figure 12 shows the evaluation of compound SP-C01 in the treatment of CFA-induced arthritis in a mouse model (AIA). 24 hours after CFA induction in AAI (25 μL / 25 g, i.p.), SP-C01 (30 mg / kg, i.g.), SP-C01, SP-C01h (30 mg / kg, i.g.), and celecoxib (30 mg / kg) were administered to C57BL / 6 mice. Figure 12(A) shows the percentage increase in pain threshold in the CFA group, CFA + SP-C01 group, CFA + SP-C01h group, and CFA + celecoxib group. Figure 12(B) shows a schematic diagram showing the time-dependent change in pain threshold percentage within 240 minutes in the CFA group, CFA + SP-C01 group, CFA + SP-C01h group, and CFA + celecoxib group. Figure 12 (C) shows the area under the curve for the percentage increase in pain threshold in the CFA group, CFA + SP-C01 group, CFA + SP-C01h group, and CFA + celecoxib group. Figure 12 (D) shows the swelling reduction rate in the CFA group, CFA + SP-C01 group, CFA + SP-C01h group, and CFA + celecoxib group. Figure 12 (E) shows a schematic diagram showing the time-dependent change in the swelling reduction rate within 12 hours in the CFA group, CFA + SP-C01 group, CFA + SP-C01h group, and CFA + celecoxib group. Figure 12 (F) shows the area under the curve for the swelling reduction rate within 12 hours in the CFA group, CFA + SP-C01 group, CFA + SP-C01h group, and CFA + celecoxib group. Significance: ***P<0.0001, ***P<0.001, **P<0.01, *P<0.05 compared with the Mod group; ##P<0.01, #P<0.05 compared with the celecoxib group; $$P<0.001, $$P<0.01 and $P<0.05 compared with Mod.

[0208] Test Example 8: Evaluation of pharmacodynamics in an LPS-induced sepsis model Male C57BL / 6 mice (17-20 g) were intraperitoneally injected with LPS (25 mg / kg) to induce endotoxemia (n = 7). The groups were: the model group, the dexamethasone group 4 hours after modeling, the SP-B07 group 4 hours after modeling, the SP-B07 group immediately after modeling, and the lead compound A20 group immediately after modeling. Two doses were administered, 8 hours apart. As shown in Figures 13-15, the SP-B07 group 4 hours after modeling significantly prolonged the survival time of septic mice, increasing the survival rate by 42.8%. Similar effects were achieved with dexamethasone (57.1%), suggesting that this compound may have potent anti-inflammatory effects.

[0209] Figure 13 shows that treatment with SP-B07 increased the survival rate of C57B1 / 6 mice in LPS-induced inflammation. Mice treated with 25 mg / kg LPS via intraperitoneal injection (ip) (blue, n=7) showed a survival advantage compared with mice in the blank group. Figure 14 shows the expression of COX-2, sEH, NOS2, and VCAM in mouse plasma detected by Western blot. Figure 15 shows the measurement of inflammatory factors, such as IL-6, MCP-5, and TNF-α, in mouse plasma by ELISA. Significance: ****P<0.0001 compared with the LPS group.

[0210] Test Example 9 Neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve The effects of SP-C01 were further investigated in a neuropathic pain model induced by chronic constriction injury (CCI) of the sciatic nerve in SD rats. Rats were randomly assigned to either an orally administered (±)-EC-5026 (30 mg / kg / d) group or an SP-C01 group. The SP-C01 group included 30 mg / kg / d and 100 mg / kg / d groups, as well as an additional group receiving SP-C01 30 mg / kg / d via intraperitoneal injection. After oral administration of (±)-EC-5026 (30 mg / kg / d) and SP-C01 (30 mg / kg / d) with a 12-hour dosing interval (BID), the rats were evaluated for pain relief on days 1, 3, and 7 throughout the study using the von Frey test. Pain relief, as indicated by an increase in mechanical paw withdrawal threshold (PWT), was assessed throughout the study. The study demonstrated that SP-C01 had a consistent analgesic effect without apparent tolerance (Figures 4A-B). After oral administration of SP-C01 (30 mg / kg / d) and intraperitoneal injection of SP-C01 (100 mg / kg / d) and SP-C01 (30 mg / kg / d) at a 12-hour dosing interval (BID), mechanical paw withdrawal thresholds (PWT) were assessed using the von Frey test during the first 7 hours of the study. The antineuropathic pain effect increased dose-dependently, with oral administration being nearly equivalent to that of intraperitoneal administration (Figure 16). The experimental results indicated that the overall analgesic effect of SP-C01 had a cumulative effect over time, and that its therapeutic effect from day 7 onward was significantly superior to that of the positive control drug EC5026.

[0211] Figure 16 shows that SP-C01 blocks pain as measured by the von Frey test (mechanical withdrawal threshold) in a chronic constriction injury model of nerve pathology in male SD rats. Data are presented as mean ± standard error of the mean. SP-C01, prepared in 10% DMSO and 90% corn oil, was orally administered at the indicated doses with a 12-hour dosing interval (BID). (n=8 per group). Figure 16 (A) shows that (±)-EC-5026 (30 mg / kg / day) and SP-C01 (30 mg / kg / day) were orally administered to assess pain relief for 7 hours on Day 1. Figure 16 (B) shows that (±)-EC-5026 (30 mg / kg / day) and SP-C01 (30 mg / kg / day) were orally administered to assess pain relief on Days 1, 3, and 7 throughout the course of the study. Figure 16(C) shows the dose-dependent pain-reducing effect of SP-C01 after oral administration of SP-C01 (30 mg / kg / day) and SP-C01 (100 mg / kg / day) and intraperitoneal injection of SP-C01 (30 mg / kg / day). This study evaluated the effect of SP-C01 on various administration methods. This was characterized by an increase in the mechanical paw withdrawal threshold (PWT). Figure 16(D) summarizes the AUC values of all experimental results. Significance: ***P<0.01, **P<0.01, and *P<0.05, compared with the Mod group; P<0.01 and #P<0.05, compared with the Mod group.

[0212] Test Example 10 L-arginine-induced acute pancreatitis model Acute pancreatitis is a potentially life-threatening gastrointestinal disease, and its incidence has been increasing over the past few decades. Currently, no effective treatment is available, necessitating urgent research into therapeutic agents for acute pancreatitis. Given the association between sEH and the pathogenesis of acute pancreatitis, we evaluated treatment of an L-arginine-induced acute pancreatitis model with the sEH inhibitor SP-C01 at doses of 5 mg / kg and 10 mg / kg, and compared it with celecoxib (5 mg / kg) and urinastatin (5 mg / kg) in male C57BL / 6 mice (20–22 g). Histological analysis of the pancreas was performed to determine whether SP-C01 treatment reduced the severity of L-arginine-induced pancreatitis. Pathological changes were investigated in H&E-stained pancreatic sections (Figure 17).

[0213] Figure 17 shows the results of histological analysis of the pancreas from mice treated with control, Mod, celecoxib, urinastatin, and compound SP-C01. Representative H&E-stained sections of pancreas from an in vivo efficacy study are shown. Figure 18 shows the results of histological analysis of the pancreas from mice treated with control, Mod, celecoxib, urinastatin, and compound SP-C01. (A) Edema; (B) Inflammatory cells (monocytes and polymorphonuclear cells); (C) Parenchymal atrophy; (D) Total score (edema, mononuclear cells, polymorphonuclear cells, and parenchymal atrophy) (n=5 per group). *p<0.05, **p<0.01 vs. Mod.

[0214] As expected, the L-arginine model group (5.75 ± 1.64) exhibited pancreatic damage representative of AP, including edema (Figure 18A), inflammatory cell infiltration (Figure 18B), and parenchymal atrophy (Figure 18C). In contrast, both SP-C01 at 5 mg / kg (2.40 ± 1.20) and SP-C01 at 10 mg / kg (1.60 ± 0.49) ameliorated L-arginine-induced AP pancreatic injury. Compound SP-C01 at a dose of 10 mg / kg was superior to compound SP-C01 at a dose of 5 mg / kg, and compound SP-C01 at a dose of 5 mg / kg (2.40 ± 1.20) was more effective than celecoxib at a dose of 5 mg / kg (3.50 ± 1.80) in reversing pancreatic injury, edema, and neutrophil infiltration. Compound SP-C01 at 10 mg / kg (1.60±0.49) was more effective than urinastatin at 5 mg / kg (2.00±0.71) in reversing pancreatic injury and edema.

[0215] Test Example 11 Diabetes model induced by CD60 diet combined with streptozotocin Diabetes mellitus (DDM) is a chronic metabolic disease primarily characterized by elevated blood glucose levels, and its incidence has been increasing over the past several decades. Currently, no effective therapeutic agents are available, and drug research is urgently needed to treat diabetes and related complications, such as diabetic pain. Considering the association between sEH and PPARs and the pathogenesis of diabetes and related complications, we evaluated the efficacy of sEH inhibitors SP-C01 and SP-B07 at doses of 30 mg / kg and 90 mg / kg to treat diabetes and diabetic nephropathy induced by a CD60 diet combined with streptozotocin in male C57BL / 6 mice (20–22 g) and compared them with pioglitazone (3 mg / kg). Blood glucose levels were analyzed to determine whether treatment with SP-C01 and SP-B07 reduced the severity of diabetes and related complications (Figures 20–21).

[0216] Figure 20 shows the blood glucose analysis results for control, Mod, pioglitazone, compound SP-C01, and compound SP-B07-treated mice. Figure 21 shows the corresponding treatment results for diabetic neuropathic pain measured using the hot plate method (Figures 21A-B) and Von-Frey mechanical stimulation (Figure 21C). Compared to the control group, ****P<0.0001, ***P<0.001, **P<0.01, and *P<0.05.

[0217] As expected, the model group suffered from diabetes complications such as hair loss, increased secretions around the eyes, and limited movement, while the drug-treated group showed no obvious behavioral abnormalities compared to healthy mice. Both SP-C01 and SP-B07 effectively lowered blood glucose and achieved an improvement in diabetic neuropathic pain that was not achieved by pioglitazone, a PPARγ single-target agonist.

[0218] Test Example 12: Effect of oral administration of SP-C01 on complete Freund's adjuvant-induced rheumatoid arthritis model in mice and chronic granuloma in rats Seventy-two female ICR mice weighing 19-26g were selected and randomly divided into normal control, model control, celecoxib, SP-C01 low-dose, SP-C01 medium-dose, and SP-C01 high-dose groups, with 10 animals per group, according to their body weight. Except for the normal group, animals in other groups were injected with 25μL of complete Freund's adjuvant per animal into the right plantar region. Before administration, various drugs were prepared to the corresponding concentrations using pure water. 30 minutes after modeling, animals in each group were orally administered 20mL / kg of different test substances once on the same day by intragastric administration. The normal control and model control groups were given equal volumes of pure water. Each group was then heated on a hot plate. Using a CT scan, paw pain thresholds were detected before the first administration (pain threshold screening before modeling) and 30, 60, 120, and 240 minutes after the first administration. The percentage increase in pain threshold was calculated as follows: Pain threshold increase (%) = (pain threshold after administration - pain threshold before administration) / pain threshold before administration x 100%. The thickness of the right paw was measured 1, 2, 4, 6, 8, and 12 hours after administration. On the 20th day after modeling, all model animals were regrouped according to their articular index score and intragastrically administered 20 mL / kg of steroids once a day for 7 consecutive days. The articular index score of each group was evaluated on days 3 and 7 after administration. After the final administration, the pain thresholds of the animals were measured using a hot plate device.

[0219] Table 9. Group and Dose Design [Table 9]

[0220] Effect of SP-C01 on chronic granuloma in rats Fifty SD rats, half male and half female, weighing 210-260g, were selected after passing quarantine and randomly divided into three groups (10 animals per group) according to body weight: model control group, celecoxib group, SP-C01 low-dose group, SP-C01 medium-dose group, and SP-C01 high-dose group. The animals were anesthetized with isoflurane inhalation and then implanted with approximately 50mg of cotton balls in the groin on both sides of the rats. Strict aseptic technique was observed during surgery, and penicillin was injected intraperitoneally after surgery to suppress inflammation. Before administration to each group, each drug was diluted to a concentration of 0.5mg / mL in purified water. The test substances were orally and intragastrically administered at 10mL / kg once daily for 7 consecutive days. The model control group was given an equal volume of purified water. After the final administration, the animals were anesthetized by isoflurane inhalation, exsanguinated, and the cotton ball granulomas were removed and weighed to calculate the degree of swelling (wet weight of cotton ball granuloma - dry weight of cotton ball).

[0221] Table 10. Group and Dose Design [Table 10]

[0222] Data processing and statistical analysis The test data was rounded to the nearest significant figure and statistical analysis was performed according to the SOP regulations. The software used for statistics was SPSS22.0. The measurement data was The data are represented by JPEG2025527059000031.jpg1161. Normality and homogeneity of variance were tested using the Levene's test. If there was no statistical significance (P > 0.05), statistical analysis was performed using one-way analysis of variance (ANOVA). If the ANOVA was statistically significant (P ≤ 0.05), comparative analysis was performed using the LSD test (parametric method). If the variances were heterogeneous (P ≤ 0.05), the Kruskal-Wallis test was used. If the Kruskal-Wallis test was statistically significant (P ≤ 0.05), comparative analysis was performed using the Dunnett's test (nonparametric method). For statistical results, α = 0.05 was used as the test limit, with P ≤ 0.05 indicating statistical significance and P ≤ 0.01 indicating highly significant differences.

[0223] Experimental results Effect of SP-C01 on a complete Freund's adjuvant-induced mouse model of rheumatoid arthritis Effect of SP-C01 on the degree of acute mouse paw swelling in mice As shown in Table 11, the degree of acute mouse paw swelling in the model control group was significantly increased compared with that in the normal group at 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, and 7 days after administration (P≦0.01). Compared with the model control group, the degree of acute mouse paw swelling in the SP-C01 low-dose group was significantly decreased at 4 hours and 6 hours after administration (P≦0.01). The degree of paw swelling in the SP-C01 medium-dose group was significantly decreased at 2 hours, 4 hours, and 7 days after administration (P≦0.01). The degree of paw swelling in the SP-C01 high-dose group was significantly decreased at 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, and 7 days after administration (P≦0.01).

[0224] Effect of SP-C01 on acute pain threshold elevation in mice As shown in Table 12, the acute pain threshold elevation rate of mice in the model control group at 0.5, 1, 2, and 4 hours after administration was significantly lower than that of the normal group (P ≤ 0.01). Compared with the model control group, the pain threshold elevation rate of mice in the low-dose SP-C01 group was significantly increased at 2 and 4 hours after administration (P ≤ 0.01). The pain threshold elevation rate of mice in the medium-dose SP-C01 group was significantly increased at 1, 2, and 4 hours after administration (P ≤ 0.01). The pain threshold elevation rate of mice in the high-dose SP-C01 group was significantly increased at 0.5, 1, 2, and 4 hours after administration (P ≤ 0.01).

[0225] Effect of SP-C01 on pain threshold in mice As shown in Table 13, the pain thresholds of mice with acute inflammation in the model control group were all significantly lower than those of the normal group at 0.5, 1, 2, and 4 hours after administration (P≦0.01). Compared with the model control group, the pain thresholds of mice in the SP-C01 low-dose group were significantly increased at 0.5, 1, 2, and 4 hours after administration (P≦0.01). The pain thresholds of mice in the SP-C01 medium-dose group were significantly increased at 0.5, 1, 2, and 4 hours after administration (P≦0.01). The pain thresholds of mice in the SP-C01 high-dose group were significantly increased at 0.5, 1, 2, and 4 hours after administration (P≦0.01). The pain threshold of mice with chronic inflammation was significantly decreased in the model control group compared with the normal group (P≦0.01), and the pain threshold of mice in the high-dose SP-C01 group was significantly increased compared with the model control group (P≦0.05).

[0226] Table 11. Effect of SP-C01 on the degree of acute mouse paw swelling in mice (n=10) [Table 11] Note: Compared with the normal control group, ++P ≤ 0.01; compared with the model control group, **P ≤ 0.01, *P ≤ 0.05.

[0227] Table 12. Effect of SP-C01 on the rate of increase in acute pain threshold in mice [Table 12] Note: Compared with the normal control group, ++P ≤ 0.01; compared with the model control group, **P ≤ 0.01, *P ≤ 0.05.

[0228] Table 13. Effect of SP-C01 on pain threshold in mice (n=10) [Table 13] Note: Compared with the normal control group, ++P ≤ 0.01; compared with the model control group, **P ≤ 0.01, *P ≤ 0.05.

[0229] Effect of SP-C01 on joint index scores in chronic inflammatory conditions in mice As shown in Table 14, the joint index scores of the chronic inflammatory state of mice in the SP-C01 high-dose group on the third day of administration were significantly reduced compared with the model control group (P≦0.05), and after 7 days of administration, the joint index scores of the chronic inflammatory state of mice in the SP-C01 low-dose group, SP-C01 medium-dose group, and SP-C01 high-dose group were significantly reduced (P≦0.01).

[0230] Table 14. Effect of SP-C01 on joint index score in chronic inflammatory state in mice (n=10) [Table 14] Note: Compared with the model control group, **P ≤ 0.01, *P ≤ 0.05

[0231] Effect of SP-C01 on a rat model of chronic granuloma Effect of SP-C01 on chronic granuloma in rats As shown in Table 15, compared with the model control group, the degree of chronic granulomatosis in rats in the SP-C01 low-dose group, SP-C01 medium-dose group, and SP-C01 high-dose group was significantly reduced (P≦0.01).

[0232] Table 15. Effect of SP-C01 on chronic granuloma in rats (n=10) [Table 15] Note: P ≤ 0.01 compared with the normal control group.

[0233] Summary of the experiment Regarding the effects of SP-C01 on a mouse model of rheumatoid arthritis induced with complete Freund's adjuvant, under acute inflammatory conditions, the degree of paw swelling in mice receiving the low dose of SP-C01 was significantly reduced at 4 and 6 hours after administration (P ≤ 0.01), indicating that low-dose SP-C01 had an antagonistic effect on inflammation in the mouse model of rheumatoid arthritis induced by complete Freund's adjuvant at 4 and 6 hours after administration. The pain threshold of mice receiving low-dose SP-C01 was significantly increased at 0.5, 1, 2, and 4 hours after administration (P ≤ 0.01), indicating that low-dose SP-C01 had a significant analgesic effect on the mouse model of rheumatoid arthritis induced with complete Freund's adjuvant at 0.5, 1, 2, and 4 hours after administration. The degree of swelling in the mouse paws was significantly reduced at 2 hours, 4 hours, and 7 days after administration of the medium dose of SP-C01 (P ≤ 0.01), and at 6 hours and 24 hours after administration (P ≤ 0.05), indicating that the medium dose of SP-C01 had an antagonistic effect on inflammation in the mouse model of rheumatoid arthritis induced by complete Freund's adjuvant at 2 hours, 4 hours, 6 hours, 24 hours, and 7 days after administration. The pain threshold of the mouse was significantly increased at 0.5 hours, 1 hour, 2 hours, and 4 hours after administration of the medium dose of SP-C01 (P ≤ 0.01), indicating that the medium dose of SP-C01 had a clear analgesic effect on the mouse model of rheumatoid arthritis induced by complete Freund's adjuvant at 0.5 hours, 1 hour, 2 hours, and 4 hours after administration.The degree of paw swelling in mice in the high-dose SP-C01 group was significantly reduced at 1, 2, 4, 6, 8, 12, 24, and 7 days after administration (P ≤ 0.01), indicating that high-dose SP-C01 had an antagonistic effect on inflammation in complete Freund's adjuvant-induced rheumatoid arthritis model mice at 1, 2, 4, 6, 8, 12, 24, and 7 days after administration. The rate of pain threshold elevation in mice in the high-dose SP-C01 group was significantly increased at 0.5, 1, 2, and 4 hours after administration (P ≤ 0.01), indicating that high-dose SP-C01 had a significant analgesic effect on complete Freund's adjuvant-induced rheumatoid arthritis model mice at 0.5, 1, 2, and 4 hours after administration.

[0234] Under chronic inflammatory conditions, the pain threshold of mice treated with high-dose SP-C01 for 7 consecutive days significantly increased (P ≤ 0.05), indicating that high-dose SP-C01 administered to mice for 7 consecutive days had a significant analgesic effect on the complete Freund's adjuvant-induced rheumatoid arthritis model mice. On day 3 after administration, the articular index scores of mice in the high-dose SP-C01 group significantly decreased (P ≤ 0.05). After 7 days of administration, the articular index scores of mice in the low-dose, medium-dose, and high-dose SP-C01 groups significantly decreased (P ≤ 0.01), indicating that 7 days of low-dose SP-C01, 7 days of medium-dose SP-C01, and 3 and 7 days of high-dose SP-C01 administration had a modulating effect on the ankle joints of the complete Freund's adjuvant-induced rheumatoid arthritis model mice.

[0235] Regarding the effect of SP-C01 on chronic granuloma in rats, the degree of chronic granulomatosis in rats administered low-, medium-, and high-dose SP-C01 was significantly reduced (P ≤ 0.01), indicating that low-, medium-, and high-dose SP-C01 were effective against granulomatous swelling in the chronic granuloma model rats.

[0236] The above results show the following: Under acute inflammatory conditions, low-dose SP-C01 showed antagonistic effects on inflammation in complete Freund's adjuvant-induced rheumatoid arthritis model mice after administration (4 hours, 6 hours), medium-dose SP-C01 after administration (2 hours, 4 hours, 6 hours, 24 hours, 7 days), and high-dose SP-C01 after administration (1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, 7 days). Under acute inflammatory conditions, low-dose SP-C01 showed antagonistic effects on inflammation in complete Freund's adjuvant-induced rheumatoid arthritis model mice after administration (0.5 hours, 1 hour, 2 hours, 4 hours), medium-dose SP-C01 after administration (0.5 hours, 1 hour, 2 hours, 4 hours). ), when high doses of SP-C01 were administered to mice in a chronic inflammatory state for 7 consecutive days (0.5 hours, 1 hour, 2 hours, 4 hours), it had a clear analgesic effect on complete Freund's adjuvant-induced rheumatoid arthritis model mice, while the positive drug celecoxib showed an analgesic effect 2 hours after administration in an acute inflammatory state. SP-C01 has anti-inflammatory and analgesic effects on complete Freund's adjuvant-induced rheumatoid arthritis model mice, with the onset of action being significantly faster than celecoxib and the duration of the drug effect being longer than celecoxib.

[0237] In chronic inflammatory conditions, administration of low-dose SP-C01 for 7 days, medium-dose SP-C01 for 7 days, and high-dose SP-C01 for 3 and 7 days had a regulatory effect on the ankle joints of mice with complete Freund's adjuvant-induced rheumatoid arthritis. Compared to the active agent celecoxib, all dose groups of SP-C01 showed more potent effects than celecoxib.

[0238] Low-, medium-, and high-dose SP-C01 were effective in suppressing granuloma swelling in a rat chronic granuloma model. Compared with the active drug celecoxib, the low- and medium-dose SP-C01 groups showed similar effects to celecoxib, while the high-dose SP-C01 group was more effective than celecoxib.

[0239] Although the above-mentioned embodiments describe the present application in detail, they are only a part of the embodiments of the present application, not all of the embodiments, and other embodiments can be obtained based on the present embodiments without inventive step, and all of these embodiments belong to the protection scope of the present application.

Claims

1. A compound having the structure shown in Formula I, II, III, IV, V or VI: 【Chemical 1】 【change】 Of these, R １ is a memanthyl group, an aryl group, an alkyl-substituted aryl group, a haloaryl group, a haloalkyl-substituted aryl group, a haloalkoxy-substituted aryl group, or a haloaryloxy-substituted aryl group; R ２ is hydrogen, a hydroxyl group, an alcoholic hydroxyl group, an amine group, a carboxyl group, an acyl group, an amide group, or an ester group; R ３ is hydrogen, an alkyl group, an alkoxy group, a hydroxyl group, a cyano group, or a carboxyl group, and R ４ is hydrogen or an alkyl group, and R ５ is hydrogen, an alkyl group, an alkoxy group, a hydroxyl group, a cyano group, or a carboxyl group, and R ６ is hydrogen, a hydroxyl group, an alkyl group, an ester group, or an amine group; A is a cycloalkyl group, a heterocyclyl group, or an aryl group; B is a single bond, a cycloalkyl group, a heterocyclyl group, or an aryl group; W is a single bond, -CH ２ -, -O-, -S-, -NH- or 【change】 and Y is a single bond, -CH ２ -, -O-, -S- or -NH-; Z is =CH ２ , =O, =S or =NH; A compound characterized in that n is an integer of 0 to 12.

2. the alkyl groups in the alkyl-substituted aryl group and the haloalkyl-substituted aryl group are independently methyl, ethyl, propyl, butyl, pentyl, isobutyl, isopropyl, isopentyl, or tertbutyl; the alkoxy groups in the haloalkoxy-substituted aryl group are methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy, cyclohexyloxy, phenoxy, or benzyloxy; and the halogens in the haloaryl group, haloalkyl-substituted aryl group, and haloalkoxy-substituted aryl group are independently —F, —Cl, or —Br; The cycloalkyl group is an unsubstituted or substituted C3 to C8 cycloalkyl group, and the substituents of the substituted C3 to C8 cycloalkyl group are independently —F, —Cl, —Br, —OH, —NH ２ , -NHCH ３ , -N(CH ３ ) ２ or a C1-C6 alkyl group, wherein the heterocyclyl group is independently an unsubstituted or substituted 3- to 10-membered heterocyclyl group, and the substituents of the substituted 3- to 10-membered heterocyclyl group are independently —F, —Cl, —Br, —OH, —NH ２ , -NHCH ３ , -N(CH ３ ) ２ or a C1 to C6 alkyl group, wherein the aryl groups are independently substituted or unsubstituted phenyl groups, substituted or unsubstituted pyridyl groups, or substituted or unsubstituted naphthyl groups, and the substituents of the substituted phenyl groups, substituted pyridyl groups, or substituted naphthyl groups are independently —F, —Cl, —Br, —OH, —NH ２ , -NHCH ３ , -N(CH ３ ) ２ or a C1 to C6 alkyl group.

3. The R １ is a memanthyl group, a haloaryl group, a haloalkyl-substituted aryl group, or a haloalkoxy-substituted aryl group, ２ is hydrogen or an ester group, and the R ３ is hydrogen or an alkyl group, and the R ４ is hydrogen, a methyl group, or an ethyl group, and the R ５ is hydrogen or an alkyl group, and the R ６ is a hydroxyl group, an amino group, an alkyl group, or an ester group, A is a cyclohexyl group or a phenyl group, B is a single bond or a phenyl group, W is a single bond or -O-, Y is a single bond, -O-, or -NH-, Z is ═O, and n is an integer of 0 to 2.

4. The R １ teeth, The R ２ is hydrogen or -CH ２ —C(O)—CH ３ and R ３ is hydrogen or a methyl group, and the R ４ is hydrogen, and the R ５ is hydrogen or a methyl group, and the R ６ is a hydroxyl group, -NH ２ , methyl group, —C(O)—O—CH ２ -CH ３ or a sec-butyl group.

5. The compound of claim 1, having any of the following structures: 【Chemistry 2】

6. A method for producing the compound of claim 1, comprising the steps of: (1) Producing a compound having the structure shown in Formula I, the method comprising: performing a first substitution reaction between compound a and compound b to obtain compound c; a step of subjecting the compound c and the compound d to a first condensation reaction to obtain a compound e; performing a first hydrolysis reaction on compound e to obtain compound f; performing a first nucleophilic substitution reaction on the compounds f, w, and af to obtain a compound g; the compound g is a compound having a structure represented by formula I in which a thiazolidinedione group is bonded to a double bond; and performing a first reduction reaction on compound g to obtain a compound having the structure shown in Formula I, in which the thiazolidinedione group is bonded to a single bond; The structural formulae of Compound a, Compound b, Compound c, Compound d, Compound e, Compound f, Compound g, Compound w, and Compound af are as follows: 【Chemistry 3】 Among these, Q of compound a is H, a hydroxyl group, an amino group, a mercapto group, a carboxyl group, or an acyl chloride, and X of compound b is H, a hydroxyl group, a halogen, or a haloalkyl group; (2) Producing a compound having the structure shown in Formula II, the method comprising: performing a first substitution reaction between compound a and compound h to obtain compound i; subjecting compound i to a first hydrolysis reaction to obtain compound j; performing a second substitution reaction between compound j and compound aa to obtain compound k; performing a second hydrolysis reaction on compound k to obtain compound l; and performing a nucleophilic substitution reaction on compound l, compound w, and compound af to obtain a compound having the structure shown in Formula II, The structural formulae of Compound h, Compound i, Compound j, Compound k, Compound l, and Compound aa are as follows: 【Chemistry 4】 Among these, X in compound h is H, a hydroxyl group, a halogen, or a haloalkyl group; (3) Producing a compound having the structure shown in Formula III, the method comprising: performing a first substitution reaction between compound m and compound b to obtain compound n; performing a first condensation reaction between the compound n and the compound d to obtain a compound o; performing a first hydrolysis reaction on the compound o to obtain a compound p; a step of performing a first nucleophilic substitution reaction on the compound p, the compound w, and the compound af to obtain a compound q, the compound q being a compound having a structure represented by formula III in which a thiazolidinedione group is bonded to a double bond, and performing a first reduction reaction on compound q to obtain a compound having a structure shown in Formula III, wherein the thiazolidinedione group in the structure is bonded to a single bond; The structural formulae of Compound m, Compound n, Compound o, Compound p, and Compound q are as follows: 【Chemistry 5】 Among these, Q of the chemical substance m is H, a hydroxyl group, an amino group, a mercapto group, a carboxyl group, or an acyl chloride; (4) Producing a compound having the structure shown in formula IV, the method comprising: performing a first substitution reaction between compound m and compound h to obtain compound r; performing a first hydrolysis reaction on the compound r to obtain a compound s; performing a second substitution reaction between compound s and compound aa to obtain compound t; performing a second hydrolysis reaction on the compound t to obtain a compound u; and performing a first nucleophilic substitution reaction on compound u, compound w, and compound af to obtain a compound having the structure shown in Formula IV: The structural formulae of the compounds r, s, t, and u are as follows: 【Chemistry 6】 (5) Producing a compound having the structure shown in formula V, the production method comprising: performing a first substitution reaction between compound a and compound h to obtain compound i; performing a first hydrolysis reaction on compound i to obtain compound v; and performing a first nucleophilic substitution reaction on compound v, compound w, and compound af to obtain a compound having the structure shown in formula V: The structural formulae of Compound a, Compound h, Compound i, and Compound v are as follows: 【Chemistry 7】 (6) Producing a compound having the structure shown in formula VI, the method comprising: performing a first substitution reaction between compound a and compound x to obtain compound y; performing a first hydrolysis reaction on compound y to obtain compound z; and performing a first nucleophilic substitution reaction on compound z, compound w, and compound af to obtain a compound having the structure shown in formula VI: The structural formulae of the compounds a, x, y, and z are as follows: 【Chemistry 8】 X in compound x is H, a hydroxyl group, a halogen, or a haloalkyl group; (7) When Y of the compound having the structure represented by formula V or VI is —NH—, the method for producing the compound having the structure represented by formula V or VI is a step of performing a first substitution reaction between compound a and compound ab to obtain compound ac; performing a first hydrolysis reaction on the compound ac to obtain a compound ad; performing a nucleophilic substitution reaction on the compound ad, the compound w, and the compound af to obtain a compound ae; subjecting compound ae to a first reduction reaction to obtain a compound having the structure shown in formula VI; and condensing the compound having the structure of formula VI with compound ag to obtain a compound having the structure of formula V, 【Chemistry 9】 The method for producing compound ab, wherein X is H, a hydroxyl group, a halogen, or a haloalkyl group.

7. Use of the compound according to any one of claims 1 to 5, and its pharmaceutically acceptable deuterated salt, salt or hydrate, or the compound produced by the production method according to claim 6, in the production of a peroxisome proliferator-activated receptor agonist and / or a soluble epoxide hydrolase inhibitor.

8. The peroxisome proliferator-activated receptor agonists and soluble epoxide hydrolase inhibitors are used to treat soluble epoxidase and peroxisome proliferator-activated receptor mediated diseases; The diseases mediated by said soluble epoxidase and peroxisome proliferator-activated receptors include inflammatory diseases, pain, sepsis, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications and depression, liver fibrosis, renal failure, chronic obstructive pulmonary disease, or pulmonary hypertension; or The peroxisome proliferator-activated receptor agonists and soluble epoxide hydrolase inhibitors are used to treat soluble epoxidase and peroxisome proliferator-activated receptor mediated diseases; The diseases mediated by said soluble epoxidase and peroxisome proliferator-activated receptors include inflammatory diseases, pain, sepsis, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications and depression, liver fibrosis, renal failure, chronic obstructive pulmonary disease, or pulmonary hypertension; The use according to claim 7, wherein the inflammatory disease includes non-alcoholic steatohepatitis and chronic nephritis, and the pain includes neuropathic pain.

9. 10. Use of a compound according to any one of claims 1 to 5 and its pharmaceutically acceptable deuterated forms, salts or hydrates in the treatment of soluble epoxidase and peroxisome proliferator-activated receptor mediated diseases, comprising: The disease mediated by the soluble epoxidase and peroxisome proliferator-activated receptor includes inflammatory diseases, pain, sepsis, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications and depression, liver fibrosis, renal failure, chronic obstructive pulmonary disease, or pulmonary hypertension.

10. A drug comprising the compound according to any one of claims 1 to 5 and a pharmaceutically acceptable deuterated product, salt or hydrate thereof, or a compound produced by the production method according to claim 6.

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