Memantine urea derivatives and methods for their preparation and use in the preparation of medicaments for treating soluble epoxide hydrolase-mediated diseases

Abstract

The present application provides memantine urea derivatives and their preparation and use, which relate to the field of pharmaceutical technology. The memantine urea derivatives provided by the present application have a typical urea structure as the primary pharmacophore of sEH. Molecular docking has shown that the memantine moiety, as a hydrophobic fragment, generates hydrophobic forces with the receptor, particularly when R1 and R2 are both methyl groups (i.e., 3,5-dimethyl group substitution), which can enhance van der Waals forces. Therefore, the memantine urea derivatives provided by the present application have high inhibitory activity against human sEH (HsEH) and mouse sEH (MsEH) and can be used as sEH inhibitors to prepare drugs for treating soluble epoxide hydrolase-mediated diseases.

Description

[Technical Field]

[0001] This application claims priority to a Chinese patent application filed with the China Patent Office on November 18, 2022, bearing application number CN202211458374.9 and entitled "Memantine urea derivatives and their preparation methods and use in preparing drugs for treating soluble epoxide hydrolase-mediated diseases," the entire contents of which are incorporated herein by reference.

[0002] The present application relates to the field of pharmaceutical technology, specifically to memantine urea derivatives and methods for their preparation and use in the preparation of medicaments for treating soluble epoxide hydrolase-mediated diseases. [Background technology]

[0003] In mammals, arachidonic acid is a polyunsaturated fatty acid metabolized by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYPs). The COX and LOX pathways primarily lead to the production of proinflammatory lipid mediators such as prostaglandins and leukotrienes, which have drug targeting properties (Non-Patent Document 1). In contrast, CYP450 enzymes act on long-chain polyunsaturated fatty acids to form EpFAs by epoxidation of the double bond (Non-Patent Document 2), a highly selective process. EpFAs are classified into epoxyeicosatrienoic acids (EETs), epoxyeicosatetraenoic acids (EEQs), and epoxyeicosapentaenoic acids (EDPs) depending on the position of the epoxidized double bond (Non-Patent Document 3). All types of EpFAs can be hydrolyzed to diols by sEH, with EETs, in particular, being hydrolyzed to diols with the lowest activity (Non-Patent Document 4).

[0004] sEH is a member of the α / β hydrolase family. Studies have revealed that in mammals, sEH is a homodimer composed of two 60 kD subunits arranged in an antiparallel arrangement, each with C-terminal hydrolase and N-terminal phosphatase properties. The C-terminal domain possesses typical α / β hydrolase properties, hydrolyzing epoxides by adding water to the three-membered oxirane ring. The N-terminal domain possesses phosphatase activity capable of hydrolyzing lipid phosphates, but its specific biological function in mammals remains unknown. sEH is a group of enzymes with similar functions, classified into eight different subtypes, including mammalian, plant, and microsomal peroxidases (Non-Patent Document 5), of which the mammalian subtype is the most important. In mammals, sEH is widely distributed in various organs throughout the body, and is most active in the liver, kidney, intestine, and vascular system.

[0005] Pain is a complex signaling process resulting from the release of noxious substance damage and inflammatory mediators, such as cytokines, ions, bradykinin, prostaglandins, and leukotrienes, which act directly on pain receptors to drive action potentials and produce the sensation of pain (Non-Patent Document 6). Pain is typically a signal to avoid further damage. While many methods currently offer pain relief, most of these methods have dose-dependent or use-limiting side effects. Therefore, new therapies for treating pain are needed. Inflammatory pain is caused by inflammation of biological or chemical origin. The alleviation of inflammatory pain through inhibition of sEH activity stems from studies of the anti-inflammatory effects of sEH inhibitors. In a lipopolysaccharide-induced sepsis model, sEH inhibition was found to alter not only the levels of epoxyeicosatrienoic acid (EET) and diol metabolites but also the levels of several other metabolites in the cyclooxygenase (COX) and lipoxygenase (LOX) metabolic pathways of the arachidonic acid cascade (Non-Patent Document 7). Notably, inhibition of sEH activity with small molecules reduces levels of prostaglandin 2 (PGE2), an inflammatory mediator and pain-inducing substance. This discovery is groundbreaking because it demonstrates that stabilization of endogenous bioactive lipids represents a new strategy for limiting inflammation. Previous studies have shown that sEH inhibitors inhibit cyclooxygenase 2 (COX-2), and we first investigated their synergistic activity with nonsteroidal anti-inflammatory drugs (NSAIDs), which selectively inhibit COX-2, in an inflammatory pain model (Non-Patent Document 8). The results showed that sEH inhibitors and NSAIDs synergistically reduced PGE2 and COX-2 expression levels in mice and prolonged thermal escape latency. Remarkably, these improvements occurred in the absence of significant changes in the prostacyclin-to-thromboxane ratio. The adverse side effect of thrombosis caused by NSAIDs, which are selective COX-2 inhibitors, is suspected to be caused by an alteration in the homeostatic balance of COX metabolites (Non-Patent Document 9).Subsequent studies have tested sEH inhibitors alone to determine whether they can counteract hyperalgesia. Inceoglu et al. found that local administration of two different sEH inhibitors effectively increased the thermal withdrawal latency and pain threshold in a rat lipopolysaccharide (LPS)-induced inflammatory pain model (Non-Patent Document 10). This study further demonstrated that EpFA metabolites counteract hyperalgesia by increasing the thermal withdrawal latency to LPS pain. This suggests that inhibiting sEH activity may be an effective method for treating inflammatory pain.

[0006] In 2011, PAIN, the official academic journal of the International Association of Spatial and Neuropathic Pain Society (IASP), published a new definition of neuropathic pain (NPP): pain directly caused by damage or disease of the somatosensory nervous system, which may be secondary to various diseases or injuries, such as stroke or diabetes. NPP is currently one of the most difficult diseases to treat, placing a significant burden on society and individuals. Therefore, there is an urgent need to develop new methods for treating neuropathic pain. Preliminary studies on the effects of sEH inhibitors in neuropathy aim to compare the relationship between COX levels and inflammatory pain in pain models. Inceoglu et al. found that sEH inhibitors can block diabetic neuropathy in a chronic pain model, and thus were proposed as a negative control model (Non-Patent Document 11). This is very exciting, as most NSAIDs that block COX have little effect on neuropathic pain (Non-Patent Document 12). Inceoglu et al. investigated the effects of sEH inhibitors on diabetic neuropathy in a preclinical model and found a dose-dependent improvement in mechanical pain threshold with sEH inhibitors, demonstrating superiority over standard treatment with gabapentin (Non-Patent Document 13). This antihyperalgesia was independent of changes in glucose tolerance, insulin resistance, and glucose-stimulated insulin secretion. Wagner et al. further demonstrated the effects of sEH inhibitors in a congenital Akita mouse model of type 1 diabetes (Non-Patent Document 14). In a study using the Akita mouse model, sEH inhibitors were found to be effective against murine diabetic neuropathy, and sEH activity correlated with the severity of the disease. Guedes et al. found that sEH inhibitors were more effective than conventional standard treatments in a study to treat severe equine laminitis, and that sEH inhibitors continue to be successful as a method for treating this disease (Non-Patent Document 15). This suggests that sEH inhibitors may be an effective strategy for treating neuropathic pain.

[0007] Considering the importance of sEH inhibitors and EpFAs in the development and progression of inflammation and pain, as well as their protective effects on multiple organs such as the heart, kidney, and brain, inhibiting sEH activity can improve and stabilize the content of EpFAs, such as EETs, in the body, thereby exerting analgesic, anti-inflammatory, and protective effects on multiple organs. Therefore, developing novel and efficient sEH inhibitors is highly urgent and necessary for the treatment of pain. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Toxicol.2014,114,83-91. [Non-patent document 2] Biochimica Et Biophysica Acta,2011,1814(1):210-222 [Non-patent document 3] Journal of Lipid Research,2010,51(12):3481-3490. [Non-patent document 4] Neuron,2007,55(3):353-364. [Non-Patent Document 5] Biochimie,2013,95(1):91-95. [Non-patent document 6] Neuron,2007,55(3):353-364. [Non-Patent Document 7] Proc Natl Acad Sci USA,2005,102(28):9772-9777. [Non-patent document 8] Proc Natl Acad Sci USA,2006,103(37):13646-13651. [Non-Patent Document 9] N Engl J Med,2004,351:1709-1711. [Non-Patent Document 10] Life Sciences,2006,79(24):2311-2319. [Non-Patent Document 11] Proceedings of the National Academy of Sciences of the United States of America, 2008, 105(48):18901-18906. [Non-Patent Document 12] European Journal of Pharmacology,2013,700(1-3):93-101. [Non-Patent Document 13] Proc Natl Acad Sci USA,2012,109(28):11390-11395. [Non-Patent Document 14] Behavioral Brain Research,2017,326:69-76. [Non-Patent Document 15] Equine Veterinary Journal,2017,49(3):345-351. Summary of the Invention [Problem to be solved by the invention]

[0009] The objective of the present application is to provide a memantine urea derivative and a method for preparing the same, as well as its use in preparing a medicament for treating a soluble epoxide hydrolase-mediated disease. The memantine urea derivative provided by the present application has high inhibitory activity against human-derived sEH (HsEH) and mouse-derived sEH (MsEH), has few side effects, and can be used as an sEH inhibitor for preparing a medicament for treating a soluble epoxide hydrolase-mediated disease. [Means for solving the problem]

[0010] To achieve the above objectives of the invention, the present application provides the following technical solutions:

[0011] The present application provides memantine urea derivatives, having a structure represented by Formula A or Formula B: TIFF2025538342000002.tif36120 formula A TIFF2025538342000003.tif33144 type B wherein R1 and R2 are independently selected from -H, -OH, -NH2, -SH, -CN, a halogen group, an alkyl group, an alkoxy group, an aryl group, or a heteroaryl group; R3 is selected from -H, -OH, -NH2, -SH, -CN, a halogen group, an alkyl group, or an alkoxy group; R4 is -OH, -NH2, a hydroxylamine group, an amine group substituted with an alkyl group, an amine group substituted with an alkoxy group, an amine group substituted with an alcohol group, an amine group substituted with a phenyl group, an amine group substituted with a naphthyl group, or Selected from TIFF2025538342000004.tif2641, Y is -H, TIFF2025538342000005.tif2425, TIFF2025538342000006.tif2224 or Selected from TIFF2025538342000007.tif1118, R5 is selected from an alkyl group or a heterocyclic group, and the alkyl group is a linear alkyl group or a cycloalkyl group; R6 is selected from an amino group substituted with an alkyl group or an alkyl group substituted with an alcohol group; X is -CH2 or Selected from JPEG2025538342000008.jpg2118, L is selected from none or -NH-; D is JPEG2025538342000009.jpg1818 or Selected from JPEG2025538342000010.jpg1517, n is 1 or 2, The Z and M are independently selected from =O or =S.

[0012] Preferably, R1 and R2 are independently selected from -H, -OH, -NH2, -SH, -CN, -F, -Cl, -Br, methyl, ethyl, propyl, butyl, pentyl, isobutyl, isopropyl, isopentyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy, cyclohexyloxy, phenoxy, and benzyloxy.

[0013] Preferably, R3 is selected from -H, -OH, -NH2, -SH, -CN, -F, -Cl, -Br, an unsubstituted or substituted C1 to C6 alkyl group, and an unsubstituted or substituted C1 to C6 alkoxy group, and substituents on the substituted C1 to C6 alkyl group and substituted C1 to C6 alkoxy group are independently selected from -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2, or a C1 to C6 alkyl group.

[0014] Preferably, the alkyl-substituted amino group selected by R4 is an amino group substituted with an unsubstituted or substituted C1-C6 alkyl group, the alkoxy-substituted amino group selected by R4 is an amino group substituted with an unsubstituted or substituted C1-C6 alkoxy group, the phenyl-substituted amine group selected by R4 is an amino group substituted with an unsubstituted or substituted phenyl group, the naphthyl-substituted amine group selected by R4 is an amine group substituted with an unsubstituted or substituted naphthyl group, and the alcohol-substituted amine group selected by R4 is an amine group substituted with an unsubstituted or substituted C1-C6 alcohol group, and the substituents on the substituted C1-C6 alkoxy group, substituted phenyl group, substituted naphthyl group, and substituted C1-C6 alcohol group are independently selected from -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2, or a C1-C6 alkyl group.

[0015] Preferably, the chain alkyl group selected by R5 is an unsubstituted or substituted C1-C6 saturated or unsaturated chain alkyl group, and a substituent on the substituted C1-C6 saturated or unsaturated chain alkyl group is selected from -OH, -NH2 or a C1-C6 alkyl group; The cycloalkyl group selected for R5 is an unsubstituted or substituted C3-C6 cycloalkyl group, and the substituent on the substituted C3-C6 cycloalkyl group is selected from -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2 or a C1-C6 alkyl group; The heterocyclic group selected by R5 is an unsubstituted or substituted C3 to C6 saturated or unsaturated heterocyclic group, and the substituents on the substituted C3 to C6 saturated or unsaturated heterocyclic group are independently selected from -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2, or a C1 to C6 alkyl group.

[0016] Preferably, the amino group substituted with an alkyl group selected for R6 is an amino group substituted with an unsubstituted or substituted C1 to C6 alkyl group, and the alkyl group substituted with an alcohol group is an alkyl group substituted with an unsubstituted or substituted C1 to C6 alcohol group.

[0017] Preferably, (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxamide, 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(((S)-3-(4-propionyl-1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)phenyl)urea, 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-( ((3S)-3-(4-(2-methylbutanoyl)-1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)phenyl)urea, (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-dimethylpiperidine-3-carboxamide, (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-diethylpiperidine-3-carboxamide, (S)- 1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-bis(2-hydroxyethyl)piperidine-3-carboxamide, 1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-bis(2-hydroxyethyl)piperidine-4-carboxamide, (S)-N-(1,3-dihydroxypropan-2-yl)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-bis(2-hydroxyethyl)piperidine-4-carboxamide (3S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxypropyl)piperidine-3-carboxamide, (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N-(2-hydroxyethyl)piperidine-3-carboxamide, (S)-N-(1,3-Dihydroxy-2-(hydroxymethyl)propan-2-yl)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxamide, 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(((S)-3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)piperidin-1-yl)methyl)phenyl)urea, N-(1,3-dihydroxy-2-(hydroxymethyl)propane- 2-yl)-1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxamide, 1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxamide, N-(1,3-dihydroxypropan-2-yl)-1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxamide, 1-(4-(3-(( 1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N-(2-hydroxypropyl)piperidine-4-carboxamide, 1-(4-(((S)-3-(4-acryloyl-1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea, 1-(4-((S)-3-(4-(cyclopropanecarbonyl)-1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl) 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea, 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(((3S)-3-(1-(2-methylbutanoyl)azacyclohexane-4-carbonyl)piperidin-1-yl)methyl)phenyl)urea, (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylic acid, 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(4-(2-(1-(2-methylbutanoyl)piperidin-4-yl)acetyl)-1,4-diaza-1-carbonyl)phenyl)urea, 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(4-(2-(1-propionylpiperidin-4-yl)acetyl)-1,4-diaza-1-carbonyl)phenyl)urea, 1-(4-(4-(2-(1-acetylpiperidin-4-yl)acetyl)-1,4-dia (S)-1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N,N-diethylpiperidine-3-carboxamide, 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N,N-diethylpiperidine-4-carboxamide, 1-((1r,3R,5S) ,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)piperidine-1-carbonyl)phenyl)urea, (3S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxypropyl)piperidine-3-carboxamide, 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl (S)-1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxypropyl)piperidine-4-carboxamide, N-(1,3-dihydroxypropan-2-yl)-1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-4-carboxamide, (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxyethyl)piperidine-3-carboxamide, 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((S)-3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)piperidine-1-carbonyl)phenyl)urea, 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(4-(4-(2-(1-(1-(dimethylamino)propanol) 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(1-propionylpiperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)phenyl)urea, 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(1-(2-methylbutanoyl)piperidin-4-yl) 1-(4-((4-(2-(1-acetylpiperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea, 4-(2-(4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-1,4-diaz-1-yl)-2-oxoethyl)piperidine-1-carboxylate methyl 1-( (1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(1-(2-hydroxyethyl)piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)phenyl)urea, 1-(4-((4-(2-(1-(2,3-dihydroxypropyl)piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea, 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(4-((4-(2-(1-(2-(dimethylamino)ethyl)piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)-2-fluorophenyl)urea, 1-(4-((4-(2-(1-(2-(diethylamino)ethyl)piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea, 1-(4-((S)-3-(4-acetyl-1,4-diaza-1-cal 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((S)-3-(4-propionyl-1,4-diaza-1-carbonyl)piperidine-1-carbonyl)phenyl)urea, 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((3S)-3-(4-(2-methylbutanoyl) -1,4-diaza-1-carbonyl)piperidine-1-carbonyl)phenyl)urea, 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro-N-((1r,4R)-4-((2-hydroxyethyl)carbamoyl)cyclohexyl)benzamide, 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro-N-((1r,4R)-4-((2-hydroxypropyl)carbamoyl)cyclohexyl)benzamide, N-((1r, 4R)-4-(bis(2-hydroxyethyl)carbamoyl)cyclohexyl)-4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide, N-((1r,4R)-4-carbamoylcyclohexyl)-4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide, N-((1r,4R)-4-((1,3-dihydroxypropan-2-yl)carbamoyl)cyclohexyl)-4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide, N-((1r,4R)-4-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)carbamoyl)cyclohexyl)-4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro, tert-butyl 4-(2-((1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxamido)ethyl)piperazine-1-carboxylate, 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro-N-((1r,4R)-4-((2-hydroxyethyl)carbamoyl)cyclohexyl)benzamide.

[0018] The present application provides a method for preparing memantine urea derivatives according to the above technical solution, (1) Preparation of memantine urea derivatives having the structure represented by formula A: (1-1) X= JPEG2025538342000011.jpg2118, L is None, D is JPEG2025538342000012.jpg1517 and R4 is If not TIFF2025538342000013.tif2641, the method for preparing a memantine urea derivative having a structure represented by Formula A is subjecting compound 1 and compound a to a first acylation reaction to obtain compound b; subjecting compound b to a first reduction reaction to obtain compound c; Compound 2 and compound 4 are subjected to a second acylation reaction to form an intermediate compound TIFF2025538342000014.tif2446 or obtaining TIFF2025538342000015.tif2345; subjecting the intermediate compound and compound c to a first nucleophilic substitution reaction to obtain compound d; subjecting compound d to a first hydrolysis reaction to obtain a memantine urea derivative having a structure represented by Formula A, wherein R4 is -OH; mixing compound 3 with a memantine urea derivative having a structure represented by formula A, wherein R4 is -OH, and subjecting the mixture to a third acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine urea derivative having a structure represented by formula A; The structural formulae of Compound 1 and Compound 2 are, in order: JPEG2025538342000016.jpg4352, JPEG2025538342000017.jpg4250, Compound 3 is NH3, hydroxylamine, alkylamine, alkoxyamine, alcoholamine, phenylamine or naphthylamine; Compound 4 is solid phosgene or thiophosgene; The structural formulas of the compounds a, b, c, and d are: JPEG2025538342000018.jpg67151, wherein R7 in the structural formulae of Compound 1, Compound b, Compound c, and Compound d is selected from C1 to C6 alkyl groups; (1-2) X is -CH2-, L is absent, and D is JPEG2025538342000019.jpg1517 and R4 is If not TIFF2025538342000020.tif2641, the method for preparing a memantine urea derivative having a structure represented by Formula A is subjecting compound a to a second reduction reaction to obtain compound e; subjecting compound e to a second nucleophilic substitution reaction with a brominating reagent to obtain compound f; subjecting compound f and compound 1 to a third nucleophilic substitution reaction to obtain compound g; subjecting compound g to a third reduction reaction to obtain compound h; subjecting the intermediate compound and compound h to a fourth nucleophilic substitution reaction to obtain compound i; subjecting compound i to a second hydrolysis reaction to obtain a memantine urea derivative having a structure represented by Formula A, wherein R4 is -OH; mixing compound 3 with a memantine urea derivative having a structure represented by formula A, wherein R4 is —OH, and subjecting the mixture to a fourth acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine urea derivative having a structure represented by formula A; The structural formulas of the compounds e, f, g, h and i are: JPEG2025538342000021.jpg54148, wherein R7 in the structural formulae of Compound g, Compound h, and Compound i is selected from C1 to C6 alkyl groups; (1-3) X= JPEG2025538342000022.jpg2118, where L is -NH- and D is JPEG2025538342000023.jpg1818 and R4 is If not TIFF2025538342000024.tif2641, the method for preparing a memantine urea derivative having a structure represented by Formula A is subjecting compound z and compound a to a fifth acylation reaction to obtain compound j; subjecting the intermediate compound and compound j to a fifth nucleophilic substitution reaction to obtain compound y; subjecting compound y to a third hydrolysis reaction to obtain a memantine urea derivative having a structure represented by Formula A, wherein R4 is -OH; mixing compound 3 with a memantine urea derivative having a structure represented by formula A, wherein R4 is —OH, and subjecting the mixture to a sixth acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine urea derivative having a structure represented by formula A; The structural formula of the compound z is: JPEG2025538342000025.jpg4061, The structural formula of the compound j is: JPEG2025538342000026.jpg4588, The structural formula of the compound y is: JPEG2025538342000027.jpg60153, wherein R7 in the structural formulas of compounds z, j, and y is selected from C1 to C6 alkyl groups; (1-4) X is -CH2-, L is -NH-, and D is JPEG2025538342000028.jpg1818 and R4 is If not TIFF2025538342000029.tif2641, the method for preparing a memantine urea derivative having a structure represented by Formula A is subjecting compound f and compound z to a sixth nucleophilic substitution reaction to obtain compound k; subjecting compound k to a fourth reduction reaction to obtain compound 5; subjecting the intermediate compound and compound 5 to a seventh nucleophilic substitution reaction to obtain compound 6; subjecting compound 6 to a fourth hydrolysis reaction to obtain a memantine urea derivative having a structure represented by Formula A, wherein R4 is —OH; mixing compound 3 with a memantine urea derivative having a structure represented by formula A, wherein R4 is —OH, and subjecting the mixture to a seventh acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine urea derivative having a structure represented by formula A; The structural formulas of Compound k, Compound 5, and Compound 6 are: JPEG2025538342000030.jpg4588, JPEG2025538342000031.jpg55104, JPEG2025538342000032.jpg67152, wherein R7 in the structural formulae of Compound k, Compound 5, and Compound 6 is selected from C1 to C6 alkyl groups; (1-5) X= JPEG2025538342000033.jpg2118, L is None, D is JPEG2025538342000034.jpg1517 and R4 is TIFF2025538342000035.tif2641, the method for preparing a memantine urea derivative having a structure represented by Formula A is: subjecting compound 7 and compound L to an eighth acylation reaction to obtain compound m; subjecting compound m to a first deprotection reaction under acidic conditions to obtain compound n, a memantine urea derivative having a structure represented by Formula A, wherein Y is -H; The compound n and the compound 8 are mixed and subjected to a ninth acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine, to form Y. obtaining a memantine urea derivative having a structure represented by Formula A, The compound n and the compound 9 are subjected to a tenth acylation reaction to form a compound Y. obtaining a memantine urea derivative having the structure set forth in Formula A, which is TIFF2025538342000037.tif2526; Compound n and compound 10 are subjected to an eighth nucleophilic substitution reaction to form Y. obtaining a memantine urea derivative having the structure set forth in Formula A, Here, the structural formula of the compound 7 is: JPEG2025538342000039.jpg4641, The structural formula of compound 8 is: TIFF2025538342000040.tif2129, The structural formula of compound 9 is: TIFF2025538342000041.tif4451, The structural formula of the compound 10 is R6-C l and The structural formulas of the compounds L, m and n are: JPEG2025538342000042.jpg52133, JPEG2025538342000043.jpg61167, JPEG2025538342000044.jpg59165, (1-6) X=-CH2-, L is absent, and D is JPEG2025538342000045.jpg1517 and R4 is TIFF2025538342000046.tif2641, the method for preparing a memantine urea derivative having a structure represented by Formula A is: subjecting compound 7 and compound o to an eleventh acylation reaction to obtain compound 11; subjecting compound 11 to a second deprotection reaction under acidic conditions to obtain compound 12, a memantine urea derivative having a structure represented by Formula A, wherein Y is -H; Compound 12 and compound 8 are mixed and subjected to acylation reaction 12 in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine, to form Y. obtaining a memantine urea derivative having a structure represented by Formula A, Compound 12 and compound 9 are subjected to a 13th acylation reaction to form a compound having Y as a obtaining a memantine urea derivative having the structure set forth in Formula A, which is TIFF2025538342000048.tif2526; Compound 12 and compound 10 are subjected to a ninth nucleophilic substitution reaction to form a compound having Y. obtaining a memantine urea derivative having the structure set forth in Formula A, Compound o is JPEG2025538342000050.jpg47147, The structural formula of compound 11 is: JPEG2025538342000051.jpg52164, The structural formula of compound 12 is: JPEG2025538342000052.jpg50166, (2) Preparation of memantine urea derivatives having the structure represented by formula B: (2-1) X is JPEG2025538342000053.jpg2118, the method for preparing a memantine urea derivative having a structure represented by Formula B is: subjecting compound 7 and compound a to a fourteenth acylation reaction to obtain compound p; subjecting compound p to a fifth reduction reaction to obtain compound q; subjecting the intermediate compound and compound q to a tenth nucleophilic substitution reaction to obtain compound r; subjecting compound r to a third deprotection reaction under acidic conditions to obtain compound s; subjecting compound 13 and compound s to a fifteenth acylation reaction to obtain compound t; subjecting compound t to a fourth deprotection reaction under acidic conditions to obtain compound u, a memantine urea derivative having a structure represented by Formula B, wherein Y is -H; The compound u and the compound 8 are mixed and subjected to a 16th acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine, to form Y. obtaining a memantine urea derivative having a structure represented by Formula B, The compound u and the compound 9 are subjected to a 17th acylation reaction to form a compound Y. obtaining a memantine urea derivative having a structure according to formula B, Compound u and compound 10 are subjected to an eleventh nucleophilic substitution reaction to form Y obtaining a memantine urea derivative having the structure set forth in Formula B, The structural formula of compound 13 is: JPEG2025538342000057.jpg3971, The structural formulas of the compounds p, q, r, s, t and u are: JPEG2025538342000058.jpg72138, (2-2) When X is —CH—, the method for preparing a memantine urea derivative having a structure represented by formula B is: subjecting compound g and compound 7 to a twelfth nucleophilic substitution reaction to obtain compound v; subjecting compound v to a sixth reduction reaction to obtain compound w; subjecting the intermediate compound and compound w to a thirteenth nucleophilic substitution reaction to obtain compound x, a memantine urea derivative having a structure represented by Formula B, wherein Y is -H; The compound x and the compound 8 are mixed and subjected to an acylation reaction of the compound 18 in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine, to form Y. obtaining a memantine urea derivative having a structure represented by Formula B, The compound x and the compound 9 are subjected to a 19th acylation reaction to form a compound Y. obtaining a memantine urea derivative having a structure according to formula B, Compound x and compound 10 are subjected to a fourteenth nucleophilic substitution reaction to form Y obtaining a memantine urea derivative having the structure set forth in Formula B, The structural formulas of the compounds v, w and x are: JPEG2025538342000062.jpg20137.

[0019] The present application provides the use of memantine urea derivatives in the preparation of medicaments for treating soluble epoxide hydrolase-mediated diseases as described in the above technical solution.

[0020] Preferably, the soluble epoxide hydrolase-mediated disease comprises an inflammatory disease, pain, cardiovascular disease, neurodegenerative disease, diabetes, diabetic complications, chronic nephritis, renal failure, chronic obstructive pulmonary disease or pulmonary hypertension disease. [Effects of the Invention]

[0021] The present application provides memantine urea-based derivatives, which have a typical urea structure as the primary pharmacophore of sEH. The memantine moiety, acting as a hydrophobic fragment, generates hydrophobic forces with the receptor. Molecular docking has shown that the memantine moiety generates hydrophobic forces with the receptor, particularly when R1 and R2 are both methyl groups (i.e., 3,5-dimethyl group substitutions), which can enhance van der Waals forces. Therefore, the memantine urea-based derivatives provided by the present application have high inhibitory activity against human sEH (HsEH) and mouse sEH (MsEH) and can be used as sEH inhibitors to prepare drugs for treating soluble epoxide hydrolase-mediated diseases. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 is a reaction pathway diagram of a memantine urea derivative having a structure represented by Formula A in the present application. [Figure 2] FIG. 1 is a reaction pathway diagram of a memantine urea derivative having a structure represented by Formula A in the present application. [Figure 3] FIG. 1 is a reaction pathway diagram of a memantine urea derivative having a structure represented by Formula A in the present application. [Figure 4] FIG. 1 is a reaction pathway diagram of a memantine urea derivative having a structure represented by Formula A in the present application. [Figure 5] FIG. 1 is a reaction pathway diagram of a memantine urea derivative having a structure represented by Formula A in the present application. [Figure 6] FIG. 1 is a reaction pathway diagram of a memantine urea derivative having a structure represented by Formula A in the present application. [Figure 7] FIG. 1 is a reaction pathway diagram of a memantine urea derivative having a structure represented by Formula B in the present application. [Figure 8] FIG. 1 is a reaction pathway diagram of a memantine urea derivative having a structure represented by Formula B in the present application. DETAILED DESCRIPTION OF THE INVENTION

[0023] The present application provides memantine urea derivatives, having structures represented by Formula A and Formula B: TIFF2025538342000063.tif38125 formula A TIFF2025538342000064.tif34145 type B wherein R1 and R2 are independently selected from -H, -OH, -NH2, -SH, -CN, a halogen group, an alkyl group, an alkoxy group, an aryl group, or a heteroaryl group; R3 is selected from -H, -OH, -NH2, -SH, -CN, a halogen group, an alkyl group, or an alkoxy group; R4 is -OH, -NH2, a hydroxylamine group, an amine group substituted with an alkyl group, an amine group substituted with an alkoxy group, an amine group substituted with an alcohol group, an amine group substituted with a phenyl group, an amine group substituted with a naphthyl group, or Selected from TIFF2025538342000065.tif2641, Y is -H, TIFF2025538342000066.tif2425, TIFF2025538342000067.tif2224 or Selected from TIFF2025538342000068.tif1118, R5 is selected from an alkyl group or a heterocyclic group, and the alkyl group is a linear alkyl group or a cycloalkyl group; R6 is selected from an amino group substituted with an alkyl group or an alkyl group substituted with an alcohol group; X is -CH2 or Selected from JPEG2025538342000069.jpg2118, L is selected from none or -NH-; D is JPEG2025538342000070.jpg1818 or Selected from JPEG2025538342000071.jpg1517, n is 1 or 2, The Z and M are independently selected from =O or =S.

[0024] In the present application, R1 and R2 are preferably independently selected from -H, -OH, -NH2, -SH, -CN, -F, -Cl, -Br, methyl, ethyl, propyl, butyl, pentyl, isobutyl, isopropyl, isopentyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy, cyclohexyloxy, phenoxy, and benzyloxy. In the present application, R1 and R2 are preferably methyl.

[0025] In the present application, R3 is preferably selected from -H, -OH, -NH2, -SH, -CN, -F, -Cl, -Br, an unsubstituted or substituted C1-C6 alkyl group, and an unsubstituted or substituted C1-C6 alkoxy group, and substituents on the substituted C1-C6 alkyl group and substituted C1-C6 alkoxy group are independently selected from -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2, or a C1-C6 alkyl group. In the present application, R3 is also -F.

[0026] In the present application, the alkyl-substituted amino group preferably selected by R4 is an amino group substituted with an unsubstituted or substituted C1-C6 alkyl group, the alkoxy-substituted amino group selected by R4 is an amino group substituted with an unsubstituted or substituted C1-C6 alkoxy group, the phenyl-substituted amine group selected by R4 is an amino group substituted with an unsubstituted or substituted phenyl group, the naphthyl-substituted amine group selected by R4 is an amine group substituted with an unsubstituted or substituted naphthyl group, and the alcohol-substituted amine group selected by R4 is an amine group substituted with an unsubstituted or substituted C1-C6 alcohol group, and the substituents on the substituted C1-C6 alkoxy group, substituted phenyl group, substituted naphthyl group, and substituted C1-C6 alcohol group are independently selected from -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2, or a C1-C6 alkyl group. In the present application, R4 may further be selected from the group consisting of -OH, -NH2, -N(CH3)2, -N(CH2CH3)2, -N(CH2CH2OH)2, -NHCH(CH2OH)2, -NHC(CH2OH)3, -NHCH2CH2OH, -NHCH2CHCH3OH, -N(CH3)2, TIFF2025538342000072.tif2558 or The file is TIFF2025538342000073.tif1948.

[0027] In the present application, the chain alkyl group preferably selected for R5 is an unsubstituted or substituted C1 to C6 saturated or unsaturated chain alkyl group, and the substituent on the substituted C1 to C6 saturated or unsaturated chain alkyl group is selected from -OH, -NH2 or a C1 to C6 alkyl group, and the cycloalkyl group preferably selected for R5 is an unsubstituted or substituted C3 to C6 cycloalkyl group, and the substituent on the substituted C3 to C6 cycloalkyl group is is selected from -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2 or a C1 to C6 alkyl group, and the heterocyclic group preferably selected for R5 is an unsubstituted or substituted C3 to C6 saturated or unsaturated heterocyclic group, and the substituents on the substituted C3 to C6 saturated or unsaturated heterocyclic group are independently selected from -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2 or a C1 to C6 alkyl group. In the present application, R5 is further selected from -CH3, -CH2CH3, -CHCH3CH2CH3, -OCH3, TIFF2025538342000074.tif818, TIFF2025538342000075.tif1818 or TIFF2025538342000076.tif1818.

[0028] In the present application, the alkyl-substituted amino group preferably selected for R6 is an amino group substituted with an unsubstituted or substituted C1-C6 alkyl group, and the alcohol-substituted alkyl group is an alkyl group substituted with an unsubstituted or substituted C1-C6 alcohol group. In the present application, R6 is furthermore -CHCH3CH2N(CH3)2, -CH2CH2N(CH2CH3)2, -CH2CH2N(CH3)2, -CH2CH2OH or -CH2CHOHCH2OH.

[0029] In the present application, furthermore, said n is 2.

[0030] In the present application, furthermore, the memantine urea derivatives include (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxamide (CL-101), 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(((S)-3-(4-propionyl-1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)phenyl)urea (CL-102), 1-((1r,3R,5S,7S)-3,5 -dimethyladamantan-1-yl)-3-(2-fluoro-4-(((3S)-3-(4-(2-methylbutanoyl)-1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)phenyl)urea (CL-103), (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-dimethylpiperidine-3-carboxamide (CL-105), (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urei (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-bis(2-hydroxyethyl)piperidine-3-carboxamide (CL-107), 1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-bis(2-hydroxyethyl)piperidine-4-carboxamide (CL-109) ), (S)-N-(1,3-dihydroxypropan-2-yl)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxamide (CL-112), (3S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxypropyl)piperidine-3-carboxamide (CL-113), (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N-(2-hydroxyethyl)piperidine-3-carboxamide (CL-114), (S)-N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxamide (CL-115), 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-( 2-Fluoro-4-(((S)-3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)piperidin-1-yl)methyl)phenyl)urea (CL-116), N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxamide (CL-117), 1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro benzyl)piperidine-4-carboxamide (CL-118), N-(1,3-dihydroxypropan-2-yl)-1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxamide (CL-119), 1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N-(2-hydroxypropyl)piperidine-4-carboxamide (CL-120), 1-(4-(((S)-3-(4 -acryloyl-1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea (CL-201), 1-(4-((S)-3-(4-(cyclopropanecarbonyl)-1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea (CL-204), 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(((3S)-3-(1-(2-methylbutanoyl)azacyclohexane-4-carbonyl)piperidin-1-yl)methyl)phenyl)urea (CL-205), (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylic acid (CL-5), 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(4-( 2-(1-(2-methylbutanoyl)piperidin-4-yl)acetyl)-1,4-diaza-1-carbonyl)phenyl)urea (CC-103), 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(4-(2-(1-propionylpiperidin-4-yl)acetyl)-1,4-diaza-1-carbonyl)phenyl)urea (CC-105), 1-(4-(4-(2-(1-acetylpiperidin-4-yl)acetyl)-1,4-diaza-1-carbonyl)-2-fluorophenyl) )-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea (CC-106), (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N,N-diethylpiperidine-3-carboxamide (CC-110), 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N,N-diethylpiperidine-4-carboxamide (CC-111), 1 -((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)piperidine-1-carbonyl)phenyl)urea (CC-112), (3S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxypropyl)piperidine-3-carboxamide (CC-113), 1-(4-(3-((1r,3R,5S,7r)-3,1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxyethyl)piperidine-4-carboxamide (CC-114), 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxypropyl)piperidine-4-carboxamide (CC-115), N-(1,3-dihydroxypropan-2-yl)-1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3 -fluorobenzoyl)piperidine-4-carboxamide (CC-116), (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxyethyl)piperidine-3-carboxamide (CC-120), 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((S)-3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)piperidine-1-carbonyl)phenyl)urea (CC- 121), 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(4-(4-(2-(1-(1-(dimethylamino)propan-2-yl)piperidin-4-yl)acetyl)-1,4-diaza-1-carbonyl)-2-fluorophenyl)urea (CC-124), 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(1-propionylpiperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)phenyl)urea (GL-1), 1 -((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(1-(2-methylbutanoyl)piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)phenyl)urea (GL-2), 1-(4-((4-(2-(1-acetylpiperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea (GL-3), 4-(2-(4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-1,4-diaz-1-yl)-2-oxoethyl)piperidine-1-carboxylate methyl (GL-4), 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(1-(2-hydroxyethyl)piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)phenyl)urea (GL-21), 1-(4-((4-(2-(1-(2,3-dihydroxypropyl)piperidine-4-yl)methyl)phenyl)urea (GL-22), 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(4-((4-(2-(1-(2-(dimethylamino)ethyl)piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)-2-fluorophenyl)urea (GL-23), 1-(4-((4-(2-(1-(2-(diethylamino)ethyl)piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)-2-fluorophenyl)urea (GL-24), 1-(4-((S)-3-(4-acetyl-1,4-diaza-1-carbonyl)piperidine-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea (GL-24), 1-(4-((S)-3-(4-acetyl-1,4-diaza-1-carbonyl)piperidine-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea (GL-101), 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea (GL-25), Fluoro-4-((S)-3-(4-propionyl-1,4-diaza-1-carbonyl)piperidine-1-carbonyl)phenyl)urea (GL-102), 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((3S)-3-(4-(2-methylbutanoyl)-1,4-diaza-1-carbonyl)piperidine-1-carbonyl)phenyl)urea (GL-104), 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro-N-((1r,4R)-4-((2-hydroxyethyl)carbamoyl)cyclohexyl)benzamide (ZT-110), 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro-N-((1r,4R)-4-((2-hydroxypropyl)carbamoyl)cyclohexyl)benzamide (ZT-111), N-((1r,4R)-4-(bis(2-hydroxyethyl)carbamoyl)cyclohexyl, N-((1r,4R)-4-carbamoylcyclohexyl)-4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide (ZT-112), N-((1r,4R)-4-carbamoylcyclohexyl)-4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide (ZT-113), N-((1r ,4R)-4-((1,3-dihydroxypropan-2-yl)carbamoyl)cyclohexyl)-4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide (ZT-114), N-((1r,4R)-4-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)carbamoyl)cyclohexyl) 4-(2-((1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide (ZT-115), 4-(2-((1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide)cyclohexane-1-carboxamido)ethyl)pi Examples of the compounds include, but are not limited to, tert-butyl perazine-1-carboxylate (ZT-116), 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro-N-((1r,4R)-4-((2-hydroxyethyl)carbamoyl)cyclohexyl)benzamide (ZT-117), and the structural formula thereof is specifically as follows: TIFF2025538342000077.tif128156

[0031] The present application provides a preparation method for the memantine urea derivatives described in the above technical solutions, and the present application selects the preparation method according to the specific structure of the memantine urea derivatives, which will be specifically described below.

[0032] In the first case, a memantine urea derivative having a structure represented by formula A is prepared. As shown in FIG. 1, the specific preparation method includes the steps (1-1): (1-1) X= JPEG2025538342000078.jpg2118, L is None, D is JPEG2025538342000079.jpg1517 and R4 is If not TIFF2025538342000080.tif2641, the method for preparing a memantine urea derivative having a structure represented by Formula A is subjecting compound 1 and compound a to a first acylation reaction to obtain compound b; subjecting compound b to a first reduction reaction to obtain compound c; Compound 2 and compound 4 are subjected to a second acylation reaction to form an intermediate compound TIFF2025538342000081.tif2446 or obtaining TIFF2025538342000082.tif2242; subjecting the intermediate compound and compound c to a first nucleophilic substitution reaction to obtain compound d; subjecting compound d to a first hydrolysis reaction to obtain a memantine urea derivative having a structure represented by Formula A, wherein R4 is -OH; mixing compound 3 with a memantine urea derivative having a structure represented by formula A, wherein R4 is -OH, and subjecting the mixture to a third acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine urea derivative having a structure represented by formula A; The structural formulae of Compound 1 and Compound 2 are, in order: JPEG2025538342000083.jpg4352, JPEG2025538342000084.jpg4250, Compound 3 is NH3, hydroxylamine, alkylamine, alkoxyamine, alcoholamine, phenylamine or naphthylamine; Compound 4 is solid phosgene or thiophosgene; The structural formulas of the compounds a, b, c, and d are: JPEG2025538342000085.jpg67151, Here, R7 in the structural formulae of Compound 1, Compound b, Compound c and Compound d is selected from C1 to C6 alkyl groups.

[0033] In the present application, compound 1 and compound a are subjected to a first acylation reaction to obtain compound b. In the present application, the molar ratio of compound 1, compound a, organic base, and condensing agent is preferably (1.0-1.5):1:(2-4):(1.2-2), and more preferably 1.2:1:3:1.5. In the present application, the organic base is preferably triethylamine, pyridine, or N,N-diisopropylethylamine, more preferably N,N-diisopropylethylamine. In the present application, the condensing agent is preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, or N,N'-dicyclohexylcarbodiimide, more preferably 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate. The organic solvent is preferably dichloromethane, trichloromethane, or tetrahydrofuran, preferably in the presence of tetrahydrofuran. In the present application, the temperature of the first acylation reaction is preferably 10 to 30°C, more preferably 25°C. The time is preferably 30 to 60 minutes, more preferably 30 minutes. After the first acylation reaction, the present application preferably concentrates the resulting reaction solution under reduced pressure to remove the solvent, adds water, adds ethyl acetate for extraction, and then dries, followed by suction filtration and concentration to obtain compound b.

[0034] After obtaining compound b, the present application subjects compound b to a first reduction reaction to obtain compound c. In the present application, the molar ratio of compound b to catalyst is preferably 1:(0.1 to 0.2), more preferably 1:0.1. In the present application, the reducing agent used in the first reduction reaction is preferably hydrogen gas, the catalyst used is preferably Pd-C, and the first reduction reaction is preferably carried out in the presence of absolute ethanol. In the present application, the temperature of the first reduction reaction is preferably 25 to 70°C, more preferably 60°C, and the time is preferably 10 to 15 hours, more preferably 12 hours. After the first reduction reaction, the present application preferably cools the reaction solution to room temperature, filters it with suction, and concentrates the filtrate under reduced pressure to obtain compound c.

[0035] In the present application, compound 2 and compound 4 are subjected to a second acylation reaction to obtain an intermediate compound. In the present application, the intermediate compound is prepared as follows. The molar ratio of compound 2 to compound 4 is preferably 1:(0.3 to 0.5), more preferably 1:0.5. In the present application, the reaction to prepare the intermediate compound is preferably carried out in the presence of triethylamine and dichloromethane. In the present application, the reaction temperature to prepare the intermediate compound is preferably −78 to −30°C, more preferably −78°C, and the reaction time to prepare the intermediate compound is preferably 30 to 60 minutes, more preferably 30 minutes. After the reaction to prepare the intermediate compound, in the present application, the obtained reaction solution is preferably concentrated under reduced pressure at 40°C for use.

[0036] The intermediate compound and compound c are subjected to a first nucleophilic substitution reaction to obtain compound d. In the present application, the process of the first nucleophilic substitution reaction is as follows: The molar ratio of compound c to triethylamine is preferably 1:(4-6), more preferably 1:6. In the present application, the first nucleophilic substitution reaction is preferably carried out in the presence of triethylamine and dichloromethane. In the present application, the temperature of the first nucleophilic substitution reaction is preferably -10 to -30°C, more preferably 25°C, and the time of the first nucleophilic substitution reaction is preferably 30 to 60 minutes, more preferably 30 minutes. After the first nucleophilic substitution reaction, water is added, ethyl acetate is added for extraction, dried, and then suction filtered and concentrated to obtain compound d.

[0037] Compound d is subjected to a first hydrolysis reaction to obtain a memantine urea derivative having a structure represented by formula A, in which R4 is -OH. Compound 3 is mixed with a memantine urea derivative having a structure represented by formula A, in which R4 is -OH, and the resulting mixture is subjected to a third acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine urea derivative having a structure represented by formula A. In the present application, the molar ratio of compound d to compound 3 is preferably 1:(1.5-2.0), more preferably 1:2. In the present application, the molar ratio of compound d, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and N,N-diisopropylethylamine is preferably 1:(1.2-1.7):(2-3), more preferably 1:1.2:2.4. In the present application, the temperature of the third acylation reaction is preferably 25-35°C, more preferably 30°C, and the time is preferably 1-3 hours, more preferably 2 hours. After the third acylation reaction, the present application preferably pours the resulting reaction solution into water, extracts with dichloromethane, and then washes successively with 1 mol / L hydrochloric acid, 5 wt% aqueous sodium carbonate solution, water, and saturated saline, dries over anhydrous sodium sulfate, and suction-filters the resulting filtrate. The resulting filtrate is concentrated under reduced pressure and subjected to column chromatography to obtain a memantine urea derivative having a structure represented by Formula A. In the examples of the present application, it may specifically be compound CC-110, CC-111, CC-112, CC-113, CC-114, CC-115, CC-116, CC-120 or CC-121.

[0038] In the second case, a memantine urea derivative having the structure represented by formula A is prepared. As shown in FIG. 2, the specific preparation method includes steps (1-2): (1-2) X is -CH2-, L is absent, and D is JPEG2025538342000086.jpg1517 and R4 is If not TIFF2025538342000087.tif2641, the method for preparing a memantine urea derivative having a structure represented by Formula A is subjecting compound a to a second reduction reaction to obtain compound e; subjecting compound e to a second nucleophilic substitution reaction with a brominating reagent to obtain compound f; subjecting compound f and compound 1 to a third nucleophilic substitution reaction to obtain compound g; subjecting compound g to a third reduction reaction to obtain compound h; subjecting the intermediate compound and compound h to a fourth nucleophilic substitution reaction to obtain compound i; subjecting compound i to a second hydrolysis reaction to obtain a memantine urea derivative having a structure represented by Formula A, wherein R4 is -OH; mixing compound 3 with a memantine urea derivative having a structure represented by formula A, wherein R4 is —OH, and subjecting the mixture to a fourth acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine urea derivative having a structure represented by formula A; The structural formulas of the compounds e, f, g, h and i are: JPEG2025538342000088.jpg54148, Here, R7 in the structural formulas of compounds g, h, and i is selected from C1 to C6 alkyl groups.

[0039] In the present application, compound a is subjected to a second reduction reaction to obtain compound e. In the present application, the molar ratio of compound a to the reducing agent is preferably 1:(1.2-3), more preferably 1:2. In the present application, the reducing agent preferably includes borane, lithium aluminum hydride, or diisobutylaluminum hydride, more preferably borane. The organic solvent preferably includes acetonitrile, acetone, and tetrahydrofuran, and is preferably performed in the presence of tetrahydrofuran. In the present application, the temperature of the second reduction reaction is preferably -10 to 10°C, more preferably 0°C, and the time is preferably 8 to 12 hours, more preferably 10 hours. After the second reduction reaction, in the present application, the resulting reaction solution is preferably concentrated under reduced pressure to obtain compound e.

[0040] After obtaining compound e, the present application subjects compound e and a brominating reagent to a second nucleophilic substitution reaction to obtain compound f. In the present application, the molar ratio of compound e to the brominating reagent is preferably 1:(1.2-2), more preferably 1:1.5. In the present application, the brominating reagent preferably includes hydrogen bromide, thionyl bromide, phosphorus tribromide, phosphorus pentabromide, or carbon tetrabromide, more preferably phosphorus tribromide. The organic solvent preferably includes acetonitrile, dichloromethane, and tetrahydrofuran, preferably in the presence of dichloromethane. The organic base preferably includes triethylamine, pyridine, or N,N-diisopropylethylamine, more preferably N,N-diisopropylethylamine. In the present application, the temperature of the second nucleophilic substitution reaction is preferably 25-50°C, more preferably 30°C, and the time is preferably 8-15 hours, more preferably 10 hours. After the second nucleophilic substitution reaction, water is added, and the mixture is extracted with ethyl acetate, dried, and then suction filtered and concentrated to obtain compound f.

[0041] After obtaining compound f, the present application subjects compound f and compound 1 to a third nucleophilic substitution reaction to obtain compound g. In the present application, the molar ratio of compound f to compound 1 is preferably 1:(1.2-2), more preferably 1:1.5, the molar ratio of compound f to acid binder is preferably 1:(2-4), more preferably 1:2, the organic solvent preferably includes acetonitrile, acetone, and tetrahydrofuran, and is preferably performed in the presence of tetrahydrofuran, the acid binder preferably includes triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, cesium carbonate, or sodium carbonate, more preferably potassium carbonate, and in the present application, the temperature of the third nucleophilic substitution reaction is preferably 50-80°C, more preferably 60°C, and the time is preferably 4-8 hours, more preferably 6 hours. After the third nucleophilic substitution reaction, water is added, and the mixture is extracted with ethyl acetate, dried, and then suction filtered and concentrated to obtain compound g.

[0042] After obtaining compound g, the present application subjects compound g to a third reduction reaction to obtain compound h. In the present application, the reducing agent, type of third catalyst, conditions for the third reduction reaction, and post-treatment method used in the third reduction reaction are preferably the same as those used in the first reduction reaction in step (1-1), and therefore further description thereof is omitted here.

[0043] After obtaining compound h, the present application subjects the intermediate compound and compound h to a fourth nucleophilic substitution reaction to obtain compound i. In the present application, the reaction conditions and post-treatment method used in the fourth nucleophilic substitution reaction are preferably the same as those in the first nucleophilic substitution reaction in step (1-1), and therefore, further description thereof will be omitted here.

[0044] After obtaining compound i, the present application subjects compound i to a second hydrolysis reaction to obtain a memantine urea derivative having a structure represented by formula A, in which R4 is -OH. The memantine urea derivative having a structure represented by formula A, in which R4 is -OH, is mixed with compound 3, and the mixture is subjected to a fourth acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine urea derivative having a structure represented by formula A. In the present application, the reaction conditions and post-treatment method used in the fourth acylation reaction are preferably the same as those in the third acylation reaction in step (1-1), and therefore will not be described here. In the examples of the present application, the compound may specifically be compound CL-101, CL-105, CL-106, CL-107, CL-109, CL-112, CL-114, CL-115, CL-116, CL-117, CL-118, CL-119 or CL-120.

[0045] In the third case, a memantine urea derivative having the structure represented by formula A is prepared. As shown in FIG. 3, the specific preparation method includes steps (1-3): (1-3) X= JPEG2025538342000089.jpg2118, where L is -NH- and D is JPEG2025538342000090.jpg1818 and R4 If not TIFF2025538342000091.tif2642, the method for preparing a memantine urea derivative having a structure represented by Formula A is subjecting compound z and compound a to a fifth acylation reaction to obtain compound j; subjecting the intermediate compound and compound j to a fifth nucleophilic substitution reaction to obtain compound y; subjecting compound y to a third hydrolysis reaction to obtain a memantine urea derivative having a structure represented by Formula A, wherein R4 is -OH; mixing compound 3 with a memantine urea derivative having a structure represented by formula A, wherein R4 is —OH, and subjecting the mixture to a sixth acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine urea derivative having a structure represented by formula A; The structural formula of the compound z is: JPEG2025538342000092.jpg4061, The structural formula of the compound j is: JPEG2025538342000093.jpg4588, The structural formula of the compound y is: JPEG2025538342000094.jpg60153, where R7 in the structural formulas of compounds z, j, and y is selected from C1 to C6 alkyl groups.

[0046] In the present application, compound z and compound a are subjected to a fifth acylation reaction to obtain compound j. In the present application, the reaction conditions and post-treatment method used in the fifth acylation reaction are preferably the same as those in the first acylation reaction in step (1-1), and therefore, a description thereof will be omitted here.

[0047] The intermediate compound and compound j are subjected to a fifth nucleophilic substitution reaction to obtain compound y. The present application prepares a memantine urea derivative having a structure represented by formula A according to step (1-1). In the examples of the present application, the memantine urea derivative may specifically be compound ZT-110, ZT-111, ZT-112, ZT-113, ZT-114, ZT-115, ZT-116, or ZT-117.

[0048] In the fourth case, a memantine urea derivative having the structure represented by formula A is prepared. As shown in FIG. 4, the specific preparation method includes steps (1-4): (1-4) X is -CH2-, L is -NH-, and D is JPEG2025538342000095.jpg1818 and R4 If not TIFF2025538342000096.tif2641, the method for preparing a memantine urea derivative having a structure represented by Formula A is subjecting compound f and compound z to a sixth nucleophilic substitution reaction to obtain compound k; subjecting compound k to a fourth reduction reaction to obtain compound 5; subjecting the intermediate compound and compound 5 to a seventh nucleophilic substitution reaction to obtain compound 6; subjecting compound 6 to a fourth hydrolysis reaction to obtain a memantine urea derivative having a structure represented by Formula A, wherein R4 is —OH; mixing compound 3 with a memantine urea derivative having a structure represented by formula A, wherein R4 is —OH, and subjecting the mixture to a seventh acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine urea derivative having a structure represented by formula A; The structural formulas of Compound k, Compound 5, and Compound 6 are: JPEG2025538342000097.jpg4588, JPEG2025538342000098.jpg55104, JPEG2025538342000099.jpg67152, Here, R7 in the structural formulae of Compound k, Compound 5 and Compound 6 is selected from C1 to C6 alkyl groups.

[0049] In the present application, compound f and compound z are subjected to a sixth nucleophilic substitution reaction to obtain compound k. In the present application, the reaction conditions and post-treatment method used in the sixth nucleophilic substitution reaction are preferably the same as those in the third nucleophilic substitution reaction in step (1-2), and therefore, a description thereof will be omitted here.

[0050] Based on the compound k, a memantine urea derivative having a structure represented by formula A is prepared according to step (1-2).

[0051] In the fifth case, a memantine urea derivative having the structure represented by formula A is prepared. As shown in FIG. 5, the specific preparation method includes steps (1-5): (1-5) X= JPEG2025538342000100.jpg2118, L is None, D is JPEG2025538342000101.jpg1517 and R4 is TIFF2025538342000102.tif2642, the method for preparing a memantine urea derivative having a structure represented by Formula A is: subjecting compound 7 and compound L to an eighth acylation reaction to obtain compound m; subjecting compound m to a first deprotection reaction under acidic conditions to obtain compound n, a memantine urea derivative having a structure represented by Formula A, wherein Y is -H; The compound n and the compound 8 are mixed and subjected to a ninth acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine, to form Y. obtaining a memantine urea derivative having a structure represented by Formula A, The compound n and the compound 9 are subjected to a tenth acylation reaction to form a compound Y. obtaining a memantine urea derivative having the structure set forth in Formula A, which is TIFF2025538342000104.tif2526; Compound n and compound 10 are subjected to an eighth nucleophilic substitution reaction to form Y. obtaining a memantine urea derivative having the structure set forth in Formula A, Here, the structural formula of the compound 7 is: JPEG2025538342000106.jpg4641, The structural formula of compound 8 is: TIFF2025538342000107.tif2130, The structural formula of compound 9 is: TIFF2025538342000108.tif4451, The structural formula of compound 10 is R6-Cl, The structural formulas of the compounds L, m and n are: JPEG2025538342000109.jpg49124, JPEG2025538342000110.jpg61167, The file is JPEG2025538342000111.jpg59165.

[0052] In the present application, compound 7 and compound L are subjected to an eighth acylation reaction to obtain compound m. In the present application, the reaction conditions and post-treatment method used in the eighth acylation reaction are preferably the same as those in the first acylation reaction in step (1-1), and therefore, further explanation is omitted here.

[0053] In the present application, compound m is subjected to a first deprotection reaction to obtain compound n. In the present application, the molar ratio of compound m to an acidic reagent is preferably 1:(3-10), more preferably 1:5. In the present application, the acidic conditions preferably include methanol or ethyl acetate, trifluoroacetic acid, more preferably 4-6 mol / L HCl in trifluoroacetic acid, and the organic solvent preferably includes acetonitrile, dichloromethane, and tetrahydrofuran, preferably in the presence of dichloromethane. In the present application, the temperature of the first deprotection reaction is preferably -20 to 50°C, more preferably 30°C, and the time is preferably 2 to 8 hours, more preferably 3 hours. After the first deprotection reaction, in the present application, the resulting reaction solution is preferably concentrated under reduced pressure to obtain compound n.

[0054] Compound n is a memantine urea derivative having a structure represented by formula A, in which Y is -H. The present application describes a method for preparing a compound n and a compound 8, which are mixed together and subjected to a ninth acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine, to obtain a compound having Y of formula A. A memantine urea derivative having a structure represented by Formula A, TIFF2025538342000112.tif2224, is obtained. In the present application, the reaction conditions and post-treatment method used in the ninth acylation reaction are preferably the same as those in the first acylation reaction in step (1-1), and therefore will not be described here. In the examples of the present application, the compound may be GL-101, GL-102, or GL-104.

[0055] The compound n and the compound 9 are subjected to a tenth acylation reaction to form a compound Y. A memantine urea derivative having the structure set forth in Formula A (TIFF2025538342000113.tif2526) is obtained. In the present application, the molar ratio of Compound n to Compound 9 is preferably 1:(1.5-2.5), more preferably 1:2. In the present application, the tenth acylation reaction is preferably carried out in the presence of triethylamine and dichloromethane. In the present application, the temperature of the tenth acylation reaction is preferably room temperature, and the time is preferably 1.5-2.5 hours, more preferably 2 hours. After the tenth acylation reaction, the present application preferably pours the resulting reaction solution into water and extracts it with dichloromethane. The resulting organic layer is washed successively with 6 mol / L hydrochloric acid, 5 wt% aqueous sodium carbonate solution, water, and saturated saline, dried over anhydrous sodium sulfate, and subjected to suction filtration. The resulting filtrate is concentrated under reduced pressure and subjected to column chromatography to obtain a memantine urea derivative having the structure set forth in Formula A.

[0056] After obtaining compound n, the present application provides compound n and compound 10 for an eighth nucleophilic substitution reaction to obtain Y. A memantine urea derivative having the structure shown in Formula A, TIFF2025538342000114.tif1118, is obtained. In the present application, the reaction conditions and post-treatment methods used in the eighth nucleophilic substitution reaction are preferably the same as those in the third nucleophilic substitution reaction in step (1-2), and therefore, further description thereof is omitted here.

[0057] In the sixth case, a memantine urea derivative having the structure represented by formula A is prepared. As shown in FIG. 6, the specific preparation method includes steps (1-6): (1-6) X=-CH2-, L is absent, and D is JPEG2025538342000115.jpg1517 and R4 is TIFF2025538342000116.tif2642, the method for preparing a memantine urea derivative having a structure represented by Formula A is: subjecting compound 7 and compound o to an eleventh acylation reaction to obtain compound 11; subjecting compound 11 to a second deprotection reaction under acidic conditions to obtain compound 12, a memantine urea derivative having a structure represented by Formula A, wherein Y is -H; Compound 12 and compound 8 are mixed and subjected to acylation reaction 12 in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine, to form Y. obtaining a memantine urea derivative having a structure represented by Formula A, Compound 12 and compound 9 are subjected to a 13th acylation reaction to form a compound having Y as a obtaining a memantine urea derivative having the structure set forth in Formula A, which is TIFF2025538342000118.tif2526; Compound 12 and compound 10 are subjected to a ninth nucleophilic substitution reaction to form a compound having Y. obtaining a memantine urea derivative having the structure set forth in Formula A, Compound o is JPEG2025538342000120.jpg47147, The structural formula of compound 11 is: JPEG2025538342000121.jpg52164, The structural formula of compound 12 is: JPEG2025538342000122.jpg50166.

[0058] The present application relates to the compound o, According to TIFF2025538342000123.tif25110, a memantine urea derivative having a structure represented by Formula A is prepared according to steps (1-5). In the examples of the present application, the specific examples may be compounds CL-102, CL-103, CL-201, CL-204, or CL-205.

[0059] In the seventh case, a memantine urea derivative having the structure represented by formula B is prepared. As shown in FIG. 7, the specific preparation method includes the steps (2-1): (2-1) X is JPEG2025538342000124.jpg2118, the method for preparing a memantine urea derivative having a structure represented by Formula B is subjecting compound 7 and compound a to a fourteenth acylation reaction to obtain compound p; subjecting compound p to a fifth reduction reaction to obtain compound q; subjecting the intermediate compound and compound q to a tenth nucleophilic substitution reaction to obtain compound r; subjecting compound r to a third deprotection reaction under acidic conditions to obtain compound s; subjecting compound 13 and compound s to a fifteenth acylation reaction to obtain compound t; subjecting compound t to a fourth deprotection reaction under acidic conditions to obtain compound u, a memantine urea derivative having a structure represented by Formula B, wherein Y is -H; The compound u and the compound 8 are mixed and subjected to a 16th acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine, to form Y. obtaining a memantine urea derivative having a structure represented by Formula B, The compound u and the compound 9 are subjected to a 17th acylation reaction to form a compound Y. obtaining a memantine urea derivative having a structure according to formula B, Compound u and compound 10 are subjected to an eleventh nucleophilic substitution reaction to form Y obtaining a memantine urea derivative having the structure set forth in Formula B, The structural formula of compound 13 is: JPEG2025538342000128.jpg3971, The structural formulas of the compounds p, q, r, s, t and u are: JPEG2025538342000129.jpg72138.

[0060] In the present application, compound 7 and compound a are subjected to a fourteenth acylation reaction to obtain compound p. In the present application, the reaction conditions and post-treatment method used in the fourteenth acylation reaction are preferably the same as those in the first acylation reaction in step (1-1), and therefore, further explanation is omitted here.

[0061] In the present application, compound p is subjected to a fifth reduction reaction to obtain compound q. In the present application, the reaction conditions and post-treatment method used in the fifth reduction reaction are preferably the same as those in the first reduction reaction in step (1-1), and therefore, a description thereof will be omitted here.

[0062] After obtaining compound q, the present application subjects the intermediate compound and compound q to a tenth nucleophilic substitution reaction to obtain compound r. In the present application, the reaction conditions and post-treatment method used in the tenth nucleophilic substitution reaction are preferably the same as those of the first nucleophilic substitution reaction in step (1-1), and therefore, description thereof will be omitted here.

[0063] After obtaining compound r, the present application subjects compound r to a third deprotection reaction under acidic conditions to obtain compound s. In the present application, the reaction conditions and post-treatment method used in the third deprotection reaction are preferably the same as those in the first deprotection reaction in step (1-5), and therefore, the description thereof will be omitted here.

[0064] In the present application, compound 13 and compound s are subjected to a fifteenth acylation reaction to obtain compound t. In the present application, the reaction conditions and post-treatment method used in the fifteenth acylation reaction are preferably the same as those in the first acylation reaction in step (1-1), and therefore, further explanation is omitted here.

[0065] After obtaining compound t, the present application subjects compound t to a fourth deprotection reaction under acidic conditions to obtain compound u. In the present application, the reaction conditions and post-treatment method used in the fourth deprotection reaction are preferably the same as those in the first deprotection reaction in step (1-5), and therefore, the description thereof will be omitted here.

[0066] Based on compound u, memantine urea derivatives having a structure represented by formula B are prepared according to steps (1-5). In the examples of the present application, the memantine urea derivatives may be specifically compounds CC-103, CC-105, CC-106 or CC-124.

[0067] In the eighth case, a memantine urea derivative having the structure represented by formula B is prepared. As shown in FIG. 8, the specific preparation method includes the steps (2-2): (2-2) When X is —CH—, the method for preparing a memantine urea derivative having a structure represented by formula B is: subjecting compound g and compound 7 to a twelfth nucleophilic substitution reaction to obtain compound v; subjecting compound v to a sixth reduction reaction to obtain compound w; subjecting the intermediate compound and compound w to a thirteenth nucleophilic substitution reaction to obtain compound x, a memantine urea derivative having a structure represented by Formula B, wherein Y is -H; The compound x and the compound 8 are mixed and subjected to an acylation reaction of the compound 18 in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine, to form Y. obtaining a memantine urea derivative having a structure represented by Formula B, The compound x and the compound 9 are subjected to a 19th acylation reaction to form a compound Y. obtaining a memantine urea derivative having a structure according to formula B, Compound x and compound 10 are subjected to a fourteenth nucleophilic substitution reaction to form Y obtaining a memantine urea derivative having the structure set forth in Formula B, The structural formulas of the compounds v, w and x are: JPEG2025538342000133.jpg20137.

[0068] In the present application, compound g and compound 7 are subjected to a twelfth nucleophilic substitution reaction to obtain compound v. In the present application, the reaction conditions and post-treatment method used in the twelfth nucleophilic substitution reaction are preferably the same as those in the third nucleophilic substitution reaction in step (1-2), and therefore, a description thereof will be omitted here.

[0069] In the present application, compound v is subjected to a sixth reduction reaction to obtain compound w. In the present application, the reaction conditions and post-treatment method used in the sixth reduction reaction are preferably the same as those in the first reduction reaction in step (1-1), and therefore, further explanation is omitted here.

[0070] After obtaining compound w, the present application subjects the intermediate compound and compound w to a thirteenth nucleophilic substitution reaction to obtain compound x. In the present application, the reaction conditions and post-treatment method used in the thirteenth nucleophilic substitution reaction are preferably the same as those in the first nucleophilic substitution reaction in step (1-1), and therefore, description thereof will be omitted here.

[0071] Based on the compound x, a memantine urea derivative having a structure represented by formula B is prepared according to step (2-1). In the examples of the present application, the specific examples may be compounds GL-1, GL-2, GL-3, GL-4, GL-21, GL-22, GL-23, or GL-24.

[0072] Example 1 Synthesis of ethyl 1-(3-fluoro-4-nitrobenzoyl)piperidine-4-carboxylate 3-Fluoro-4-nitrobenzoic acid (3.0 g, 16.2 mmol) and dry tetrahydrofuran (40 mL) were added to a single-neck flask. After the 3-fluoro-4-nitrobenzoic acid was dissolved, HATU (7.39 g, 19.5 mmol) and DIEA (5.03 g, 38.90 mmol) were added and stirred for 60 min. The solution turned pale yellow, and ethyl 4-piperidinecarboxylate (2.9 g, 16.2 mmol) was added dropwise. After 15 min, the reaction was complete as determined by TLC, and the reaction was stopped. Concentrated under reduced pressure to remove tetrahydrofuran, added water (20 mL), extracted with DCM (15 mL × 2), combined organic layers, washed once with 1N hydrochloric acid (20 mL), washed once with saturated sodium carbonate (20 mL), washed once with water (20 mL), washed once with saturated saline (20 mL), concentrated the organic phase under reduced pressure to obtain 5.7 g of pale yellow oil, loaded 5 times with silica gel into a column, mixed with the sample with 1.2 times with silica gel, eluent (EA:PE = 1:1), subjected to column chromatography to obtain white solid 1-(3-fluoro-4-nitrobenzoyl)piperidine-4-carboxylate ethyl, yield 4.8 g, yield 92%.

[0073] Example 2 Synthesis of ethyl 1-(4-amino-3-fluorobenzoyl)piperidine-4-carboxylate Ethyl 1-(3-fluoro-4-nitrobenzoyl)piperidine-4-carboxylate (3.60 g, 11.6 mmol), 5% Pd-C (0.4 g), and absolute ethanol (50 mL) were added to a single-neck flask, and the mixture was purged with argon gas three times and with hydrogen gas three times. The temperature was raised to 60°C and the mixture was stirred for 12 hours. Completion of the reaction was monitored by TLC, and after the reaction mixture was cooled to room temperature (25°C), it was suction filtered and the filtrate was concentrated under reduced pressure to give 4.0 g of a yellow oily substance, ethyl 1-(4-amino-3-fluorobenzoyl)piperidine-4-carboxylate, in a yield of 90%.

[0074] Example 3 Synthesis of ethyl 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-4-carboxylate Solid phosgene (1.06 g, 3.8 mmol) and dry DCM (30 mL) were placed in a three-neck flask, and the temperature was lowered to below -78 °C using a cold trap. A solution of ethyl 1-(4-amino-3-fluorobenzoyl)piperidine-4-carboxylate (2.13 g, 7.6 mmol) and triethylamine (1.06 g, 3.980 mmol) in dry dichloromethane (60 mL) was added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 0.5 h to react. The reaction was then stopped, and the resulting reaction solution was concentrated under reduced pressure to dryness. The residue was dissolved in dry DCM (10 mL) to obtain an isocyanate solution, which was ready for use. A three-neck flask was charged with memantine (1.36 g, 7.6 mmol), triethylamine (1.54 g, 15.2 mmol), and dry dichloromethane (25 mL). The isocyanate solution was added dropwise and allowed to react at room temperature for 0.5 h. TLC showed the reaction was complete. The reaction mixture was poured into water (40 mL) and extracted with DCM (40 mL × 3). The mixture was then washed sequentially with 1 mol / L HCl (40 mL × 2), water (40 mL × 2), and saturated brine (40 mL), dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure to give 3.4 g of ethyl 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-4-carboxylate as a pale yellow oil. The yield was 5.3 g, or 79%.

[0075] Example 4 Synthesis of 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-4-carboxylic acid Ethyl 1-(4-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-4-carboxylate (3.4 g, 7.0 mmol) was dissolved in tetrahydrofuran (20 mL) in a one-necked flask, and sodium hydroxide (0.36 g, 9.00 mmol) and water (10 mL) were added and the mixture was refluxed. After 12 h, TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran, and water (300 mL) was added to the residue. The mixture was placed in a cold trap and the pH was adjusted to 3 with 6N hydrochloric acid (10 mL). A pale yellow solid was precipitated, which was suction filtered, and the filter cake was rinsed with water (20 mL) and dried to obtain 2.96 g of a crude product (dried in an oven at 60°C for 24 h). The crude product was purified by trituration with petroleum ether and diethyl ether to obtain 2.1 g of a pale yellow solid, (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid, a yield of 90%.

[0076] Example 5 Synthesis of ethyl (S)-1-(3-fluoro-4-nitrobenzoyl)piperidine-3-carboxylate 3-Fluoro-4-nitrobenzoic acid (3.0 g, 16.2 mmol) and dry tetrahydrofuran (40 mL) were added to a single-neck flask. After the 3-fluoro-4-nitrobenzoic acid was dissolved, HATU (7.39 g, 19.5 mmol) and DIEA (5.03 g, 38.90 mmol) were added and stirred for 60 min. The solution turned pale yellow, and (S)-ethyl piperidine-3-carboxylate (2.9 g, 16.2 mmol) was added dropwise. After 15 min, the reaction was complete as determined by TLC, and the reaction was stopped. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, water (20 mL) was added, and the mixture was extracted with DCM (15 mL × 2). The organic layers were combined, washed once with 1N hydrochloric acid (20 mL), once with saturated sodium carbonate (20 mL), once with water (20 mL), once with saturated brine (20 mL), and the organic phase was concentrated under reduced pressure to obtain 5.7 g of a pale yellow oil. 5 times the amount of silica gel was loaded onto a column, and 1.2 times the amount of silica gel was mixed with the sample. The eluent was (EA:PE=1:1). Column chromatography was carried out to obtain white solid (S)-1-(3-fluoro-4-nitrobenzoyl)piperidine-3-carboxylate ethyl, with a yield of 4.8 g and a yield of 92%.

[0077] Example 6 Synthesis of ethyl (S)-1-(4-amino-3-fluorobenzoyl)piperidine-3-carboxylate The procedure of Example 2 was followed, except that ethyl 1-(3-fluoro-4-nitrobenzoyl)piperidine-4-carboxylate was replaced with ethyl (S)-1-(4-amino-3-fluorobenzoyl)piperidine-3-carboxylate. The final white solid obtained was ethyl (S)-1-(4-amino-3-fluorobenzoyl)piperidine-3-carboxylate, in an amount of 4.1 g, representing a yield of 90%.

[0078] Example 7 Synthesis of ethyl (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylate The procedure of Example 3 was followed, except that ethyl 1-(4-amino-3-fluorobenzoyl)piperidine-4-carboxylate was replaced with ethyl (S)-1-(4-amino-3-fluorobenzoyl)piperidine-3-carboxylate, and the final white solid obtained was ethyl (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylate, in an amount of 5.4 g, representing a yield of 80%.

[0079] Example 8 Synthesis of (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylic acid The method of Example 4 was followed, except that ethyl 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-4-carboxylate was replaced with ethyl (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylate; the final white solid obtained was (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylic acid, yielding 4.8 g, a 90% yield.

[0080] Example 9 Synthesis of (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxyethyl)piperidine-3-carboxamide (CC-120) A single-neck flask was charged with 1-(4-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-4-carboxylic acid (0.4 g, 0.85 mmol) and dry tetrahydrofuran (10 mL). After the 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-4-carboxylic acid was dissolved, HATU (0.5 g, 1.28 mmol) was added and stirred for 15 min. DIEA (0.33 g, 2.55 mmol) was added dropwise, and the mixture was stirred for 30 min. A solution of 2-aminoethanol-1-ol (0.038 g, 0.85 mmol) in dry THF (5 mL) was added dropwise. After 15 min, the reaction was complete as determined by TLC, and the reaction was stopped. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, water (20 mL) was added, and the mixture was extracted with DCM (15 mL × 2). The combined organic layers were washed once with 1N hydrochloric acid (20 mL), once with saturated sodium carbonate (20 mL), once with water (20 mL), and once with saturated brine (20 mL). The organic phase was concentrated under reduced pressure to obtain 0.6 g of a pale yellow oil. The mixture was loaded onto a column with 5 volumes of silica gel and mixed with the sample using 1.2 volumes of silica gel. The eluent was (EA:PE = 1:1). Column chromatography was performed to obtain a white solid, CC-120, with a yield of 0.21 g and a 23% yield. The mp was 128-129 °C. 1 H NMR(400MHz,DMSO-d6):δ(ppm)8.30(s,1H),8.20(t,1H,J=8.4Hz),7.91(s,1H),7.20(dd,1H, J=1.6Hz,11.7Hz),7.08(d,1H,J=8.4Hz),6.58(s,1H),4.66(s,1H),4.34(s,1H),3.62(s,1H), 3.36(s,2H),3.09(s,2H),2.89(s,2H),2.36-2.30(m,1H),2.09(s,1H),1.87-1.84(m,1H),1. 76(s,2H),1.62-1.55(m,5H),1,35-1.32(m,3H),1.27-1.24(m,3H),1.12(s,2H),0.83(s,6H). 13C NMR(100MHz,DMSO-d6):δ173.03,168.33,153.81,152.15,149.75,123.84,119.24,114.44,114.24,60.25,60.25, 52.14,50.71,47.99,47.99,42.76,42.76,41.81,32.39,32.39,32.39,30.52,30.52,30.52,30.04,30.04,28.19.

[0081] Example 10 Synthesis of 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((S)-3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)piperidine-1-carbonyl)phenyl)urea (CC-121) Using the procedure of Example 9, starting from 2-(piperazin-1-yl)ethan-1-ol (i.e., the amine in Example 9 is specifically 2-(piperazin-1-yl)ethan-1-ol, and the acid is 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylic acid), a white solid, CC-121, was obtained in an amount of 0.21 g, a yield of 23%, and an mp of 141-145°C. 1 H NMR(400MHz,DMSO-d6):δ(ppm)8.30(s,1H),8.20(t,1H,J=8.4Hz),7.24(d,1H,J =11.8Hz),7.11(d,1H,J=8.5Hz),6.58(s,1H),4.43(s,1H),4.32(s,1H),3.49(s ,6H),3.05(s,1H),2.79(s,2H),2.38(s,5H),2.09(s,1H),1.82-1.76(m,3H),1. 58(s,8H),1.35-1.32(m,2H),1.27-1.24(m,3H),1.18-1.12(m,3H),0.83(s,6H). 13C NMR (100MHz, DMSO-d6): δ168.44,153.81,152.16,149.76,123.75,119.34,114.31,114.11,60.44,58.79,54.04,53.29,52.13,52. 13,50.71,47.98,47.98,45.19,42.76,42.76,41.39,38.29,32.38,32.38,32.38,32.38,30.52,30.52,30.52,30.04,30.04,27.98.

[0082] Example 11 Synthesis of (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N,N-diethylpiperidine-3-carboxamide (CC-110) The procedure was carried out according to the method of Example 9, using diethylamine as the starting material (i.e., the amine in Example 9 is specifically diethylamine, and the acid is 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylic acid), to obtain a white solid, CC-110, in an amount of 0.25 g, with a yield of 26% and an mp of 125-127°C. 1 H NMR (400MHz, CDCl3): δ(ppm)8.20(t,J=8.0Hz,1H),7.57-7.54(m,1H),7.07-6 .99(m,2H),5.63(br,1H),4.63(br,1H),3.81(s,1H),3.48-3.35(m,4H),3.18 -2.99(m,2H),2.73-2.56(m,1H),2.13(s,1H),1.91(s,2H),1.84(s,3H),1.63 (s,4H),1.38-1.35(m,2H),1.29-1.24(m,4H),1.18-1.10(m,7H),0.83(s,6H). 13C-NMR(100MHz,CDCl3):δ(ppm)172.26,169.89,154.13,136.38,130.30,127.80,123.48,12 0.02,113.97,52.72,50.62,48.01,42.72,42.02,40.61,40.38,32.37,30.13,14.95,13.06.

[0083] Example 12 Synthesis of (3S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxypropyl)piperidine-3-carboxamide (CC-113) The procedure of Example 9 was followed, using 1-aminopropan-2-ol as the starting material (i.e., the amine in Example 9 is specifically 1-aminopropan-2-ol, and the acid is 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylic acid), to obtain a white solid, CC-113, in an amount of 0.27 g, a yield of 29%, and an mp of 131-132°C. 1 H NMR (400MHz, CDCl3): δ(ppm)8.20(s,1H),7.61(s,1H),7.05-7.03(m,2H),5.85(br,1H),4.05(b r,1H),3.86(br,1H),3.55(br,4H),3.38-3.35(m,1H),3.29-3.20(m,1H),3.2-2.95(m,1H),2.8 1(br,1H),2.48(br,1H),2.13(br,1H),2.06-2.02(m,1H),1.88-1.84(m,1H),1.81(s,2H),1.62 (s,5H),1.44-1.43(m,1H),137-1.34(m,2H),1.30-1.24(m,3H),1.44-1.11(m,5H),0.84(m,6H). 13C NMR(100MHz,CDCl3):δ(ppm)173.03,169.72,154.14,130.26,130.17,127.87,123.27,120.48,113.8 5,52.82,50.04,47.98,42.72,41.98,40.56,40.47,38.49,32.39,30.17,30.13,28.82,15.06,13.10.

[0084] Example 13 Synthesis of 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(4-(4-(2-hydroxyethyl)piperazine-1-carbonyl))piperidine-1-carbonyl)phenyl)urea (CC-112) Using the procedure of Example 9, starting from 2-(piperazin-1-yl)ethan-1-ol (i.e., the amine in Example 9 is specifically 2-(piperazin-1-yl)ethan-1-ol, and the acid is (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid), a white solid, CC-112, was obtained in an amount of 0.21 g, a yield of 25%, and an MP of 128-129°C. 1 H NMR(400MHz,DMSO-d6):δ(ppm)8.29(s,1H),8.19(t,1H,J=8.24Hz),7.20(d,1H,J=11.72 Hz),7.08(d,1H,J=8.32Hz),6.58(s,1H),4.44(s,1H),3.50-3.49(m,4H),3.43(s,2H),2. 92(s,2H),2.40-2.37(m,4H),2.33(s,2H),2.09(s,1H),1.76(s,2H),1.58(s,6H),1.49-1 .46(m,3H),1.35-1.32(m,2H),1.27-1.24(m,3H),1.12(s,2H),1.05(s,2H),0.83(s,6H). 13C NMR (100MHz, DMSO-d6): δ172.43,168.26,153.82,152.19,149.78,123.82,119.28,114.42,114.21,60.54,58.93,58.93,54.20,53. 43,52.13,50.71,47.99,47.99,46.15,45.28,42.76,42.76,41.60,37.41,32.39,32.39,32.39,30.52,30.52,30.52,30.03,28.88.

[0085] Example 14 Synthesis of 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxyethyl)piperidine-4-carboxamide (CC-114) The procedure of Example 9 was followed, using 2-aminoethanol-1-ol as the starting material (i.e., the amine in Example 9 is specifically 2-aminoethanol-1-ol, and the acid is (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid), to obtain a white solid, CC-114, in an amount of 0.24 g, with a yield of 27% and an mp of 125-126°C. 1 H NMR(400MHz,DMSO-d6):δ(ppm)8.30(s,1H),8.20(t,1H,J=8.3Hz),7.82(t,1H,J=5.2Hz),7.20(d,1H, J=11.6Hz),7.09(d,1H,J=8.4Hz),6.58(s,1H),4.65(t,1H,J=5.5Hz),4.33(s,1H),3.72(s,1H),3.40- 3.37(m,1H),3.10(q,2H,J=5.9Hz),2.91(s,2H),2.42-2.37(m,1H),2.09(s,1H),1.76(s,2H),1.68(s ,2H),1.58(s,4H),1.50-1.48(m,2H),1.35-1.32(m,2H),1.27-1.24(m,2H),1.12(s,2H),0.83(s,6H). 13C NMR(100MHz,DMSO-d6):δ174.32,168.27,153.81,149.77,123.80,119.30,114.38,114.17,60.33,60.33,52.13,52.13, 50.71,47.99,47.99,42.76,42.76,42.19,41.85,32.38,32.38,32.38,32.38,30.52,30.52,30.52,30.03,30.03,29.04.

[0086] Example 15 Synthesis of 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxypropyl)piperidine-4-carboxamide (CC-115) The procedure of Example 9 was followed, using 1-aminopropan-2-ol as the starting material (i.e., the amine in Example 9 is specifically 1-aminopropan-2-ol, and the acid is (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid), to obtain a white solid, CC-115, in an amount of 0.23 g, a yield of 26%, and an MP of 115-116°C. 1 H NMR(400MHz,DMSO-d6):δ(ppm)8.30(s,1H),8.19(t,1H,J=8.4Hz),7.63(d,1H,J=7.7Hz),7.20 (q,1H,J=1.7,11.7Hz),7.09(d,1H,J=8.4Hz),6.58(s,1H),4.52(s,1H),3.43(s,1H),2.89(s,2 H),2.36-2.30(m,1H),2.09(s,1H),1.78-1.76(m,2H),1.72-1.71(m,2H),1.58(s,4H),1.49-1 .46(m,2H),1.35-1.32(m,2H),1.27-1.32(m,4H),1.17-1.15(m,4H),1.21(s,3H),0.83(s,6H). 13C NMR (100MHz, DMSO-d6): δ173.42,168.28,153.81,152.18,149.77,123.81,119.30,114.38,114.17,68.63,52.13,50.71,47. 99,47.99,47.42,42.76,42.76,42.24,42.24,34.40,34.40,32.38,32.38,32.38,30.73,30.52,30.52,30.52,30.04,29.00.

[0087] Example 16 Synthesis of N-(1,3-dihydroxypropan-2-yl)-1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-4-carboxamide (CC-116) Using the procedure of Example 9, starting from 2,2'-azadiyldi(ethan-1-ol) (i.e., the amine in Example 9 is specifically 2,2'-azadiyldi(ethan-1-ol, and the acid is (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid), a white solid, CC-116, was obtained in an amount of 0.23 g, with a yield of 26% and an mp of 113-114°C. 1 H NMR(400MHz,DMSO-d6):δ(ppm)8.36(s,1H),8.20(t,1H,J=8.3Hz),7.63(d,1H,J=8.0Hz),7.21(d,1 H,J=11.7Hz),7.09(d,1H,J=8.68Hz),6.67(s,1H),4.62(t,2H,J=5.4Hz),3.71-3.66(m,1H),3.40-3 .39(m,2H),3.08-3.06(m,4H),2.10(s,1H),1.76(s,1H),1.68(s,1H),1.59(s,3H),1.50-1.48(m,2 H),1.41-1.35(m,1H),1.32(s,1H),1.28-1.24(m,3H),1.21-1.18(m,5H),1.12(s,2H),0.83(s,6H). 13C NMR(100MHz,DMSO-d6):δ174.24,168.29,153.86,152.19,149.79,123.80,119.35,114.38,114.17,60.59,60.59,53.16 ,52.13,50.72,47.99,47.99,45.87,45.87,42.77,42.19,32.38,32.38,32.38,30.53,30.53,30.53,30.03,29.03,8.94.

[0088] Example 17 Synthesis of 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N,N-diethylpiperidine-4-carboxamide (CC-111) The procedure was carried out according to the method of Example 9, using diethylamine as the starting material (i.e., the amine in Example 9 is specifically diethylamine, and the acid is (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid), to obtain a white solid, CC-111, in an amount of 0.33 g, a yield of 36%, and an MP of 102-104°C. 1 H NMR (400MHz, CDCl3): δ(ppm)8.15(t,J=8.5Hz,1H),7.33(br,1H),7.07-7.05(m ,2H),5.65(br,1H),4.61(br,1H),3.93(br,1H),3.41-3.33(m,4H),3.03-2.95 (m,2H),2.75-2.69(m,1H),2.14-2.13(m,1H),1.82(s,2H),1.72(br,3H),1.64 (s,5H),1.39-1.36(m,2H),1.29-1.23(m,6H),1.16-1.09(m,5H),0.82(s,6H). 13C NMR(100MHz,CDCl3):δ(ppm)173.03,169.72,154.14,130.26,130.17,127.87,123.27,120.48,113.8 5,52.82,50.04,47.98,42.72,41.98,40.56,40.47,38.49,32.39,30.17,30.13,28.82,15.06,13.10.

[0089] Example 18 Synthesis of 3-fluoro-4-nitrobenzyl alcohol 3-Fluoro-4-nitrobenzoic acid (20 g, 0.11 mol) and tetrahydrofuran (THF, 200 mL) were added to a three-necked flask, the temperature was lowered to 0°C using a cold trap, and a solution of borane in THF (160 mL) was added dropwise. After the addition was completed, the reaction was allowed to proceed at 0°C for 10 hours. Completion of the reaction was monitored by TLC, and the resulting reaction solution was concentrated under reduced pressure to remove the THF, yielding 17.8 g of 3-fluoro-4-nitrobenzyl alcohol as a white solid, with a yield of 95%.

[0090] Example 19 Synthesis of 4-(bromomethyl)-2-fluoro-1-nitrobenzene 3-Fluoro-4-nitrobenzyl alcohol (17.0 g, 99.4 mmol), phosphorus tribromide (18.5 g, 50 mmol), and N,N-diisopropylethylamine (20 mL) were added to a single-neck flask and stirred at 30°C for 10 h. The reaction was monitored by TLC to confirm completion of the reaction. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL), dried, suction filtered, and concentrated to give a yellow solid, 4-(bromomethyl)-2-fluoro-1-nitrobenzene, in an amount of 17.4 g and a yield of 92%.

[0091] Example 20 Synthesis of ethyl (S)-1-(3-fluoro-4-nitrobenzyl)piperidine-3-carboxylate A single-neck flask was charged with 4-(bromomethyl)-2-fluoro-1-nitrobenzene (2.8 g, 12.9 mmol) and dry acetonitrile (35 mL). After the 4-(bromomethyl)-2-fluoro-1-nitrobenzene was dissolved, potassium carbonate (2.13 g, 15.4 mmol), potassium iodide (0.15 g, 1.29 mmol), and (S)-ethyl piperidine-3-carboxylate (2.03 g, 12.9 mmol) were added and the reaction was refluxed. After 6 h, the reaction was monitored for completion by TLC. The mixture was concentrated under reduced pressure to remove acetonitrile, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic layers were combined, washed with water (20 mL), and washed once with saturated brine (25 mL). The organic phase was concentrated under reduced pressure to obtain 5.2 g of yellow oil. 4 times the amount of silica gel was loaded into a column, and 1.2 times the amount of silica gel was mixed with the sample. The eluent was (EA:PE=1:40). The mixture was subjected to column chromatography to obtain 4.4 g of yellow oil, the yield of which was 82%. (S)-1-(3-fluoro-4-nitrobenzyl)piperidine-3-carboxylate was obtained.

[0092] Example 21 Synthesis of ethyl (S)-1-(4-amino-3-fluorobenzyl)piperidine-3-carboxylate A single-necked flask was charged with (S)-ethyl 1-(3-fluoro-4-nitrobenzyl)piperidine-3-carboxylate (3.48 g, 11.6 mmol), 5% Pd-C (0.4 g), and absolute ethanol (50 mL). The mixture was purged with argon gas three times and with hydrogen gas three times. The temperature was raised to 60°C and the reaction was stirred for 12 hours. Completion of the reaction was monitored by TLC. After the reaction mixture was cooled to room temperature (25°C), it was suction filtered and the filtrate was concentrated under reduced pressure to give 2.76 g of a yellow oily substance, ethyl (S)-1-(4-amino-3-fluorobenzyl)piperidine-3-carboxylate, in a yield of 86%.

[0093] Example 22 Synthesis of ethyl (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylate Solid phosgene (1.06 g, 3.8 mmol) and dry DCM (30 mL) were placed in a three-neck flask, and the temperature was lowered to below -78 °C using a cold trap. A solution of ethyl (S)-1-(4-amino-3-fluorobenzyl)piperidine-3-carboxylate (2.10 g, 7.6 mmol) and triethylamine (1.06 g, 3.980 mmol) in dry dichloromethane (60 mL) was added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 0.5 h to react. The reaction was then stopped, and the resulting reaction solution was concentrated under reduced pressure to dryness. The residue was dissolved in dry DCM (10 mL) to obtain an isocyanate solution, which was then ready for use. A three-neck flask was charged with memantine (1.36 g, 7.6 mmol), triethylamine (1.54 g, 15.2 mmol), and dry dichloromethane (25 mL). The isocyanate solution was added dropwise and allowed to react at room temperature for 0.5 h. TLC showed the reaction was complete. The reaction mixture was poured into water (40 mL), extracted with DCM (40 mL × 3), washed sequentially with 1 mol / L HCl (40 mL × 2), water (40 mL × 2), and saturated brine (40 mL), dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure to give 3.3 g of a pale yellow oil: ethyl (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylate. This was used directly in the next step without further purification.

[0094] Example 23 Synthesis of (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylic acid Ethyl (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylate (3.3 g, 7.0 mmol) was dissolved in tetrahydrofuran (20 mL) in a one-neck flask, and sodium hydroxide (0.36 g, 9.00 mmol) and water (10 mL) were added and the mixture was refluxed. After 12 h, TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran, and water (300 mL) was added to the residue. The mixture was placed in a cold trap and the pH was adjusted to 3 with 6N hydrochloric acid (10 mL). A pale yellow solid was precipitated, which was suction filtered, and the filter cake was rinsed with water (20 mL) and dried to give 2.96 g of crude product (dried in an oven at 60°C for 24 hours). The crude product was purified by trituration with petroleum ether and diethyl ether to give 2.7 g of a pale yellow solid, (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylic acid, a yield of 86%.

[0095] Example 24 Synthesis of ethyl 1-(3-fluoro-4-nitrobenzyl)piperidine-4-formate The procedure of Example 20 was followed, except that ethyl (S)-piperidine-3-carboxylate was replaced with ethyl 4-piperidineformate. The final white solid obtained was ethyl 1-(3-fluoro-4-nitrobenzyl)piperidine-4-formate in an amount of 4.7 g, representing a yield of 84%.

[0096] Example 25 Synthesis of ethyl 1-(4-amino-3-fluorobenzyl)piperidine-4-formate The procedure of Example 21 was followed, except that ethyl (S)-1-(3-fluoro-4-nitrobenzyl)piperidine-3-carboxylate was replaced with ethyl 1-(3-fluoro-4-nitrobenzyl)piperidine-4-formate, and the final white solid obtained was ethyl 1-(4-amino-3-fluorobenzyl)piperidine-4-formate, in an amount of 2.7 g and a yield of 81%.

[0097] Example 26 Synthesis of ethyl 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxylate The method of Example 22 was followed except that ethyl (S)-1-(4-amino-3-fluorobenzyl)piperidine-3-carboxylate was replaced with ethyl 1-(4-amino-3-fluorobenzyl)piperidine-4-formate, and the final white solid obtained was ethyl 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxylate; the crude product was not purified.

[0098] Example 27 Synthesis of 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxylic acid (CL-5) The method of Example 23 was followed except that ethyl (S)-1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylate was replaced with ethyl 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxylate, and the final white solid obtained was 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxylic acid in an amount of 2.4 g, a yield of 75%.

[0099] Example 28 Synthesis of (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-dimethylpiperidine-3-carboxamide (CL-105) (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylic acid (0.4 g, 0.85 mmol) and dry tetrahydrofuran (10 mL) were placed in a single-neck flask. After (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylic acid was dissolved, HATU (0.5 g, 1.28 mmol) was added and the mixture was stirred for 15 min. DIEA (0.33 g, 2.55 mmol) was added dropwise, and the mixture was stirred for 30 min. A solution of dimethylamine (0.038 g, 0.85 mmol) in dry THF (5 mL) was added dropwise. After 15 min, TLC showed the reaction was complete, and the reaction was stopped. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, water (20 mL) was added, and the mixture was extracted with DCM (15 mL × 2). The organic layers were combined and washed once with 1N hydrochloric acid (20 mL), once with saturated sodium carbonate (20 mL), once with water (20 mL), and once with saturated brine (20 mL). The organic phase was concentrated under reduced pressure to obtain 0.6 g of a pale yellow oil. Five volumes of silica gel were loaded onto a column, and the mixture was mixed with 1.2 volumes of silica gel. The eluent was (EA:PE = 1:1). Column chromatography was performed to obtain 0.22 g of a white solid, CL-105, with a yield of 51% and an mp of 111-112 °C. 1 H NMR (400MHz, CDCl3): δ(ppm)7.93(t,J=8.92Hz,1H),7.13-7.12(m,1H),6.91-6.85( m,2H),5.53(s,1H),3.39-3.27(m,2H),2.94(s,3H),2.83(s,3H),2.79-2.72(m,3H) ,2.07-2.02(m,2H),1.89-1.85(m,1H),1.76-1.70(m,3H),1.62-1.54(m,6H),1.42- 1.39(m,1H),1.30-1.27(m,2H),1.21-1.18(m,2H),1.10-1.02(m,2H),0.75(s,6H). 13C-NMR(100MHz,DMSO-d6):δ(ppm)174.5,154.5,153.4,151.1,124.9,120.9,115.2,115.1,65.6,62.5,55 .6,53.6,52.7,50.7,48.1,42.8,40.7,39.6,37.2,35.6,32.4,30.5,30.2,30.2,29.7,27.3,24.9,13.7.

[0100] Example 29 Synthesis of (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-diethylpiperidine-3-carboxamide (CL-106) According to the method of Example 9, diethylamine was used as the raw material (i.e., the amine in Example 9 is specifically diethylamine), and a white solid, CL-106, was obtained in an amount of 0.27 g, with a yield of 57% and an mp of 159-160°C. 1 H NMR(400MHz,DMSO-d6):δ(ppm)8.27-8.22(m,2H),7.42-7.14(m,2H),6.55(s,1H),4.31-4.24(m,1H),3.27-3.17(m,6H),2.91(s ,3H),2.09(s,1H),1.75(s,5H),1.57(s,4H),1.41(s,2H),1.40-1.25(m,5H),1.12-1.09(m,5H),1.00-0.98(m,3H),0.83(s,6H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)172.5,153.8,152.0,150.4,129.9,127.5,119.8,117.3,59.3,54.0 ,52.2,52.1,52.1,52.0,50.7,48.0,42.7,42.3,41.8,32.5,32.3,30.5,30.0,28.9,26.8,23.0,22.9.

[0101] Example 30 Synthesis of (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-bis(2-hydroxyethyl)piperidine-3-carboxamide (CL-107) According to the method of Example 9, diethanolamine was used as the raw material (i.e., the amine in Example 9 is specifically diethanolamine), and a white solid, CL-107, was obtained in an amount of 0.30 g, with a yield of 64% and an mp of 123-124°C. 1 H NMR (400MHz, CDCl3): δ(ppm)8.08(t,J=8.36Hz,1H),6.95-6.90(m,2H),5.67(s, 1H),3.73-3.62(m,2H),3.45-3.43(m,1H),3.14(q,J=8.00Hz,2H),2.86(s,2H), 2.45(s,1H),2.14(s,2H),1.98-1.97(m,3H),1.89-1.83(m,3H),1.65(s,4H),1. 57(s,2H),1.42-1.33(m,5H),1.30-1.24(m,5H),1.15-1.14(m,2H),0.75(s,6H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)174.8,154.5,154.4,153.5,151.1,125.3,120.9,115.1,125.3,120.9,115.1,69 .7,62.5,60.4,54.3,54.1,52.8,50.6,48.1,47.3,42.7,40.7,33.8,32.4,30.9,30.2,26.7,22.2,21.1,14.2,8.9.

[0102] Example 31 Synthesis of (S)—N-(1,3-dihydroxypropan-2-yl)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxamide (CL-112) The procedure of Example 9 was followed, using 2-amino-1,3-propanediol as the starting material (i.e., the amine in Example 9 is specifically 2-amino-1,3-propanediol), to obtain a white solid, CL-112, in an amount of 0.12 g, with a yield of 28% and an mp of 113-114°C. 1 H NMR (400MHz, CDCl3): δ(ppm)7.87-7.86(m,1H),7.45(s,1H),7.04-7.01(m,1H),6.85-6.83(m,1H),5.88(s,1H),3.87(s,1H),3.67 -3.30(m,7H),3.01-2.70(m,2H),2.43(s,1H),2.03(s,1H),1.73(s,3H),1.55(s,7H),1.28-1.77(m,7H),1.05(s,3H),0.74(s,6H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)166.5,150.0,148.9,146.5,122.8,120.7,116.0,110.9,57.2,57.0,55.7,4 9.4,47.9,47.6,45.9,43.4,41.9,37.9,35.8,27.6,27.2,25.4,24.9,24.6,22.1,17.9,17.6,16.3,9.4,9.3.

[0103] Example 31 Synthesis of (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N-(2-hydroxypropyl)piperidine-3-carboxamide (CL-113) The procedure of Example 9 was followed, using 1-amino-2-propanol as the starting material (i.e., the amine in Example 9 is specifically 1-amino-2-propanol), to obtain a white solid, CL-113, in an amount of 0.18 g, with a yield of 32% and an mp of 91-92°C. 1H NMR (400MHz, CDCl3): δ(ppm)7.98(t,J=7.36Hz,1H),7.01-6.94(m,3H),5.29(s,1H),3.91-3.85(m,1H),3.50-3.26(m,4H),3.10-3.07(m,3) H),2.81(s,2H),2.51(s,1H),2.30(s,2H),2.14(s,1H),1.84(s,3H), 1.15-1.58(m,7H),1.27-1.22(m,4H),1.16-1.14(m,4H),0.84(s,6H). 13 C-NMR (100MHz, DMSO-d6): δ(ppm)176.5,154.3,153.6,151.2,125.3,121.3,115.6,115.4,67.4,67.3,62. 3,54.2,53.9,52.9,50.6,48.1,47.3,47.0,46.9,42.7,40.7,32.4,30.2,30.1,26.7,22.5,20.9,8.8,8.6.

[0104] Example 32 Synthesis of (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N-(2-hydroxyethyl)piperidine-3-carboxamide (CL-114) According to the method of Example 9, ethanolamine was used as the raw material (i.e., the amine in Example 9 is specifically ethanolamine), and a white solid, CL-114, was obtained in an amount of 0.19 g, with a yield of 35% and an mp of 94-95°C. 1 H NMR(400MHz,CDCl3):δ(ppm)8.00(t,J=8.33Hz,1H),7.08(s,1H),7.00-6.9 5(m,2H),5.46(s,1H),3.64-3.62(m,2H),3.51-3.45(m,1H),3.37-3.35(m,3 H),3.16-3.09(m,2H),2.79(s,1H),2.49(s,1H),2.29(s,2H),2.14(s,1H),1 .83(s,2H),1.65-1.62(m,6H),1.42-1.26(m,8H),1.14(s,4H),0.84(s,6H). 13C-NMR(100MHz,DMSO-d6):δ(ppm)176.4,154.3,151.2,127.3,125.3,121.1,115.5,115.3,62.3,6 2.1,54.1,52.9,50.6,48.1,47.2,42.7,42.2,40.7,32.4,30.2,30.1,26.7,22.6,22.5,14.1,8.9.

[0105] Example 33 Synthesis of (S)—N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxamide (CL-115) Using the method of Example 9 and 2-amino-2-(hydroxymethyl)propane-1,3-diol as the starting material (i.e., the amine in Example 9 is specifically 2-amino-2-(hydroxymethyl)propane-1,3-diol), a white solid, CL-115, was obtained in an amount of 0.19 g, with a yield of 31% and an mp of 111-112°C. 1 H NMR (400MHz, CDCl3): δ(ppm)7.88(t,J=8.16Hz,1H),7.16-7.09(m,2H),6.96-6 .94(m,1H),5.50(s,1H),4.63(s,2H),3.67-3.60(m,4H),3.46-3.35(m,2H),3. 12(q,J=7.28Hz,2H),2.81-2.78(m,2H),2.50(s,1H),2.29(s,1H),2.13(s,1H) ,1.81(s,3H),1.63(s,6H),1.37-1.26(m,7H),1.17-1.10(m,2H),0.84(s,6H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)175.4,154.1,152.5,150.9,127.7,125.3,119.9,115.6,62.6,61.9 ,61.1,60.6,55.6,53.3,52.0,50.7,48.1,46.2,42.7,32.4,32.4,32.3,30.6,30.5,30.0,27.7,23.8.

[0106] Example 34 Synthesis of 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(((S)-3-(4-(2-hydroxyethyl)piperazine)-1-carbonyl)piperidin-1-yl)methyl)phenyl)urea (CL-116) The procedure of Example 9 was followed, using 2-(piperazin-1-yl)ethan-1-ol as the starting material (i.e., the amine in Example 9 is specifically 2-(piperazin-1-yl)ethan-1-ol), to obtain a white solid, CL-116, in an amount of 0.24 g, with a yield of 32% and an mp of 116-117°C. 1 H NMR (400MHz, CDCl3): δ(ppm)7.99(t,J=8.24Hz,1H),7.01-6.98(m,2H),6.80(s,1H),5.12 (s,1H),3.65-3.62(m,3H),3.49-3.47(m,5H),3.65-3.62(m,3H),3.49-3.47(m,5H),2.89 -2.78(m,4H),2.55(t,J=5.32Hz,2H),2.50-2.40(m,4H),2.15-2.14(m,3H),1.84-1.73(m ,4H),1.66(s,4H),1.36-1.33(m,2H),1.31-1.25(m,4H),1.16-1.15(m,2H),0.84(s,6H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)172.6,154.0,153.5,151.1,125.1,120.9,115.4,115.2,62.3,59.2,57.8,55.6 ,53.7,53.2,52.9,52.6,50.6,48.2,46.8,45.5,42.7,41.6,40.7,32.7,30.2,30.1,29.7,27.3,24.7,22.7,9.2.

[0107] Example 35 Synthesis of (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxamide (CL-101) The procedure was carried out according to the method of Example 9, using aqueous ammonia as the raw material (i.e., the amine in Example 9 is specifically aqueous ammonia), to obtain CL-101, a white solid, with a yield of 0.32 g and a 42% yield, and a mp of 87-88°C. 1 H NMR (400MHz, CDCl3): δ(ppm)8.27-8.17(m,1H),7.81-7.56(m,1H),7.04-7.00(m,2H),3.83-3.46(m,8H),2.43-2.35(m,2H),2.12 -2.11(m,1H),2.01(s,1H),1.79(s,2H),1.62-1.61(m,5H),1.37-1.33(m,2H),1.29-1.26(m,3H),1.18-1.10(m,5H),0.83(s,6H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)173.7,170.9,154.1,153.9,130.2,128.1,122.7,120.0,113.4,52.7, 52.6,50.8,50.6,48.0,46.9,46.1,42.7,40.6,40.6,32.4,30.2,30.1,29.7,28.3,26.8,26.2,9.6,9.5.

[0108] Example 36 Synthesis of 1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-bis(2-hydroxyethyl)piperidine-4-carboxamide (CL-109) The procedure was carried out according to the method of Example 9, using diethanolamine as the starting material (i.e., the amine in Example 9 is specifically diethanolamine, and the acid in Example 7 is specifically 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxylic acid), to obtain a white solid, CL-109, in an amount of 0.28 g, with a yield of 45% and an mp of 104-105°C. 1H NMR (400MHz, CDCl3): δ(ppm)7.88(t,J=8.44Hz,1H),7.03-6.94(m,2H),6.61( s,1H),4.92(s,1H),3.83-3.77(m,3H),3.54-3.52(m,2H),3.44(s,1H),2.89- 2.81(m,3H),2.57(s,1H),2.15(s,1H),2.03-1.97(m,2H),1.84(s,2H),1.68- 1.66(m,4H),1.43(s,2H),1.37-1.21(m,8H),1.20-1.15(m,5H),0.84(s,6H). 13 C-NMR (100MHz, DMSO-d6): δ(ppm)177.7,154.0,124.9,121.1,115.4,115.2,61.7,60.8,53.0,52.6,51. 7,50.6,50.3,48.2,46.6,42.7,40.7,38.8,32.5,31.6,30.2,30.1,29.7,28.7,26.9,22.6,14.1,10.1.

[0109] Example 37 Synthesis of 1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxamide (CL-118) The procedure was carried out according to the method of Example 9, using aqueous ammonia as the raw material (i.e., the amine in Example 9 is specifically aqueous ammonia, and the acid in Example 7 is specifically 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxylic acid), to obtain a white solid, CL-118, in an amount of 0.29 g, a yield of 38%, and an mp of 117-118°C. 1 H NMR(400MHz,CDCl3):δ(ppm)8.10(s,1H),7.25-7.01(m,2H),6.77(s,1H),6.48(s,1H),3.34(s,2H),3 .09(s,1H),2.90(s,2H),2.51(s,2H),2.10(s,3H),1.76-1.58(m,8H),1.40-1.12(m,8H),0.83(s,6H). 13C-NMR(100MHz,DMSO-d6):δ(ppm)176.5,161.4,154.0,152.4,150.8,125.8,119.9,115.9,52.4 ,52.0,50.2,48.2,48.1,46.2,43.8,42.9,42.7,42.2,32.4,32.3,30.7,30.5,30.0,28.7,28.0.

[0110] Example 38 Synthesis of N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxamide (CL-117) Using the procedure of Example 9 and 2-amino-2-(hydroxymethyl)propane-1,3-diol as starting material (i.e., the amine in Example 9 is specifically 2-amino-2-(hydroxymethyl)propane-1,3-diol, and the acid in Example 7 is specifically 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxylic acid), a white solid, CL-117, was obtained in an amount of 0.19 g, a yield of 27%, and an mp of 117-118°C. 1 H NMR(400MHz,DMSO-d6):δ(ppm)8.06-8.01(m,2H),7.08-7.04(m,2H),6.97-6.95 (m,1H),6.45(s,1H),4.75(t,J=5.60Hz,2H),3.51-3.50(m,5H),3.41-3.33(m,4H ),2.87-2.79(m,1H),2.22(s,1H),2.09-2.08(m,1H),1.97-1.84(m,2H),1.77-1. 74(m,2H),1.65-1.51(m,7H),1.34-1.24(m,6H),1.15-1.11(m,2H),0.83(s,6H). 13C-NMR(100MHz,DMSO-d6):δ(ppm)173.8,154.1,152.5,150.9,132.1,125.2,119.9,115.4,72.7,61.9,60.7,60 .6,60.5,55.7,53.3,52.9,52.0,50.7,48.1,46.2,42.8,42.7,42.6,32.3,30.5,30.0,29.5,27.7,24.2,22.5.

[0111] Example 39 Synthesis of N-(1,3-dihydroxypropan-2-yl)-1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxamide (CL-119) Using the procedure of Example 9 and 2-amino-1,3-propanediol as the starting material (i.e., the amine in Example 9 is specifically 2-amino-1,3-propanediol, and the acid in Example 7 is specifically 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxylic acid), a white solid, CL-119, was obtained in an amount of 0.17 g, a yield of 28%, and an MP of 150-151°C. 1 H NMR(400MHz,DMSO-d6):δ(ppm)8.61-8.60(m,1H),8.39(dd,J=8.36Hz,1.12Hz,1H),8.36( s,1H),8.12(t,J=8.44Hz,1H),7.67(d,J=7.88Hz,1H),7.41-7.38(m,2H),7.15(d,J=8.64H z,1H),6.75(s,1H),4.66(s,2H),3.95(s,2H),3.68-3.64(m,1H),3.39-3.38(m,6H),2.09( s,1H),1.80-1.76(m,5H),1.61-1.54(m,4H),1.36-1.27(m,4H),1.11(s,3H),0.83(s,6H). 13C-NMR(100MHz,DMSO-d6):δ(ppm)173.4,154.0,152.0,150.4,129.1,128.0,119.7,118.1,61.4,60.9,58 .9,58.2,54.8,53.6,51.0,50.7,49.0,48.2,42.7,32.5,32.2,30.6,29.5,28.8,26.2,25.6,22.8,22.5.

[0112] Example 40 Synthesis of 1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N-(2-hydroxypropyl)piperidine-4-carboxamide (CL-120) The procedure of Example 9 was followed, using 1-amino-2-propanol as the starting material (i.e., the amine in Example 9 is specifically 1-amino-2-propanol, and the acid in Example 7 is specifically 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxylic acid), to obtain 0.15 g of a white solid, CL-120, with a yield of 28% and an mp of 99-100°C. 1 H NMR(400MHz,CDCl3):δ(ppm)7.88(t,J=8.24Hz,1H),7.02-6.93(m,2H),6.84(s,1H),6.28(s,1H),5.12(s,1H),3.92-3.88(m,1H),3.41(s,3H),3 .14-2.96(m,3H),2.88-2.86(m,2H),2.14-1.96(m,4H),1.83-1.72(m,5H ),1.68-1.62(m,4H),1.38-1.26(m,4H),1.18-1.15(m,4H),0.86(s,6H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)176.5,154.4,151.5,126.5,124.8,121.3,115.3,115.1,6 7.4,62.0,52.9,52.8,50.6,48.2,46.9,43.0,42.7,40.7,32.4,30.2,30.1,28.7,20.9,9.6.

[0113] Example 41 Synthesis of methyl (1r,4r)-4-(3-fluoro-4-nitrobenzamido)cyclohexane-1-carboxylate The procedure of Example 5 was followed, except that ethyl (S)-piperidine-3-carboxylate was replaced with methyl (1r,4r)-4-aminocyclohexane-1-carboxylate. The final white solid obtained was methyl (1r,4r)-4-(3-fluoro-4-nitrobenzamido)cyclohexane-1-carboxylate, in an amount of 2.4 g and a yield of 91%.

[0114] Example 42 Synthesis of (1r,4r)-4-(4-amino-3-fluorobenzamido)cyclohexane-1-carboxylate The procedure of Example 6 was followed, except that ethyl (S)-1-(3-fluoro-4-nitrobenzyl)piperidine-3-carboxylate was replaced with methyl (1r,4r)-4-(3-fluoro-4-nitrobenzamido)cyclohexane-1-carboxylate; the final white solid obtained was methyl (1r,4r)-4-(4-amino-3-fluorobenzamido)cyclohexane-1-carboxylate, in an amount of 2.1 g, a yield of 90%.

[0115] Example 43 Synthesis of methyl (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylate The method of Example 7 was followed except that ethyl (S)-1-(4-amino-3-fluorobenzyl)piperidine-3-carboxylate was replaced with methyl (1r,4r)-4-(4-amino-3-fluorobenzamido)cyclohexane-1-carboxylate, and the final white solid obtained was methyl (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylate in an amount of 3.4 g, a yield of 80%.

[0116] Example 44 Synthesis of (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid The method of Example 8 was followed except that ethyl (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylate was replaced with methyl (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylate; the final white solid obtained was (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid in an amount of 2.5 g, a 90% yield.

[0117] Example 45 Synthesis of methyl (1r,4r)-4-((3-fluoro-4-nitrobenzyl)amino)cyclohexane-1-carboxylate A single-neck flask was charged with 4-(bromomethyl)-2-fluoro-1-nitrobenzene (3.0 g, 12.9 mmol) and dry acetonitrile (35 mL). After the 4-(bromomethyl)-2-fluoro-1-nitrobenzene was dissolved, potassium carbonate (2.13 g, 15.4 mmol), potassium iodide (0.15 g, 1.29 mmol), and methyl (1r,4r)-4-aminocyclohexane-1-carboxylate (2.24 g, 12.9 mmol) were added and the reaction was refluxed. After 6 h, the reaction was monitored for completion by TLC. The mixture was concentrated under reduced pressure to remove acetonitrile, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic layers were combined, washed with water (20 mL), and washed once with saturated brine (25 mL). The organic phase was concentrated under reduced pressure to obtain 5.2 g of a yellow oil. 4 times the amount of silica gel was loaded onto a column, and the sample was mixed with 1.2 times the amount of silica gel. The eluent was (EA:PE=1:40). Column chromatography was performed to obtain 4.2 g of a yellow oil, methyl (1r,4r)-4-((3-fluoro-4-nitrobenzyl)amino)cyclohexane-1-carboxylate, with a yield of 82%.

[0118] Example 46 Synthesis of methyl (1r,4r)-4-((4-amino-3-fluorobenzyl)amino)cyclohexane-1-carboxylate A single-neck flask was charged with (1r,4r)-4-((3-fluoro-4-nitrobenzyl)amino)methyl cyclohexane-1-carboxylate (3.60 g, 11.5 mmol), 5% Pd-C (0.4 g), and absolute ethanol (50 mL). The mixture was purged with argon gas three times and then with hydrogen gas three times. The temperature was raised to 60°C and the reaction was stirred for 12 hours. Completion of the reaction was monitored by TLC. After the reaction mixture was cooled to room temperature (25°C), it was suction filtered and the filtrate was concentrated under reduced pressure to give 2.96 g of a yellow oily substance, methyl (1r,4r)-4-((4-amino-3-fluorobenzyl)amino)cyclohexane-1-carboxylate, in a yield of 89%.

[0119] Example 47 Synthesis of methyl (1R,4r)-4-((4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)amino)cyclohexane-1-carboxylate Solid phosgene (1.06 g, 3.8 mmol) and dry DCM (30 mL) were placed in a three-neck flask, and the temperature was lowered to below −78°C using a cold trap. A solution of methyl (1R,4r)-4-((4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)amino)cyclohexane-1-carboxylate (2.23 g, 7.6 mmol) and triethylamine (1.06 g, 3.980 mmol) in dry dichloromethane (60 mL) was added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 0.5 h. The reaction was then stopped, and the resulting reaction solution was concentrated under reduced pressure to dryness. The residue was dissolved in dry DCM (10 mL) to obtain an isocyanate solution, which was then ready for use. A three-neck flask was charged with memantine (1.36 g, 7.6 mmol), triethylamine (1.54 g, 15.2 mmol), and dry dichloromethane (25 mL). The isocyanate solution was added dropwise and reacted at room temperature for 0.5 h. TLC showed the reaction was complete. The reaction mixture was poured into water (40 mL) and extracted with DCM (40 mL × 3). The mixture was then washed sequentially with 1 mol / L HCl (40 mL × 2), water (40 mL × 2), and saturated brine (40 mL), dried over anhydrous sodium sulfate, and suction filtered. The filtrate was concentrated under reduced pressure to give 3.4 g of a pale yellow oil: methyl (1R,4r)-4-((4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)amino)cyclohexane-1-carboxylate. This was used directly in the next step without further purification.

[0120] Example 48 Synthesis of (1R,4r)-4-((4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)amino)cyclohexane-1-carboxylic acid Methyl (1R,4r)-4-((4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)amino)cyclohexane-1-carboxylate (3.4 g, 6.9 mmol) was dissolved in tetrahydrofuran (20 mL) in a one-neck flask, and sodium hydroxide (0.36 g, 9.00 mmol) and water (10 mL) were added and the mixture was refluxed. After 12 h, TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran, and water (300 mL) was added to the residue. The mixture was placed in a cold trap and the pH was adjusted to 3 with 6N hydrochloric acid (10 mL). A pale yellow solid was precipitated, which was suction filtered, and the filter cake was rinsed with water (20 mL) and dried to obtain 2.96 g of a crude product (dried in an oven at 60°C for 24 hours). The crude product was purified by trituration with petroleum ether and diethyl ether to obtain 2.9 g of a pale yellow solid, (1R,4r)-4-((4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)amino)cyclohexane-1-carboxylic acid, a yield of 89.5%.

[0121] Example 49 Synthesis of 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro-N-((1r,4R)-4-((2-hydroxyethyl)carbamoyl)cyclohexyl)benzamide (ZT-110) Using the procedure of Example 9, starting from 2-aminoethan-1-ol (i.e., the amine in Example 9 is specifically 2-aminoethan-1-ol, and the acid is (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid), a white solid, ZT-110, was obtained in an amount of 0.14 g, a yield of 16%, and an MP of 117-118°C. 1H NMR(400MHz,DMSO-d6)δ8.38(s,1H),8.23(t,1H,J=8.40Hz),8.09(d,1H,J=7.8Hz),7.73(t ,1H,J=5.3Hz),7.66-7.59(m,2H),6.64(s,1H),4.64(s,1H),3.71-3.69(m,1H),3.24(s,1H) ),3.12-3.08(m,2H),3.01-3.00(m,1H),2.09(s,2H),1.87-1.84(m,2H),1.76(s,4H),1.59 (s,4H),1.47-1.41(m,2H),1.37-1.32(m,4H),1.28-1.25(m,2H),1.12(s,2H),0.83(s,6H). 13 C NMR(100MHz,DMSO-d6):δ175.40,164.27,153.71,152.09,149.70,124.07,118.50,114.21,114.01,60.44,60.44,52.16, 52.16,50.70,48.36,47.98,47.98,46.01,43.70,42.75,41.80,32.39,32.39,32.00,30.51,30.51,30.04,28.86,28.86.

[0122] Example 50 Synthesis of 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro-N-((1r,4R)-4-((2-hydroxypropyl)carbamoyl)cyclohexyl)benzamide (ZT-111) Using the procedure of Example 9, starting from 1-aminopropan-2-ol (i.e., the amine in Example 9 is specifically 1-aminopropan-2-ol, and the acid is (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid), a white solid, ZT-111, was obtained in an amount of 0.16 g, with a yield of 18% and an mp of 123-124°C. 1H NMR(400MHz,DMSO-d6)δ8.35(d,1H,J=2.96Hz),8.23(t,1H,J=8.52Hz),8.09(d,1H,J=7.92Hz),7.69- 7.59(m,3H),6.60(s,1H),4.63(s,1H),3.74-3.67(m,1H),3.64-3.59(m,1H),2.98(t,2H,J=5.88Hz), 2.13-2.09(m,2H),1.87-1.84(m,2H),1.76(s,3H),1.59(s,3H),1.48-1.42(m,2H),1.35-1.34(m,1H) ,1.32(s,2H),1.28(s,2H),1.23(s,2H),1.17(s,1H),1.12(s,2H),1.00(d,3H,J=6.2Hz),0.83(s,6H). 13 C NMR(100MHz,DMSO-d6):175.40,164.27,153.69,152.10,149.71,124.04,118.50,114.22,114.01,65.75,65.75,52.17, 52.17,50.71,48.38,47.99,47.99,46.67,43.68,42.76,32.39,32.39,32.00,30.51,30.51,30.05,28.93,28.84,21.51.

[0123] Example 51 Synthesis of N-((1r,4R)-4-(bis(2-hydroxyethyl)carbamoyl)cyclohexyl)-4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide (ZT-112) Using the procedure of Example 9, starting from 2,2'-azadiylbis(ethan-1-ol) (i.e., the amine in Example 9 is specifically 2,2'-azadiylbis(ethan-1-ol), and the acid is (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid), a white solid, ZT-112, was obtained in an amount of 0.12 g, a yield of 14%, and an MP of 104-105°C. 1H NMR(400MHz,DMSO-d6)δ8.38(d,1H,J=2.72Hz),8.23(t,1H,J=8.52Hz),8.11(d,1H,J=7.6Hz),7.66-7.5 9(m,2H),6.63(s,1H),4.88(s,1H),4.67(s,1H),3.71-3.69(m,1H),3.52-3.51(m,2H),3.44-3.43(m,4H) ),3.34-3.32(m,1H),2.61-2.55(m,1H),2.10(s,1H),1.88-1.85(m,2H),1.76-1.70(m,4H),1.59(s,4H) ,1.48-1.44(m,2H),1.41-1.38(m,2H),1.35-1.32(m,3H),1.28-1.25(m,2H),1.12(s,2H),0.83(s,6H). 13 C NMR (100MHz, DMSO-d6): δ175.61,164.37,153.70,152.09,149.69,124.09,118.51,114.24,114.03,59.81,59.40,52.16,50. 89,50.70,48.76,48.66,47.98,47.98,42.76,39.12,32.39,32.39,32.39,31.89,30.51,30.51,30.51,30.04,28.91,28.91.

[0124] Example 52 Synthesis of N-((1r,4R)-4-carbamoylcyclohexyl)-4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide (ZT-113) The procedure was carried out according to the method of Example 9, using aqueous ammonia as the raw material (i.e., the amine in Example 9 is specifically aqueous ammonia, and the acid is (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid), to obtain a white solid, ZT-113, in an amount of 0.18 g, with a yield of 20% and an mp of 107-108°C. 11H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.22(t,1H,J=8.12Hz),8.15(d,1H,J= 7.64Hz),7.68-7.60(m,2H),7.26(s,1H),6.88(s,1H),6.70(s,1H),3.69(s, 1H),3.05(q,4H,J=6.84Hz),2.69(s,1H),2.09(s,1H),1.77(s,3H),1.59(s, 3H),1.45-1.35(m,4H),1.32(s,2H),1.27(s,2H),1.12(s,2H),0.83(s,6H). 13 C NMR(100MHz,DMSO-d6):δ177.47,164.29,153.82,152.11,149.71,124.07,118.57,114.21,114.02,52.15,50.72 ,48.41,47.99,45.76,45.76,43.46,42.77,38.71,32.38,32.38,32.00,30.53,30.53,30.03,28.79,8.89,8.89.

[0125] Example 53 Synthesis of 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro-N-((1r,4R)-4-((2-hydroxypropyl)carbamoyl)cyclohexyl)benzamide (ZT-114) Using the procedure of Example 9, starting from 2-aminopropane-1,3-diol (i.e., the amine in Example 9 is specifically 2-aminopropane-1,3-diol, and the acid is (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid), a white solid, ZT-114, was obtained in an amount of 0.18 g, with a yield of 20% and an mp of 110-111°C. 11H NMR(400MHz,DMSO-d6)δ8.38(s,1H),8.22(t,1H,J=8.5Hz),8.09(d,1H,J=7.9Hz),7 .65-7.59(m,2H),7.42(d,1H,J=8.1Hz),6.64(s,1H),4.62(s,2H),3.71-3.66(m,2H) ,3.39-3.38(m,4H),2.10(s,1H),1.86-1.84(m,2H),1.76(s,3H),1.59(s,4H),1.47- 1.41(m,2H),1.37-1.32(m,4H),1.28(s,2H),1.25(s,2H),1.12(s,2H),0.83(s,6H). 13 C NMR(100MHz,DMSO-d6):δ175.33,164.23,153.72,152.10,149.71,124.05,118.52,114.21,114.01,60.67,60.67,53.04, 52.16,52.16,50.70,48.37,47.98,47.98,43.66,42.76,32.39,32.39,32.39,32.00,30.52,30.52,30.04,28.92,28.92.

[0126] Example 54 Synthesis of N-((1r,4R)-4-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)carbamoyl)cyclohexyl)-4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide (ZT-115) Using the procedure of Example 9, starting from 2-amino-2-(hydroxymethyl)propane-1,3-diol (i.e., the amine in Example 9 is specifically 2-amino-2-(hydroxymethyl)propane-1,3-diol, and the acid is (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid), a white solid, ZT-115, was obtained in an amount of 0.20 g, a yield of 24%, and an MP of 121-122°C. 1H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.22(t,1H,J=8.4Hz),8.14(d,1H,J=7.8Hz), 7.67-7.60(m,2H),7.29(s,1H),6.89(s,1H),4.88(s,3H),3.70(s,1H),3.52(s,5H) ,3.17(d,1H,J=5.2Hz),2.26(s,1H),2.09(s,1H),1.85-1.77(m,6H),1.59(s,3H), 1.46-1.40(m,2H),1.36-1.32(m,4H),1.27-1.25(m,3H),1.12(s,2H),0.83(s,6H). 13 C NMR(100MHz,DMSO-d6):δ177.09,164.28,153.84,152.11,149.72,124.08,118.59,114.21,114.00,62.62,61.27,61.27,52.15, 52.15,50.73,49.04,48.35,47.99,47.99,43.86,42.77,38.71,32.38,32.38,32.38,31.89,30.53,30.53,30.53,30.03,28.98.

[0127] Example 55 Synthesis of tert-butyl 4-(2-((1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxamido)ethyl)piperazine-1-carboxylate (ZT-116) Using the procedure of Example 9, starting from 2-amino-2-(hydroxymethyl)propane-1,3-diol (i.e., the amine in Example 9 is specifically 2-amino-2-(hydroxymethyl)propane-1,3-diol, and the acid is (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid), a white solid, ZT-116, was obtained in an amount of 0.21 g, a yield of 25%, and an mp of 131-132°C. 1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),8.23(t,1H,J=8.52Hz),8.09(d,1H,J=7.88Hz),7. 68-7.59(m,3H),6.62(s,1H),3.75-3.66(m,1H),3.29(s,3H),3.16(s,2H),2.33(s,5H), 2.10-2.06(m,2H),1.87-1.85(m,2H),1.76(s,4H),1.59(s,4H),1.47-1.45(m,1H),1.3 9(s,10H),1.34-1.32(m,4H),1.28(s,2H),1.25-1.23(m,2H),1.12(s,2H),0.83(s,6H). 13 C NMR(150MHz,DMSO-d6):δ175.21,164.27,154.25,153.69,152.09,149.70,1 24.04,118.47,114.22,114.01,79.21,57.44,52.91,52.16,52.16,50.70,48 .38,47.98,47.98,46.12,43.72,43.72,42.76,42.76,36.45,32.39,32.39,31.98,31.98,30.51,30.51,30.04,30.04,28.83,28.83,28.52,28.52,28.52.

[0128] Example 56 Synthesis of 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro-N-((1r,4R)-4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)cyclohexyl)benzamide (ZT-117) Using the procedure of Example 9, starting from 2-(piperazin-1-yl)ethan-1-ol (i.e., the amine in Example 9 is specifically 2-(piperazin-1-yl)ethan-1-ol, and the acid is (1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxylic acid), a white solid, ZT-117, was obtained in an amount of 0.21 g, a yield of 25%, and an MP of 126-127°C. 1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),8.23(t,1H,J=8.4Hz),8.13(d,1H,J=7.6Hz),7.66-7.6 0(m,2H),6.61(s,1H),4.44(s,1H),3.71(s,1H),3.53-3.44(m,6H),2.42-2.41(m,4H),2.35 (s,2H),2.10(s,1H),1.87–1.85(m,2H),1.76-1.69(m,4H),1.59(s,4H),1.46(s,1H),1.43( s,1H),1.40(s,1H),1.35(s,1H),1.32(s,2H),1.28-1.23(m,4H),1.12(s,2H),0.83(s,6H). 13 C NMR(100MHz,DMSO-d6):δ173.30,164.38,153.69,152.07,149.68,124.15,118.46,114.26,114.05,60.54,58.90,54.26,53.45,52.16, 52.16,50.70,48.70,47.98,47.98,45.29,42.75,42.75,41.50,38.71,32.39,32.39,31.83,31.83,30.51,30.51,30.39,30.39,28.68.

[0129] Example 57 Synthesis of ethyl (S)-1-(4-amino-3-fluorobenzoyl)piperidine-3-carboxylate The procedure was carried out according to the method of Example 6, except that ethyl (S)-1-(3-fluoro-4-nitrobenzyl)piperidine-3-carboxylate was replaced with ethyl (S)-1-(4-amino-3-fluorobenzoyl)piperidine-3-carboxylate. The final white solid obtained was ethyl (S)-1-(4-amino-3-fluorobenzoyl)piperidine-3-carboxylate, in an amount of 4.1 g and a yield of 90%.

[0130] Example 58 Synthesis of ethyl (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylate The method of Example 7 was followed, except that ethyl (S)-1-(4-amino-3-fluorobenzyl)piperidine-3-carboxylate was replaced with ethyl (S)-1-(4-amino-3-fluorobenzoyl)piperidine-3-carboxylate, and the final white solid obtained was ethyl (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylate, in an amount of 5.4 g, representing a yield of 80%.

[0131] Example 59 Synthesis of (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylic acid The method of Example 8 was followed except that ethyl (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylate was replaced with ethyl (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylate, and the final white solid obtained was (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylic acid in an amount of 4.8 g, a yield of 90%.

[0132] Example 60 Synthesis of tert-butyl 4-((S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carbonyl)-1,4-diaza-1-carboxylate (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylic acid (0.80 g, 1.45 mmol) and dry tetrahydrofuran (20 mL) were added to a single-neck flask. After (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carboxylic acid was dissolved, HATU (0.83 g, 2.17 mmol) and DIEA (0.58 g, 4.34 mmol) were added and stirred for 60 min. The solution turned pale yellow, and a solution of N-Boc-homopiperazine (0.29 g, 1.45 mmol) in tetrahydrofuran (10 mL) was added dropwise. After 2 hours, the reaction was complete as determined by TLC, and the reaction was stopped. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, water (40 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (40 mL x 2), 1 N hydrochloric acid (40 mL), saturated sodium carbonate (40 mL), water (40 mL), and saturated brine (40 mL). The organic layer was concentrated under reduced pressure to give 1.2 g of a yellow oil. The mixture was loaded onto a column with 3 volumes of silica gel, mixed with 1.2 volumes of silica gel, and purified with column chromatography using EA:PE (1:1) as the eluent to give 0.68 g of a yellow oil in 75.5% yield.

[0133] Example 61 Synthesis of 1-(4-((S)-3-(1,4-diaza-1-carbonyl)piperidine-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea tert-Butyl 4-((S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-3-carbonyl)-1,4-diaza-1-carboxylate (0.6 g, 1.25 mmol) was added to a single-necked flask, dissolved in dry dichloromethane (8 mL), TFA (4 mL) was added dropwise, and after 20 min, TLC showed the reaction was complete. The mixture was concentrated under reduced pressure to remove trifluoroacetic acid and directly introduced into the next step.

[0134] Example 62 Synthesis of 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((3S)-3-(4-(2-methylbutanoyl)-1,4-diaza-1-carbonyl)piperidine-1-carbonyl)phenyl)urea (GL-104) The procedure was carried out according to the method of Example 9, using 2-methylbutyric acid as the raw material (i.e., the acid in Example 9 is specifically 2-methylbutyric acid, and the base is 1-(4-((S)-3-(1,4-diaza-1-carbonyl)piperidine-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea), to obtain a white solid, GL-104, in an amount of 0.25 g, with a yield of 36% and an mp of 149-150°C. 1 H NMR (400MHz, CDCl3): δ(ppm)8.26-8.20(m,1H),7.58(s,1H),7.24-7.08(m,2H),5.90(s,1H),4.59(s,1H),3.82-3.37(m,10H) ),3.05-2.55(m,4H),2.13-2.05(m,2H),1.80-1.62(m,11H),1.37-1.24(m,6H),1.14-1.06(m,5H),0.86(s,2H),0.83(s,6H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)175.8,172.6,168.5,153.8,121.7,150.2,130.4,128.8,123.8,119.2,52.1,50.7,48.2,47.9,4 7.8,46.8,46.7,46.2,46.1,45.1,44.2,42.7,36.7,36.6,36.5,36.4,32.4,30.5,30.0,28.7,27.4,27.3,27.2,27.2,18.0,17.7.

[0135] Example 63 Synthesis of 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((S)-3-(4-propionyl-1,4-diaza-1-carbonyl)piperidine-1-carbonyl)phenyl)urea (GL-102) The procedure was carried out according to the method of Example 9, using propionic acid as the raw material (i.e., the acid in Example 7 is specifically propionic acid, and the base is 1-(4-((S)-3-(1,4-diaza-1-carbonyl)piperidine-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea), to obtain GL-102, a white solid, in an amount of 0.31 g, with a yield of 42% and an mp of 96-98°C. 1 H NMR(400MHz,CDCl3):δ(ppm)8.30(s,1H),8.16-8.13(m,1H),7.59(s,1H),6.99(s,2H),5.88(s,1H),4.48(s,1H),3.71-3.60(m,7H),3 .07-3.04(m,3H),2.69(s,2H),2.25(s,3H),2.05(s,1H),1.74(s,6H),1.56(s,4H),1.22-1.18(m,3H),1.06-1.01(m,5H),0.76(s,6H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)173.9,169.7,168.4,154.0,152.2,150.6,130.4,130.3,120.1,124.8,54.7,52.8,50.6,47.9,47.4,47.3,42.8,42.7,40.6,32.4,30.2,30.1,29.7,27.7,26.5,26.1,25.9,18.5,17.1,12.2,9.6,9.5,9.4.

[0136] Example 64 Synthesis of 1-(4-((S)-3-(4-acetyl-1,4-diaza-1-carbonyl)piperidine-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea (GL-101) The procedure was carried out according to the method of Example 9, using acetic acid as the raw material (i.e., the acid in Example 9 is specifically acetic acid, and the base is 1-(4-((S)-3-(1,4-diaza-1-carbonyl)piperidine-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea), to obtain GL-101, a white solid, in an amount of 0.28 g, with a yield of 37% and an mp of 136-137°C. 1 H NMR (400MHz, CDCl3): δ(ppm)8.26-8.20(m,1H),7.60(s,1H),7.08(s,2H),5.92(s,1H),4.58(s,1H),3.74-3.47(m,9H),3.14-2.60 (m,3H),2.13-2.05(m,4H),1.87-1.80(m,6H),1.63(s,4H),1.42-1.35(m,5H),1.29-1.24(m,3H),1.18-1.11(m,2H),0.83(s,6H). 13 C-NMR (100MHz, DMSO-d6): δ (ppm) 175.8, 172.6, 168.5, 153.8, 151.7, 150.2, 130.3, 128.8, 123.8, 119.2, 52.1, 50.7, 48. 2,47.9,46.7,46.6,46.2,46.1,45.1,44.2,42.7,36.6,36.5,36.4,32.4,30.5,30.0,27.4,27.3,27.2,18.1,12.3,12.2.

[0137] Example 65 Synthesis of tert-butyl-4-((S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carbonyl)-1,4-diaza-1-carboxylate The procedure of Example 9 was followed, starting from tert-butyl 1,4-diaza-1-carboxylate (i.e., the amine in Example 9 is specifically tert-butyl 1,4-diaza-1-carboxylate, and the acid is (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylic acid), to obtain 3.4 g of tert-butyl 4-((S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carbonyl)-1,4-diaza-1-carboxylate as a white solid, for a yield of 86%.

[0138] Example 66 Synthesis of 1-(4-(((S)-3-(1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea In a single-neck flask, tert-butyl 4-((S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carbonyl)-1,4-diaza-1-carboxylate (3.0 g, 55.6 mmol) was added, dissolved in dry dichloromethane (8 mL), TFA (4 mL) was added dropwise, and after 20 min, TLC showed the reaction was complete. The mixture was concentrated under reduced pressure to remove trifluoroacetic acid and directly introduced into the next step.

[0139] Example 67 Synthesis of 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(((S)-3-(5-(propionyl-1,5-diazocane-1-carbonyl)piperidin-1-yl)methyl)phenyl)urea (CL-102) The procedure was carried out according to the method of Example 9, using propionic acid as the raw material (i.e., the acid in Example 9 is specifically propionic acid, and the amine in Example 9 is 1-(4-(((S)-3-(1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea), to obtain 0.25 g of a white solid, CL-102, with a yield of 38% and an mp of 99-100°C. 1 H-NMR(400MHz,CDCl3):δ(ppm)8.02-7.97(m,1H),7.02-7.69(m,2H),6.85(br,1H),5.20(m,1H),3.84-3.73(m,1H),3.69-3.58(m,2H),3.56-3.49(m,4H),3.47-3.33(m,4H),2.90-2.75(m,3H),2.37-28(m,2H),2.15-2.14(m,2H),1.98-1.92(m,1H),1.84(s,4H),1.74-1.69(m,2H),1.66(s,4H),1.64-1.59(m,1H),1.55-1.46(m,1H),1.40-1.37(m,2H),1.33-1.24(m,3H),1.20-1.13(m,3H),1.12-1.08(m,2H),0.85(s,6H). 13 C-NMR(151MHz,CDCl3):δ(ppm)174.19,173.76,173.59,173.16,154.02,125.08,120.93,115.33,115.14,62.39,56.09,55.92,53.42,52.95,50.66,48.56,47.47,47.38,46.92,46.21,44.53,44.29,42.74,40.78,39.47,32.45,30.11,27.84,27.67,27.08,26.54,25.99,24.75,9.57,9.41.

[0140] Example 68 Synthesis of 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(((3S)-3-(5-(2-methylbutanoyl)-1,5-diazocane-1-carbonyl)piperidin-1-yl)methyl)phenyl)urea (CL-103) The procedure was carried out according to the method of Example 9, using 2-methylbutyric acid as the raw material (i.e., the acid in Example 9 is specifically 2-methylbutyric acid, and the amine in Example 9 is 1-(4-(((S)-3-(1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea), to obtain a white solid, CL-103, in an amount of 0.19 g, with a yield of 31% and an mp of 108-110°C. 1 H-NMR (400MHz, CDCl3): δ(ppm)8.04-7.95(m,1H),7.02-7.95(m,2H),6.83(br,1H),5.18(m,1H), 3.87-3.74(m,1H),3.66-3.55(m,4H),3.53-3.46(m,4H),3.40-3.38(m,2H),2.84-2.73(m,3H),2. 55-2.51(m,1H),2.15(s,2H),2.00-1.84(m,6H),1.71-1.62(m,7H),1.58-1.53(m,2H),1.43-1.37 (m,3H),1.31(s,1H),1.26-1.24(m,1H),1.19-1.15(m,2H),1.12-1.05(m,2H),0.88-0.83(m,9H). 13 C-NMR (151MHz, CDCl3): δ(ppm)176.63,176.48,174.21,174.12,154.05,125.02,120.92,115.30,115.11,62.45,56.20,56.10,55.99,53.51,52. 95,50.66,48.22,42.75,40.78,37.34,32.46,30.23,30.11,28.04,27.8 8,27.68,27.42,27.35,27.26,27.13,27.01,24.81,17.90,17.46,10.04.

[0141] Example 69 Synthesis of 1-(4-(((S)-3-(4-acryloyl-1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea (CL-201) The procedure was carried out according to the method of Example 9, using acrylic acid as the raw material (i.e., the acid in Example 9 is specifically acrylic acid, and the amine in Example 7 is specifically 1-(4-(((S)-3-(1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea), to obtain a white solid, CL-201, in an amount of 0.15 g, with a yield of 28% and an mp of 62-65°C. 1 H NMR(400MHz,DMSO-d6):δ(ppm)8.93-8.85(m,2H),8.17(s,2H),7.20-7.09(m,2H),6.52(s,1H),6.51-5.59(m,1H),3.65-3.5 9(m,8H),3.53-3.51(m,6H),2.09(s,1H),1.75-1.60(m,6H),1.58(s,5H),1.34-1.32(m,5H),1.28-1.23(m,3H),0.86(s,6H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)168.5,165.7,165.3,153.9,150.5,128.9,128.3,128.0,119.8,52.9 ,52.7,52.6,52.2,52.1,50.7,48.2,44.8,44.3,42.7,32.4,30.5,30.0,27.7,27.3,25.6,25.2,24.8.

[0142] Example 70 Synthesis of 1-(4-(((S)-3-(4-(cyclopropanecarbonyl)-1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea (CL-204) According to the method of Example 9, cyclopropanecarboxylic acid was used as the starting material (i.e., the acid in Example 9 is specifically cyclopropanecarboxylic acid, and the amine in Example 9 is 1-(4-(((S)-3-(1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea), and a white solid, CL-204, was obtained in an amount of 0.19 g, representing a yield of 29%. mp106~108℃. 1 H NMR(400MHz,DMSO-d6):δ(ppm)8.00-7.96(m,1H),7.05-6.98(m,2H),6.74(s,1H) ),5.04(s,1H),3.76-3.48(m,12H),2.87-2.78(m,3H),2.16-2.14(m,1H),1.93- 1.90(m,1H),1.83-1.73(m,4H),1.72-1.66(m,8H),1.40-1.37(m,2H),1.28-1.2 6(m,2H),1.20-1.12(m,2H),0.96-0.91(m,2H),0.85(s,6H),0.77-0.75(m,2H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)169.6,168.8,168.4,167.7,149.5,149.1,120.5,116.4,110.7,49.3,48.7,48.1,45.9,43 .6,43.1,42.7,42.5,40.3,39.7,37.9,37.4,36.1,28.0,27.7,25.6,25.1,23.7,23.7,23.0,22.4,21.9,6.4,4.4,3.0,2.8.

[0143] Example 71 Synthesis of 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((S)-3-(4-methacryloyl-1,4-diaza-1-carbonyl)piperidine (CL-205) The procedure was carried out according to the method of Example 9, using methacrylic acid as the raw material (i.e., the acid in Example 9 is specifically methacrylic acid, and the amine in Example 9 is 1-(4-(((S)-3-(1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea), to obtain a white solid, CL-205, in an amount of 0.23 g, with a yield of 32% and an mp of 79-81°C. 1 H NMR(400MHz,DMSO-d6):δ(ppm)7.99(s,1H),7.19-7.02(m,2H),5.15(s,1H),4.96-4.93(s,1H),3.60-3.49(m,7H),3.13-3.11(m,4H),2.15-2.08 (m,1H),1.93-1.90(m,2H),1.84(m,2H),1.77-1.76(m,2H),1.66(m,3H) ,1.31-1.25(m,14H),1.17-1.15(m,2H),0.85(s,6H),0.80-0.77(m,2H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)171.9,171.4,153.9,152.1,150.5,141.0,119.8,115.1,114.5,60.1,52.1,50.7,49.4 ,48.5,48.0,46.7,46.4,45.6,44.9,43.9,43.3,42.7,32.5,32.4,32.2,30.5,30.0,28.2,28.0,23.0,20.7,20.6,19.1.

[0144] Example 72 Synthesis of tert-butyl 4-(3-fluoro-4-nitrobenzoyl)-1,4-diaza-1-carboxylate 3-Fluoro-4-nitrobenzoic acid (3.0 g, 16.2 mmol) and dry tetrahydrofuran (40 mL) were added to a single-neck flask. After the 3-fluoro-4-nitrobenzoic acid was dissolved, HATU (7.39 g, 19.5 mmol) and DIEA (5.03 g, 38.90 mmol) were added and stirred for 60 min. The solution turned pale yellow, and N-Boc homopiperazine (3.25 g, 16.2 mmol) was added dropwise. After 15 min, the reaction was complete as determined by TLC, and the reaction was stopped. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, water (20 mL) was added, and the mixture was extracted with DCM (15 mL × 2). The organic layers were combined, washed once with 1N hydrochloric acid (20 mL), once with saturated sodium carbonate (20 mL), once with water (20 mL), and once with saturated brine (20 mL). The organic phase was concentrated under reduced pressure to obtain 6.7 g of a pale yellow oil. Five times the amount of silica gel was loaded onto a column, and 1.2 times the amount of silica gel was mixed with the sample. The eluent was (EA:PE=1:1). Column chromatography was carried out to obtain a white solid, tert-butyl 4-(3-fluoro-4-nitrobenzoyl)-1,4-diaza-1-carboxylate, with a yield of 4.8 g and a yield of 82%.

[0145] Example 73 Synthesis of tert-butyl 4-(4-amino-3-fluorobenzoyl)-1,4-diaza-1-carboxylate The procedure of Example 6 was followed, except that ethyl (S)-1-(3-fluoro-4-nitrobenzyl)piperidine-3-carboxylate was replaced with tert-butyl 4-(3-fluoro-4-nitrobenzoyl)-1,4-diaza-1-carboxylate. The final white solid obtained was tert-butyl 4-(4-amino-3-fluorobenzoyl)-1,4-diaza-1-carboxylate, in an amount of 4.1 g, a yield of 90%.

[0146] Example 74 Synthesis of tert-butyl 4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-1,4-diaza-1-carboxylate The procedure of Example 7 was followed, except that ethyl (S)-1-(4-amino-3-fluorobenzyl)piperidine-3-carboxylate was replaced with tert-butyl 4-(4-amino-3-fluorobenzoyl)-1,4-diaza-1-carboxylate. The final white solid obtained was tert-butyl 4-(4-amino-3-fluorobenzoyl)-1,4-diaza-1-carboxylate, in an amount of 5.3 g, representing a yield of 78%.

[0147] Example 75 Synthesis of 1-(4-(1,4-diaza-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea 4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-1,4-diaza-1-carboxylate tert-butyl ester (2.0 g, 35.6 mmol) was added to a single-neck flask, dissolved in dry dichloromethane (8 mL), and TFA (4 mL) was added dropwise. After 20 min, TLC showed the reaction was complete. The flask was concentrated under reduced pressure to remove trifluoroacetic acid and then directly introduced into the next step.

[0148] Example 76 Synthesis of tert-butyl 4-(2-(4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-1,4-diaz-1-yl)-2-oxoethyl)piperidine-1-carboxylate The procedure was carried out according to the method of Example 9, starting from 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (i.e., the acid in Example 9 is specifically 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid, and the base in Example 7 is specifically 1-(4-(1,4-diaza-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S, tert-Butyl 4-(2-(4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea), white solid tert-butyl 4-(2-(4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-1,4-diaza-1-yl)-2-oxoethyl)piperidine-1-carboxylate was obtained in an amount of 1.9 g, a yield of 85%.

[0149] Example 77 Synthesis of 1-(4-(1,4-diaza-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea tert-Butyl 4-(2-(4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-1,4-diaza-1-yl)-2-oxoethyl)piperidine-1-carboxylate (5.0 g, 65.6 mmol) was added to a single-necked flask, dissolved in dry dichloromethane (8 mL), and TFA (4 mL) was added dropwise. After 20 min, TLC showed the reaction was complete. The flask was concentrated under reduced pressure to remove trifluoroacetic acid and then directly introduced into the next step.

[0150] Example 78 Synthesis of 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(4-(2-(1-(2-methylbutanoyl)piperidin-4-yl)acetyl)-1,4-diaza-1-carbonyl)phenyl)urea (CC-103) The procedure was carried out according to the method of Example 9, using 2-methylbutyric acid as the raw material (i.e., the acid in Example 9 is specifically 2-methylbutyric acid, and the base is 1-(4-(1,4-diaza-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea), to obtain a white solid, CC-103, in an amount of 0.24 g, with a yield of 35% and an mp of 106-107°C. 1 H NMR (400MHz, CDCl3): δ(ppm)8.26-8.21(m,1H),7.57-7.42(m,1H),7.05-7.00(m,2H) ),4.63(s,1H),3.73-3.46(m,9H),3.02(s,1H),2.66-2.59(m,2H),2.30-2.27(m,2H) ,2.14(s,2H),1.99(s,1H),1.82(s,4H),1.71-1.64(m,5H),1.40-1.36(m,3H),1.30 -1.19(m,3H),1.19-1.10(m,3H),1.10-1.07(m,4H),0.90-0.87(m,3H),0.83(s,6H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)175.1,171.2,171.0,170.8,153.9,130.2,128.3,122.8,120.1,133.6,60.4,52.8 ,50.7,48.1,45.7,42.7,42.11,40.7,39.6,39.1,36.9,33.3,33.2,32.4,30.2,30.1,27.1,21.1,17.3,14.2,10.7.

[0151] Example 79 Synthesis of 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(4-(2-(1-propionylpiperidin-4-yl)acetyl)-1,4-diaza-1-carbonyl)phenyl)urea (CC-105) The procedure was carried out according to the method of Example 9, using propionic acid as the raw material (i.e., the acid in Example 9 is specifically propionic acid, and the base is 1-(4-(1,4-diaza-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea), to obtain a white solid, CC-105, in an amount of 0.25 g, with a yield of 37% and an mp of 95-96°C. 1 H NMR(400MHz,CDCl3):δ(ppm)8.27-8.22(m,1H),7.68-7.56(m,1H),7.04-7.02(m,2H),4.60(s,1H),3.72-3.46(m,9H),3.62(s,1H) ,2.58(s,1H),2.37-2.25(m,4H),2.13-1.99(m,4H),1.81(s,4H),1.63(s,5H),1.38-1.24(m,4H),1.14-1.11(m,7H),0.84(s,6H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)171.2,171.0,170.9,154.1,130.4,130.3,128.1,122.7,120.1,113.5,60.4,52.7,50.6,48 .1,46.4,45.7,43.9,42.7,41.9,40.6,39.6,39.1,33.2,33.1,32.4,32.0,30.2,30.1,29.7,29.3,26.6,21.1,14.2,9.7,9.7.

[0152] Example 80 Synthesis of 1-(4-(4-(2-(1-acetylpiperidin-4-yl)acetyl)-1,4-diaza-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea (CC-106) The procedure was carried out according to the method of Example 9, using acetic acid as the raw material (i.e., the acid in Example 9 is specifically acetic acid, and the base is 1-(4-(1,4-diaza-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea), to obtain a white solid, CC-106, in an amount of 0.31 g, with a yield of 42% and an mp of 101-102°C. 1 H NMR (400MHz, CDCl3): δ(ppm)8.27-8.22(m,1H),7.68-7.55(m,1H),7.04-7.02(m,2H),4.60(s,1H),3.72-3.46(m,9H),3.02(s,1H) ,2.58(s,1H),2.37-2.25(m,4H),2.13-1.99(m,4H),1.88(s,4H),1.63(s,5H),1.38-1.26(m,4H),1.14-1.11(m,7H),0.84(s,6H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)169.9,169.8,168.1,153.0,129.4,129.3,127.1,121.7,119.1,112.5,59.4,52.8,51.8,4 9.6,47.1,45.6,41.7,41.0,40.8,39.6,32.0,31.9,31.7,31.7,31.4,30.9,29.2,29.1,20.4,20.0,17.6,16.4,13.2,10.9.

[0153] Example 81 Synthesis of 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(4-(4-(2-(1-(1-(dimethylamino)propan-2-yl)piperidin-4-yl)acetyl)-1,4-diaza-1-carbonyl)-2-fluorophenyl)urea (CC-124) 1-(4-(1,4-diaza-1-carbonyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea (0.5 g, 1.4 mmol) and dry acetonitrile (35 mL) were added to a single-neck flask. After 4-(bromomethyl)-2-fluoro-1-nitrobenzene had dissolved, potassium carbonate (0.3 g, 1.6 mmol), potassium iodide (0.02 g, 0.2 mmol), and 2-chloro-N,N-dimethylpropan-1-amine (0.2 g, 1.4 mmol) were added and the reaction was refluxed. After 6 h, the reaction was monitored by TLC for completion. The mixture was concentrated under reduced pressure to remove acetonitrile, water (20 mL) was added, and extracted with ethyl acetate (30 mL × 2). The organic layers were combined, washed with water (20 mL), and once with saturated brine (25 mL). The organic phase was concentrated under reduced pressure to obtain 0.8 g of a yellow oil. The mixture was loaded onto a column with 4 times the amount of silica gel, mixed with the sample with 1.2 times the amount of silica gel, and subjected to column chromatography with EA:PE = 1:40 to obtain 0.34 g of a white solid (CC-124). The yield was 35%. 1 H NMR (400MHz, CDCl3): δ(ppm)8.28-8.20(m,1H),7.76-7.57(m,1H),7.05-7.02(m,2H) ,5.97-5.84(m,1H),3.81-3.40(m,9H),2.88-2.80(m,3H),2.47-2.43(m,1H),2.31-2. 25(m,7H),2.25-2.23(m,2H),2.13-2.12(m,2H),2.04-1.91(m,3H),1.80(s,2H),1.6 7-1.62(m,6H),1.37-1.26(m,7H),1.81-1.11(m,2H),1.01-0.99(m,4H),0.84(s,6H). 13 C-NMR(100MHz,DMSO-d6):δ(ppm)174.3,168.3,153.9,151.8,150.2,130.3,123.8,119.4,114.2,73.6,6 1.5,60.6,58.2,53.2,52.1,50.7,47.9,46.6,45.9,42.7,42.2,32.4,32.3,30.5,30.0,29.4,29.1,19.2.

[0154] Example 82 Synthesis of tert-butyl 4-(3-fluoro-4-nitrobenzyl)-1,4-diaza-1-carboxylate The procedure of Example 5 was followed, except that ethyl (S)-piperidine-3-carboxylate was replaced with N-Boc homopiperazine. The final white solid obtained was tert-butyl 4-(3-fluoro-4-nitrobenzyl)-1,4-diaza-1-carboxylate, in an amount of 4.1 g and a yield of 94%.

[0155] Example 83 Synthesis of tert-butyl 4-(4-amino-3-fluorobenzyl)-1,4-diaza-1-carboxylate The procedure of Example 6 was followed, except that ethyl (S)-1-(3-fluoro-4-nitrobenzyl)piperidine-3-carboxylate was replaced with tert-butyl 4-(3-fluoro-4-nitrobenzyl)-1,4-diaza-1-carboxylate. The final white solid obtained was tert-butyl 4-(4-amino-3-fluorobenzyl)-1,4-diaza-1-carboxylate, in an amount of 3.5 g, representing a yield of 90%.

[0156] Example 84 Synthesis of tert-butyl 4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-1,4-diaza-1-carboxylate The method of Example 7 was followed except that tert-butyl 4-(4-amino-3-fluorobenzyl)-1,4-diaza-1-carboxylate was substituted for ethyl (S)-1-(4-amino-3-fluorobenzyl)piperidine-3-carboxylate, and the final white solid obtained was tert-butyl 4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-1,4-diaza-1-carboxylate in an amount of 5.4 g, a yield of 86%.

[0157] Example 85 Synthesis of 1-(4-((1,4-diazal-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea 4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-1,4-diaza-1-carboxylate tert-butyl ester (2.0 g, 35.6 mmol) was added to a single-neck flask, dissolved in dry dichloromethane (8 mL), and TFA (4 mL) was added dropwise. After 20 min, TLC showed the reaction was complete. The mixture was concentrated under reduced pressure to remove trifluoroacetic acid and then directly added to the next step. The yield was 1.7 g, with a yield of 89%.

[0158] Example 86 Synthesis of tert-butyl 4-(2-(4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-1,4-diaz-1-yl)-2-oxoethyl)piperidine-1-carboxylate Into a single-neck flask were placed 1-(4-((1,4-diazal-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea (0.80 g, 1.35 mmol) and dry tetrahydrofuran (20 mL). After the 1-(4-((1,4-diazal-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea had dissolved, HATU (0.83 g, 2.17 mmol) and DIEA (0.58 g, 4.34 mmol) were added and stirred for 60 min. The solution turned pale yellow, and a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (0.29 g, 1.35 mmol) in tetrahydrofuran (10 mL) was added dropwise. After 2 h, the reaction was complete as determined by TLC, and the reaction was stopped. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, water (40 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with water (40 mL × 2), washed once with 1N hydrochloric acid (40 mL), washed once with saturated sodium carbonate (40 mL), washed once with water (40 mL), and washed once with saturated saline (40 mL). The organic phase was concentrated under reduced pressure to obtain 1.2 g of yellow oil. 3 times the amount of silica gel was loaded into a column, and 1.2 times the amount of silica gel was mixed with the sample. Column chromatography was carried out with EA:PE=1:1 to obtain 0.7 g of yellow oil, with a yield of 75.5%.

[0159] Example 87 Synthesis of 1-(4-(((S)-3-(1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea In a single-necked flask, tert-butyl 4-(2-(4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-1,4-diaza-1-yl)-2-oxoethyl)piperidine-1-carboxylate (0.7 g, 3.6 mmol) was added, dissolved in dry dichloromethane (8 mL), and TFA (4 mL) was added dropwise. After 20 minutes, TLC showed the reaction was complete. The mixture was concentrated under reduced pressure to remove trifluoroacetic acid and then directly used in the next step. The yield was 0.6 g, a yield of 89%.

[0160] Example 88 Synthesis of 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(1-propionylpiperidin-4-yl)acetyl)-1,4-diazal-1-yl)methyl)phenyl)urea (GL-1) The procedure was carried out according to the method of Example 9, using propionic acid as the raw material (i.e., the acid in Example 9 is specifically propionic acid, and the base is 1-(4-(((S)-3-(1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea), to obtain GL-1, a white solid, in an amount of 0.13 g, with a yield of 29% and an mp of 86-89°C. 1 H NMR (400MHz, CDCl3): δ(ppm)8.04-7.99(m,1H),7.10-7.09(s,1H),7.01-6.93(m,3H),5.45- 5.41(m,1H),4.65-4.58(m,1H),3.85-3.82(d,1H,J=12.56Hz),3.71-3.43(m,6H),3.07-3.01 (m,1H),2.66(s,1H),2.60-2.56(m,4H),2.35(q,2H,J=7.48Hz),2.26-2.14(m,4H),1.85-1.8 4(m,4H),1.67(s,5H),1.39-1.36(m,2H),1.30-1.27(m,3H),1.16-1.12(m,6H),0.85(s,6H). 13C NMR(100MHz,CDCl3):δ172.36,172.32,171.17,171.10,154.26,154.23,124.57,120.86,120.77,61.93,61.59,55.55,55.41,55.07,52.83, 52.81,50.67,48.18,45.81,45.76,42.75,40.75,39.56,39.54,33.24 ,33.21,32.89,32.43,32.05,30.22,30.14,26.65,26.64,9.72,9.68.

[0161] Example 89 Synthesis of 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(1-(2-methylbutanoyl)piperidin-4-yl)acetyl)-1,4-diazal-1-yl)methyl)phenyl)urea (GL-2) The procedure was carried out according to the method of Example 9, using 2-methylbutyric acid as the raw material (i.e., the acid in Example 9 is specifically 2-methylbutyric acid, and the base is 1-(4-(((S)-3-(1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea), to obtain GL-2, a white solid, in an amount of 0.18 g, with a yield of 31% and an mp of 96-100°C. 1 H NMR (400MHz, CDCl3): δ(ppm)7.99(t,1H,J=8.36Hz),7.17(d,1H,J=7.48Hz),7.06(s,1H),6.99(s,1H ),6.96-6.93(m,1H),5.50-5.48(m,1H),4.68-4.61(m,1H),3.97-3.83(d,1H,J=12.76Hz),3.75-3.4 4(m,6H),3.08-3.02(m,1H),2.65-2.55(m,6H),2.27-2.14(m,4H),1.84(s,5H),1.66(s,5H),1.39-1 .36(m,3H),1.30-1.26(m,3H),1.16-1.14(m,2H),1.11-1.08(m,4H),0.89-0.87(m,3H),0.84(s,6H). 13C NMR(100MHz,CDCl3):δ175.04,171.22,171.14,154.31,154.31,124.56,121 .00,120.87,114.94,114.75,61.91,61.59,55.53,55.43,52.81,52.78,50. 68, 48.20, 47.17, 45.81, 45.35, 44.49, 42.76, 42.18, 40.74, 39.56, 36.95, 33.37, 33.27, 30.22, 30.13, 28.46, 27.51, 27.06, 17.39, 17.20, 12.01, 11.91.

[0162] Example 90 Synthesis of 1-(4-((4-(2-(1-acetylpiperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea (GL-3) The procedure was carried out according to the method of Example 9, using acetic acid as the raw material (i.e., the acid in Example 9 is specifically acetic acid, and the base is 1-(4-(((S)-3-(1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea), to obtain 0.12 g of a white solid, GL-3, with a yield of 23% and an mp of 92-95°C. 1 H NMR (400MHz, CDCl3): δ(ppm)8.05-8.00(m,1H),7.11(s,1H),7.03-6.99(m,2H),6.95-6.93(m,1H),5.47( s,1H),4.63-4.57(m,1H),3.81-3.78(m,1H),3.72-3.65(m,2H),3.56-3.49(m,3H),3.46-3.43(m,1H),3. 11-3.05(m,1H),2.67(s,1H),2.59-2.57(m,4H),2.26-2.23(m,1H),2.18(s,1H),2.15-2.14(m,1H),2.09 (s,3H),1.84(s,4H),1.67(s,5H),1.39-1.36(m,2H),1.31-1.26(m,3H),1.19-1.11(m,4H),0.85(s,6H).13 C NMR(100MHz,CDCl3):δ171.12,171.04,169.01,168.98,154.25,154.22,151.15,124.58,120.72,61.94,61.58,55.54,55.34,55.14,53.6 8,52.83,52.81,50.66,48.19,46.74,46.70,44.49,42.75,41.91,41 .86,40.75,39.51,33.10,32.80,32.43,31.98,30.21,30.14,21.50.

[0163] Example 91 Synthesis of 1-(4-((4-(2-(1-acetylpiperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea (GL-4) The procedure of Example 9 was followed, using methanol as the starting material (i.e., replacing (S)-1-(4-amino-3-fluorobenzyl)piperidine-3-carboxylate with 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)phenyl)urea in Example 9, and replacing memantine with methanol), to obtain GL-4, a white solid, in an amount of 0.11 g, a yield of 19%, and an MP of 121-122°C. 1H NMR (400MHz, CDCl3): δ(ppm)8.05-8.00(m,1H),7.24-7.20(m,1H),7.00-6.93(m,2H),5.61-5.60(m ,1H),4.13-4.12(m,2H),3.68(s,3H),3.64-3.59(m,2H),3.53-3.51(m,3H),3.46(s,1H),2.78(s,2H) ),2.64-2.60(m,2H),2.56-2.55(m,2H),2.25-2.19(m,2H),2.13-2.12(m,1H),1.83-1.78(m,4H),1. 74-1.72(m,2H),1.65(s,4H),1.38-1.35(m,2H),1.29-1.26(m,3H),1.15-1.14(m,3H),0.85(s,6H). 13 C NMR(150MHz,DMSO-d6):171.32,171.26,156.04,154.13,124.56,120.86,114.84,61.85,61.85,55.63,55.58,55.02,53.77,52.8 8,52.56,50.64,48.19,48.19,47.15,44.50,44.11,42.73,40.76,39.70,39.66,33.04,32.15,32.15,30.20,30.12,30.12,27.48.

[0164] Example 92 Synthesis of 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(1-(2-hydroxyethyl)piperidin-4-yl)acetyl)-1,4-diazal-1-yl)methyl)phenyl)urea (GL-21) Into a single-neck flask were placed 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(piperidin-4-yl)acetyl)-1,4-diazal-1-yl)methyl)phenyl)urea (0.5 g, 2.31 mmol) and dry acetonitrile (10 mL). After the 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)phenyl)urea was dissolved, potassium carbonate (0.67 g, 6.70 mmol), potassium iodide (0.15 g, 1.29 mmol), and 2-chloroethyl-1-ol (0.15 g, 2.31 mmol) were added and the reaction was refluxed. After 6 h, the reaction was monitored by TLC for completion. The mixture was concentrated under reduced pressure to remove acetonitrile, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic layers were combined, washed with water (10 mL), and washed once with saturated brine (15 mL). The organic phase was concentrated under reduced pressure to give 0.41 g of a white solid. The mixture was loaded onto a column with 4 volumes of silica gel and mixed with the sample with 1.2 volumes of silica gel. The eluent was EA:PE = 1:5. Column chromatography was performed to give 0.21 g of a white solid, 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(1-(2-hydroxyethyl)piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)phenyl)urea. The yield was 34%. The mp was 101-102°C. 1 H NMR(400MHz,DMSO-d6):δ(ppm)8.14(s,1H),8.04-8.00(m,1H),7.08-7.04(m,1HHz) ,6.96-6.94(m,1H),6.57(s,1H),5.34(s,1H),4.48(s,1H),3.52-3.46(m,10H),2.90 -2.88(m,2H),2.59(s,1H),2.44(s,3H),2.21-2.17(m,2H),2.08-2.05(m,3H),1.75( s,4H),1.65-1.62(m,4H),1.57(s,4H),1.34-1.31(m,4H),1.11(s,2H),0.82(s,6H).13 C NMR (100MHz, DMSO-d6): δ170.97,154.17,153.00,150.61,124.67,120.04,115.09,114.90,63.05,60.72,60.62,58.61,56.03,55.22,54. 52,54.01,53.79,52.48,51.99,50.75,48.09,47.75,46.73,44.99,4 4.39,42.80,32.66,32.37,31.90,30.55,30.05,28.50,27.42,7.66.

[0165] Example 93 Synthesis of 1-(4-((4-(2-(1-(2,3-dihydroxypropyl)piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea (GL-22) The procedure was carried out according to the method of Example 93, using 3-chloropropane-1,2-diol as the starting material (i.e., the chlorinated product in Example 93 is specifically 3-chloropropane-1,2-diol), to obtain a white solid, GL-22, in an amount of 0.24 g, with a yield of 27% and an mp of 104-105°C. 1 H NMR(400MHz,DMSO-d6):δ(ppm)8.14(s,1H),8.03-7.99(m,1H),7.09-7.04(m,1H), 6.98-6.94(m,1H),6.57(s,1H),5.33(s,4H),5.01(s,1H),3.67(s,1H),3.52-3.43 (m,10H),2.99(s,3H),2.60-2.59(m,2H),2.21-2.19(m,4H),2.09(s,1H),1.75(s, 5H),1.68(s,5H),1.57(s,3H),1.34(s,1H),1.31(s,1H),1.11(s,2H),0.82(s,6H). 13C NMR(100MHz,DMSO-d6):δ170.90,154.18,127.62,124.68,120.08,65.23,63.07,56.03,55.20,54.51,53.83,52.50,52.5 0,50.76,48.10,48.10,47.74,46.71,44.41,42.80,42.80,32.38,32.38,30.55,30.55,30.05,28.48,27.39,7.67,7.67.

[0166] Example 94 Synthesis of 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(4-((4-(2-(1-(2-(dimethylamino)ethyl)piperidin-4-yl)acetyl)-1,4-diazal-1-yl)methyl)-2-fluorophenyl)urea (GL-23) The procedure was carried out according to the method of Example 93, using 2-chloro-N,N-dimethyl-1-amine as the starting material (i.e., the chlorinated compound in Example 93 is specifically 2-chloro-N,N-dimethyl-1-amine), to obtain a white solid, GL-23, in an amount of 0.21 g, with a yield of 26% and an mp of 108-109°C. 1 H NMR(400MHz,CDCl3):δ(ppm)8.08-8.01(m,1H),7.01-6.96(m,1H),6.94-6.91(m,1H),5.62(s,2H),3.62-3.61(m,5H), 3.54(s,1H),3.51-3.48(m,2H),3.44-3.42(m,1H),3.08-3.06(m,2H),2.72(s,1H),2.66(s,1H),2.61(s,3H),2.57-2.5 5(m,1H),2.43(s,2H),2.37(s,2H),2.32(s,1H),2.25-2.23(m,2H),2.20-2.18(m,1H),2.13(s,1H),1.95(s,1H),1.88 (s,2H),1.80-1.77(m,4H),1.70(s,3H),1.39(s,1H),1.36(s,1H),1.25(s,4H),1.16(s,1H),1.13(s,1H),0.84(s,6H). 13C NMR(100MHz,CDCl3):δ171.33,154.79,154.73,124.48,120.86,114.79,114.61,63.43,62.07,61.59,53.95,53.01,53.01,52.75,5 0.74,48.07,47.26,45.30,45.15,44.34,42.83,40.70,39.37,32.51,32.51,32.40,31.62,31.53,30.20,29.69,28.69,27.92,8.13.

[0167] Example 95 Synthesis of (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-bis(2-hydroxyethyl))piperidine-3-carboxamide (GL-24) The procedure was carried out according to the method of Example 93, using diethanolamine as the raw material (i.e., the chlorinated compound in Example 93 is specifically diethanolamine), to obtain a white solid, GL-24, with a yield of 0.22 g and a yield of 27%, with an mp of 110-111°C. 1 H NMR (400MHz, CDCl3): δ(ppm)8.06-7.98(m,1H),6.94-6.89(m,1H),6.83-6.77(m,1H),5.57(s,2H),4.55(s,3H),3.57-3.55 (m,5H),3.46-3.43(m,3H),3.35(s,1H),3.10-3.07(m,1H),3.01-2.98(m,2H),2.95-2.93(m,2H),2.86-2.84(m,2H),2.80- 2.78(m,2H),2.63(s,1H),2.55(s,2H),2.51(s,1H),2.23-2.15(m,2H),2.05(s,1H),1.91(s,1H),1.82(s,1H),1.74(s,3H) ,1.65(s,2H),1.32-1.29(m,2H),1.24(s,1H),1.22-1.21(m,3H),1.18-1.15(m,5H),1.09(s,1H),1.05(s,1H),0.77(s,6H). 13C NMR (100MHz, CDCl3): δ171.29,171.10,154.99,154.90,124.63,63.47,61.60,55.76,55.44,55.13,54.78,53.82,53.04,53.04,52 .69,50.78,48.31,48.02,48.02,47.09,44.09,42.87,40.68,39.19,32.38,32.38,32.07,31.46,31.19,30.23,30.23,29.68,8.15.

[0168] Test Example 1 1. Inhibitory activity test Detection principle: The specific substrate (3-phenyl-oxy)-acetic acid cyano-(6-methoxy-naphthalen-2-yl)methyl ester, or PHOME, is non-fluorescent in itself, but is hydrolyzed by the sEH enzyme to produce the product 6-methoxy-2-naphthaldehyde, which can be excited by 330 nm light and emit fluorescence at a wavelength of 465 nm. The intensity of the detected fluorescent signal is inversely proportional to the strength of the inhibitory effect on the sEH enzyme. Based on this principle, the inhibition rates of samples at different concentrations were calculated compared with the positive control group. The IC of the compound was calculated using SPSS 20 software based on the inhibition rate and concentration. 50 values ​​were calculated.

[0169] 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 pure water, the pH was adjusted to 7.4 with hydrochloric acid, and the volume was adjusted to 500 mL. PHOME solution: 0.79 mg of PHOME was taken and dissolved in 106 μL of 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 sample powder to be tested was dissolved in DMSO to a 20 mM solution, stored in a refrigerator at -20°C, and diluted to the corresponding concentration with Tris-HCl buffer when used.

[0170] 3. Experimental group assignment Experimental design: vehicle group, 100% activity group (A), inhibitor group (B), positive control group (C), specifically as shown in Table 1.

[0171] JPEG2025538342000134.jpg49170

[0172] 4. Experimental steps (a) 148 μL / well of Tris-HCl buffer was added to a 96-well black-bottom microplate. (b) 2 μL of the sample solution to be tested was added, the solvent group and 100% active group were replaced with an equal amount of DMSO, and the lead compound t-TUCB was added to the positive control group. (c) The inhibitor group had a total of 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 was 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 was 50 μM), and the mixture was incubated in a 37° C. incubator for 10 min. (f) Fluorescence signal data was detected by a microplate reader, and the excitation wavelength was 330 nm and the emission wavelength was 465 nm.

[0173] 5. Data analysis Three replicate wells were set up for each sample. The average fluorescence value (F) of the tested compound was calculated as the inhibition rate (%) = [(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. Based on the inhibition rate and concentration, the IC of the compound was calculated using SPSS 20 software. 50 values ​​were calculated.

[0174] Table 1 shows the inhibitory activities of the CL, CC, GL, and ZT series compounds against human sEH (HsEH) and mouse sEH (MsEH).

[0175] JPEG2025538342000135.jpg180170

[0176] From Table 1, the compounds CL, CC, GL and ZT series compounds provided by the present application are HsEH IC 50 The compounds CL, CC, GL and ZT series compounds provided by the present application have good inhibitory effects on MsEH IC 50 It was also found that they had excellent inhibitory effects with IC50 values ​​ranging from 0.058 nM to 4.14 nM. The experimental results showed that the inhibitory activities of CL-101, CL-102, CL-103, and CL-115 against HsEH were superior to those of the lead compound t-TUCB, with compound CL-102 having the strongest inhibitory activity, with an IC50 of 0.05 nM. The experimental results showed that all compounds, except for compound CL-104, had superior inhibitory activity against MsEH to the lead compound t-TUCB, with compound CL-118 having the strongest inhibitory activity, with an IC50 of 0.05 nM. 50 Finally, compounds CL-101, CL-102, CL-103, CL-107, CL-112, CL-113, CL-115, and CC-113 had better HsEH IC50 and MsEH IC50 values ​​than the lead compound t-TUCB. Among them, compound CL-102 had the strongest inhibitory activity, with an HsEH IC50 of 0.05 nM and an MsEH IC50 of 0.14 nM, indicating excellent prospects for development.

[0177] The above are only preferred embodiments of the present application, and those skilled in the art may make some improvements and modifications without departing from the principles of the present application, and these improvements and modifications should also be regarded as the protection scope of the present application.

Claims

1. A memantine urea derivative having a structure represented by Formula A or Formula B: Formula A Formula B In the formula, R １ and R ２ are independently —H, —OH, —NH ２ , —SH, —CN, a halogen group, an alkyl group, an alkoxy group, an aryl group, or a heteroaryl group; R ３ is -H, -OH, -NH ２ , —SH, —CN, a halogen group, an alkyl group or an alkoxy group; R ４ is -OH, -NH ２ , a hydroxylamine group, an amine group substituted with an alkyl group, an amine group substituted with an alkoxy group, an amine group substituted with an alcohol group, an amine group substituted with a phenyl group, an amine group substituted with a naphthyl group, or is selected from Y is -H, 、 or is selected from R ５ is selected from an alkyl group, an alkoxy group, or a heterocyclic group, and the alkyl group is selected from a chain alkyl group or a cycloalkyl group; R ６ is selected from an amino group substituted with an alkyl group or an alkyl group substituted with an alcohol group; X is -CH ２ or is selected from L is selected from none or —NH—; D is or is selected from n is 1 or 2; A memantine urea derivative, wherein Z and M are independently selected from =O or =S.

2. The R １ and R ２ are independently —H, —OH, —NH ２ 2. The memantine urea derivative of claim 1, wherein the aryl group is selected from the group consisting of -SH, -CN, -F, -Cl, -Br, methyl, ethyl, propyl, butyl, pentyl, isobutyl, isopropyl, isopentyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy, cyclohexyloxy, phenoxy, and benzyloxy.

3. The R １ and R ２ The memantine urea derivative according to claim 2, characterized in that is a methyl group.

4. The R ３ is -H, -OH, -NH ２ , -SH, -CN, -F, -Cl, -Br, an unsubstituted or substituted C1 to C6 alkyl group, an unsubstituted or substituted C1 to C6 alkoxy group, and the substituents on the substituted C1 to C6 alkyl group and the substituted C1 to C6 alkoxy group are independently selected from -F, -Cl, -Br, -OH, -NH ２ , -NHCH ３ , -N(CH ３ ) ２ or a C1 to C6 alkyl group.

5. The R ３ The memantine urea derivative according to claim 4, wherein is -F.

6. R ４ The alkyl-substituted amino group selected by R is an amino group substituted with an unsubstituted or substituted C1-C6 alkyl group, ４ The amino group substituted with an alkoxy group selected by R is an amino group substituted with an unsubstituted or substituted C1-C6 alkoxy group, ４ The phenyl-substituted amine group selected by is an amino group substituted with an unsubstituted or substituted phenyl group, and R ４ The naphthyl-substituted amine group selected by R is an unsubstituted or substituted naphthyl-substituted amine group, ４ The amine group substituted with an alcohol group selected by is an amine group substituted with an unsubstituted or substituted C1-C6 alcohol group, and the substituents on the substituted C1-C6 alkoxy group, substituted phenyl group, substituted naphthyl group and substituted C1-C6 alcohol group are independently -F, -Cl, -Br, -OH, -NH ２ , -NHCH ３ , -N(CH ３ ) ２ or a C1 to C6 alkyl group.

7. The aforesaid R ４ is -OH, -NH ２ , -N(CH ３ ) ２ , -N(CH ２ CH ３ ) ２ , -N(CH ２ CH ２ OH) ２ , -NHCH(CH ２ OH) ２ , -NHC(CH ２ OH) ３ , -NHCH ２ CH ２ OH, -NHCH ２ CHCH ３ OH, -N(CH ３ ) ２ , or The memantine urea derivative according to claim 6,

8. The R ５ The chain alkyl group selected by is an unsubstituted or substituted C1-C6 saturated or unsaturated chain alkyl group, and the substituent on the substituted C1-C6 saturated or unsaturated chain alkyl group is -OH, -NH ２ or a C1 to C6 alkyl group; The R ５ The cycloalkyl group selected by is an unsubstituted or substituted C3 to C6 cycloalkyl group, and the substituents on the substituted C3 to C6 cycloalkyl group are -F, -Cl, -Br, -OH, -NH ２ , -NHCH ３ , -N(CH ３ ) ２ or a C1 to C6 alkyl group; The R ５ The heterocyclic group selected by is an unsubstituted or substituted C3-C6 saturated or unsaturated heterocyclic group, and the substituents on the substituted C3-C6 saturated or unsaturated heterocyclic group are independently -F, -Cl, -Br, -OH, -NH ２ , -NHCH ３ , -N(CH ３ ) ２ or a C1 to C6 alkyl group.

9. R ５ は、-CH ３ 、-CH ２ CH ３ 、-CHCH ３ CH ２ CH ３ ,-OCH ３ 、 、 or The memantine urea derivative according to claim 8,

10. The R ６ The memantine urea derivative according to claim 1, wherein the amino group substituted with an alkyl group selected from (a) is an amino group substituted with an unsubstituted or substituted C1-C6 alkyl group, and the alkyl group substituted with an alcohol group is an alkyl group substituted with an unsubstituted or substituted C1-C6 alcohol group.

11. The R ６ is -CHCH ３ CH ２ N (CH ３ ) ２ , -CH ２ CH ２ N (CH ２ CH ３ ) ２ , -CH ２ CH ２ N (CH ３ ) ２ , -CH ２ CH ２ OH or -CH ２ CHOHCH ２ 11. The memantine urea derivative according to claim 10, wherein:

12. The memantine urea derivative according to claim 1, wherein n is 2.

13. (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxamide, 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(((S)-3-(4-propionyl-1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)phenyl)urea, 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(((3S) -3-(4-(2-methylbutanoyl)-1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)phenyl)urea, (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-dimethylpiperidine-3-carboxamide, (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-diethylpiperidine-3-carboxamide, (S)-1-( 4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-bis(2-hydroxyethyl)piperidine-3-carboxamide, 1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-bis(2-hydroxyethyl)piperidine-4-carboxamide, (S)-N-(1,3-dihydroxypropan-2-yl)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N,N-bis(2-hydroxyethyl)piperidine-4-carboxamide (3S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxamide, (3S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxypropyl)piperidine-3-carboxamide, (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N-(2-hydroxyethyl)piperidine-3-carboxamide, (S)-N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxamide, 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(((S)-3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)piperidin-1-yl)methyl)phenyl)urea, N-(1,3-dihydroxy-2-(hydroxymethyl)propane- 2-yl)-1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxamide, 1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxamide, N-(1,3-dihydroxypropan-2-yl)-1-(4-(3-((1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-4-carboxamide, 1-(4-(3-(( 1r,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-N-(2-hydroxypropyl)piperidine-4-carboxamide, 1-(4-(((S)-3-(4-acryloyl-1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea, 1-(4-((S)-3-(4-(cyclopropanecarbonyl)-1,4-diaza-1-carbonyl)piperidin-1-yl)methyl)-2-fluorophenyl) 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)urea, 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(((3S)-3-(1-(2-methylbutanoyl)azacyclohexane-4-carbonyl)piperidin-1-yl)methyl)phenyl)urea, (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylic acid, 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(4-(2-(1-(2-methylbutanoyl)piperidin-4-yl)acetyl)-1,4-diaza-1-carbonyl)phenyl)urea, 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(4-(2-(1-propionylpiperidin-4-yl)acetyl)-1,4-diaza-1-carbonyl)phenyl)urea, 1-(4-(4-(2-(1-acetylpiperidin-4-yl)acetyl)-1,4-diaza (S)-1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N,N-diethylpiperidine-3-carboxamide, 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N,N-diethylpiperidine-4-carboxamide, 1-((1r,3R,5S ,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-(4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)piperidine-1-carbonyl)phenyl)urea, (3S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxypropyl)piperidine-3-carboxamide, 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl 1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxypropyl)piperidine-4-carboxamide, N-(1,3-dihydroxypropan-2-yl)-1-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)piperidine-4-carboxamide, (S)-1-(4-(3-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzoyl)-N-(2-hydroxyethyl)piperidine-3-carboxamide, 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((S)-3-(4-(2-hydroxyethyl)piperazine-1-carbonyl)piperidine-1-carbonyl)phenyl)urea, 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(4-(4-(2-(1-(1-(dimethylamino)propanol) 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(1-propionylpiperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)phenyl)urea, 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(1-(2-methylbutanoyl)piperidin-4-yl) 1-(4-((4-(2-(1-acetylpiperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea, 4-(2-(4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)-1,4-diaz-1-yl)-2-oxoethyl)piperidine-1-carboxylate methyl 1-( (1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((4-(2-(1-(2-hydroxyethyl)piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)phenyl)urea, 1-(4-((4-(2-(1-(2,3-dihydroxypropyl)piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea, 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(4-((4-(2-(1-(2-(dimethylamino)ethyl)piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)-2-fluorophenyl)urea, 1-(4-((4-(2-(1-(2-(diethylamino)ethyl)piperidin-4-yl)acetyl)-1,4-diaz-1-yl)methyl)-2-fluorophenyl)-3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)urea, 1-(4-((S)-3-(4-acetyl-1,4-diaza-1-carboxamide) 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((S)-3-(4-propionyl-1,4-diaza-1-carbonyl)piperidine-1-carbonyl)phenyl)urea, 1-((1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)-3-(2-fluoro-4-((3S)-3-(4-(2-methylbutanoyl) -1,4-diaza-1-carbonyl)piperidine-1-carbonyl)phenyl)urea, 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro-N-((1r,4R)-4-((2-hydroxyethyl)carbamoyl)cyclohexyl)benzamide, 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro-N-((1r,4R)-4-((2-hydroxypropyl)carbamoyl)cyclohexyl)benzamide, N-((1r, 4R)-4-(bis(2-hydroxyethyl)carbamoyl)cyclohexyl)-4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide, N-((1r,4R)-4-carbamoylcyclohexyl)-4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide, N-((1r,4R)-4-((1,3-dihydroxypropan-2-yl)carbamoyl)cyclohexyl)-4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide, N-((1r,4R)-4-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)carbamoyl)cyclohexyl)-4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamide, 2. The memantine urea derivative of claim 1, comprising tert-butyl 4-(2-((1R,4r)-4-(4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzamido)cyclohexane-1-carboxamido)ethyl)piperazine-1-carboxylate, 4-(3-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)ureido)-3-fluoro-N-((1r,4R)-4-((2-hydroxyethyl)carbamoyl)cyclohexyl)benzamide.

14. A method for preparing the memantine urea derivative according to any one of claims 1 to 13, comprising: (1) Preparation of memantine urea derivatives having the structure represented by formula A: (1-1) X = and L is absent and D is and R ４ but, is not, the method for preparing a memantine urea derivative having a structure represented by Formula A comprises: subjecting compound 1 and compound a to a first acylation reaction to obtain compound b; subjecting compound b to a first reduction reaction to obtain compound c; Compound 2 and compound 4 are subjected to a second acylation reaction to form an intermediate compound or and subjecting the intermediate compound and compound c to a first nucleophilic substitution reaction to obtain compound d; Compound d is subjected to a first hydrolysis reaction to form R ４ obtaining a memantine urea derivative having a structure represented by Formula A, wherein is —OH; R ４ is —OH, and compound 3, and subjecting the mixture to a third acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine urea derivative having a structure represented by Formula A; The structural formulae of Compound 1 and Compound 2 are, in order: 、 and The compound 3 is NH ３ , hydroxylamine, alkylamine, alkoxyamine, alcoholamine, phenylamine or naphthylamine, Compound 4 is solid phosgene or thiophosgene, The structural formulas of the compounds a, b, c, and d are: and Here, R in the structural formulas of Compound 1, Compound b, Compound c, and Compound d ７ is C １ ~C ６ and the alkyl group is selected from the group consisting of (1-2) X is -CH ２ -, L is absent, and D is and R ４ but is not, the method for preparing a memantine urea derivative having a structure represented by Formula A comprises: subjecting compound a to a second reduction reaction to obtain compound e; subjecting compound e to a second nucleophilic substitution reaction with a brominating reagent to obtain compound f; subjecting compound f and compound 1 to a third nucleophilic substitution reaction to obtain compound g; subjecting compound g to a third reduction reaction to obtain compound h; subjecting the intermediate compound and compound h to a fourth nucleophilic substitution reaction to obtain compound i; Compound i is subjected to a second hydrolysis reaction to form R ４ obtaining a memantine urea derivative having a structure represented by Formula A, wherein is —OH; R ４ is —OH, and compound 3, and subjecting the mixture to a fourth acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine urea derivative having a structure represented by formula A; The structural formulas of the compounds e, f, g, h and i are: and Here, R in the structural formula of compound g, compound h, and compound i ７ is C １ ~C ６ and the alkyl group is selected from the group consisting of (1-3) X = L is -NH- and D is and R ４ but is not, the method for preparing a memantine urea derivative having a structure represented by Formula A comprises: subjecting compound z and compound a to a fifth acylation reaction to obtain compound j; subjecting the intermediate compound and compound j to a fifth nucleophilic substitution reaction to obtain compound y; Compound y is subjected to a third hydrolysis reaction to form R ４ obtaining a memantine urea derivative having a structure represented by Formula A, wherein is —OH; R ４ is —OH, and compound 3, and subjecting the mixture to a sixth acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine urea derivative having a structure represented by Formula A; The structural formula of the compound z is: and The structural formula of the compound j is: and The structural formula of the compound y is: and Here, R in the structural formula of compound z, compound j, and compound y ７ is C １ ~C ６ and the alkyl group is selected from the group consisting of (1-4) X is -CH ２ -, L is -NH-, and D is and R ４ but is not, the method for preparing a memantine urea derivative having a structure represented by Formula A comprises: subjecting compound f and compound z to a sixth nucleophilic substitution reaction to obtain compound k; subjecting compound k to a fourth reduction reaction to obtain compound 5; subjecting the intermediate compound and compound 5 to a seventh nucleophilic substitution reaction to obtain compound 6; Compound 6 is subjected to a fourth hydrolysis reaction to form R ４ obtaining a memantine urea derivative having a structure represented by Formula A, wherein is —OH; R ４ is —OH, and compound 3, and subjecting the mixture to a seventh acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine to obtain a memantine urea derivative having a structure represented by formula A; The structural formulas of Compound k, Compound 5, and Compound 6 are: 、 、 and Here, R in the structural formulas of Compound k, Compound 5, and Compound 6 ７ is C １ ~C ６ and the alkyl group is selected from the group consisting of (1-5) X = and L is absent and D is and R ４ but wherein the method for preparing a memantine urea derivative having a structure represented by formula A comprises: subjecting compound 7 and compound L to an eighth acylation reaction to obtain compound m; subjecting compound m to a first deprotection reaction under acidic conditions to obtain compound n, a memantine urea derivative having a structure represented by Formula A, wherein Y is —H; The compound n and the compound 8 are mixed and subjected to a ninth acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine, to form Y. obtaining a memantine urea derivative having a structure represented by Formula A, The compound n and the compound 9 are subjected to a tenth acylation reaction to form a compound Y. obtaining a memantine urea derivative having the structure set forth in Formula A, Compound n and compound 10 are subjected to an eighth nucleophilic substitution reaction to form a compound Y. and obtaining a memantine urea derivative having the structure set forth in Formula A, Here, the structural formula of the compound 7 is: and The structural formula of compound 8 is: and The structural formula of compound 9 is: and The structural formula of compound 10 is R ６ -Cl, The structural formulas of the compounds L, m and n are: 、 、 and (1-6) X=-CH ２ -, L is absent, and D is and R ４ but wherein the method for preparing a memantine urea derivative having a structure represented by formula A comprises: subjecting compound 7 and compound o to an eleventh acylation reaction to obtain compound 11; subjecting compound 11 to a second deprotection reaction under acidic conditions to obtain compound 12, a memantine urea derivative having a structure represented by Formula A, wherein Y is —H; Compound 12 and compound 8 are mixed and subjected to a 12th acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine, to form a compound having a structure in which Y is obtaining a memantine urea derivative having a structure represented by Formula A, Compound 12 and compound 9 are subjected to a thirteenth acylation reaction to form a compound having Y as a obtaining a memantine urea derivative having the structure set forth in Formula A, Compound 12 and compound 10 are subjected to a ninth nucleophilic substitution reaction to form a compound having Y. and obtaining a memantine urea derivative having the structure set forth in Formula A, Compound o is and The structural formula of compound 11 is: and The structural formula of compound 12 is: and (2) Preparation of memantine urea derivatives having the structure represented by formula B: (2-1) X is wherein the method for preparing a memantine urea derivative having a structure represented by formula B comprises: subjecting compound 7 and compound a to a fourteenth acylation reaction to obtain compound p; subjecting compound p to a fifth reduction reaction to obtain compound q; subjecting the intermediate compound and compound q to a tenth nucleophilic substitution reaction to obtain compound r; subjecting compound r to a third deprotection reaction under acidic conditions to obtain compound s; subjecting compound 13 and compound s to a fifteenth acylation reaction to obtain compound t; subjecting compound t to a fourth deprotection reaction under acidic conditions to obtain compound u, a memantine urea derivative having a structure represented by Formula B, wherein Y is —H; The compound u and the compound 8 are mixed and subjected to a sixteenth acylation reaction in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine, to form a compound Y. obtaining a memantine urea derivative having a structure represented by Formula B, The compound u and the compound 9 are subjected to a seventeenth acylation reaction to form a compound Y. obtaining a memantine urea derivative having the structure set forth in formula B, Compound u and compound 10 are subjected to an eleventh nucleophilic substitution reaction to form Y. and obtaining a memantine urea derivative having the structure set forth in Formula B, The structural formula of compound 13 is: and The structural formulas of the compounds p, q, r, s, t and u are: and (2-2) X is -CH ２ -, the method for preparing a memantine urea derivative having a structure represented by formula B is subjecting compound g and compound 7 to a twelfth nucleophilic substitution reaction to obtain compound v; subjecting compound v to a sixth reduction reaction to obtain compound w; subjecting the intermediate compound and compound w to a thirteenth nucleophilic substitution reaction to obtain compound x, a memantine urea derivative having a structure represented by Formula B, wherein Y is —H; The compound x and the compound 8 are mixed and subjected to an acylation reaction of the 18th compound in the presence of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and N,N-diisopropylethylamine, to form Y. obtaining a memantine urea derivative having a structure represented by Formula B, The compound x and the compound 9 are subjected to a 19th acylation reaction to form a compound Y. obtaining a memantine urea derivative having the structure set forth in formula B, Compound x and compound 10 are subjected to a fourteenth nucleophilic substitution reaction to form a compound Y. and obtaining a memantine urea derivative having the structure set forth in Formula B, The structural formulas of the compounds v, w and x are A preparation method characterized by:

15. Use of the memantine urea derivative according to any one of claims 1 to 13 or the memantine urea derivative prepared by the preparation method according to claim 14 in the preparation of a medicament for treating a soluble epoxide hydrolase-mediated disease.

16. The use of claim 15, wherein the soluble epoxide hydrolase-mediated disease comprises an inflammatory disease, pain, cardiovascular disease, neurodegenerative disease, diabetes, diabetic complications, chronic nephritis, renal failure, chronic obstructive pulmonary disease or pulmonary hypertension.

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