A compound, a preparation method thereof, and applications in preparing sEH inhibitors and PPARs agonists

Abstract

The present invention belongs to the field of pharmaceutical technology, and particularly relates to a compound, a preparation method thereof, and applications in the preparation of sEH inhibitors and PPARs agonists. The present invention provides a compound having the structure shown in Formula III. The compound provided by the present invention has a typical urea structure as the primary pharmacophore of soluble epoxide hydrolase (sEH), and the thiazolidinedione moiety as the primary pharmacophore of peroxisome proliferator-activated receptor (PPARs). The sEH inhibitor and PPARs agonist compound provided by the present invention has high inhibitory activity against human-derived HsEH and high agonist activity against PPAR, and can be used as an sEH inhibitor and PPARs agonist compound for the preparation of drugs for treating diseases mediated by soluble epoxide hydrolase and peroxisome proliferator-activated receptor.

Description

[0001] This application is a divisional application of a Chinese patent application filed with the China National Intellectual Property Administration on March 22, 2023, with the application number 202310282598.7 and the invention title "A Dual-Target Compound and Its Preparation Method and Application in the Preparation of sEH Inhibitor and PPARs Agonist". Technical Field

[0002] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a compound, its preparation method, and its application in the preparation of sEH inhibitor and PPARs agonist. Background Art

[0003] Pain sensation is mediated by the action of a specialized subset of sensory afferent neurons (nociceptors), which are activated in response to thermal, mechanical, and chemical stimuli through multiple mechanisms. Studies have shown that ion channel regulation includes Transient Receptor Potential (TRP) channels, G protein-coupled receptor (GPCR) activation, and changes in the cell membrane, all of which demonstrate the mechanism of lipid mediator signal transduction in nociceptors (Nature, 2001, 413(6852): 203-210).

[0004] Research has shown that cyclooxygenase and lipoxygenase metabolites, prostaglandins and leukotrienes, can cause pain and inflammation, thereby demonstrating the role of lipid mediators in pain signal transduction. Specific long-chain polyunsaturated fatty acids (PUFAs) are metabolized by cytochrome P450 enzymes (CYP450) to form epoxide metabolites, namely epoxy fatty acids (EpFAs). Researchers have found that these metabolites mediate analgesic effects in several types of pain pathologies, such as acute pain, chronic pain, cancer pain, or intractable pain.

[0005] Arachidonic acid (ARA) is a 20-carbon PUFA with four unsaturated double bonds that can be metabolized by CYP450 enzymes into epoxy metabolites (EETs) of any one or several of the four double bonds, including 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET. EpFAs, including EETs, limit pain and inflammation through multiple direct and indirect mechanisms, including nuclear receptor agonism, limiting endoplasmic reticulum stress, and blocking mitochondrial dysfunction. In animal models of inflammatory pain and diabetic neuropathic pain, small molecule inhibitors of soluble epoxide hydrolase have shown strong analgesic effects (Neurotherapeutics, 2020, 17, 900-916). EETs are readily metabolized and inactivated by soluble epoxide hydrolase (sEH) in vivo, and the EET metabolite dihydroxy metabolite DHETs have pro-inflammatory effects. Small molecule inhibitors of soluble epoxide hydrolase can stabilize EpFAs in vivo. Therefore, by inhibiting sEH activity and increasing the amount of EETs in the body, it has become a new method for treating EET-related diseases.

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

[0007] There is substantial evidence that the role of EpFAs in nociception includes blocking inflammatory pain and neuropathic pain. Therefore, sEH inhibitors and EpFA mimetics have great potential in relieving human pain.

[0008] Epidemiological studies have confirmed the association between inflammatory biomarkers and the development of type 2 diabetes mellitus (T2DM) and its complications. The triggering mechanism of T2DM inflammation remains unclear. Inflammatory responses may lead to the development of T2DM by causing insulin resistance. The obese environment results in adipose tissue dysfunction, macrophage infiltration, and greater release of cytokines such as IL-6 and TNF-α. Long-term elevated levels of these molecules promote insulin resistance in skeletal muscle and endothelial dysfunction in the vascular system, as well as the release of acute-phase proteins from the liver. Chronically elevated specific inflammatory markers, such as IL-6 and TNF-α, seem to be associated with metabolic disorders and can alter insulin sensitivity by triggering different key steps in the insulin signaling pathway. Hyperglycemia can also induce the production of IL-6 in endothelial cells and macrophages. In addition, hyperglycemia enhances the role of suppressor of cytokine signaling (SOCS), thereby impairing insulin release and signal transduction and promoting long-term complications of diabetes. Targeting the inflammatory pathway may be an integral part of strategies for preventing and controlling diabetes and related complications.

[0009] PPAR agonists have been shown to inhibit the expression of cytokines - such as resistin, tumor necrosis factor α (TNFα), and interleukin 6 - which promote insulin resistance. PPAR agonists trigger an increase in plasma adiponectin concentration. Adiponectin is a hormone secreted from adipose tissue and is present at lower levels in the plasma of patients with T2DM. Adiponectin increases fatty acid oxidation in the liver and skeletal muscle. Overall, adiponectin improves insulin sensitivity in skeletal muscle and the liver and reduces glucose production in the liver, thereby lowering circulating FFA and TG, as well as glucose levels. Macrophage infiltration in obese adipose tissue is involved in local inflammation that enhances insulin resistance. It has recently been shown that PPAR in macrophages partially mediates the antidiabetic effects of TZDs. Inactivation of PPAR in macrophages leads to impaired alternative macrophage activation, glucose intolerance, and insulin resistance in skeletal muscle and the liver.

[0010] Currently, the analgesics used clinically mainly include opioid analgesics, non-steroidal anti-inflammatory drugs, etc. Both of these have certain side effects. For example, traditional opioid analgesics have strong effects but also strong addiction, respiratory depression, blood pressure reduction, nausea, vomiting, constipation, and difficulty urinating, etc. Non-steroidal anti-inflammatory drugs are divided into non-selective non-steroidal anti-inflammatory drugs and selective cyclooxygenase-2 (COX-2) inhibitors. Although they also have good analgesic effects, non-selective non-steroidal anti-inflammatory drugs have relatively severe gastrointestinal irritation, are prone to causing gastric ulcers, and often have adverse reactions on the coagulation and hematopoietic systems. Selective COX-2 inhibitors, although without the adverse reaction of gastrointestinal irritation, are prone to causing an imbalance between prostacyclin and thromboxane, thereby leading to cardiovascular diseases and generally having little effect on neuropathic pain.

[0011] Currently, the hypoglycemic drugs used clinically mainly include insulin, insulin secretagogues, insulin sensitizers, α-glucosidase inhibitors, GLP-1 agonists, dipeptidyl peptidase-4 inhibitors, etc., all of which have certain drawbacks. For example, α-glucosidase inhibitors cannot be used alone to treat diabetes and usually need to be combined with other drugs for blood glucose control. Insulin secretagogues can cause gastrointestinal symptoms (such as nausea, upper abdominal fullness), headache, etc. Insulin must be administered by injection, resulting in poor patient compliance. Other drugs are difficult to counter diabetes inflammatory complications and concurrent neuropathic pain, etc.

[0012] The dual-target compound RB394 of sEH inhibitor and PPARs agonist, for which there have been reports so far, sEH IC 50 = 0.3 μM, PPARγ EC 50 = 0.3 μM, has shown certain efficacy in the fields of diabetic nephropathy and non-alcoholic steatohepatitis, but it still needs further development and exploration. Given that the dual-target compound of sEH inhibitor and PPARs agonist can not only lower blood glucose, but is also effective against diabetes inflammatory complications, non-alcoholic fatty liver disease and neuropathic pain, reducing the drug-drug interactions that patients previously needed to take multiple medications simultaneously. Therefore, it is very urgent and necessary to develop new and more efficient dual-target compounds of sEH inhibitor and PPARs agonist for the treatment of diabetes, non-alcoholic fatty liver, pain and depression. Summary of the Invention

[0013] The object of the present invention is to provide a compound, its preparation method and its application in the preparation of sEH inhibitor and PPARs agonist. The compound provided by the present invention has high activity against human sEH (HsEH) and PPARs, and has small side effects, and can be used as a dual-target compound of sEH inhibitor and PPARs agonist for the preparation of drugs for treating diabetes and its inflammatory complications, neuropathic pain and depression.

[0014] The present invention provides a compound having the structure shown in Formula III:

[0015]

[0016] Wherein, R1 is memantine group, aryl, alkyl-substituted aryl, halogenated aryl, halogenated alkyl-substituted aryl, halogenated alkoxy-substituted aryl, halogenated aryloxy-substituted aryl; R2 is hydrogen, hydroxyl group, alcoholic hydroxyl group, amino group, carboxyl group, acyl group, amide group or ester group; B is a single bond, cycloalkyl, heterocyclic group or aryl;

[0017] W is a single bond, -CH2-, -O-, -S-, -NH- or

[0018] Z is =CH2, =O, =S or =NH.

[0019] The present invention provides a compound having the structure shown in Formula III. The compound provided by the present invention has a typical urea structure as the primary pharmacophore of soluble epoxide hydrolase (sEH), and the thiazolidinedione moiety as the primary pharmacophore of peroxisome proliferator-activated receptors (PPARs). The sEH inhibitor provided by the present invention and the PPARs agonist compound have high inhibitory activity against human-derived HsEH and high agonistic activity against PPAR, and can be used as an sEH inhibitor and a PPARs agonist compound for preparing a drug for treating diseases mediated by soluble epoxide hydrolase and peroxisome proliferator-activated receptors. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It is a reaction route diagram of the sEH inhibitor and the PPARs agonist compound having the structure shown in Formula III in the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention provides a compound having the structure shown in Formula III:

[0022]

[0023] Wherein, R1 is adamantyl, aryl, alkyl-substituted aryl, haloaryl, haloalkyl-substituted aryl or haloalkoxy-substituted aryl, haloaryloxy-substituted aryl; R2 is hydrogen, hydroxyl, alcohol hydroxyl, amino, carboxyl, acyl, amide or ester group; B is a single bond, cycloalkyl, heterocyclic group or aryl;

[0024] W is a single bond, -CH2-, -O-, -S-, -NH- or

[0025] Z is independently =CH2, =O, =S or =NH.

[0026] In the present invention, the alkyl in the alkyl-substituted aryl and the haloalkyl-substituted aryl is independently preferably methyl, ethyl, propyl, butyl, pentyl, isobutyl, isopropyl, isopentyl or tert-butyl; the alkoxy in the haloalkoxy-substituted aryl is preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopentyloxy, cyclohexyloxy, phenoxy or benzyloxy; the halogen in the haloaryl, haloalkyl-substituted aryl and haloalkoxy-substituted aryl is independently preferably -F, -Cl, -Br.

[0027] In the present invention, the cycloalkyl group is an unsubstituted or substituted C3-C8 cycloalkyl group; the substituents of the substituted C3-C8 cycloalkyl group are independently preferably -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2 or a C1-C6 alkyl group; the heterocyclic group is independently an unsubstituted or substituted 3-10 membered heterocyclic group; the substituents of the substituted 3-10 membered heterocyclic group are independently preferably -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2 or a C1-C6 alkyl group; the aryl group is independently a substituted or unsubstituted phenyl group, pyridyl group or naphthyl group; the substituents of the substituted phenyl group, pyridyl group or naphthyl group are independently preferably -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2 or a C1-C6 alkyl group.

[0028] In the present invention, R1 is preferably adamantyl, halogenated aryl, halogenated alkyl-substituted aryl or halogenated alkoxy-substituted aryl; R2 is preferably hydrogen or an ester group; B is preferably a single bond or a phenyl group; W is preferably a single bond or -O-; Z is =O.

[0029] In the present invention, R1 is preferably adamantyl, R2 is preferably hydrogen or -CH2-C(O)-CH3.

[0030] In the present invention, in formula III is

[0031] In the present invention, the compound preferably has any one of the following structures:

[0032]

[0033] The present invention provides a preparation method of the compound according to the above technical solution, comprising the following steps:

[0034] Performing a first substitution reaction on compound m and compound b to obtain compound n;

[0035] Performing a first condensation reaction on the compound n and compound d to obtain compound o;

[0036] Performing a first hydrolysis reaction on the compound o to obtain compound p;

[0037] Performing a first nucleophilic substitution reaction on the compound p, compound w and compound af to obtain compound q; the compound q is a compound having the structure shown in formula III with a double bond connected to the thiazolidinedione group in the structure;

[0038] The compound q is subjected to a first reduction reaction to obtain a compound having the structure shown in Formula III in which the thiazolidinedione group in the structure is connected by a single bond;

[0039] The structural formulas of the compound b, compound d, compound w, and compound af are as follows:

[0040]

[0041] Among them, X in compound b is H, hydroxyl, halogen, and haloalkyl;

[0042] The structural formulas of the compound m, compound n, compound o, compound p, and compound q are as follows:

[0043]

[0044] Among them, Q in chemical compound m is H, hydroxyl, amino, mercapto, carboxyl, or acyl chloride.

[0045] In the present invention, unless otherwise specified, all preparation raw materials / components are commercially available products well-known to those skilled in the art.

[0046] As Figure 1 shown in the reaction route diagram: In the present invention, the compound m and the compound b are subjected to a nucleophilic substitution reaction to obtain the compound n. In the present invention, the molar ratio of the compound m to the compound b is preferably 1:1. In the present invention, the nucleophilic substitution reaction is preferably carried out in the presence of triphenylphosphine and DIAD. In the present invention, the molar ratio of the compound m, compound b, triphenylphosphine, and DIAD is preferably 1:1:1.5:1.5. In the present invention, the solvent for the nucleophilic substitution reaction is preferably tetrahydrofuran, the nucleophilic substitution reaction is preferably carried out under an ice-salt bath condition, and the time for the nucleophilic substitution reaction is preferably 8 - 12 h. After the nucleophilic substitution reaction, column chromatography purification is used.

[0047] In the present invention, the compound n and the compound d are subjected to a Claisen - Schmidt condensation reaction to obtain the compound o. In the present invention, the condensation reaction is preferably carried out in the presence of pyridine or piperidine and acetic acid or benzoic acid. In the present invention, the molar ratio of the compound n, compound d, base, and acid is preferably 1:1:0.5:0.5. In the present invention, the nucleophilic substitution reaction is preferably carried out at 110 °C, the solvent for the condensation reaction is preferably toluene, and the time for the condensation reaction is preferably 4 - 8 h. After the condensation reaction, filtration is carried out at room temperature.

[0048] After obtaining compound o, compound o is subjected to a first hydrolysis reaction to obtain compound p. The first hydrolysis reaction is: a deprotection reaction is carried out under acidic conditions; in the present invention, the reagent providing the acidic condition is preferably trifluoroacetic acid, and the deprotection reaction is preferably carried out under dichloromethane conditions. In the present invention, the temperature of the deprotection reaction is preferably room temperature, and the time is preferably 1.5 to 2.5 h. After the deprotection reaction, in the present invention, the obtained reaction solution is preferably subjected to reduced pressure distillation, water and dichloromethane are added to the obtained residue, and the pH value of the system is adjusted to 12 with solid sodium hydroxide under an ice bath condition, the organic layer is separated and removed, the aqueous layer is extracted with dichloromethane (100 mL×2), and then successively washed with water, saturated brine and dried over anhydrous sodium sulfate, filtered by suction, and the obtained filtrate is concentrated under reduced pressure to obtain compound p.

[0049] After obtaining compound p, in the present invention, compound p and compound af are subjected to a nucleophilic substitution reaction to obtain compound q. Compound q is a compound having the structure shown in Formula III in which the thiazolidinedione group in the structure is connected by a double bond; compound q is subjected to a first reduction reaction to obtain a compound having the structure shown in Formula III in which the thiazolidinedione group in the structure is connected by a single bond. In the present invention, the molar ratio of compound p, triphosgene and base is preferably 1:(0.33 - 0.6):3, more preferably 1:(0.4 - 0.5):3. In the present invention, the nucleophilic substitution reaction is preferably carried out in the presence of triethylamine, with DCM as the solvent. In the present invention, the nucleophilic substitution reaction is preferably carried out under an ice bath condition, and the time of the nucleophilic substitution reaction is preferably 10 to 50 min, more preferably 30 min. After the nucleophilic substitution reaction, purification is carried out by column chromatography.

[0050] When R4 is H, the above compound is subjected to an ester hydrolysis reaction under basic conditions. In the present invention, the reagent providing the basic condition is preferably LiOH, and the ester hydrolysis reaction is preferably carried out under THF / H2O conditions. In the present invention, the temperature of the ester hydrolysis reaction is preferably room temperature, and the time is preferably 1.5 to 2.5 h. After the ester hydrolysis reaction, in the present invention, the obtained reaction solution is preferably subjected to reduced pressure distillation, water and dichloromethane are added to the obtained residue, and the pH value of the system is adjusted to 2 with 6N HCl under an ice bath condition, extracted with dichloromethane (40 mL×3), and then successively washed with water, saturated brine and dried over anhydrous sodium sulfate, filtered by suction, and the obtained filtrate is concentrated under reduced pressure.

[0051] The present invention provides the application of the described compound and its pharmaceutically acceptable deuterated compounds, salts or hydrates or the compounds prepared by the preparation method described in the above technical solution in the preparation of peroxisome proliferator-activated receptor agonists and soluble epoxide hydrolase inhibitors.

[0052] In the present invention, the peroxisome proliferator-activated receptor agonist and soluble epoxide hydrolase inhibitor are used for treating diseases mediated by soluble epoxide hydrolase and peroxisome proliferator-activated receptor; the diseases mediated by soluble epoxide hydrolase and peroxisome proliferator-activated receptor preferably include inflammatory diseases, pain, sepsis, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications, depression, liver fibrosis, renal failure, chronic obstructive pulmonary disease or pulmonary hypertension diseases.

[0053] In the present invention, the inflammatory disease preferably includes non-alcoholic steatohepatitis or chronic nephritis; the pain includes neuropathic pain.

[0054] The present invention provides a compound of sEH inhibitor and PPARs agonist. The compound of sEH inhibitor and PPARs agonist provided by the present invention has a typical urea structure as the primary pharmacophore of sEH and a thiazolidinedione moiety as the primary pharmacophore of PPARs. The compound of sEH inhibitor and PPARs agonist provided by the present invention has high inhibitory activity against human-derived HsEH and high agonist activity against PPAR, and can be used as a compound of sEH inhibitor and PPARs agonist for preparing a medicament for treating diseases mediated by soluble epoxide hydrolase and peroxisome proliferator-activated receptor.

[0055] The present invention provides a compound of sEH inhibitor and PPARs agonist or a pharmaceutically acceptable composition thereof, and a preparation method and application thereof, belonging to the technical field of medicine. The compound of sEH inhibitor and PPARs agonist provided by the present invention has a structure shown in Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI. The sEH inhibitor part provided by the present invention can stabilize the endogenous substance epoxy fatty acid with broad physiological activities and has a strong inhibitory effect on human recombinant sEH. It can regulate the generation of various pro-inflammatory cytokines, reduce endoplasmic reticulum stress, prevent or reverse endothelial dysfunction, and stabilize mitochondrial function through multiple mechanisms of action. The PPAR agonist can synergistically act with the sEH inhibitor to inhibit the expression of cytokines - such as resistin, tumor necrosis factor α (TNFα) and interleukin 6 - which promote insulin resistance. The PPAR agonist causes an increase in the plasma adiponectin concentration. Adiponectin is a hormone secreted from adipose tissue and is present in low levels in the plasma of type 2 diabetes patients. Adiponectin increases fatty acid oxidation in the liver and skeletal muscle. Therefore, the compounds involved in the present invention can be used for diseases mediated by soluble epoxide hydrolase and peroxisome proliferator-activated receptor, including inflammatory diseases, pain, sepsis, cardiovascular diseases, neurodegenerative diseases, diabetes, diabetic complications, depression, non-alcoholic steatohepatitis, liver fibrosis, chronic nephritis, renal failure, chronic obstructive pulmonary disease or pulmonary hypertension diseases.

[0056] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below in conjunction with the accompanying drawings and embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0057] Example 1 Synthesis of tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate

[0058] To a 100 mL three-necked flask were successively added trans-4-aminocyclohexanol hydrochloride (5.00 g, 32.98 mmol), sodium carbonate (10.49 g, 98.98 mmol), water (25 mL). The temperature was lowered to 0 °C in an ice bath, and a DCM solution (5 mL) of Boc2O (7.92 g, 36.28 mmol) was added dropwise. The addition was completed within 3 minutes, and then the temperature was allowed to rise to room temperature naturally. After 4 hours, TLC monitoring (EA:PE = 1:3, stained with phosphomolybdic acid) showed that the reaction occurred, and the reaction was stopped. The reaction solution was poured into 50 mL of water, extracted with DCM (30 mL × 3), extracted with EA (30 mL × 3). The organic layers were combined, washed with water (30 mL), washed with saturated NaCl (30 mL), and dried over anhydrous magnesium sulfate. Filtration was carried out under suction, and the filter cake was washed with EA. The filtrate was concentrated under reduced pressure to dryness to obtain 8.0 g of a crude product as a white powdery solid. The crude product was directly used in the next step without purification.

[0059] Example 2 Synthesis of 4-aminophenyl 4-nitrobenzoate

[0060] To a 100 mL three-necked flask were successively added cis-4-Boc-aminocyclohexanol (7.10 g, 32.98 mmol), p-nitrobenzoic acid (5.51 g, 98.98 mmol), triphenylphosphine (12.98 g, 49.47 mol), THF (20 mL). The temperature was lowered to below -10 °C in an ice-salt bath, and a THF solution (20 mL) of DIAD (10 g, 49.47 mol) was added dropwise. After 2 hours, TLC monitoring showed that the reaction was completed. The solvent was removed by distillation under reduced pressure to obtain 35.6 g of a crude product. The crude product was purified by silica gel column chromatography, with 1.5 times of sample mixing and 5 times of silica gel for column packing. The eluent was EA:PE = 1:10, and 5.53 g of a white solid was obtained.

[0061] Example 3 tert-butyl (4-hydroxyphenyl)carbamate

[0062] To a 100 mL three-necked flask, 4-aminophenyl 4-nitrobenzoate (5.53 g, 14.88 mmol), NaOH (1.79 g, 44.65 mmol), THF (20 mL), and H2O (20 mL) were added successively. The reaction was carried out at room temperature. After 4 h, TLC was used for monitoring. After the reaction was completed, it was concentrated to dryness under reduced pressure. EA (30 mL) was added, and it was extracted with saturated sodium carbonate (20 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered by suction, and concentrated to dryness under reduced pressure to obtain 3.01 g of a white solid with a yield of 94.08%.

[0063] Example 4 tert-Butyl ((1r,4r)-4-(4-formylphenoxy)cyclohexyl)carbamate

[0064] To a 500 mL three-necked flask, cis-N-BOC-4-aminocyclohexanol (2.50 g, 11.61 mmol, 1 eq), p-hydroxybenzaldehyde (1.42 g, 11.61 mmol, 1 eq), triphenylphosphine (4.57 g, 17.42 mmol, 1.5 eq), and THF (10 mL) were added successively. The temperature was lowered to below -10 °C in an ice-salt bath, and a THF solution (5 mL) of DIAD (3.52 g, 17.42 mmol, 1.5 eq) was added dropwise, controlling the dropping rate at one drop every two seconds. After 72 h, TLC was used for monitoring (EA:PE = 1:1). When most of the reaction occurred, the reaction was stopped. THF was removed by concentration under reduced pressure to obtain 12.21 g of a brownish-yellow oily substance. The crude product was purified by silica gel column chromatography, with 1.5 times of sample mixing and 10 times of silica gel for column packing. The eluent was EA:PE = 1:30, and 2.85 g of a white solid was obtained with a yield of 76.82%.

[0065] Synthesis of Example 5 tert-Butyl ((1r,4r)-4-{4-[(Z)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)carbamate

[0066] To a 100 mL round-bottomed flask, tert-butyl [(1r,4r)-4-(4-formylphenoxy)cyclohexyl]carbamate (2.85 g, 8.93 mmol, 1 eq), 2,4-thiazolidinedione (1.05 g, 8.93 mmol, 1 eq), pyridine (0.35 g, 4.46 mmol, 0.5 eq), glacial acetic acid (0.27 g, 4.46 mmol, 0.5 eq), and toluene (10 mL) were added successively, and the temperature was raised to reflux. As the reaction proceeded, a solid precipitated. After 8 h, TLC was used for monitoring. After the reaction was completed, the reaction was stopped. The reaction solution was cooled to room temperature and filtered by suction. The filter cake was rinsed with a small amount of toluene to obtain 2.03 g of a white solid. ESI-MS (m / z): 424.1 [M+H] +

[0067] Synthesis of 5-{(Z)-4-[(1r,4r)-4-aminocyclohexyl]oxybenzylidene}thiazolidine-2,4-dione in Example 6

[0068] To a 500 mL three-necked flask, successively add tert-butyl ((1r,4r)-4-{4-[(Z)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)carbamate (2.03 g, 4.85 mmol), DCM (15 mL), and cool to 0 °C in an ice bath. Dropwise add TFA (4 mL). After 0.5 h, monitor by TLC. When the reaction is complete, stop the reaction. Remove TFA from the reaction solution by distillation under reduced pressure. Add water (30 mL), and extract with DCM (30 mL × 3). Combine the organic layers and concentrate to dryness under reduced pressure. Obtain 1.17 g of a brown solid as the crude product. The crude product is directly used in the next step without purification.

[0069] Synthesis of 1-[(1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl]-3-((1r,4R)-4-{4-[(E)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)urea (SP-B01) in Example 7

[0070] Add memantine, dry dichloromethane, and a dichloromethane solution of BTC (2 mL) to a 50 mL single-necked flask. Cool to below -10 °C in an ice-salt bath, and slowly dropwise add a DCM solution of TEA. Evaporate the solution to dryness, add 20 mL of DCM, then add 5-{(Z)-4-[(1r,4r)-4-aminocyclohexyl]oxybenzylidene}thiazolidine-2,4-dione, and reflux the reaction. After 3 h, monitor by TLC. When the reaction is complete, stop the reaction. Pour into 30 mL of water, filter by suction to obtain a small amount of white solid without fluorescence. Extract the filtrate with 30 mL of DCM three times, wash once with water, once with saturated brine, dry over anhydrous magnesium sulfate, and evaporate to dryness to obtain 1.2 g of a white solid. Mix 1.2 g of the sample with silica gel, load 10 g of silica gel onto a column, and use EA:PE = 1:7 as the eluent. Obtain 0.15 g of a yellow solid. ESI-MS (m / z): 522.0 [M-H] - 。

[0071] Synthesis of 1-[(1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl]-3-((1r,4R)-4-{4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)urea (SP-A01) in Example 8

[0072] Add 1-[(1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl]-3-((1r,4R)-4-{4-[(E)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)urea, 10% Pd / C into a 50 mL single-necked flask. Replace the air with hydrogen three times and then with Ar three times. React at 30 °C. After 3.5 hours, the reaction is completed. Stop the reaction, perform suction filtration. Wash the filter cake with a small amount of water and dry to obtain 0.15 g of white solid. ESI-MS (m / z): 524.1 [M-H] - 。 1 H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.90 - 6.83 (m, 2H), 5.58 (d, J = 7.6 Hz, 1H), 5.41 (s, 1H), 4.85 (dd, J = 9.1, 4.3 Hz, 1H), 4.25 (tt, J = 9.3, 3.8 Hz, 1H), 3.28 (d, J = 4.4 Hz, 1H), 3.04 (dd, J = 14.2, 9.1 Hz, 1H), 2.04 (p, J = 3.1 Hz, 1H), 1.98 (dd, J = 12.9, 4.1 Hz, 2H), 1.87 - 1.78 (m, 2H), 1.67 (d, J = 3.2 Hz, 2H), 1.50 (s, 3H), 1.36 (ddd, J = 12.8, 9.8, 3.2 Hz, 2H), 1.32 - 1.24 (m, 2H), 1.26 - 1.19 (m, 3H), 1.19 - 1.12 (m, 1H), 1.07 (s, 2H), 0.80 (s, 6H).

[0073] Example 9 Synthesis of 1-((1r,4r)-4-{4-[(E)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)-3-[3-fluoro-4-(trifluoromethoxy)phenyl]urea (SP-B07)

[0074] Add 3-fluoro-4-(trifluoromethoxy)aniline (1.21 g, 4.72 mmol, 1.5 eq), Et3N (0.95 g, 18.70 mmol, 3 eq) and dry DCM (10 mL) into a 100 mL three-necked flask in sequence. Cool the mixture to -15 °C with a cold trap and dropwise add a DCM solution (15 mL) of BTC (0.48 g, 1.60 mmol, 0.51 eq) within 3 minutes. After dropping, let the temperature rise to room temperature naturally. Monitor the reaction by TLC after 2 hours. When the reaction is complete, stop the reaction.

[0075] To a 100 mL three-necked flask, 5-{(Z)-4-[(1r,4r)-4-aminocyclohexyl]oxybenzylidene}thiazolidine-2,4-dione (1.17 g, 3.68 mmol, 1 eq), Et3N (0.95 g, 18.7 mmol, 3 eq), DCM (6 mL), and a DCM (20 mL) solution of 3-fluoro-4-(trifluoromethoxy)phenyl isocyanate were added successively. The reaction was carried out at room temperature. After 6 hours, the reaction was monitored by TLC. When the reaction was complete, the reaction was stopped. The DCM was removed by concentration under reduced pressure. 30 mL of 1N hydrochloric acid was added and stirred for 5 minutes. The mixture was filtered by suction, and the filter cake was washed with 20 mL of water to obtain 1.46 g of a crude white solid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 times the amount of silica gel, and a column was packed with 10 times the amount of silica gel. The eluent was EA:PE = 1:7, and 0.34 g of a white solid was obtained. 1 1H NMR (400 MHz, DMSO-d6): δ (ppm) 12.49 (s, 1H), 8.71 (s, 1H), 7.75 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.55 - 7.36 (m, 1H), 7.13 - 7.08 (m, 3H), 6.31 (d, J = 7.6 Hz, 1H), 4.50 - 4.44 (m, 1H), 3.58 - 3.51 (m, 1H), 2.08 - 2.05 (m, 2H), 1.96 - 1.91 (m, 2H), 1.54 - 1.34 (m, 4H). 13 13C NMR (100 MHz, DMSO-d6): δ (ppm) 168.4, 167.9, 159.7, 155.4, 154.6, 152.9, 141.8, 132.6, 125.7, 124.7, 120.6, 116.7, 114.0, 106.2, 106.0, 74.9, 47.7, 30.3, 30.1. ESI MS: m / z 540.0 [M+H] + .

[0076] Example 10 Synthesis of 1-((1r,4r)-4-{4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)-3-[3-fluoro-4-(trifluoromethoxy)phenyl]urea (SP-A07)

[0077] To a 100 mL single-necked flask, 1-((1r,4r)-4-{4-[(E)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)-3-[3-fluoro-4-(trifluoromethoxy)phenyl]urea (1.65 g, 3.06 mmol, 1 eq), 10% Pd / C (0.17 g), and anhydrous methanol (10 mL) were added successively, and the mixture was stirred at 30 °C. After 3 hours, the reaction was monitored by TLC. When the reaction was complete, the reaction was terminated. The mixture was filtered by suction and concentrated under reduced pressure to obtain 40 mg of a white solid. 1 1H NMR (400 MHz, DMSO-d6): δ (ppm) 12.01 (s, 1H), 8.73 (s, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.65 - 7.40 (m, 1H), 7.38 - 7.09 (m, 3H), 6.88 (d, J = 8.6 Hz, 2H), 6.30 (d, J = 7.6 Hz, 1H), 4.88 - 4.84 (m, 1H), 4.32 - 4.27 (m, 1H), 3.56 - 3.49 (m, 1H), 3.28 (s, 1H), 3.07 - 3.02 (m, 1H), 2.50 - 2.01 (m, 4H), 1.93 - 1.41 (m, 4H). 13 13C NMR (100 MHz, DMSO-d6): δ (ppm) 168.4, 167.9, 159.7, 155.4, 154.6, 152.9, 141.8, 132.6, 125.7, 124.7, 120.6, 116.7, 114.0, 106.0, 74.9, 47.7, 30.3, 30.1. ESI MS: m / z 542.1 [M+H] + .

[0078] Example 11 Synthesis of tert-butyl 4-(4-formylphenoxy)piperidine-1-carboxylate

[0079] To a 500 mL three-necked flask, N-Boc-4-hydroxypiperidine (5.00 g, 0.25 mol), 4-hydroxybenzaldehyde (15.18 g, 0.25 mol), triphenylphosphine (48.92 g, 0.37 mol), and THF (75 mL) were added successively. The temperature was lowered to below -10 °C in an ice-salt bath, and a THF solution (80 mL) of DIAD (37.74 mg, 0.37 mol) was added dropwise at a rate of one drop every two seconds. After 5 hours, the reaction was monitored by TLC. When the reaction was complete, the reaction was stopped. THF was removed by concentration under reduced pressure to obtain 127.01 g of a brownish-yellow oil. The crude product was directly used in the next step without purification. 11H NMR (400 MHz, CDCl3): δ (ppm) 9.88 (s, 1H), 7.82 (d, J = 2.0 Hz, 2H), 7.01 (d, J = 2.0 Hz, 2H), 4.64 - 4.59 (m, 1H), 3.73 - 3.67 (m, 2H), 3.42 - 3.35 (m, 2H), 1.99 - 1.92 (m, 2H), 1.82 - 1.74 (m, 2H), 1.77 (s, 9H).

[0080] Example 12 Synthesis of 4-(Piperidin-4-yloxy)benzaldehyde

[0081] To a 500 mL three-necked flask, 4-(4-Formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (127.01 g) and DCM (180 mL) were successively added, and the temperature was lowered to 0 °C in an ice bath. TFA (119.04 g, 1.04 mol) was added dropwise. After 37 hours, the reaction was monitored by TLC. When the reaction was complete, the reaction was stopped. TFA in the reaction solution was removed by distillation under reduced pressure. DCM (50 mL) was added, and the mixture was extracted with 1N HCl (200 mL × 6). The aqueous layers were combined, adjusted to pH 10 with solid NaOH, and then extracted with n-butanol (200 mL × 12). The organic layers were combined, concentrated to dryness under reduced pressure, slurried with acetone (12 mL), filtered, and the filter cake was washed with acetone (2 mL) and dried to obtain 17.45 g of a crude product as a brownish-red solid. The overall yield of the two steps was 34%. The crude product was used directly in the next step without purification.

[0082] Example 10 Synthesis of (Z)-5-[4-(Piperidin-4-yloxy)benzylidene]thiazolidine-2,4-dione

[0083] To a 250 mL round-bottom flask, 4-(Piperidin-4-yloxy)benzaldehyde (4.00 g, 19.50 mmol), 2,4-Thiazolidinedione (2.28 g, 19.50 mmol), pyridine (0.77 g, 9.75 mmol), glacial acetic acid (0.59 g, 9.75 mmol), and toluene (15 mL) were successively added, and the temperature was raised to reflux. As the reaction proceeded, a solid precipitated. After 8 hours, the reaction was monitored by TLC. When the reaction was complete, the reaction was stopped. The reaction solution was cooled to room temperature, filtered, and the filter cake was rinsed with a small amount of toluene to obtain 3 g of a pale yellow solid. ESI MS: m / z 304.10 [M + H] + .

[0084] Example 11 Synthesis of N-[(1r,3R,5S,7r)-3,5-Dimethyladamantan-1-yl[-4-{4-[(Z)-(2,4-Dioxothiazolidin-5-ylidene)methyl]phenoxy}piperidine-1-carboxamide (SP-B02)

[0085] Add memantine (16.51 g, 0.031 mol), Et3N (10.71 g, 0.11 mol), dry DCM (50 mL) into a 250 mL three-necked flask in sequence. Cool the mixture to -10 °C in an ice-salt bath, and dropwise add a DCM solution (50 mL) of BTC (8.01 g, 0.027 mol). Finish the dropping within 30 minutes. After the dropping, let it warm up to room temperature naturally and continue the reaction for 4 hours. Stop the reaction and concentrate the solvent under reduced pressure until it is completely evaporated.

[0086] Add (Z)-5-[4-(piperidin-4-yloxy)benzylidene]thiazolidine-2,4-dione (6.33 g, 0.021 mol), Et3N (6.33 g, 0.062 mol), DCM (30 mL) into a 250 mL three-necked flask in sequence. At room temperature, dropwise add the above-mentioned DCM (30 mL) solution of memantine isocyanate. Finish the dropping within 30 minutes and monitor by TLC. Pour the reaction solution into water (30 mL), extract with DCM (30 mL × 3), combine the organic layers, wash with water (30 mL), wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter by suction, and concentrate under reduced pressure to obtain 12.5 g of a yellow oily liquid. The crude product is purified by silica gel column chromatography, with 1.5 times of sample mixing and 5 times of silica gel for column packing. The eluent is EA:PE = 1:3 to obtain 6.11 g of a pale yellow solid with a melting point of 83 - 83 °C. 1 1H NMR (400 MHz, CDCl3): δ (ppm) 9.07 (s, 1H), 7.80 (s, 1H), 7.45 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 4.57 (s, 1H), 3.57 (d, J = 8.3 Hz, 2H), 3.30 - 3.29 (m, 2H), 2.16 (d, J = 10.0 Hz, 2H), 1.98 (d, J = 4.2 Hz, 4H), 1.83 (s, 5H), 1.38 (d, J = 12.1 Hz, 2H), 1.28 (d, J = 12.0 Hz, 2H), 1.20 - 1.11 (m, 2H), 0.85 (s, 6H). ESI MS: m / z 510.3 [M+H] + .

[0087] Synthesis of N-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl[-4-{4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}piperidine-1-carboxamide (SP-A02) in Example 12

[0088] To a 50 mL single-necked flask, N-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl[-4-{4-[(Z)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}piperidine-1-carboxamide (0.2 g, 0.39 mmol), 10% Pd / C (0.02 g), and anhydrous methanol (10 mL) were successively added, and the mixture was stirred at 30 °C. After 3 hours, the reaction was monitored by TLC and found to be complete, then the reaction was terminated. The mixture was filtered by suction and concentrated under reduced pressure to obtain 0.18 g of a white solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.38 (s, 1H), 7.14 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.3 Hz, 2H), 4.46 (ddt, J = 17.9, 7.2, 3.7 Hz, 2H), 4.26 (s, 1H), 3.57 (ddd, J = 12.5, 7.7, 3.7 Hz, 2H), 3.44 (dd, J = 14.2, 4.0 Hz, 1H), 3.24 (ddd, J = 13.0, 7.8, 4.1 Hz, 2H), 3.11 (dd, J = 14.2, 9.4 Hz, 1H), 2.14 (p, J = 3.3 Hz, 1H), 1.92 (ddd, J = 11.9, 8.0, 3.7 Hz, 2H), 1.85 - 1.71 (m, 3H), 1.77 (s, 1H), 1.38 (d, J = 12.4 Hz, 2H), 1.27 (dd, J = 15.7, 9.6 Hz, 4H), 1.14 (t, J = 10.4 Hz, 2H), 0.85 (s, 6H).

[0089] Example 13 Synthesis of (Z)-4-{4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}-N-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide (SP-B05)

[0090] To a 100 mL three-necked flask, p-trifluoromethoxyaniline (0.58 g, 3.28 mmol), Et3N (0.66 g, 6.56 mmol), and dry DCM (10 mL) were successively added, and the temperature was lowered to -10 °C in an ice-salt bath. A DCM solution (10 mL) of BTC (0.34 g, 1.12 mmol) was added dropwise within 3 minutes. After the addition was complete, the mixture was allowed to warm to room temperature naturally. After 2 hours, the reaction was monitored by TLC and found to be complete, then the reaction was stopped.

[0091] To a 100 mL three-necked flask, 5-{(Z)-4-[(1r,4r)-4-aminocyclohexyl]oxybenzylidene}thiazolidine-2,4-dione (1.00 g, 3.28 mmol), Et3N (0.66 g, 6.56 mmol), DCM (6 mL), and a DCM (20 mL) solution of p-trifluoromethoxyphenyl isocyanate were added successively. The reaction was carried out at room temperature for half an hour. Then DMSO (6 mL) was added, and the reaction temperature was raised to reflux. After 6 hours, the reaction was monitored by TLC and was found to be complete, so the reaction was stopped. The DCM was removed by rotary evaporation under reduced pressure. 30 mL of 1N hydrochloric acid was added and stirred for 5 minutes. The mixture was filtered by suction, and the filter cake was washed with 20 mL of water to obtain 1.46 g of a crude white solid. The crude product was purified by silica gel column chromatography, with 1.5 times the sample loading and 5 times the amount of silica gel for column packing. The eluent was EA:PE = 1:5, and 0.46 g of a white solid was obtained. 1 1H NMR (400 MHz, DMSO-d6): δ (ppm) 12.48 (s, 1H), 8.75 (s, 1H), 7.73 (s, 1H), 7.56 (s, 4H), 7.23 - 7.15 (m, 4H), 4.73 (s, 1H), 3.82 (s, 2H), 3.30 (s, 2H), 2.00 (s, 2H), 1.62 (s, 2H). 13 13C NMR (100 MHz, DMSO-d6): δ (ppm) 168.8, 159.2, 155.2, 143.0, 140.4, 132.6, 131.8, 126.1, 121.6, 121.1, 119.8, 116.9, 72.8, 30.9.

[0092] Example 14 Synthesis of 4-{4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}-N-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide (SP-A05)

[0093] To a 50 mL single-necked flask, (Z)-4-{4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}-N-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide (1.65 g, 3.06 mmol, 1 eq), 10% Pd / C (0.20 g), and anhydrous methanol (10 mL) were added successively. The mixture was stirred at 30 °C. After 3 hours, the reaction was monitored by TLC and was found to be complete, so the reaction was terminated. The mixture was filtered by suction, and the solvent was removed by rotary evaporation under reduced pressure to obtain 0.18 g of a white solid. 11H NMR (400 MHz, DMSO-d6): δ (ppm) 12.01 (s, 1H), 8.73 (s, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.65 - 7.40 (m, 1H), 7.38 - 7.09 (m, 3H), 6.88 (d, J = 8.6 Hz, 2H), 6.30 (d, J = 7.6 Hz, 1H), 4.88 - 4.84 (m, 1H), 4.32 - 4.27 (m, 1H), 3.56 - 3.49 (m, 1H), 3.28 (s, 1H), 3.07 - 3.02 (m, 1H), 2.50 - 2.01 (m, 4H), 1.93 - 1.41 (m, 4H). 13 13C NMR (100 MHz, DMSO-d6): δ (ppm) 168.4, 167.9, 159.7, 155.4, 154.6, 152.9, 141.8, 132.6, 125.7, 124.7, 120.6, 116.7, 114.0, 106.0, 74.9, 47.7, 30.3, 30.1. ESI MS: m / z 542.1 [M+H] + .

[0094] Example 15 Synthesis of (Z)-4-{4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}-N-[3-fluoro-4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide (SP-B06)

[0095] To a 100 mL three-necked flask, 3-fluoro-4-trifluoromethoxyaniline (1.21 g, 4.72 mmol, 1.5 eq), Et3N (0.95 g, 18.70 mmol, 3 eq), and dry DCM (10 mL) were added successively. The temperature was cooled to -15 °C with a cold trap, and a DCM solution (15 mL) of BTC (0.48 g, 1.60 mmol, 0.51 eq) was added dropwise within 3 minutes. After the addition, the temperature was allowed to rise to room temperature naturally. After 2 hours, the reaction was monitored by TLC and found to be complete, and the reaction was stopped.

[0096] To a 100 mL three-necked flask, 5-{(Z)-4-[(1r,4r)-4-aminocyclohexyl]oxybenzylidene}thiazolidine-2,4-dione (1.17 g, 3.68 mmol, 1 eq), Et3N (0.95 g, 18.7 mmol, 3 eq), DCM (6 mL), and a DCM (20 mL) solution of 3-fluoro-4-(trifluoromethoxy)phenyl isocyanate were added successively. The reaction was carried out at room temperature. After 6 hours, the reaction was monitored by TLC. When the reaction was complete, the reaction was stopped. The DCM was removed by concentration under reduced pressure. 30 mL of 1N hydrochloric acid was added and stirred for 5 minutes. The mixture was filtered by suction, and the filter cake was washed with 20 mL of water to obtain 1.46 g of a crude white solid. The crude product was purified by silica gel column chromatography. The sample was mixed at 1.5 times the amount, the column was packed with 10 times the amount of silica gel, and the eluent was EA:PE = 1:7 to obtain 0.34 g of a white solid with a yield of 39.48%. 1 1H NMR (400 MHz, DMSO-d6): δ (ppm) 12.49 (s, 1H), 8.71 (s, 1H), 7.75 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.55 - 7.36 (m, 1H), 7.13 - 7.08 (m, 3H), 6.31 (d, J = 7.6 Hz, 1H), 4.50 - 4.44 (m, 1H), 3.58 - 3.51 (m, 1H), 2.08 - 2.05 (m, 2H), 1.96 - 1.91 (m, 2H), 1.54 - 1.34 (m, 4H). 13 13C NMR (100 MHz, DMSO-d6): δ (ppm) 168.4, 167.9, 159.7, 155.4, 154.6, 152.9, 141.8, 132.6, 125.7, 124.7, 120.6, 116.7, 114.0, 106.2, 106.0, 74.9, 47.7, 30.3, 30.1. ESI MS: m / z 540.0 [M+H] + .

[0097] Example 16 Synthesis of 4-{4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}-N-[3-fluoro-4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide (SP-A06)

[0098] To a 50 mL single-necked flask were successively added (Z)-4-{4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}-N-[3-fluoro-4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide (1.65 g, 3.06 mmol, 1 eq), 10% Pd / C (0.20 g), anhydrous methanol (10 mL), and the mixture was stirred at 30 °C. After 3 hours, the reaction was monitored by TLC and found to be complete, then the reaction was terminated. The mixture was filtered by suction and concentrated under reduced pressure to obtain 1.04 g of a white solid. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 12.01 (s, 1H), 8.73 (s, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.65 - 7.40 (m, 1H), 7.38 - 7.09 (m, 3H), 6.88 (d, J = 8.6 Hz, 2H), 6.30 (d, J = 7.6 Hz, 1H), 4.88 - 4.84 (m, 1H), 4.32 - 4.27 (m, 1H), 3.56 - 3.49 (m, 1H), 3.28 (s, 1H), 3.07 - 3.02 (m, 1H), 2.50 - 2.01 (m, 4H), 1.93 - 1.41 (m, 4H). 13 C NMR (100 MHz, DMSO-d6): δ (ppm) 168.4, 167.9, 159.7, 155.4, 154.6, 152.9, 141.8, 132.6, 125.7, 124.7, 120.6, 116.7, 114.0, 106.0, 74.9, 47.7, 30.3, 30.1. ESI MS: m / z 542.1 [M+H] + .

[0099] Example 17 Synthesis of (Z)-5-[4-(piperidin-4-yloxy)benzylidene]imidazolidine-2,4-dione

[0100] To a 100 mL round-bottomed flask were successively added 2,4-imidazolidinedione (1.95 g, 19.50 mmol), water (5 mL), and the mixture was heated to 70 °C and adjusted to pH 7 with saturated aqueous sodium bicarbonate. Ethanolamine (2.38 g, 19.50 mmol) was added to the mixture, and the temperature was raised to 100 °C. A solution of 4-(piperidin-4-yloxy)benzaldehyde (4 g, 19.50 mmol) in EtOH (15 mL) was added dropwise. A solid precipitated during the reaction. After 16 hours, the reaction was monitored by TLC and found to be complete, then the reaction was stopped. The reaction mixture was cooled to room temperature, filtered by suction, and the filter cake was washed with a small amount of water to obtain 1.8 g of a white solid. ESI MS: m / z 287.13 [M+H] + .

[0101] Synthesis of Example 18 N-[(1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl]-4-{4-[(Z)-(2,5-dioxoimidazolin-4-ylidene)methyl]phenoxy}piperidine-1-carboxamide (SP-B03)

[0102] Add memantine (1.10 g, 3.46 mmol), Et3N (0.70 g, 6.92 mmol), dry DCM (5 mL) into a 100 mL three-necked flask in sequence. Cool the mixture to -10 °C in an ice-salt bath, and dropwise add a DCM solution (4 mL) of BTC (0.51 g, 1.73 mmol). Finish dropping within 3 minutes. After dropping, let the temperature rise to room temperature naturally, continue the reaction for 4 hours, stop the reaction, and concentrate the solvent under reduced pressure until it is evaporated to dryness.

[0103] Add (Z)-5-[4-(piperidin-4-yloxy)benzylidene]imidazoline-2,4-dione (0.89 g, 3.08 mmol), Et3N (0.70 g, 6.92 mmol), DCM (10 mL) into a 100 mL three-necked flask in sequence. At room temperature, dropwise add the above-mentioned DCM (10 mL) solution of memantine isocyanate. Finish dropping within 20 minutes. Monitor the reaction by TLC until the reaction is completed. Concentrate the reaction solution under reduced pressure to obtain 3.14 g of a white solid. The crude product is purified by silica gel column chromatography, with 1.5 times of sample mixing and 5 times of silica gel for column packing. The eluent is EA:PE = 1:3 to obtain 1.02 g of a white solid. 1 1H NMR (400 MHz, DMSO-d6): δ (ppm) 11.11 (s, 1H), 10.40 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.38 (s, 1H), 5.70 (s, 1H), 4.62 - 4.58 (m, 1H), 3.64 - 3.61 (m, 2H), 3.09 - 3.02 (m, 2H), 2.06 - 2.05 (m, 1H), 1.91 - 1.80 (m, 2H), 1.76 (s, 1H), 1.76 (s, 1H), 1.59 - 1.43 (m, 6H), 1.31 - 1.16 (m, 4H), 1.06 (s, 2H), 0.81 (s, 6H).

[0104] Synthesis of Example 19 (Z)-4-[4-(2,5-dioxoimidazolin-4-ylidene)methyl]phenoxy)-N-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide (SP-B04)

[0105] To a 100 mL three-necked flask, p-trifluoromethoxyaniline (0.41 g, 3.50 mmol), Et3N (0.70 g, 7.00 mmol), and dry DCM (10 mL) were added successively. The temperature was lowered to -10 °C in an ice-salt bath, and a DCM solution (10 mL) of BTC (0.33 g, 1.13 mmol) was added dropwise. The addition was completed within 3 minutes, and after completion, the temperature was allowed to rise to room temperature naturally. After 2 hours, TLC monitoring was carried out, (EA:PE = 1:1, 2 drops of glacial acetic acid), and the reaction was complete, so the reaction was stopped.

[0106] To a 100 mL three-necked flask, (Z)-5-[4-(piperidin-4-yloxy)benzylidene]imidazolidine-2,4-dione (0.50 g, 1.75 mmol), Et3N (0.71 g, 7.00 mmol), DCM (5 mL), and a DCM (20 mL) solution of p-trifluoromethoxyphenyl isocyanate were added successively. The reaction was carried out at room temperature for half an hour, DMSO (6 mL) was added, and the reaction temperature was raised to reflux. After 12 hours, TLC monitoring was carried out, and the reaction was complete, so the reaction was stopped. DCM was removed by rotary evaporation under reduced pressure. 30 mL of 1N hydrochloric acid was added and stirred for 5 minutes. Filtration was carried out by suction, and the filter cake was washed with 20 mL of water to obtain 0.65 g of a crude white solid.

[0107] The crude product was purified by silica gel column chromatography. The sample was mixed at 1.5 times the amount, the column was filled with 5 times the amount of silica gel, and the eluent was EA:PE = 1:5 to obtain 0.42 g of a white solid. 1 1H NMR (400 MHz, DMSO-d6): δ (ppm) 11.25 (s, 1H), 10.42 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.41 - 7.39 (m, 2H), 7.37 - 7.13 (m, 1H), 7.13 - 7.12 (m, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.39 (s, 1H), 5.75 (s, 1H), 3.81 (d, J = 49 Hz, 2H), 3.44 (d, J = 49 Hz, 2H), 2.01 (s, 2H), 1.69 (s, 2H). 13 13C NMR (100 MHz, DMSO-d6): δ (ppm) 166.1, 157.6, 156.1, 153.4, 151.7, 131.7, 129.7, 126.7, 126.2, 125.6, 122.4, 116.6, 109.1, 72.0, 55.4, 30.6.

[0108] Example 20 Synthesis of 4-{((1R,4R)-4-[(tert-butoxycarbonyl)amino]cyclohexyl)oxy}phenyl acetate

[0109] To a 500 mL three-necked flask, trans-4-Boc-aminocyclohexanol (9.27 g, 43.08 mmol, 1 eq), 4-hydroxyphenyl acetate (6.55 g, 43.08 mmol, 1 eq), triphenylphosphine (16.94 g, 64.62 mmol, 1.5 eq), and THF (25 mL) were added successively. The temperature was lowered to below -10 °C in an ice-salt bath, and a THF solution (12.5 mL) of DIAD (13.07 g, 64.62 mmol, 1.5 eq) was added dropwise, controlling the dropping rate at one drop every two seconds. After 72 hours, the reaction was monitored by TLC. When the reaction was completed, the reaction was stopped. THF was removed by concentration under reduced pressure to obtain 35.57 g of a brownish-yellow oil. The crude product was purified by silica gel column chromatography, with 1.5 times the sample loading, 10 times the silica gel packed in the column, and the eluent being EA:PE = 1:30, to obtain 2.33 g of a white solid.

[0110] Example 21 Synthesis of tert-butyl [(1r,4r)-4-(4-hydroxyphenoxy)cyclohexyl]carbamate

[0111] To a 25 mL single-necked flask, 4-{((1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl)oxy}phenyl acetate (0.16 g, 0.46 mmol, 1 eq), THF (5 mL), H2O (0.5 mL), and LiOH (0.03 g, 1.37 mmol, 3 eq) were added successively, and the mixture was stirred at room temperature. After 50 min, the reaction was monitored by TLC. When the reaction was stopped, THF was removed by concentration under reduced pressure, and the mixture was extracted with EA (30 mL). The pH was adjusted to 4 with 1N HCl, and then extracted with DCM (30 mL × 3). The organic layer was dried over anhydrous magnesium sulfate, filtered by suction, and concentrated to dryness under reduced pressure to obtain 0.10 g of a crude pale yellow solid. ESIMS: m / z 330.2 [M+H] + .

[0112] Example 22 Synthesis of methyl 2-(4-{((1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl)oxy}phenoxy)acetate

[0113] To a 25 mL single-necked flask, tert-butyl [(1r,4r)-4-(4-hydroxyphenoxy)cyclohexyl]carbamate (0.43 g, 1.40 mmol, 1 eq), MeCN (15 mL) were successively added, then K2CO3 (0.58 g, 4.20 mmol, 3 eq) and KI (0.023 g, 0.14 mmol, 0.1 eq) were added. Methyl bromoacetate (0.32 g, 2.10 mmol, 1.5 eq) was added dropwise. After three Ar replacements, the temperature was raised to reflux. After 16 h, the reaction was monitored by TLC, stopped, concentrated to dryness under reduced pressure, water (30 mL) was added, and extraction was carried out with DCM (30 mL×3). The organic layers were combined, washed with water (30 mL), saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered by suction, and concentrated under reduced pressure to obtain 0.78 g of a brownish-black oily liquid. The crude product was purified by silica gel column chromatography, with 1.5 times sample mixing and 3 times silica gel for column packing. The eluent was EA:PE = 1:5, and 0.40 g of a white solid was obtained with a yield of 75.35%. ESI MS: m / z 402.1 [M+H]+.

[0114] Example 23 Synthesis of methyl 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetate

[0115] To a 25 mL single-necked flask, methyl 2-(4-{(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl}oxy)phenoxy)acetate (0.30 g, 0.79 mmol) and DCM (10 mL) were successively added. The temperature was cooled to 0 °C in an ice bath, and TFA (3 ml) was added dropwise. After 2 h, the reaction was monitored by TLC, and when the reaction was complete, the reaction was stopped. TFA in the reaction solution was removed by distillation under reduced pressure to obtain 0.21 g of a crude product as a brown oily substance.

[0116] Example 24 Synthesis of methyl 2-[4-((1r,4r)-4-{3-[3-fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)acetate (SP-C03)

[0117] To a 25 mL single-necked flask, BTC (0.08 g, 0.27 mmol, 0.34 eq), Et3N (0.16 g, 1.58 mmol, 3 eq), and dry DCM (5 mL) were successively added. The temperature was cooled to -80 °C in a cold trap, and a DCM solution (5 mL) of 3-fluoro-4-trifluoromethoxyaniline (0.21 g, 0.79 mmol, 1 eq) was added dropwise within 3 minutes. After the addition was complete, the temperature was allowed to rise to room temperature naturally. After 10 min, the reaction was monitored by TLC, and when the reaction was complete, the reaction was stopped.

[0118] Add a DCM (10 mL) solution of 3-fluoro-4-trifluoromethoxyphenyl isocyanate, Et3N (0.16 g, 1.58 mmol, 3 eq) to a 25 mL three-necked flask. Cool the mixture to 0 °C in an ice bath and add dropwise a DCM solution (10 mL) of methyl 2-{4-[(1r,4r)-4-aminocyclohexyloxy]phenoxy}acetate (0.22 g, 0.79 mmol, 1 eq). After the addition is complete, stir the reaction mixture at room temperature. Monitor the reaction by TLC after 30 min. When the reaction is complete, stop the reaction. Concentrate the reaction mixture under reduced pressure to remove DCM, obtaining 0.44 g of a crude white solid. Purify the crude product by silica gel column chromatography, loading 1.5 times the sample and packing 10 times the amount of silica gel. The eluent is EA:PE = 1:5, obtaining 0.10 g of a white solid with a yield of 25.6%. ESI MS: m / z 523.0 [M+Na] + .

[0119] Example 25 Synthesis of 2-[4-((1r,4r)-4-{3-[3-fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyloxy)phenoxy]acetic acid (SP-C02)

[0120] Add methyl 2-[4-((1r,4r)-4-{3-[3-fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyloxy)phenoxy]acetate (70 mg, 0.14 mmol, 1 eq), THF (2 mL), H2O (0.5 mL), and LiOH (10 mg, 0.42 mmol, 3 eq) to a 25 mL single-necked flask in sequence. Stir the mixture at room temperature. Monitor the reaction by TLC after 50 min. When the reaction is complete, stop the reaction. Concentrate the reaction mixture under reduced pressure to remove THF. Add EA (30 mL) and extract with water (20 mL × 2). Adjust the pH of the aqueous layer to 2 with 1N HCl and filter by suction to obtain 20.02 mg of a white solid. The yield is 29.06%. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 13.04 (s, 1H), 9.02 (s, 1H), 7.68 (dd, J = 13.4 Hz, 2.2 Hz, 1H), 7.38 (t, J = 8.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), 6.55 (d, J = 7.6 Hz, 1H), 4.49 (s, 2H), 3.51 - 3.49 (m, 2H), 1.99 (d, J = 9.6 Hz, 2H), 1.89 (d, J = 9.6 Hz, 2H), 1.46 - 1.23 (m, 4H). 1313C NMR (101 MHz, DMSO-d6) δ 171.46, 155.36, 154.74, 152.91, 152.60, 151.84, 142.12, 142.02, 128.75, 128.62, 124.65, 124.52, 121.97, 119.42, 117.47, 115.78, 113.93, 106.06, 105.83, 75.32, 66.10, 47.72, 30.34, 30.26. ESIMS: m / z 484.8 [M-H] - .

[0121] Example 26 Synthesis of Ethyl 2-(4-{(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl}oxy)phenoxy)acetate

[0122] To a 25 mL single-necked flask, methyl 2-(4-{(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl}oxy)phenoxy)acetate (4.00 g, 13.02 mmol, 1 eq), MeCN (20 mL) were added successively. Then K2CO3 (5.40 g, 39.06 mmol, 3 eq) and KI (0.22 g, 1.30 mmol, 0.1 eq) were added. Ethyl chloroacetate (2.39 g, 19.53 mmol, 1.5 eq) was added dropwise. The reaction system was purged with Ar for 3 times and then heated to reflux. After 16 h, the reaction was monitored by TLC and then stopped. The reaction mixture was concentrated under reduced pressure to dryness. Water (30 mL) was added and the mixture was extracted with DCM (30 mL × 3). The organic layers were combined, washed with water (30 mL), saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered by suction, and concentrated under reduced pressure to obtain 0.78 g of a brownish-black oily liquid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 times of silica gel and the column was packed with 3 times of silica gel. The eluent was EA:PE = 1:5, and 4.06 g of a white solid was obtained

[0123] Example 27 Synthesis of Ethyl 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetate

[0124] To a 100 mL single-necked flask, ethyl 2-(4-{(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl}oxy)phenoxy)acetate (4.06 g, 10.33 mmol) and DCM (20 mL) were added successively. The reaction system was cooled to 0 °C in an ice bath and TFA (6 mL) was added dropwise. After 6 h, the reaction was monitored by TLC and when the reaction was complete, the reaction was stopped. DCM and TFA in the reaction solution were removed by distillation under reduced pressure to obtain 4.40 g of a brown oily crude product, which was used directly in the next step without purification

[0125] Example 28 Synthesis of Ethyl 2-[4-((1r,4r)-4-{3-[3-Fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)acetate (SP-C04)

[0126] BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) were successively added to a 25 mL single-necked flask. The temperature was lowered to -80 °C in a cold trap, and a DCM solution (15 mL) of 3-fluoro-4-trifluoromethoxyaniline (0.21 g, 0.79 mmol, 1 eq) and Et3N (0.24 g, 2.37 mmol, 3 eq) was added dropwise. The addition was completed within 30 minutes, and then the temperature was allowed to rise to room temperature naturally. After 10 min, TLC monitoring showed that the reaction was complete, and the reaction was stopped.

[0127] A DCM (25 mL) solution of 3-fluoro-4-trifluoromethoxyphenyl isocyanate, Et3N (0.24 g, 2.37 mmol, 3 eq) was added to a 100 mL three-necked flask. The temperature was cooled to 0 °C in an ice bath, and a DCM solution (10 mL) of ethyl 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetate (0.23 g, 0.79 mmol, 1 eq) was added dropwise. After the addition, the reaction was carried out at room temperature. After 30 min, TLC monitoring showed that the reaction was complete, and the reaction was stopped. DCM was removed by concentration under reduced pressure to obtain 0.62 g of a crude white solid. The crude product was purified by silica gel column chromatography, with 1.5 times the sample loading, 12 times the silica gel for column packing, and the eluent being EA:PE = 1:10, to obtain 0.27 g of a white solid with a yield of 69.23%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.68 (dd, J = 13.4, 2.5 Hz, 1H), 7.44 - 7.34 (m, 1H), 7.09 (ddd, J = 9.0, 2.6, 1.3 Hz, 1H), 6.92 - 6.79 (m, 4H), 6.31 (d, J = 7.6 Hz, 1H), 4.69 (s, 2H), 4.16 (q, J = 7.1 Hz, 3H), 3.55 - 3.45 (m, 1H), 2.05 - 1.97 (m, 2H), 1.95 - 1.87 (m, 2H), 1.50 - 1.25 (m, 4H), 1.21 (t, J = 7.1 Hz, 3H). 1313C NMR (101 MHz, DMSO-d6) δ 169.44, 154.63, 152.93, 152.18, 141.95, 141.84, 128.85, 124.73, 121.97, 117.48, 115.98, 114.01, 106.15, 105.92, 75.29, 65.72, 61.00, 47.78, 30.38, 30.27, 14.52. ESI MS: m / z 537.1 [M+Na] + .

[0128] Example 29 Synthesis of Methyl 2-[4-((1r,4r)-4-{3-[3-Fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)-2-methylpropionate (SP-C06)

[0129] To a 25 mL three-necked flask was added a DCM (10 mL) solution of 3-fluoro-4-trifluoromethoxyphenyl isocyanate, Et3N (0.24 g, 2.37 mmol, 3 eq). The mixture was cooled to 0 °C in an ice bath, and a DCM solution (10 mL) of methyl 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)-2-methylpropionate (0.24 g, 0.79 mmol, 1 eq) was added dropwise. After the addition, the reaction was carried out at room temperature. After 30 min, TLC monitoring showed that the reaction was complete, and the reaction was stopped. The DCM was removed by concentration under reduced pressure to obtain 0.47 g of a crude white solid. The crude product was purified by silica gel column chromatography, with 1.5 times of sample mixing and 10 times of silica gel for column packing. The eluent was EA:PE = 1:5, and 0.32 g of a white solid was obtained, with a yield of 76.19%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.68 (dd, J = 13.5, 2.5 Hz, 1H), 7.39 (t, J = 8.9 Hz, 1H), 7.09 (dt, J = 9.3, 1.9 Hz, 1H), 6.89 - 6.81 (m, 2H), 6.79 - 6.71 (m, 2H), 6.30 (d, J = 7.6 Hz, 1H), 4.21 (dt, J = 9.9, 5.6 Hz, 1H), 3.70 (s, 3H), 3.50 (s, 1H), 3.43 - 3.36 (m, 2H), 2.01 (d, J = 15.5 Hz, 2H), 1.95 - 1.87 (m, 2H), 1.45 (s, 10H). 1313C NMR (101 MHz, DMSO-d6) δ 174.26, 154.63, 153.28, 148.83, 141.94, 141.84, 128.85, 124.72, 121.97, 121.76, 119.42, 116.85, 114.01, 106.16, 105.92, 79.60, 75.05, 52.69, 47.79, 30.42, 30.31, 25.37, 15.62. ESI MS: m / z 551.2 [M+Na] + .

[0130] Example 30 Synthesis of 2-[4-((1r,4r)-4-{3-[3-Fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyloxy)phenoxy]-2-methylpropanoic acid (SP-C05)

[0131] To a 25 mL single-necked flask, 2-[4-((1r,4r)-4-{3-[3-Fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyloxy)phenoxy]-2-methylpropyl methanoate (0.20 g, 0.38 mmol, 1 eq), THF (5 mL), H2O (0.5 mL), and LiOH (30 mg, 1.20 mmol, 3 eq) were successively added and stirred at room temperature. After 3 h, the reaction was monitored by TLC and stopped. THF was removed by concentration under reduced pressure. DCM (30 mL) was added, and the mixture was extracted with water (10 mL × 2). The aqueous layer was adjusted to pH = 2 with 1N HCl and filtered by suction to obtain 0.15 g of a white solid. The yield was 76.92%. 1 1H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.78 (s, 1H), 7.68 (dd, J = 13.5, 2.5 Hz, 1H), 7.44 - 7.35 (m, 1H), 7.09 (ddd, J = 9.1, 2.6, 1.3 Hz, 1H), 6.90 - 6.82 (m, 2H), 6.82 - 6.75 (m, 2H), 6.34 (d, J = 7.6 Hz, 1H), 4.21 (dq, J = 9.6, 5.6, 4.7 Hz, 1H), 3.57 - 3.46 (m, 1H), 2.05 - 1.97 (m, 2H), 1.91 (dd, J = 12.8, 4.2 Hz, 2H), 1.50 - 1.26 (m, 10H). 1313C NMR (101 MHz, DMSO-d6) δ 175.60, 155.37, 154.64, 152.93, 149.26, 141.96, 141.86, 124.71, 121.97, 121.32, 116.88, 114.00, 106.14, 105.90, 79.27, 75.08, 47.77, 30.40, 30.29, 25.46. ESIMS: m / z 512.8 [M-H] - .

[0132] Example 31 Synthesis of Methyl 2-[4-((1r,4r)-4-{3-[4-(Trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)acetate (SP-C09)

[0133] BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) were successively added to a 25 mL single-necked flask. The temperature was lowered to -80 °C in a cold trap, and a DCM solution (20 mL) of p-trifluoromethoxyaniline (0.14 g, 0.79 mmol, 1 eq) and Et3N (0.24 g, 2.37 mmol, 3 eq) was added dropwise within 30 minutes. After the addition was completed, the temperature was allowed to rise to room temperature naturally. After 10 min, TLC monitoring showed that the reaction was complete, and the reaction was stopped.

[0134] A DCM (10 mL) solution of p-trifluoromethoxyaniline isocyanate, Et3N (0.24 g, 2.37 mmol, 3 eq), was added to a 25 mL three-necked flask. The temperature was cooled to 0 °C in an ice bath, and a DCM solution (10 mL) of methyl 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetate (0.22 g, 0.79 mmol, 1 eq) was added dropwise. After the addition was completed, the reaction was carried out at room temperature. After 30 min, TLC monitoring showed that the reaction was complete, and the reaction was stopped. The DCM was removed by concentration under reduced pressure to obtain 0.50 g of a crude white solid. The crude product was purified by silica gel column chromatography, with 1.5 times the sample loading, 10 times the silica gel packed column, and the eluent being EA:PE = 1:10, to obtain 0.31 g of a white solid.

[0135] 11H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.51 - 7.43 (m, 2H), 7.21 (d, J = 8.2 Hz, 2H), 6.91 - 6.80 (m, 4H), 6.18 (d, J = 7.6 Hz, 1H), 4.71 (s, 2H), 4.19 (dt, J = 9.8, 5.7 Hz, 1H), 3.69 (s, 3H), 3.57 - 3.46 (m, 1H), 2.00 (dd, J = 11.5, 4.1 Hz, 2H), 1.96 - 1.87 (m, 2H), 1.49 - 1.26 (m, 4H). 13 13C NMR (101 MHz, DMSO-d6) δ 169.93, 154.87, 152.21, 152.17, 142.43, 140.29, 122.09, 119.01, 117.50, 115.95, 75.34, 65.62, 52.19, 47.71, 30.48, 30.29. ESI MS: m / z 505.0 [M+Na] + .

[0136] Example 32 Synthesis of 2-[4-((1r,4r)-4-{3-[4-(trifluoromethoxy)phenyl]ureido}cyclohexyloxy)phenoxy]acetic acid (SP-C08)

[0137] To a 25 mL single-necked flask, 2-[4-((1r,4r)-4-{3-[4-(trifluoromethoxy)phenyl]ureido}cyclohexyloxy)phenoxy]methyl acetate (0.20 g, 0.41 mmol, 1 eq), THF (5 mL), H2O (0.5 mL), and LiOH (30 mg, 1.20 mmol, 3 eq) were added successively and stirred at room temperature. After 3 h, the reaction was monitored by TLC and stopped. THF was removed by concentration under reduced pressure. DCM (30 mL) was added, and the mixture was extracted with water (10 mL × 2). The aqueous layer was adjusted to pH = 2 with 1N HCl and filtered by suction to obtain 0.15 g of a white solid. The yield was 78.94%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 7.51 - 7.44 (m, 2H), 7.21 (d, J = 8.6 Hz, 2H), 6.91 - 6.76 (m, 4H), 6.40 (d, J = 7.6 Hz, 1H), 4.52 (s, 2H), 4.17 (tt, J = 9.7, 4.0 Hz, 1H), 3.55 - 3.45 (m, 1H), 2.04 - 1.95 (m, 2H), 1.94 - 1.86 (m, 2H), 1.36 (dddd, J = 40.3, 20.2, 16.5, 10.0 Hz, 5H). 1313C NMR (101 MHz, DMSO-d6) δ 171.14, 154.96, 152.56, 151.89, 142.35, 140.44, 122.04, 118.97, 117.49, 115.79, 75.39, 66.00, 47.67, 30.45, 30.29. ESI MS: m / z 466.8 [M-H] - .

[0138] Example 33 Synthesis of Ethyl 2-[4-((1r,4r)-4-{3-[4-(Trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)acetate (SP-C10)

[0139] BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) were successively added to a 25 mL single-necked flask. The temperature was lowered to -80 °C with a cold trap, and a DCM solution (15 mL) of p-trifluoromethoxyaniline (0.14 g, 0.79 mmol, 1 eq) and Et3N (0.24 g, 2.37 mmol, 3 eq) was added dropwise within 30 minutes. After the addition, the temperature was allowed to rise to room temperature naturally. After 10 min, TLC monitoring (EA:PE = 1:3) showed that the reaction was complete, and the reaction was stopped.

[0140] A DCM (10 mL) solution of p-trifluoromethoxyphenyl isocyanate, Et3N (0.24 g, 2.37 mmol, 3 eq) were added to a 25 mL three-necked flask. The temperature was cooled to 0 °C in an ice bath, and a DCM solution (10 mL) of ethyl 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetate (0.23 g, 0.79 mmol, 1 eq) was added dropwise. After the addition, the reaction was carried out at room temperature. After 30 min, TLC monitoring showed that the reaction was complete, and the reaction was stopped. The DCM was removed by concentration under reduced pressure to obtain 0.93 g of a crude white solid. The crude product was purified by silica gel column chromatography, with 1.5 times sample loading and 12 times silica gel for column packing. The eluent was EA:PE = 1:10, and 0.24 g of a white solid was obtained.

[0141] 1 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.50 - 7.43 (m, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.92 - 6.80 (m, 4H), 6.18 (d, J = 7.6 Hz, 1H), 4.69 (s, 2H), 4.19 - 4.09 (m, 2H), 3.60 - 3.42 (m, 1H), 2.04 - 1.96 (m, 2H), 1.92 (d, J = 13.7 Hz, 2H), 1.48 - 1.24 (m, 5H), 1.21 (t, J = 7.1 Hz, 4H). 1313C NMR (101 MHz, DMSO-d6) δ 169.43, 154.87, 152.20, 142.43, 140.28, 122.08, 119.02, 117.49, 115.98, 75.34, 65.74, 61.00, 47.70, 30.48, 30.29, 14.51. ESI MS: m / z 519.1 [M+Na] + .

[0142] Example 34 Synthesis of Methyl 2-Methyl-2-[4-((1,4r)-4-{3-[4-(Trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)-2-methylpropionate (SP-C12)

[0143] Add a solution of p-trifluoromethoxyphenyl isocyanate in DCM (10 mL) to a 25 mL three-necked flask, Et3N (0.24 g, 2.37 mmol, 3 eq), cool to 0 °C in an ice bath and add dropwise a solution of methyl 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)-2-methylpropionate (0.24 g, 0.79 mmol, 1 eq) in DCM (10 mL). After the addition, react at room temperature. Monitor by TLC after 30 min. When the reaction is complete, stop the reaction. Concentrate under reduced pressure to remove DCM to obtain 0.47 g of a crude white solid. The crude product was purified by silica gel column chromatography, loaded with 1.5 times the sample and 10 times the silica gel. The eluent was EA:PE = 1:5 to obtain 0.33 g of a white solid with a yield of 76.19%. 1 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.50 - 7.42 (m, 2H), 7.21 (d, J = 8.5 Hz, 2H), 6.88 - 6.81 (m, 2H), 6.79 - 6.72 (m, 2H), 6.18 (d, J = 7.6 Hz, 1H), 4.21 (tt, J = 9.7, 3.7 Hz, 1H), 3.70 (s, 3H), 3.51 (dtd, J = 10.9, 7.3, 4.2 Hz, 1H), 2.01 (dd, J = 12.6, 4.6 Hz, 2H), 1.92 (dd, J = 13.0, 4.3 Hz, 2H), 1.51 - 1.25 (m, 11H). 13 13C NMR (101 MHz, DMSO-d6) δ 174.25, 154.88, 153.32, 148.84, 142.45, 140.29, 122.07, 121.78, 119.03, 116.88, 79.62, 75.12, 52.68, 47.72, 30.52, 30.33, 25.38. ESI MS: m / z 533.0 [M+Na] + .

[0144] Example 35 Synthesis of 2-Methyl-2-[4-((1,4R)-4-{3-[4-(Trifluoromethoxy)phenyl]ureido}cyclohexyloxy)phenoxy]-2-methylpropanoic Acid (SP-C11)

[0145] 2-Methyl-2-[4-((1,4R)-4-{3-[4-(Trifluoromethoxy)phenyl]ureido}cyclohexyloxy)phenoxy]-2-methylpropanoic acid (0.20 g, 0.39 mmol, 1 eq), THF (5 mL), H2O (0.5 mL), and LiOH (30 mg, 1.20 mmol, 3 eq) were successively added to a 25 mL single-necked flask and stirred at room temperature. After 3 h, the reaction was monitored by TLC, stopped, and concentrated under reduced pressure to remove THF. DCM (30 mL) was added, and the mixture was extracted with water (10 mL × 2). The aqueous layer was adjusted to pH = 2 with 1N HCl and filtered by suction to obtain 0.14 g of a white solid. The yield was 73.68%.

[0146] 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.51 - 7.43 (m, 2H), 7.22 (d, J = 8.6 Hz, 2H), 6.90 - 6.72 (m, 4H), 6.20 (d, J = 7.6 Hz, 1H), 4.21 (td, J = 9.6, 4.8 Hz, 1H), 3.57 - 3.45 (m, 1H), 2.08 - 1.97 (m, 2H), 1.91 (dd, J = 12.0, 4.6 Hz, 2H), 1.50 - 1.23 (m, 11H). 13 C NMR (101 MHz, DMSO-d6) δ 175.60, 154.88, 152.94, 149.26, 142.42, 140.30, 122.08, 121.31, 119.01, 116.88, 79.27, 75.13, 47.70, 30.51, 30.32, 25.46. ESI MS: m / z 494.9 [M - H] - .

[0147] Example 36 Synthesis of Methyl 2-[4-((1R,4R)-4-{3-[(1R,3R,5S,7R)-3,5-Dimethyladamantan-1-yl]ureido}cyclohexyloxy)phenoxy]acetate (SP-C15)

[0148] To a 25 mL single-necked flask, BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) were added successively. The cold trap was cooled to -80 °C, and a DCM solution (20 mL) of memantine (0.14 g, 0.79 mmol, 1 eq) and Et3N (0.24 g, 2.37 mmol, 3 eq) was added dropwise. The addition was completed within 30 minutes, and then the mixture was allowed to warm to room temperature naturally. After 10 min, TLC monitoring showed that the reaction was complete, and the reaction was stopped.

[0149] To a 25 mL three-necked flask, a DCM (10 mL) solution of memantine isocyanate and Et3N (0.24 g, 2.37 mmol, 3 eq) were added. The mixture was cooled to 0 °C in an ice bath, and a DCM solution (10 mL) of methyl 2-{4-[(1r,4r)-4-aminocyclohexyloxy]phenoxy}acetate (0.22 g, 0.79 mmol, 1 eq) was added dropwise. After the addition, the reaction was carried out at room temperature. After 30 min, TLC monitoring showed that the reaction was complete, and the reaction was stopped. The DCM was removed by rotary evaporation under reduced pressure to obtain 0.50 g of a crude white solid. The crude product was purified by silica gel column chromatography, with 1.5 times the sample loading and 10 times the silica gel for column packing. The eluent was EA:PE = 1:10, and 0.33 g of a white solid was obtained.

[0150] 1 H NMR (400 MHz, DMSO-d6) δ 6.89 - 6.79 (m, 4H), 5.58 (d, J = 7.6 Hz, 1H), 5.41 (s, 1H), 4.70 (s, 2H), 4.15 (tt, J = 10.0, 4.0 Hz, 1H), 3.69 (s, 3H), 3.35 (dt, J = 7.3, 3.6 Hz, 1H), 2.04 (p, J = 3.2 Hz, 1H), 1.96 (dt, J = 13.4, 3.9 Hz, 2H), 1.86 - 1.77 (m, 2H), 1.67 (d, J = 3.1 Hz, 2H), 1.49 (s, 4H), 1.40 - 1.11 (m, 9H), 1.07 (s, 2H), 0.79 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 169.92, 157.00, 152.25, 152.17, 117.56, 115.96, 75.50, 65.66, 52.18, 51.49, 50.87, 48.61, 47.37, 42.91, 41.00, 32.36, 30.83, 30.61, 30.40, 30.10. ESI MS: m / z 507.1 [M+Na] + .

[0151] Example 37 Synthesis of 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy}acetic acid (SP-C14)

[0152] Methyl 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy}acetate (0.20 g, 0.41 mmol, 1 eq), THF (5 mL), H2O (0.5 mL), and LiOH (30 mg, 1.24 mmol, 3 eq) were successively added to a 25 mL single-necked flask and stirred at room temperature. After 3 h, the reaction was monitored by TLC, stopped, and concentrated under reduced pressure to remove THF. DCM (30 mL) was added, and the mixture was extracted with water (10 mL × 2). The aqueous layer was adjusted to pH = 2 with 1N HCl and filtered by suction to obtain 0.15 g of a white solid.

[0153] 1 1H NMR (400 MHz, DMSO-d6) δ 6.85 - 6.78 (m, 2H), 6.78 - 6.70 (m, 2H), 5.77 (d, J = 7.6 Hz, 1H), 5.59 (s, 1H), 4.24 (s, 2H), 4.11 (tt, J = 9.5, 4.0 Hz, 1H), 3.33 (ddd, J = 11.1, 7.1, 3.7 Hz, 1H), 2.04 (p, J = 3.2 Hz, 1H), 2.00 - 1.90 (m, 2H), 1.81 (dq, J = 11.8, 3.8 Hz, 2H), 1.67 (d, J = 3.1 Hz, 2H), 1.55 - 1.43 (m, 4H), 1.42 - 1.25 (m, 4H), 1.25 - 1.09 (m, 5H), 1.07 (s, 2H), 0.79 (s, 6H). 13 13C NMR (101 MHz, DMSO-d6) δ 171.28, 157.12, 153.18, 151.45, 117.53, 115.68, 75.61, 67.74, 51.46, 50.89, 48.61, 47.33, 42.93, 40.99, 32.36, 30.79, 30.62, 30.40, 30.10.

[0154] Example 38 Synthesis of 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy}ethyl acetate (SP-C16)

[0155] To a 25 mL single-necked flask, BTC (0.08 g, 0.27 mmol, 0.34 eq), dry DCM (5 mL) were added successively. The cold trap was cooled to -80 °C, and a DCM solution (15 mL) of memantine (0.14 g, 0.79 mmol, 1 eq) and Et3N (0.24 g, 2.37 mmol, 3 eq) was added dropwise. The addition was completed within 30 minutes, and then the mixture was allowed to warm to room temperature naturally. After 10 min, TLC monitoring showed that the reaction was complete, and the reaction was stopped.

[0156] To a 25 mL three-necked flask, a DCM (10 mL) solution of memantine isocyanate, Et3N (0.24 g, 2.37 mmol, 3 eq) were added. The mixture was cooled to 0 °C in an ice bath, and a DCM solution (10 mL) of ethyl 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetate (0.23 g, 0.79 mmol, 1 eq) was added dropwise. After the addition, the reaction was carried out at room temperature. After 30 min, TLC monitoring showed that the reaction was complete, and the reaction was stopped. DCM was removed by rotary evaporation under reduced pressure to obtain 0.93 g of a crude white solid. The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 times of silica gel, and the column was packed with 15 times of silica gel. (To remove the urea formed by memantine itself that could not be detected by iodine fuming without fluorescence), the eluent was EA:PE = 1:10, and 0.20 g of a white solid was obtained.

[0157] 1 H NMR (400 MHz, DMSO-d6) δ 6.89 - 6.79 (m, 4H), 5.58 (d, J = 7.6 Hz, 1H), 5.41 (s, 1H), 4.68 (s, 2H), 4.16 (q, J = 7.1 Hz, 3H), 3.35 (dd, J = 7.1, 3.6 Hz, 1H), 2.04 (p, J = 3.2 Hz, 1H), 2.01 - 1.90 (m, 2H), 1.86 - 1.76 (m, 2H), 1.67 (d, J = 3.2 Hz, 2H), 1.49 (s, 4H), 1.40 - 1.11 (m, 11H), 1.07 (s, 2H), 0.79 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 169.43, 156.99, 152.21, 152.17, 117.51, 115.97, 75.46, 65.73, 61.00, 51.47, 50.85, 48.60, 47.36, 42.90, 40.99, 32.36, 30.84, 30.61, 30.40, 30.09, 14.52.

[0158] Synthesis of Methyl 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-Dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy}-2-methylpropionate (SP-C18) in Example 39

[0159] BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) were successively added to a 25 mL single-necked flask. The temperature was lowered to -80 °C with a cold trap, and a DCM solution (15 mL) of memantine (0.14 g, 0.79 mmol, 1 eq) and Et3N (0.24 g, 2.37 mmol, 3 eq) was added dropwise. The addition was completed within 30 minutes, and then the temperature was allowed to rise to room temperature naturally. After 10 min, TLC monitoring showed that the reaction was complete, and the reaction was stopped.

[0160] A DCM (10 mL) solution of memantine isocyanate, Et3N (0.24 g, 2.37 mmol, 3 eq) were added to a 25 mL three-necked flask. The temperature was cooled to 0 °C in an ice bath, and a DCM solution (10 mL) of methyl 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)-2-methylpropionate (0.24 g, 0.79 mmol, 1 eq) was added dropwise. After the addition, the reaction was carried out at room temperature. After 30 min, TLC monitoring showed that the reaction was complete, and the reaction was stopped. DCM was removed by concentration under reduced pressure to obtain 0.93 g of a crude white solid. The crude product was purified by silica gel column chromatography, with 1.5 times of sample mixing, 15 times of silica gel for column packing, and the eluent was EA:PE = 1:10, to obtain 0.32 g of a white solid.

[0161] 1 1H NMR (400 MHz, DMSO-d6) δ 6.87 - 6.78 (m, 2H), 6.78 - 6.69 (m, 2H), 5.58 (d, J = 7.6 Hz, 1H), 5.41 (s, 1H), 4.22 - 4.11 (m, 1H), 3.69 (s, 3H), 2.04 (p, J = 3.1 Hz, 1H), 2.01 - 1.92 (m, 2H), 1.86 - 1.77 (m, 2H), 1.67 (d, J = 3.2 Hz, 2H), 1.50 - 1.13 (m, 18H), 1.07 (s, 2H), 0.79 (s, 6H). 13 13C NMR (101 MHz, DMSO-d6) δ 174.25, 156.99, 153.32, 148.80, 121.77, 116.88, 79.61, 75.21, 52.68, 51.48, 50.86, 48.60, 47.37, 42.91, 40.99, 32.36, 30.88, 30.61, 30.44, 30.09, 25.38.

[0162] Synthesis of Example 39 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy}-2-methylpropanoic acid (SP-C17)

[0163] To a 25 mL single-necked flask, 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl]ureido}cyclohexyl)oxy]phenoxy}-2-methylpropyl methyl ester (0.20 g, 0.39 mmol, 1 eq), THF (5 mL), H2O (0.5 mL), and LiOH (30 mg, 1.24 mmol, 3 eq) were successively added and stirred at room temperature. After 3 h, the reaction was monitored by TLC, stopped, and THF was removed by concentration under reduced pressure. DCM (30 mL) was added, and the mixture was extracted with water (10 mL × 2). The aqueous layer was adjusted to pH = 2 with 1N HCl and filtered by suction to obtain 0.10 g of a white solid.

[0164] 1 1H NMR (400 MHz, DMSO-d6) δ 6.79 (s, 4H), 5.73 (d, J = 7.7 Hz, 1H), 5.54 (s, 1H), 4.14 (td, J = 9.6, 4.8 Hz, 1H), 3.33 (ddd, J = 10.8, 7.0, 3.6 Hz, 1H), 2.04 (p, J = 3.2 Hz, 1H), 2.01 - 1.91 (m, 2H), 1.85 - 1.76 (m, 2H), 1.67 (d, J = 3.2 Hz, 2H), 1.55 - 1.43 (m, 4H), 1.43 - 1.10 (m, 14H), 1.07 (s, 2H), 0.79 (s, 6H). 13 13C NMR (101 MHz, DMSO-d6) δ 175.96, 157.08, 152.49, 149.72, 121.01, 116.83, 79.75, 75.30, 51.46, 50.88, 48.60, 47.34, 42.92, 40.98, 32.36, 30.84, 30.62, 30.43, 30.09, 25.78.

[0165] Synthesis of Example 40 phenyl 4-(((1r,4r)-4-aminocyclohexyl)oxy)acetate

[0166] To a 100 mL single-necked flask, phenyl 4-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)acetate (1.69 g, 4.84 mmol), DCM (12 mL) were added successively, and TFA (6 mL) was added dropwise at room temperature. After 3 hours, TLC was monitored, EA:PE = 1:1, the reaction was complete, and the reaction was stopped. TFA in the reaction solution was removed by distillation under reduced pressure. 2.06 g of a brown oil was obtained as the crude product. It was dried in an oven at 60 °C for 12 h, and the crude product was directly used for the next step without purification.

[0167] Example 41 Synthesis of phenyl 4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)acetate (SP-C01)

[0168] To a 100 mL single-necked flask, BTC (0.51 g, 1.17 mmol, 0.34 eq), dry DCM (10 mL) were added successively, the cold trap was cooled to -78 °C, 3-fluoro-4-(trifluoromethoxy)aniline (1 g, 5.13 mmol, 1 eq), Et3N (1.65 g, 15.39 mmol, 3 eq) in DCM solution (10 mL) were added dropwise, and the addition was completed within 30 minutes. After the addition was completed, it was transferred to room temperature and stirred for another 4 h. After 4 h, TLC was monitored. Take a drop of the reaction solution in an EP tube, add memantine, EA:PE = 1:3, and iodine fuming, the reaction was complete.

[0169] To a 100 mL single-necked flask, a mixed solution of phenyl 4-(((1r,4r)-4-aminocyclohexyl)oxy)acetate·TFA (1.86 g, 5.13 mmol, 1 eq), Et3N (1.65 g, 15.39 mmol, 3 eq), DCM (5 mL) was added, and the above reaction solution was added dropwise, and the reaction was carried out at room temperature. After 2 hours, TLC was monitored (EA:PE = 1:3, AcOH 2d), the reaction was completed, and the reaction was stopped. 15 mL of water was added for extraction twice, 15 mL of saturated brine was used for washing once, dried over anhydrous magnesium sulfate, filtered by suction, concentrated under reduced pressure to dryness, 0.23 g of a crude yellow oil was obtained, packed in a column with 5 times silica gel, mixed with 1.2 times silica gel, and the eluent was (EA:PE = 1:10), 0.42 g of a white solid was obtained, and the yield was 17.3%. 11H NMR (400 MHz, DMSO-d6): δ (ppm) 8.72 7.69 (d, J = 2.5 Hz, 1H), 7.65 - 7.38 (m, 1H), 7.36 - 7.35 (m, 1H), 7.11 - 6.94 (m, 4H), 6.30 (d, J = 8.0 Hz, 1H), 4.29 (d, J = 4.0 Hz, 1H), 3.51 (s, 1H), 2.23 (s, 3H), 2.05 (d, J = 3.0 Hz, 2H), 2.02 - 1.91 (m, 2H), 1.48 - 1.34 (m, 4H). 13 13C NMR (100 MHz, DMSO-d6): δ (ppm) 169.9, 155.3, 154.6, 152.9, 144.3, 141.9, 124.7, 123.1, 116.8, 114.0, 114.0, 106.2, 105.9, 75.0, 47.8, 30.4, 30,2, 21.1. ESI MS: m / z 471.1 [M + H] + .

[0170] Example 42 Synthesis of 4 - (((1r,4r)-4-(3-(3 - fluoro - 4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)phenol (SP - C01b)

[0171] To a 100 mL single - necked flask, 4 - (((1r,4r)-4-(3-(3 - fluoro - 4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)phenyl acetate (0.24 g, 0.51 mmol, 1 eq), LiOH (2.1 g, 17.20 mmol, 34 eq), and H2O (7 mL) were added successively, and the reaction was carried out at room temperature. After 1.5 h, the reaction was monitored by TLC. When the reaction was complete, the reaction was stopped. DCM (30 mL × 3) was added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness. 0.21 g of a brown solid crude product was obtained. The yield was 96.33%.

[0172] Example 43 Synthesis of methyl 4 - (((1r,4r)-4-((tert - butoxycarbonyl)amino)cyclohexyl)oxy)benzoate

[0173] To a 100 mL single-necked flask, cis-4-BOC-amino cyclohexanol (1.00 g, 4.64 mmol), methyl 4-hydroxybenzoate (0.7 g, 4.64 mmol), triphenylphosphine (1.8 g, 6.96 mmol), type A4 molecular sieve (dried in an oven at 120 °C for 4 h), THF (10 mL) were added successively. After purging with argon three times, the temperature was lowered to below -10 °C in an ice-salt bath, and a THF solution (5 mL) of DIAD (1.4 g, 6.96 mmol) was added dropwise, controlling the dropping rate at one drop every two seconds. After 12 h, TLC monitoring was carried out with EA:PE = 1:1. The reaction was transferred to 30 °C, and 4A molecular sieve was added. After 6 h, TLC monitoring was carried out with EA:PE = 1:1. Most of the reaction was completed, and the reaction was stopped. THF was removed by rotary evaporation under reduced pressure to obtain 5.2 g of a yellowish-brown oil. After trituration, no solid was precipitated. The column was packed with 4 times the amount of silica gel, and the sample was mixed with 1.2 times the amount of silica gel. The eluent was EA:PE = 1:10, and 0.73 g of white solid product was obtained with a yield of 45.1%.

[0174] Example 44 Synthesis of Methyl 4-(((1r,4r)-4-aminocyclohexyl)oxy)benzoate

[0175] To a 100 mL single-necked flask, methyl (((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)benzoate (0.60 g, 2.09 mmol) and DCM (5 mL) were added successively. TFA (4 mL) was added dropwise at room temperature. After 3 h, TLC monitoring was carried out with EA:PE = 1:1. The reaction was complete, and the reaction was stopped. TFA in the reaction solution was removed by distillation under reduced pressure. 0.62 g of a brown oil was obtained as the crude product. It was dried in an oven at 60 °C for 12 h, and the crude product was directly used for the next step without purification.

[0176] Example 45 Synthesis of Methyl 4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoate

[0177] To a 100 mL single-necked flask, BTC (0.23 g, 0.79 mmol) and dry DCM (15 mL) were added successively. The temperature was lowered to -78 °C in a cold trap, and a DCM solution (10 mL) of free 3-fluoro-4-trifluoromethoxyaniline (0.41 g, 2.32 mmol) and Et3N (1.41 g, 13.92 mmol) was added dropwise within 30 minutes. After dropping, it was transferred to room temperature and stirred for another 4 h. After 4 h, TLC monitoring was carried out. One drop of the reaction solution was taken into an EP tube, and methyl 4-(((1r,4r)-4-aminocyclohexyl)oxy)benzoate was added with EA:PE = 1:3.

[0178] Add a mixed solution of methyl 4-(((1r,4r)-4-aminocyclohexyl)oxy)benzoate·TFA (0.58 g, 1.59 mmol), Et3N (1.41 g, 13.92 mmol), and DCM (10 mL) to a 100 mL single-necked flask, react at room temperature, monitor by TLC after 2 hours, (EA:PE = 1:3), and stop the reaction. Add 15 mL of water for extraction twice, wash once with 15 mL of saturated brine, dry over anhydrous magnesium sulfate, filter by suction, concentrate under reduced pressure to dryness, obtain 0.93 g of a crude yellow oil, load the column with 7 times the amount of silica gel, mix the sample with 1.2 times the amount of silica gel, and use the eluent (EA:PE = 1:5) to obtain 0.40 g of a white solid product with a yield of 40.0%. ESI-MS: m / z 453.2 [M+H] +

[0179] Example 46 Synthesis of 4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid (SP-C01c)

[0180] Add methyl 4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoate (2.59 g, 5.50 mmol, 1 eq), THF (20 mL), H2O (2 mL), and LiOH (0.40 g, 16.50 mmol, 3 eq) to a 100 mL single-necked flask in sequence and stir at room temperature. Monitor by TLC after 3 h, (EA:PE = 1:1), stop the reaction, concentrate under reduced pressure to remove THF, add DCM (50 mL), extract with water (15 mL×2), adjust the pH of the aqueous layer to 2 with 1N HCl, concentrate under reduced pressure until there is a small amount of solvent left, filter by suction, and wash with 5 mL of water to obtain 0.53 g of a pale yellow solid. The combined yield of 3 steps is 21.13%.

[0181] 1 H NMR (600 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.88 (s, 1H), 8.35 (s, 3H), 7.86 (d, J = 8.6 Hz, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 8.6 Hz, 5H), 6.85 (d, J = 8.3 Hz, 4H), 4.39 (tt, J = 10.0, 4.3 Hz, 1H), 3.04 (dt, J = 10.8, 5.5 Hz, 1H), 2.15 - 2.09 (m, 2H), 2.06 - 2.01 (m, 2H), 1.61 - 1.50 (m, 2H), 1.50 - 1.38 (m, 2H).

[0182] Synthesis of 4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)acetic acid phenyl ester (SP-C01d)

[0183] BTC (0.02 g, 0.07 mmol, 0.34 eq) and dry DCM (5 mL) were successively added to a 100 mL single-necked flask. The temperature was lowered to -78 °C using a cold trap, and memantine (0.04 g, 0.22 mmol, 1 eq) and a DCM solution (10 mL) of Et3N (0.07 g, 0.66 mmol, 3 eq) were added dropwise. The addition was completed within 30 minutes. After the addition, the mixture was transferred to room temperature and stirred for another 4 h. After 4 h, TLC was monitored (take a drop of the reaction solution in an EP tube, add 4-trifluoromethoxyaniline, EA:PE = 1:3), and iodine fuming was carried out. The reaction was complete.

[0184] A mixed solution of 4-(((1r,4r)-4-aminocyclohexyl)oxy)acetic acid phenyl ester·TFA (0.08 g, 0.22 mmol, 1 eq), Et3N (0.07 g, 0.66 mmol, 3 eq), and DCM (5 mL) was added to a 25 mL single-necked flask, and the above reaction solution was added dropwise. The reaction was carried out at room temperature. After 2 h, TLC was monitored, and the reaction was completed. The reaction was stopped. 15 mL of water was added for extraction twice, 15 mL of saturated brine was used for washing once, and it was dried over anhydrous magnesium sulfate, filtered by suction, and concentrated under reduced pressure to dryness to obtain 0.10 g of a crude yellow oil. It was loaded onto a silica gel column with 5 times the amount of silica gel, and 1.2 times the amount of silica gel was used for sample mixing. The eluent was (EA:PE = 1:10), and 32 mg of a white solid was obtained, with a yield of 32.0%. 1 1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.04 - 6.97 (d, 2H), 6.97 - 6.89 (d, 2H), 5.58 (d, J = 7.9 Hz, 1H), 5.41 (d, J = 3.2 Hz, 1H), 4.25 (tt, J = 9.9, 3.9 Hz, 1H), 3.35 (dd, J = 7.3, 3.7 Hz, 1H), 2.23 (s, 3H), 2.02 (ddt, J = 24.4, 8.4, 3.5 Hz, 3H), 1.87 - 1.80 (m, 2H), 1.67 (d, J = 3.1 Hz, 2H), 1.50 (s, 4H), 1.37 (ddd, J = 15.2, 9.1, 4.3 Hz, 2H), 1.31 - 1.22 (m, 4H), 1.22 - 1.16 (m, 2H), 1.16 - 1.10 (m, 1H), 1.07 (s, 2H), 0.80 (s, 6H). 1313C NMR (100 MHz, DMSO-d6): δ (ppm) 169.94, 157.00, 155.37, 144.29, 123.06, 116.77, 75.17, 51.49, 50.87, 48.61, 47.33, 42.91, 41.00, 32.36, 30.89, 30.82, 30.61, 30.31, 30.10, 21.26. ESI MS: m / z 455.2 [M+H] + .

[0185] Example 48 Synthesis of tert-Butyl ((1r,4r)-4-(4-acetylphenoxy)cyclohexyl)carbamate

[0186] To a 250 mL single-necked flask were successively added cis-4-BOC-aminocyclohexanol (1 g, 4.64 mmol, 1 eq), p-acetaminophenol (0.70 g, 4.64 mmol, 1 eq), PPh3 (1.83 g, 6.96 mmol, 1.5 eq), 4A molecular sieve (dried in an oven at 120 °C for 4 h), THF (20 mL). After purging with argon three times, the temperature was lowered to -10 °C in an ice-salt bath, and a THF solution (10 mL) of DIAD (1.21 g, 6.96 mmol, 1.5 eq) was added dropwise at a rate of one drop every two seconds. After 12 h, TLC was monitored (EA:PE = 1:2), and most of the reaction was completed, then the reaction was stopped. THF was removed by rotary evaporation under reduced pressure to obtain 5.62 g of a yellowish-brown oil. 10 mL of ethanol and 5 mL of petroleum ether were added, stirred for 2 h, slurried, and filtered to obtain 0.90 g of a pale yellow solid, with a yield of 55.9%.

[0187] Example 49 Synthesis of N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)acetamide

[0188] To a 100 mL single-necked flask were successively added tert-Butyl ((1r,4r)-4-(4-acetylphenoxy)cyclohexyl)carbamate (0.90 g, 2.58 mmol), DCM (6 mL), and TFA (4 mL) was added dropwise at room temperature. After 3 h, TLC was monitored (EA:PE = 1:1), and the reaction was complete, then the reaction was stopped. TFA in the reaction solution was removed by distillation under reduced pressure to obtain 1.06 g of a crude brown oil. It was dried in an oven at 60 °C for 12 h, and the crude product was directly used for the next step without purification.

[0189] Example 50 Synthesis of N-(4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)phenyl)acetamide (SP-C01e)

[0190] To a 50 mL single-necked flask, BTC (0.08 g, 0.26 mmol, 0.34 eq), dry DCM (10 mL) were added successively. The cold trap was cooled to -78 °C, and a solution of 3-fluoro-4-(trifluoromethoxy)aniline (0.15 g, 0.77 mmol, 1 eq) and Et3N (0.47 g, 4.61 mmol, 3 eq) in DCM (5 mL) was added dropwise. The addition was completed within 15 minutes. After the addition, the reaction mixture was transferred to room temperature and stirred for an additional 0.5 h. After 0.5 h, TLC was monitored. A drop of the reaction solution was taken into an EP tube, and N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)acetamide·TFA and EA:PE = 1:1 were added.

[0191] To a 100 mL single-necked flask, a mixed solution of N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)acetamide·TFA (0.30 g, 0.77 mmol), Et3N (0.47 g, 4.61 mmol), and DCM (5 mL) was added. The reaction was carried out at room temperature. After 0.5 h, TLC was monitored (EA:PE = 1:1), and the reaction was stopped. 15 mL of water was added for extraction twice, and 15 mL of saturated brine was used for washing once. It was dried over anhydrous magnesium sulfate, filtered by suction, and concentrated under reduced pressure to dryness to obtain 0.52 g of a crude yellow oil. It was loaded onto a silica gel column with 4 times the amount of silica gel, and 1.2 times the amount of silica gel was used for sample mixing. The eluent was (EA:PE = 1:5, EA:PE = 1:3), and 0.11 g of a white solid was obtained with a yield of 33.4%. ESI-MS: m / z 470.2 [M+H] + ,492.1 [M+Na] +

[0192] 1 1H-NMR (400 MHz, DMSO-d6): δ (ppm) 9.75 (s, 1H), 8.74 (s, 1H), 7.67 (dd, J = 13.4, 2.4 Hz, 1H), 7.44 (d, J = 8.9 Hz, 2H), 7.38 (t, J = 8.7 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.9 Hz, 2H), 6.29 (d, J = 7.6 Hz, 1H), 4.26 - 4.21 (m, 1H), 3.53 - 3.48 (m, 1H), 2.03 - 2.20 (m, 2H), 2.20 (s, 3H), 1.93 - 1.90 (m, 2H), 1.46 - 1.38 (m, 2H), 1.38 - 1.32 (m, 2H).

[0193] Example 51 Synthesis of N-(4-hydroxyphenyl)-2-methylbutyramide

[0194] Add 2-methylbutyric acid (3.0 g, 27.51 mmol, 1 eq), dry tetrahydrofuran (15 mL) to a 100 mL flask, cool to 0 °C in an ice bath, dropwise add SOCl₂ (3.93 g, 33.01 mmol, 1.2 eq), and stir for 30 min. Take a part of 1.5 mL in an EP tube, add anhydrous methanol, monitor the reaction by TLC until completion, and concentrate under reduced pressure to dryness.

[0195] Take a 100 mL round-bottom flask, add p-aminophenol (3.0 g, 27.51 mmol, 1 eq), THF (5 mL), and dropwise add the THF (10 mL) solution of the above 2-methylbutyryl chloride. After dropping, monitor by TLC. When the reaction is complete and the starting material is oxidized at the origin, stop the reaction. Concentrate under reduced pressure to remove tetrahydrofuran, add dichloromethane (20 mL), extract twice with water (20 mL), wash once with saturated brine (25 mL), dry over anhydrous magnesium sulfate, filter by suction, concentrate the organic phase under reduced pressure to obtain 16.5 g of a yellow oil. Load the column with 4 times the amount of silica gel, mix the sample with 1.2 times the amount of silica gel, and use the eluent (EA:PE = 1:5). Column chromatography gives 4.85 g of a white solid. The yield is 91.3%. ESI-MS: m / z 194.1 [M+H] + , 216.1 [M+Na] +

[0196] Synthesis of tert-butyl ((1r,4r)-4-(4-(2-methylbutanamido)phenoxy)cyclohexyl)carbamate in Example 52

[0197] Add cis-4-BOC-aminocyclohexanol (2.00 g, 9.29 mmol, 1 eq), N-(4-hydroxyphenyl)-2-methylbutanamide (1.79 g, 9.29 mmol, 1 eq), triphenylphosphine (3.65 g, 13.9 mmol, 1.5 eq), A4 molecular sieve (dried in an oven at 120 °C for 4 h), THF (15 mL) to a 100 mL single-necked flask in sequence. Replace with argon three times, cool to below -10 °C in an ice-salt bath, and dropwise add the THF solution (5 mL) of DIAD (2.43 g, 13.9 mmol, 1.5 eq), controlling the dropping rate to one drop every two seconds. After dropping, transfer to room temperature. After 12 hours, monitor by TLC with EA:PE = 1:1. When most of the reaction is completed, stop the reaction. Concentrate under reduced pressure to remove part of the THF, add 15 mL of anhydrous ethanol and 15 mL of ether to make a slurry, filter by suction to obtain 2.24 g of a light pink solid. Monitor the obtained solid by TLC, dissolve it in 20 mL of DCM, wash with saturated Na₂CO₃ (16 mL), dry the organic layer over anhydrous magnesium sulfate, filter by suction, and concentrate under reduced pressure to dryness to obtain 1.94 g of a pure white solid with a yield of 53.6%.

[0198] Synthesis of N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)-2-methylbutanamide

[0199] To a 100 mL single-necked flask, tert-butyl ((1r,4r)-4-(4-(2-methylbutanamido)phenoxy)cyclohexyl)carbamate (1.94 g, 4.97 mmol), DCM (5 mL) were added successively, and TFA (6 mL) was added dropwise at room temperature. After 3 hours, TLC was monitored with EA:PE = 1:1. The reaction was complete and the reaction was stopped. The reaction solution was concentrated under reduced pressure to remove TFA. 1.92 g of crude product, brown oil, N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)-2-methylbutanamide·TFA was obtained. It was dried in an oven at 60 °C for 12 h, and the crude product was directly used in the next step without purification.

[0200] Synthesis of N-(4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenyl)acetamide (SP-C01f)

[0201] To a 100 mL single-necked flask, BTC (0.14 g, 0.47 mmol), dry DCM (10 mL) were added successively. The temperature was lowered to -78 °C with a cold trap, and free memantine (0.25 g, 1.41 mmol), a DCM solution (10 mL) of Et3N (0.85 g, 8.46 mmol) were added dropwise. The addition was completed within 30 minutes. After the addition, it was transferred to room temperature and stirred for another 4 h.

[0202] To a 100 mL single-necked flask, a mixed solution of A4 (0.35 g, 1.41 mmol), Et3N (0.28 g, 2.82 mmol), and DCM (5 mL) was added, and the reaction was carried out at room temperature. After 2 hours, TLC was monitored and the reaction was stopped. 15 mL of water was added for extraction twice, 15 mL of saturated brine was used for washing once, dried over anhydrous magnesium sulfate, filtered by suction, and concentrated under reduced pressure to dryness. 0.52 g of crude product, yellow oil, was obtained. It was loaded on a silica gel column with 4 times the amount of silica gel, and 1.2 times the amount of silica gel was used for sample mixing. The eluent was (EA:PE = 1:5), and 0.21 g of product was obtained with a yield of 36.7%.

[0203] 11H-NMR (400 MHz, DMSO-d6): δ (ppm) 9.73 (s, 1H), 7.43 (d, J = 8.96 Hz, 2H), 6.84 (d, J = 8.96 Hz, 2H), 5.54 (d, J = 7.60 Hz, 1H), 5.41 (s, 1H), 4.22 - 4.17 (m, 1H), 3.37 - 3.34 (m, 1H), 2.05 - 2.03 (m, 1H), 1.99 (s, 3H), 1.97 - 1.94 (m, 1H), 1.84 - 1.81 (m, 2H), 1.67 - 1.66 (m, 2H), 1.52 - 1.46 (m, 4H), 1.40 - 1.34 (m, 2H), 1.30 (s, 1H), 1.27 - 1.24 (m, 4H), 1.19 - 1.14 (m, 2H), 1.07 (s, 2H), 0.79 (s, 6H).

[0204] Example 55 Synthesis of N-(4-(((1r,4r)-4-(3-(3-Fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)phenyl)-2-methylbutanamide (SP-C01g)

[0205] BTC (0.10 g, 0.35 mmol, 1 eq), dry DCM (10 mL) were successively added to a 50 mL single-necked flask. The cold trap was cooled to -78 °C, and a DCM solution (10 mL) of 3-fluoro-4-trifluoromethoxyaniline (0.2 g, 1.02 mmol, 1 eq) and Et3N (0.93 g, 9.22 mmol, 3 eq) was added dropwise within 30 minutes. After the addition, the mixture was transferred to room temperature and stirred for an additional 0.5 h. Monitored by TLC, a drop of the reaction solution was taken into an EP tube and memantine was added.

[0206] Add a mixed solution of N-(4-(((1r,4r)-4-aminocyclohexyloxy)phenyl)-2-methylbutanamide·TFA (0.41 g, 1.02 mmol, 1 eq), Et3N (0.93 g, 9.22 mmol, 3 eq), and DCM (10 mL) to a 100 mL single-necked flask and react at room temperature. After 0.5 h, monitor by TLC (EA:PE = 1:2, AcOH 1 d), and stop the reaction. Extract twice with 15 mL of water, wash once with 15 mL of saturated brine, dry over anhydrous magnesium sulfate, filter by suction, and concentrate under reduced pressure to dryness to obtain 0.74 g of a crude yellow oil. Load the column with 7 times the amount of silica gel, mix the sample with 1.2 times the amount of silica gel, and use the eluent (EA:PE = 1:5, EA:PE = 1:2) to obtain 0.13 g of a yellow solid with insufficient purity. Place the product in a 25 mL single-necked flask, dissolve the product with 0.5 mL of DCM, and then add 4 mL of petroleum ether to precipitate a white solid. Filter by suction to obtain 62 mg of the product, and recover the filtrate. The yield is 11.9%. ESI-MS: m / z 512.3 [M+H] +

[0207] 1 H-NMR (400 MHz, DMSO-d6): δ (ppm) 9.64 (s, 1H), 8.17 (s, 1H), 7.67 (dd, J = 13.4, 2.1 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.38 (t, J = 8.9 Hz, 1H), 7.10 - 7.08 (m, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.27 (d, J = 7.4 Hz, 1H), 4.26 - 4.22 (m, 1H), 3.53 - 3.52 (m, 1H), 2.36 - 2.31 (m, 1H), 2.03 - 2.00 (m, 2H), 1.93 - 1.90 (m, 2H), 1.63 - 1.56 (m, 1H), 1.48 - 1.30 (m, 5H), 1.06 (d, J = 6.7 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H).

[0208] Example 56 Synthesis of tert-Butyl ((1r,4r)-4-(4-nitrophenoxy)cyclohexyl)carbamate

[0209] To a 100 mL three-necked flask, cis-4-BOC-aminocyclohexanol (10.00 g, 0.046 mol, 1 eq), 4-nitrophenol (6.47 g, 0.046 mol, 1 eq), PPh3 (13.95 g, 0.069 mmol, 1.5 eq), and THF (10 mL) were successively added. The temperature was lowered to below -10 °C in an ice-salt bath, and a THF solution (20 mL) of DIAD (18.10 g, 0.069 mol, 1.5 eq) was added dropwise, controlling the dropping rate to one drop every two seconds. After 8 hours, TLC was monitored, with EA:PE = 1:2. The reaction was completed and the reaction was stopped. THF was removed by rotary evaporation under reduced pressure to obtain 12.21 g of a brownish-yellow oil. 50 mL of ethanol was added, stirred for 2 h, slurried, and filtered to obtain 12.46 g of a yellow solid with a yield of 80.58%.

[0210] Example 57 Synthesis of (1r,4r)-4-(4-nitrophenoxy)cyclohexan-1-amine

[0211] To a 100 mL single-necked flask, ((1r,4r)-4-(4-nitrophenoxy)cyclohexyl) tert-butyl carbamate (0.60 g, 2.09 mmol) and DCM (5 mL) were successively added. TFA (4 ml) was added dropwise at room temperature. After 3 hours, TLC was monitored, with EA:PE = 1:1. The reaction was complete and the reaction was stopped. TFA in the reaction solution was removed by distillation under reduced pressure to obtain 0.62 g of a crude brown oil. It was dried in an oven at 60 °C for 12 h, and the crude product was directly used in the next step without purification.

[0212] Example 58 Synthesis of 1-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)-3-((1r,4R)-4-(4-nitrophenoxy)cyclohexyl)urea

[0213] To a 250 mL single-necked flask, BTC (5.50 g, 18.53 mmol, 0.5 eq) and dry DCM (50 mL) were successively added. The temperature was lowered to -80 °C in a cold trap, and memantine (6.56 g, 37.06 mmol, 1 eq) and a DCM solution (50 mL) of Et3N (30.00 g, 296.48 mmol, 8 eq) were added dropwise within 4 h. After dropping, the temperature was naturally raised to room temperature. After 30 min, TLC was monitored. The reaction was complete and the reaction was stopped. The reaction solution was evaporated to dryness, DCM (50 mL) and Et3N (30.00 g, 296.48 mmol, 8 eq) were added, and the temperature was lowered to 0 °C in an ice bath. A DCM solution (50 mL) of I9 (8.89 g, 37.06 mmol, 1 eq) was added dropwise. After dropping, the reaction was carried out at room temperature. After 30 min, TLC was monitored. The reaction was complete and the reaction was stopped. DCM was removed by rotary evaporation under reduced pressure to obtain 17.82 g of a reddish-brown oil. The crude product was directly used in the next step without purification.

[0214] Example 59 Synthesis of 1-((1r,4R)-4-(4-aminophenoxy)cyclohexyl)-3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)urea (SP-C01h)

[0215] Add 2-methylbutyric acid (3.0 g, 27.51 mmol, 1 eq), dry tetrahydrofuran (10 mL), HATU (0.034 g, 0.29 mmol, 1.2 eq), and DIEA (0.18 g, 1.74 mmol, 6 eq) to a 25 mL flask and stir for 30 min. Add a solution of 1-((1r,4R)-4-(4-aminophenoxy)cyclohexyl)-3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)urea (0.1 g, 0.24 mmol, 1 eq) in THF (5 mL). Monitor the reaction by TLC. When the reaction is complete, stop the reaction and filter by suction to obtain 72 mg of a white solid. The yield is 60.56%.

[0216] 1 H NMR (400 MHz, Chloroform-d) δ 7.37 (d, J = 8.8 Hz, 2H), 7.21 (s, 1H), 6.82 (d, J = 8.8 Hz, 2H), 4.14 - 4.06 (m, 1H), 3.56 - 3.51 (m, 1H), 2.38 (q, J = 7.6 Hz, 2H), 2.17 - 1.99 (m, 6H), 1.78 (d, J = 3.1 Hz, 2H), 1.56 - 1.41 (m, 3H), 1.39 - 1.08 (m, 12H), 0.84 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 156.72, 154.42, 131.17, 121.86, 116.60, 75.57, 50.64, 48.46, 42.72, 41.02, 32.48, 31.04, 30.59, 30.23, 30.21, 30.10, 9.81.

[0217] Example 60 Synthesis of methyl 4-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)benzoate

[0218] To a 100 mL single-necked flask, cis-4-BOC-amino cyclohexanol (1.00 g, 4.64 mmol), methyl 4-hydroxybenzoate (0.7 g, 4.64 mmol), triphenylphosphine (1.8 g, 6.96 mmol), molecular sieve type A4 (dried in an oven at 120 °C for 4 h), THF (10 mL) were added successively. After purging with argon three times, the temperature was lowered to below -10 °C in an ice-salt bath. A THF solution (5 mL) of DIAD (1.4 g, 6.96 mmol) was added dropwise, controlling the dropping rate at one drop every two seconds. After 12 h, TLC was used for monitoring. The reaction was transferred to 30 °C, and 4A molecular sieve was added additionally. After 6 h, TLC was used for monitoring. When most of the reaction was completed, the reaction was stopped. THF was removed by concentration under reduced pressure to obtain 5.2 g of a yellowish-brown oily substance. After trituration, no solid was precipitated. Column chromatography was carried out with 4 times the amount of silica gel, and the sample was mixed with 1.2 times the amount of silica gel. The eluent was (EA:PE = 1:10), and 0.73 g of the product as a white solid was obtained, with a yield of 45.1%.

[0219] Example 61 Synthesis of Methyl 4-(((1r,4r)-4-aminocyclohexyl)oxy)benzoate

[0220] To a 100 mL single-necked flask, methyl 4-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)benzoate (0.60 g, 2.09 mmol) and DCM (5 mL) were added successively. TFA (4 ml) was added dropwise at room temperature. After 3 h, TLC was used for monitoring. When the reaction was complete, the reaction was stopped. TFA in the reaction solution was removed by distillation under reduced pressure. 0.62 g of a crude product as a brown oily substance was obtained. It was dried in an oven at 60 °C for 12 h, and the crude product was directly used in the next step without purification.

[0221] Example 62 Synthesis of Methyl 4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoate To a 100 mL single-necked flask, BTC (0.23 g, 0.79 mmol) and dry DCM (15 mL) were added successively. The temperature was lowered to -78 °C in a cold trap. Free 4-(trifluoromethoxy)aniline (0.41 g, 2.32 mmol) and a DCM solution (10 mL) of Et3N (1.41 g, 13.92 mmol) were added dropwise within 30 minutes. After dropping, it was transferred to room temperature and stirred for another 4 h.

[0222] Add a mixed solution of I15·TFA (0.58 g, 1.59 mmol), Et3N (1.41 g, 13.92 mmol), and DCM (10 mL) to a 100 mL single-necked flask, react at room temperature, and stop the reaction after 2 hours by TLC monitoring. Extract twice with 15 mL of water, wash once with 15 mL of saturated brine, dry over anhydrous magnesium sulfate, filter by suction, and concentrate under reduced pressure to dryness to obtain 0.93 g of a crude yellow oil. Load the column with 7 times the amount of silica gel, mix the sample with 1.2 times the amount of silica gel, and use the eluent (EA:PE = 1:5) to obtain 0.40 g of a white solid product with a yield of 40.0%. ESI-MS: m / z 453.2 [M+H] +

[0223] Example 63 Synthesis of 4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid

[0224] Add methyl 4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoate (0.15 g, 0.33 mmol), THF (3 mL), H2O (2 mL), and LiOH (39.8 mg, 0.99 mmol) to a 25 mL single-necked flask in sequence, stir at room temperature, monitor by TLC after 3 hours, a small part of the reaction occurs, heat up to 30 °C, add an additional 0.1 g of lithium hydroxide, monitor by TLC after 2 hours, a part of the reaction occurs, heat up to 50 °C, add an additional 0.2 g of lithium hydroxide, monitor by TLC after 2 hours, stop the reaction, adjust to pH = 2 with 3N HCl, concentrate under reduced pressure until there is a small amount of solvent remaining, filter by suction, and wash with 5 mL of water to obtain 70 mg of a pale yellow solid with a yield of 48.6%.

[0225] Example 64 Synthesis of 4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzamide (SP-C01i)

[0226] At room temperature, 4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid (0.17 g, 0.39 mmol) and dry tetrahydrofuran (10 mL) were added to a 25 mL flask. HATU (0.18 g, 0.46 mmol) was added thereto and stirred for 15 min. DIEA (0.12 g, 0.97 mmol) was added dropwise, and the mixture was stirred for 0.5 h. NH3·H2O (0.3 mL) was added. After 0.5 h, TLC showed that the reaction was complete. Tetrahydrofuran was removed by concentration under reduced pressure. Dichloromethane (12 mL) and water (10 mL) were added for extraction twice, and saturated brine (25 mL) was used for washing once. The organic phase was dried over anhydrous magnesium sulfate, filtered by suction, and concentrated under reduced pressure to obtain 0.20 g of a yellow oil. The product was loaded onto a silica gel column with 4 times the amount of silica gel, and the sample was mixed with 1.2 times the amount of silica gel. The eluent was (EA:PE = 1:3). Column chromatography gave 0.12 g of a pale yellow solid. The yield was 70.5%.

[0227] 1 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.82 (dd, J = 9.4, 2.7 Hz, 3H), 7.54 - 7.45 (m, 2H), 7.21 (d, J = 8.5 Hz, 2H), 7.14 (s, 1H), 7.02 - 6.94 (m, 2H), 6.48 (d, J = 7.6 Hz, 1H), 4.43 (tt, J = 9.8, 4.0 Hz, 1H), 3.54 (ddt, J = 14.2, 10.6, 5.3 Hz, 1H), 2.06 (dd, J = 12.6, 4.3 Hz, 2H), 2.01 - 1.89 (m, 2H), 1.55 - 1.30 (m, 4H). 13 13C NMR (101 MHz, DMSO-d6) δ 167.89, 160.26, 155.02, 142.36, 140.48, 129.85, 126.78, 122.03, 121.97, 119.43, 118.99, 115.28, 74.64, 47.64, 30.44, 30.15.

[0228] Example 65 Synthesis of N-(4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenyl)propanamide (SP-C01j)

[0229] Propionic acid (0.02 g, 0.24 mmol, 1 eq), dry tetrahydrofuran (10 mL), HATU (0.034 g, 0.29 mmol, 1.2 eq), and DIEA (0.18 g, 1.74 mmol, 6 eq) were added to a 25 mL flask and stirred for 30 min. A solution of 1-((1r,4R)-4-(4-aminophenoxy)cyclohexyl)-3-((1r,3R,5S,7R)-3,5-dimethyladamantan-1-yl)urea (0.1 g, 0.24 mmol, 1 eq) in THF (5 mL) was added. The reaction was monitored by TLC (EA:PE = 1:2). After the reaction was complete, the reaction was stopped and filtered to obtain 80 mg of a white solid. The yield was 71.32%.

[0230] 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.58 (d, J = 7.5 Hz, 1H), 5.42 (s, 1H), 4.22 - 4.18 (m, 1H), 2.38 - 2.31 (m, 1H), 2.05 (s, 1H), 1.97 (d, J = 10.5 Hz, 2H), 1.82 (d, J = 10.5 Hz, 2H), 1.68 (s, 2H), 1.62 - 1.55 (m, 2H), 1.07 - 1.05 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H) 0.80 (s, 6H).

[0231] Example 66 Synthesis of N-(4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)phenyl)acetamide (SP-C01k)

[0232] BTC (0.08 g, 0.26 mmol), dry DCM (10 mL) were added to a 50 mL single-necked flask in sequence. The temperature was lowered to -78 °C with a cold trap. A solution of 3-fluoro-4-trifluoromethoxyaniline (0.15 g, 0.77 mmol) and Et3N (0.47 g, 4.61 mmol) in DCM (5 mL) was added dropwise within 15 min. After the addition was complete, the reaction mixture was transferred to room temperature and stirred for another 0.5 h. After 0.5 h, the reaction was monitored by TLC (EA:PE = 1:1).

[0233] Add a mixed solution of N-(4-(((1r,4r)-4-aminocyclohexyloxy)phenyl)acetamide·TFA (0.30 g, 0.77 mmol), Et3N (0.47 g, 4.61 mmol), and DCM (5 mL) to a 100 mL single-necked flask, react at room temperature, monitor by TLC after 0.5 h, and stop the reaction. Extract twice with 15 mL of water, wash once with 15 mL of saturated brine, dry over anhydrous magnesium sulfate, filter by suction, and concentrate under reduced pressure to dryness to obtain 0.52 g of a crude yellow oil. Load the column with 4 times the amount of silica gel, mix the sample with 1.2 times the amount of silica gel, and use the eluent (EA:PE = 1:5, EA:PE = 1:3) to obtain 0.21 g of a white solid with a yield of 36.7%.

[0234] Example 67 Synthesis of Ethyl 3-((4-((((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyloxy)phenyl)amino)-3-oxopropionate (SP-C01s)

[0235] Add ethyl malonate (0.16 g, 0.12 mmol, 1 eq), dry tetrahydrofuran (5 mL), HATU (0.017 g, 0.29 mmol, 1.2 eq), and DIEA (0.09 g, 0.87 mmol, 6 eq) to a 25 mL flask and stir for 30 min. Add a solution of 1-((1r,4r)-4-(4-aminophenoxy)cyclohexyl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)urea (0.05 g, 0.12 mmol, 1 eq) in THF (5 mL), monitor by TLC, (EA:PE = 1:1, 1 drop of AcOH), stop the reaction when the reaction is complete, and filter by suction to obtain 42 mg of a white solid. The yield is 64.67%. 1 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.73 (s, 1H), 7.68 (dd, J = 13.4, 2.5 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.39 (t, J = 8.9 Hz, 1H), 7.10 (dt, J = 9.1, 1.8 Hz, 1H), 6.92 - 6.83 (m, 2H), 6.30 (d, J = 7.6 Hz, 1H), 4.24 (tt, J = 9.6, 4.0 Hz, 1H), 3.63 - 3.46 (m, 1H), 2.27 (q, J = 7.5 Hz, 2H), 2.02 (dd, J = 12.7, 4.4 Hz, 2H), 1.92 (dd, J = 12.9, 4.0 Hz, 2H), 1.51 - 1.27 (m, 4H), 1.07 (t, J = 7.5 Hz, 3H).

[0236] Synthesis of Methyl 4-(4-(((1R,4R)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)oxy)phenoxy)butyrate, Example 68

[0237] To a 25 mL single-necked flask, successively add tert-Butyl ((1R,4R)-4-(4-Hydroxyphenoxy)cyclohexyl)carbamate (0.30 g, 0.98 mmol, 1 eq), K2CO3 (0.40 g, 2.92 mmol, 3 eq), KI (0.02 g, 0.10 mmol, 0.1 eq), TBAB (0.03 g, 0.10 mmol, 0.1 eq), and add MeCN (15 mL). Dropwise add methyl 4-bromobutyrate (0.26 g, 1.46 mmol, 1.5 eq), replace with Ar three times, and heat to reflux. After 3 hours, monitor by TLC, EA:PE = 1:3, stop the reaction, concentrate under reduced pressure to dryness, add water (20 mL), extract with DCM (20 mL×2), combine the organic layers, wash with water (10 mL), wash with saturated brine (10 mL), dry over anhydrous magnesium sulfate, filter by suction, and concentrate under reduced pressure to obtain 0.46 g of a brownish-black oily liquid. The crude product was purified by silica gel column chromatography, loaded with 1.5 times the sample and 7 times the silica gel, and the eluent was EA:PE = 1:15 to obtain 0.12 g of a white solid with a yield of 30.07%.

[0238] Synthesis of Methyl 4-(4-(((1R,4R)-4-Aminocyclohexyl)oxy)phenoxy)butyrate, Example 69

[0239] To a 100 mL single-necked flask, successively add methyl 4-(4-(((1R,4R)-4-((tert-Butoxycarbonyl)amino)cyclohexyl)oxy)phenoxy)butyrate (0.12 g, 0.29 mmol, 1 eq), DCM (8 mL), cool to 0 °C in an ice bath, and dropwise add TFA (0.5 ml). After 2 hours, monitor by TLC, EA:PE = 1:3, the reaction is complete, and stop the reaction. Distill off DCM and TFA in the reaction solution under reduced pressure to obtain 0.11 g of a crude product as a pale yellow solid, and the crude product was directly used in the next step without purification. ESI MS: m / z 308.1 [M+H] + .

[0240] Synthesis of Methyl 4-(4-(((1R,4R)-4-(3-((1R,3R,5S,7R)-3,5-Dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenoxy)butyrate (SP-C20), Example 70

[0241] To a 250 mL single-necked flask, BTC (0.97 g, 3.26 mmol, 0.5 eq), dry DCM (10 mL) were added successively. The cold trap was cooled to -80 °C, and a solution of memantine (1.15 g, 6.51 mmol, 1 eq) and Et3N (5.27 g, 52.08 mmol, 8 eq) in DCM (15 mL) was added dropwise. The addition was completed within 30 min, and then the mixture was allowed to warm to room temperature naturally. After 30 min, TLC was monitored with EA:PE = 1:3. The reaction was complete, and the reaction was stopped. The reaction solution was evaporated to dryness, DCM (15 mL) and Et3N (5.27 g, 52.08 mmol, 8 eq) were added, and the mixture was cooled to 0 °C in an ice bath. A solution of methyl 4-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenoxy)butyrate (2.00 g, 6.51 mmol, 1 eq) in DCM (10 mL) was added dropwise. After the addition was completed, the reaction was carried out at room temperature. After 30 min, TLC was monitored with EA:PE = 1:2. The reaction was complete, and the reaction was stopped. DCM was removed by concentration under reduced pressure to obtain 4.05 g of a yellow oil. The oil was mixed with 1.5 times its weight of silica gel and loaded onto a column with 4 times its weight of silica gel (EA:PE = 1:7) to obtain 1.05 g of a white solid. The yield was 31.48%. 1 H NMR (400 MHz, DMSO-d6) δ 6.94 - 6.82 (m, 4H), 5.65 (d, J = 7.6 Hz, 1H), 5.49 (s, 1H), 4.19 (tt, J = 10.0, 3.9 Hz, 1H), 3.96 (t, J = 6.3 Hz, 2H), 3.66 (s, 3H), 2.51 (t, J = 7.3 Hz, 3H), 2.10 (p, J = 3.2 Hz, 1H), 2.03 - 1.93 (m, 4H), 1.92 - 1.83 (m, 2H), 1.73 (d, J = 3.1 Hz, 2H), 1.55 (s, 4H), 1.49 - 1.15 (m, 9H), 1.13 (s, 2H), 0.85 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 173.54, 157.00, 153.02, 151.71, 117.66, 115.77, 75.52, 67.31, 51.79, 51.47, 50.86, 48.60, 47.37, 42.90, 40.99, 32.36, 30.85, 30.61, 30.43, 30.09, 24.77.

[0242] Example 71 Synthesis of 4-(4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyl)oxy)phenoxy)butyric acid (SP-C21)

[0243] To a 25 mL single-necked flask, SP-C20 (0.50 g, 0.98 mmol, 1 eq), THF (15 mL), H2O (5 mL), and LiOH (0.10 g, 2.93 mmol, 3 eq) were added successively, and the mixture was stirred at room temperature. After 1.5 h, TLC was monitored with EA:PE = 1:3, the reaction was stopped, THF was removed by concentration under reduced pressure, and the residue was extracted with EA (20 mL). The aqueous layer was adjusted to pH = 2 with 1 N HCl and filtered by suction under reduced pressure to obtain 0.42 g of a pale yellow solid. The yield was 86.01%. 1 H NMR (400 MHz, DMSO-d6) δ 6.94 - 6.74 (m, 4H), 4.16 - 4.10 (m, 1H), 3.90 (t, J = 6.4 Hz, 4H), 3.90 (t, J = 6.4 Hz, 2H), 3.33 (tt, J = 10.4, 3.8 Hz, 1H), 2.37 (t, J = 7.3 Hz, 2H), 2.04 (dt, J = 6.8, 3.3 Hz, 1H), 1.97 (d, J = 4.1 Hz, 1H), 1.92 (dt, J = 14.1, 6.1 Hz, 3H), 1.82 (dd, J = 13.5, 3.6 Hz, 2H), 1.68 - 1.67 (m, 2H), 1.52 - 1.44 (m, 4H), 1.41 - 1.11 (m, 9H), 1.09 - 1.04 (m, 2H), 0.80 (s, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 174.60, 157.05, 153.08, 151.68, 117.66, 115.79, 75.50, 67.42, 51.47, 51.39, 50.86, 48.59, 48.55, 47.35, 42.94, 42.90, 40.98, 32.46, 32.36, 30.82, 30.62, 30.39, 30.09, 24.80.

[0244] Example 72 Synthesis of Methyl 4-(4-(((1r,4r)-4-(3-(3-Fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)phenoxy)butyrate (SP-C23)

[0245] To a 25 mL single-necked flask, BTC (0.03 g, 0.10 mmol, 0.34 eq), dry DCM (5 mL) were added successively. The cold trap was cooled to -80 °C, and a solution of 4-trifluoromethoxyaniline (0.05 g, 0.29 mmol, 1 eq) and Et3N (0.09 g, 0.87 mmol, 3 eq) in DCM (10 mL) was added dropwise. The addition was completed within 5 minutes, and then the mixture was allowed to warm to room temperature naturally. After 10 min, TLC monitoring was carried out with EA:PE = 1:3. The reaction was complete, and the reaction was stopped. The reaction solution was evaporated to dryness, DCM (10 mL) and Et3N (0.09 g, 0.87 mmol, 3 eq) were added, and the mixture was cooled to 0 °C in an ice bath. A solution of methyl 4-(4-(((1r,4r)-4-aminocyclohexyloxy)phenoxy)butyrate (0.09 g, 0.29 mmol, 1 eq) in DCM (5 mL) was added dropwise. After the addition was completed, the reaction was carried out at room temperature. After 30 min, TLC monitoring was carried out with EA:PE = 1:2. The reaction was complete, and the reaction was stopped. DCM was removed by concentration under reduced pressure to obtain 0.15 g of a crude white solid. The crude product was mixed with 1.5 times the amount of silica gel and loaded onto a column with 4 times the amount of silica gel (EA:PE = 1:7) to obtain 0.10 g of a white solid. The yield was 65.28%. 1 1H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 7.69 (dd, J = 13.5, 2.5 Hz, 1H), 7.37 (td, J = 9.0, 1.2 Hz, 1H), 7.12 (ddd, J = 9.0, 2.6, 1.4 Hz, 1H), 6.91 - 6.79 (m, 4H), 6.77 (d, J = 7.6 Hz, 1H), 4.17 (tt, J = 9.3, 3.8 Hz, 1H), 3.91 (t, J = 6.3 Hz, 2H), 3.61 (s, 4H), 3.57 - 3.45 (m, 1H), 2.46 (t, J = 7.3 Hz, 2H), 2.01 - 1.99 (m, 2H), 1.97 - 1.89 (m, 4H), 1.44 - 1.31 (m, 4H). 13 13C NMR (101 MHz, DMSO-d6) δ 173.53, 154.85, 153.01, 152.89, 151.67, 142.26, 142.15, 124.63, 117.61, 115.77, 113.94, 106.02, 105.78, 75.36, 51.78, 47.73, 30.43, 30.36, 30.29, 24.77.

[0246] Example 73 Synthesis of 4-(4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)cyclohexyloxy)phenoxy)butyric acid (SP-C24)

[0247] To a 25 mL single-necked flask, SP-C23 (0.50 g, 0.95 mmol, 1 eq), THF (15 mL), H2O (5 mL), and LiOH (0.10 g, 4.18 mmol, 4.4 eq) were added successively, and the mixture was stirred at room temperature. After 1.5 h, TLC was monitored with EA:PE = 1:3, the reaction was stopped, THF was removed by concentration under reduced pressure, and the residue was extracted with EA (20 mL). The aqueous layer was adjusted to pH = 2 with 1N HCl and filtered by suction under reduced pressure to obtain 0.47 g of a pale yellow solid. The yield was 96.21%. 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 9.19 (s, 1H), 7.68 (dd, J = 13.5, 2.6 Hz, 1H), 7.38 (td, J = 8.9, 1.2 Hz, 1H), 7.10 (ddd, J = 9.0, 2.6, 1.3 Hz, 1H), 6.91 - 6.79 (m, 4H), 6.57 (s, 1H), 4.19 (tt, J = 9.3, 3.8 Hz, 1H), 3.90 (t, J = 6.4 Hz, 2H), 3.54 (ddt, J = 11.1, 7.4, 3.9 Hz, 1H), 2.37 (t, J = 7.3 Hz, 2H), 2.05 - 1.97 (m, 2H), 1.96 - 1.85 (m, 4H), 1.50 - 1.21 (m, 5H). 13 C NMR (101 MHz, DMSO-d6) δ 174.62, 155.37, 154.80, 153.10, 152.92, 151.65, 142.11, 142.01, 124.70, 117.63, 115.81, 113.86, 105.95, 105.71, 75.25, 67.44, 47.62, 30.64, 30.27, 30.13, 24.82.

[0248] Example 74 Synthesis of Methyl 2-(5-((Z)-4-(((1r,4r)-4-(tert-Butoxycarbonyl)amino)cyclohexyloxy)benzylidene)-2,4-dioxothiazolidin-3-yl)acetate

[0249] To a 100 mL round-bottom flask, sequentially add tert-butyl ((1r,4r)-4-(4-formylphenoxy)cyclohexyl)carbamate (4.00 g, 12.53 mmol, 1 eq), methyl 2-(2,4-dioxothiazolidin-3-yl)acetate (2.37 g, 12.53 mmol, 1 eq), piperidine (0.50 g, 6.27 mmol, 0.5 eq), acetic acid (0.38 g, 6.27 mmol, 0.5 eq), and toluene (20 mL). Heat the mixture to reflux. As the reaction proceeds, a solid precipitates. After 8 hours, monitor the reaction by TLC (EA:PE = 1:1). When the reaction is complete, stop the reaction. Cool the reaction mixture to room temperature, filter it by suction, and wash the filter cake with a small amount of n-hexane to obtain 3.89 g of a white solid. There is no product spot in the filtrate by TLC, and the yield is 63.36%.

[0250] Example 75 Synthesis of methyl 2-(5-((Z)-4-(((1r,4r)-4-aminocyclohexyl)oxy)benzylidene)-2,4-dioxothiazolidin-3-yl)acetate

[0251] To a 100 mL single-necked flask, sequentially add methyl 2-(5-((Z)-4-(((1r,4r)-4-(tert-butoxycarbonyl)amino)cyclohexyl)oxy)benzylidene)-2,4-dioxothiazolidin-3-yl)acetate (3.89 g, 7.94 mmol, 1 eq), DCM (8 mL), and cool the mixture to 0 °C in an ice bath. Dropwise add TFA (2 mL). After 4 hours, monitor the reaction by TLC (EA:PE = 1:3). When the reaction is complete, stop the reaction. Remove DCM and TFA from the reaction mixture by distillation under reduced pressure to obtain 3.87 g of a crude product as a pale yellow solid. The crude product is directly used in the next step without purification. ESI MS: m / z 390.1 [M+H] + .

[0252] Example 76 Synthesis of methyl 2-(2,4-dioxo-5-((Z)-4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzylidene)thiazolidin-3-yl)acetate (SP-D01)

[0253] To a 25 mL single-necked flask, BTC (0.03 g, 0.10 mmol, 0.34 eq), dry DCM (5 mL) were added successively. The cold trap was cooled to -80 °C, and a DCM solution (10 mL) of 4-trifluoromethoxyaniline (0.05 g, 0.29 mmol, 1 eq) and Et3N (0.13 g, 1.30 mmol, 5 eq) was added dropwise. The addition was completed within 5 minutes, and then the mixture was allowed to warm to room temperature naturally. After 10 min, TLC monitoring showed that EA:PE = 1:3 and the reaction was complete, so the reaction was stopped. The reaction solution was evaporated to dryness, DCM (10 mL) and Et3N (0.13 g, 1.30 mmol, 5 eq) were added, and the mixture was cooled to 0 °C in an ice bath. A DCM solution (5 mL) of methyl 2-(5-((Z)-4-(((1r,4r)-4-aminocyclohexyloxy)benzylidene)-2,4-dioxothiazolidin-3-yl)acetate (0.10 g, 0.26 mmol, 1 eq) was added dropwise. After the addition was completed, the reaction was carried out at room temperature. After 30 min, TLC monitoring showed that EA:PE = 1:1 and AcOH 2d, and the reaction was complete, so the reaction was stopped. The DCM was removed by concentration under reduced pressure to obtain 0.23 g of a crude white solid. The crude product was purified by silica gel column chromatography, with 1.5 times sample loading and 5 times silica gel for column packing. The eluent was EA:PE = 1:10, and 0.10 g of a white solid was obtained, with a yield of 66.67%. ESI MS: m / z 616.0 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 7.96 (s, 1H), 7.65 - 7.57 (m, 2H), 7.54 - 7.45 (m, 2H), 7.22 (d, J = 8.6 Hz, 2H), 7.18 - 7.12 (m, 2H), 6.44 (d, J = 7.6 Hz, 1H), 4.51 (s, 2H), 3.72 (s, 3H), 3.57 - 3.53 (m, 1H), 3.28 - 3.25 (m, 1H), 2.12 - 2.03 (m, 2H), 1.98 - 1.90 (m, 2H), 1.58 - 1.32 (m, 6H).

[0254] Example 77 Synthesis of 2-(2,4-dioxo-5-((Z)-4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureido)cyclohexyloxy)benzylidene)thiazolidin-3-yl)acetic acid SP-D01 (0.08 g, 0.13 mmol, 1 eq), THF (5 mL), H2O (1 mL), and LiOH (0.01 g, 0.40 mmol, 3 eq) were successively added to a 25 mL single-necked flask and stirred at room temperature. After 1.5 h, TLC was monitored with EA:PE = 1:3, and the reaction was stopped. THF was removed by concentration under reduced pressure, and the pH was adjusted to 4 with 1N HCl. The mixture was extracted with EA (10 mL) and H2O (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by suction, and concentrated to dryness under reduced pressure to obtain 70 mg of a white solid. The yield was 92.98%. ESIMS: m / z 578.3 [M-H] - .

[0255] Example 78 Synthesis of methyl 2-(5-((Z)-4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantan-1-yl)ureido)cyclohexyloxy)benzylidene)-2,4-dioxothiazolin-3-yl)acetate

[0256] BTC (0.03 g, 0.10 mmol, 0.34 eq), dry DCM (5 mL) were successively added to a 25 mL single-necked flask, and the temperature was lowered to -80 °C in a cold trap. A solution of memantine (0.05 g, 0.28 mmol, 1 eq) and Et3N (0.28 g, 2.80 mmol, 10 eq) in DCM (10 mL) was added dropwise within 5 minutes. After the addition, the temperature was allowed to rise to room temperature naturally. After 10 min, TLC was monitored with EA:PE = 1:3, and the reaction was complete, so the reaction was stopped. The reaction solution was evaporated to dryness, DCM (10 mL) and Et3N (0.28 g, 2.80 mmol, 10 eq) were added, and a solution of N4 (0.10 g, 0.28 mmol, 1 eq) in DCM (5 mL) was added dropwise in an ice bath at 0 °C. After the addition, the reaction was carried out at room temperature. After 30 min, TLC was monitored with EA:PE = 1:1 and AcOH 2d, and the reaction was complete, so the reaction was stopped. DCM was removed by concentration under reduced pressure to obtain 0.31 g of a crude white solid. The crude product was purified by silica gel column chromatography, with 1.5 times of sample mixing and 5 times of silica gel packing. The eluent was EA:PE = 1:10, and 0.08 g of a white solid was obtained with a yield of 48.20%. ESI MS: m / z 594.66 [M-H] - . 11H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.65 - 7.56 (m, 2H), 7.18 - 7.09 (m, 2H), 5.62 (d, J = 7.6 Hz, 1H), 5.43 (s, 1H), 4.51 (s, 2H), 4.45 (dd, J = 8.9, 4.7 Hz, 1H), 3.72 (s, 3H), 2.09 - 1.99 (m, 3H), 1.89 - 1.81 (m, 2H), 1.68 (d, J = 3.1 Hz, 2H), 1.50 (s, 4H), 1.48 - 1.37 (m, 2H), 1.33 - 1.14 (m, 7H), 1.08 (s, 2H), 0.80 (s, 6H).

[0257] Example 79 Synthesis of (Z)-5-(4-Nitrobenzylidene)thiazolidine-2,4-dione

[0258] To a 100 mL round-bottom flask, p-nitrobenzaldehyde (5.00 g, 33.09 mmol, 1 eq), 2,4-thiazolidinedione (3.88 g, 33.09 mmol, 1 eq), piperidine (1.41 g, 16.55 mmol, 0.5 eq), acetic acid (1.00 g, 16.55 mmol, 0.5 eq), and toluene (40 mL) were added successively, and the temperature was raised to reflux. As the reaction proceeded, a solid precipitated. After 8 hours, TLC was monitored (EA:PE = 1:1, AcOH 1 d), and the reaction was complete. The reaction was stopped. The reaction mixture was cooled to room temperature, filtered by suction, and the filter cake was rinsed with a small amount of n-hexane to obtain 5.06 g of a red-brown solid. The filtrate was evaporated to dryness and concentrated, and slurried with DCM (10 mL) and MeOH (1 mL) to obtain 3.06 g of a yellow solid, with a yield of 98.19%. 1 1H NMR (400 MHz, DMSO-d6): δ (ppm) 1 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.31 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.81 (s, 1H). ESI MS: m / z 249.1 [M - H] - .

[0259] Example 80 Synthesis of (Z)-5-(4-Aminobenzylidene)thiazolidine-2,4-dione

[0260] To a 500 mL three-necked flask, (Z)-5-(4-nitrobenzylidene)thiazolidine-2,4-dione (8.27 g, 33.09 mmol, 1 eq), Fe (11.12 g, 198.54 mmol, 6 eq), EtOH (250 mL), H2O (70 mL), and NH4Cl (17.70 g, 330.90 mmol, 10 eq) were added successively, and the temperature was raised to reflux. After 1.5 h, TLC monitoring was carried out with EA:PE = 1:1 and 1 drop of AcOH. The reaction was complete, and the reaction was stopped. The reaction solution was cooled to room temperature, filtered by suction, the filter cake was rinsed with a small amount of DCM, the filtrate was evaporated to dryness and concentrated, removing EtOH and part of H2O. Extraction was carried out with DCM:MeOH = 10:1 (60 mL × 4), dried over anhydrous magnesium sulfate, filtered by suction, and the filtrate was concentrated under reduced pressure to obtain 2.06 g of a red-brown solid with a yield of 72.38%. ESI MS: m / z 199.3 [M-H] - .

[0261] Example 81 Synthesis of 1-((1r,3R,5S,7r)-3,5-dimethyladamantan-1-yl)-3-(4-((E)-(2,4-dioxothiazolin-5-ylidene)methyl)phenyl)urea (SP-E01)

[0262] To a 25 mL single-necked flask, BTC (0.05 g, 0.15 mmol, 0.34 eq), dry DCM (5 mL) were added successively. The cold trap was cooled to -80 °C, and memantine (0.08 g, 0.45 mmol, 1 eq) and a DCM solution (10 mL) of Et3N (0.46 g, 4.50 mmol, 10 eq) were added dropwise. The addition was completed within 5 minutes, and then the temperature was allowed to rise to room temperature naturally. After 30 min, TLC monitoring was carried out with EA:PE = 1:3. The reaction was complete, and the reaction was stopped. The reaction solution was evaporated to dryness, DCM (10 mL) and Et3N (0.46 g, 4.50 mmol, 10 eq) were added, and the mixture was cooled to 0 °C in an ice bath. A DCM solution (5 mL) of (Z)-5-(4-aminobenzylidene)thiazolidine-2,4-dione (0.10 g, 0.45 mmol, 1 eq) was added dropwise. After the addition was completed, the reaction was carried out at room temperature. After 30 min, TLC monitoring was carried out with EA:PE = 1:1 and 2 drops of AcOH. The reaction was complete, and the reaction was stopped. 1N HCl (30 mL) was added, and extraction was carried out with DCM (30 mL × 3). The organic layers were combined, washed with water (30 mL), saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered by suction, and concentrated under reduced pressure to obtain. 0.37 g of a crude yellow oil was obtained. The crude product was purified by silica gel column chromatography, with 1.5 times of sample mixing and 7 times of silica gel for column packing. The eluent was EA:PE = 1:10, and 0.11 g of a white solid was obtained with a yield of 57.49%. ESI MS: m / z 423.9 [M-H] - .

[0263] Synthesis of Example 82 (E)-1-(4-((2,4-dioxothiazolin-5-ylidene)methyl)phenyl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)urea (SP-E03)

[0264] BTC (0.05 g, 0.15 mmol, 0.34 eq) and dry DCM (5 mL) were successively added into a 25 mL single-necked flask. The temperature was lowered to -80 °C with a cold trap, and a DCM solution (10 mL) of 4-trifluoromethoxyaniline (0.08 g, 0.45 mmol, 1 eq) and Et3N (0.46 g, 4.50 mmol, 10 eq) was added dropwise. The addition was completed within 5 minutes, and then the mixture was allowed to warm up to room temperature naturally. After 30 min, TLC monitoring was carried out with EA:PE = 1:3. When the reaction was complete, the reaction was stopped. The reaction solution was evaporated to dryness, and excess phosgene was removed. DCM (10 mL) and Et3N (0.46 g, 4.50 mmol, 10 eq) were added. The mixture was cooled to 0 °C in an ice bath, and a DCM solution (5 mL) of (Z)-5-(4-aminobenzylidene)thiazolidine-2,4-dione (0.10 g, 0.45 mmol, 1 eq) was added dropwise. After the addition was completed, the reaction was carried out at room temperature. After 15 min, TLC monitoring was carried out with EA:PE = 1:1 and AcOH 2d. When the reaction was complete, the reaction was stopped. It was extracted with 1N HCl (30 mL) and DCM (30 mL × 3). The organic layers were combined, washed with water (30 mL), saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered by suction, and concentrated under reduced pressure to obtain. The crude product was a yellow oily substance of 0.31 g. The crude product was purified by silica gel column chromatography, with 1.5 times of sample mixing and 7 times of silica gel for column packing. The eluent was EA:PE = 1:10, and a white solid of 0.09 g was obtained with a yield of 47.37%. ESI MS: m / z 421.8 [M-H] - .

[0265] Test Example 1

[0266] 1. sEH inhibition activity test

[0267] Detection principle: The specific substrate (3-phenyloxy)-acetic acid cyano-(6-methoxy-naphthalen-2-yl) methyl ester, i.e., PHOME, has no fluorescence itself, but is hydrolyzed by sEH enzyme to produce the product 6-methoxy-2-naphthaldehyde. 6-Methoxy-2-naphthaldehyde can emit fluorescence with a wavelength of 465 nm under the excitation of 330 nm light wave. The intensity of the detected fluorescence signal is inversely proportional to the inhibition effect on sEH enzyme. Based on the above principle, compared with the positive control group, the inhibition rate of samples at different concentrations was calculated. According to the inhibition rate and concentration, the IC 50 value of the compound was calculated using SPSS20 software.

[0268] 2. Preparation of reagents and drugs

[0269] 25 mM Tris-HCl buffer (pH = 7.4, containing 0.1 mg / mL BSA): Take 12.5 mL of 1 M Tris-HCl buffer, add 5 mg of BAS, dilute with pure water and adjust the pH value to 7.4 with hydrochloric acid, and make up the volume to 500 mL.

[0270] PHOME solution: Dissolve 0.79 mg of PHOME in 106 μL of DMSO to obtain a PHOME solution with a concentration of 20 mM. Dilute it to 1 / 3 mM with Tris-HCl buffer before use.

[0271] sEH solution: The sEH (5 mg / mL) stock solution is stored in a -80 °C refrigerator. Dilute it to 4 μg / mL with 25 mM Tris-HCl buffer before use.

[0272] The powder of the sample to be tested is dissolved in DMSO to a 20 mM solution, stored in a -20 °C refrigerator for later use, and diluted to the corresponding concentration with Tris-HCl buffer before use.

[0273] 3. Experimental grouping

[0274] Experimental design: Solvent group, 100% viability group (A), inhibitor group (B), positive control group (C), as shown in Table 1 specifically.

[0275] Table 1 Experimental grouping

[0276] hole buffer DMSO inhibitor sEH substrate solvent group 168 μL 2 μL — — 30 μL 100% viability group (A) 148 μL 2 μL — 20 μL 30 μL inhibitor group (B) 148 μL — 2 μL 20 μL 30 μL positive control group (C) 148 μL — 2 μL 20 μL 30 μL

[0277] 4. Experimental procedures

[0278] (a) Add 148 μL / well of Tris-HCl buffer to a 96-well black-bottom microplate;

[0279] (b) Add 2 μL of the sample solution to be tested. The solvent group and the 100% viability group are replaced with an equal volume of DMSO. The positive control group is added with the lead compound GL-B401, and the structural formula is

[0280] (c) There are 5 concentrations in the inhibitor group, and the final concentrations are 10 nM, 5 nM, 2.5 nM, 1.25 nM, and 0.625 nM respectively;

[0281] (d) Add 20 μL of s-EH solution (final concentration is 400 ng / mL). The solvent group is replaced with an equal volume of Tris-HCl buffer;

[0282] (e) Add 30 μL of PHOME substrate to start the reaction (final concentration is 50 μM), and incubate in a 37 °C incubator for 10 min;

[0283] (f) Detect the fluorescence signal data with a microplate reader, excitation wavelength 330 nm, emission wavelength 465 nm.

[0284] 5. Data analysis

[0285] Set three replicate wells for each sample, and the average value of the three replicate wells is the fluorescence value (F) of the test compound. Inhibition rate % = [(AF - BF) / AF] × 100, where AF is the fluorescence value of the 100% activity group and BF is the fluorescence value of the inhibitor group. Calculate the IC of the compound using SPSS 20 software based on the inhibition rate and concentration. 50 value.

[0286] We used a biochemical method to evaluate the activity of the compound with methyl (6-methoxynaphthalen-2-yl) 2-(3-phenyloxirane-2-yl) acetate (PHOME) as the substrate using recombinant human sEH (Human sEH, HsEH) and murine sEH (Murine sEH, MsEH). The results are shown in Table 2.

[0287] Table 2 Human (HsEH) and Murine (MsEH) sEH IC of the compound 50

[0288]

[0289]

[0290] Test Example 2

[0291] 1. PPARγ agonist activity test

[0292] Detection principle: When pM-hPPAR binds to the appropriate ligand and is activated, it binds to the GAL4 DNA binding site in the plasmid pB4-RES-tk-luc, thereby initiating the expression of the downstream luciferase reporter gene. Determine whether the test compound is an agonist of PPAR by detecting the amount of luciferase.

[0293] 2. Test results: For SP-C01, the EC of PPARγ 50 = 4.2 μM, for SP-A01, the EC of PPARγ 50 = 6.77 μM, for SP-A07, the EC of PPARγ 50 = 7.75 μM, for SP-B07, the EC of PPARγ 50 = 1.43 μM.

[0294] Table 3 PPARγ of the compounds in the examples

[0295]

[0296]

[0297] Although the above embodiments have described the present invention in detail, they are only a part of the embodiments of the present invention, rather than all embodiments. Other embodiments can also be obtained based on these embodiments without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A compound, characterized in that, It has the structure shown in Formula III: Wherein, R1 is adamantyl, substituted phenyl, substituted or unsubstituted pyridyl or substituted or unsubstituted naphthyl; the substituents of the substituted phenyl, substituted pyridyl or substituted naphthyl are -F, -Cl, -Br, -OH, -NH2, -NHCH3, -N(CH3)2 or C1-C6 alkyl; R2 is hydrogen, hydroxyl, alcohol hydroxyl, amino or carboxyl; B is a single bond or phenyl; W is a single bond, -CH2-, -O-, -S-, -NH- or Z is =CH2, =O, =S or =NH.

2. The compound according to claim 1, characterized in that, The R2 is hydrogen; the W is a single bond or -O-; Z is =O.

3. The compound according to claim 2, wherein, The R1 is adamantyl, 4. The compound according to any one of claims 1 to 3, characterized in that, It has any one of the following structures:

5. A method for preparing the compound according to any one of claims 1 to 4, characterized in that, It includes the following steps: Carry out a first substitution reaction on compound m and compound b to obtain compound n; Carry out a first condensation reaction on the compound n and compound d to obtain compound o; Carry out a first hydrolysis reaction on the compound o to obtain compound p; Carry out a first nucleophilic substitution reaction on the compound p, compound w and compound af to obtain compound q; The compound q is a compound having the structure shown in Formula III in which the thiazolidinedione group in the structure is connected by a double bond; Carry out a first reduction reaction on the compound q to obtain a compound having the structure shown in Formula III in which the thiazolidinedione group in the structure is connected by a single bond; The structural formulas of the compound b, compound d, compound w and compound af are as follows: Wherein, B, R1, R2 and W are as described in any one of claims 1 to 3; X is H, hydroxyl or halogen, and Z is -O-; The structural formulas of the compound m, compound n, compound o, compound p and compound q are as follows: Wherein, Q is H, hydroxyl, amino, mercapto, carboxyl or acyl chloride.

6. Use of the compound according to any one of claims 1 to 4 and its pharmaceutically acceptable salts or the compound prepared by the preparation method according to claim 5 in the preparation of a PPARγ agonist and / or a soluble epoxide hydrolase inhibitor.

7. The application according to claim 6, characterized in that, The disease is an inflammatory disease, pain, sepsis, cardiovascular disease, neurodegenerative disease, diabetes, diabetes complication, depression, liver fibrosis, renal failure, chronic obstructive pulmonary disease or pulmonary hypertension disease.

8. The application according to claim 7, characterized in that, The inflammatory disease is non-alcoholic steatohepatitis or chronic nephritis; the pain is neuropathic pain.

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