A compound, its preparation method, and its application in the preparation of sEH inhibitors and PPARs agonists.

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to a compound, its preparation method, and its application in the preparation of sEH inhibitors and PPARs agonists. This invention provides a compound having the structure shown in Formula II. The compound provided by this invention has a typical urea structure as the primary pharmacophore of soluble epoxide hydrolase (sEH), and a thiazolidinedione moiety as the primary pharmacophore of peroxisome proliferator-activated receptors (PPARs). The sEH inhibitor and PPARs agonist compound provided by this invention exhibits high inhibitory activity against human HsEH and high agonistic activity against PPARs, and can be used as an sEH inhibitor and PPARs agonist compound in the preparation of drugs for treating diseases mediated by soluble epoxide hydrolase and peroxisome proliferator-activated receptors.

Description

[0001] This application is a divisional application of Chinese patent application filed on March 22, 2023, with application number 202310282598.7, entitled "A dual-target compound and its preparation method and its application in the preparation of sEH inhibitors and PPARs agonists". Technical Field

[0002] This invention belongs to the field of pharmaceutical technology, specifically relating to a compound, its preparation method, and its application in the preparation of sEH inhibitors and PPARs agonists. Background Technology

[0003] Pain sensation is mediated by a specialized subset of sensory afferent neurons (nociceptors), which are activated in response to thermal, mechanical, and chemical stimuli through various mechanisms. Studies have shown that ion channel regulation, including transient receptor potential (TRP) channels, G protein-coupled receptor (GPCR) activation, and cell membrane alterations, demonstrates the role of lipid mediators in signal transduction within nociceptors (Nature, 2001, 413(6852):203-210).

[0004] Studies have shown that cyclooxygenase and lipoxygenase metabolites, prostaglandins and leukotrienes, can lead to pain and inflammation, 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 epoxidized fatty acids (EpFAs). Researchers have found that these metabolites mediate analgesic effects in several types of pain pathology, such as acute pain, chronic pain, cancer pain, or intractable pain.

[0005] Arachidonic acid (ARA) is a 20-carbon PUFA containing four unsaturated double bonds. It can be metabolized by CYP450 enzymes into epoxide metabolites (EETs) of any one or more of these 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 a variety of direct and indirect mechanisms, including nuclear receptor activation, limiting endoplasmic reticulum stress, and blocking mitochondrial dysfunction. In animal models of inflammatory pain and diabetic neuropathic pain, small molecule inhibitors of soluble epoxide hydrolases 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 DHETs has inflammatory effects. Small molecule inhibitors of soluble epoxide hydrolase can stabilize EpFA in vivo. Therefore, increasing the amount of EETs in the body by inhibiting sEH activity has become a new approach to treating EETs-related diseases.

[0006] EpFA exerts its 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). EpFA can modulate cellular stress induced by reactive oxygen species (ROS) and shift the ER stress response to homeostasis rather than activating inflammatory pathways that lead to cellular senescence and death. EpFA can reduce the ER stress response and limit ROS, indirectly maintaining mitochondrial functional stability. EpFA can also directly block the effects of mitochondrial dysfunction. Inhibition of sEH activity can stabilize EpFA and limit the production of some pro-inflammatory diol metabolites. Therefore, EpFA mediates beneficial effects in all these processes, shifting the ER stress response to homeostasis and alleviating pain.

[0007] There is substantial evidence that EpFA plays a role in nociception by blocking inflammatory and neuropathic pain, thus sEH inhibitors and EpFA analogues have great potential in alleviating human pain.

[0008] Epidemiological studies have confirmed the association of inflammatory biomarkers with the development of type 2 diabetes mellitus (T2DM) and its complications. The triggering mechanisms of inflammation in T2DM remain unclear. Inflammatory responses may contribute to T2DM by inducing insulin resistance, with an obese environment leading to adipose tissue dysfunction, macrophage infiltration, and increased 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. Chronicly elevated levels of specific inflammatory markers, such as IL-6 and TNF-α, appear 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 IL-6 production in endothelial cells and macrophages. Furthermore, hyperglycemia enhances the effects of cytokine signaling inhibitors (SOCSs), thereby impairing insulin release and signal transduction, promoting long-term complications of diabetes. Targeting inflammatory pathways may be an integral part of strategies for the prevention and control of diabetes and its 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—that promote insulin resistance. PPAR agonists induce an increase in plasma adiponectin concentrations, a hormone secreted from adipose tissue and present in low levels in the plasma of patients with type 2 diabetes mellitus (T2DM). Adiponectin increases fatty acid oxidation in the liver and skeletal muscle. Overall, adiponectin enhances insulin sensitivity in skeletal muscle and liver and reduces glucose production in the liver, thereby decreasing circulating FFA and TG levels, as well as glucose levels. Macrophage infiltration in obese adipose tissue is involved in local inflammation that enhances insulin resistance. Recent studies have shown that the PPAR component in macrophages mediates the antidiabetic effects of TZD. Inactivation of PPARs in macrophages leads to impaired activation of alternative macrophages, glucose intolerance, and insulin resistance in skeletal muscle and liver.

[0010] Currently, the main analgesics used in clinical practice include opioid analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs). Both have certain side effects. For example, traditional opioid analgesics have a strong effect, but they also have strong addictive properties and side effects such as respiratory depression, low blood pressure, nausea, vomiting, constipation, and difficulty urinating. NSAIDs are divided into non-selective NSAIDs and selective cyclooxygenase-2 (COX-2) inhibitors. Although they also have good analgesic effects, non-selective NSAIDs have severe gastrointestinal irritation and can easily lead to gastric ulcers. They also often have adverse reactions on the coagulation and hematopoietic systems. Although selective COX-2 inhibitors do not have gastrointestinal irritation, they can easily cause an imbalance of prostacyclin and thromboxane, leading to cardiovascular diseases, and generally have little effect on neuropathic pain.

[0011] Currently, the main hypoglycemic drugs used in clinical practice include insulin, insulin secretagogues, insulin sensitizers, alpha-glucosidase inhibitors, GLP-1 agonists, and dipeptidyl peptidase-4 inhibitors, all of which have certain drawbacks. For example, insulin alpha-glucosidase inhibitors cannot be used alone to treat diabetes and usually need to be combined with other drugs for blood sugar control; insulin secretagogues can cause gastrointestinal symptoms (such as nausea and upper abdominal distension) and headaches; insulin must be injected for treatment, resulting in poor patient compliance; and other drugs are difficult to combat diabetic inflammatory complications and neuropathic pain.

[0012] Currently reported dual-target compounds for sEH inhibitors and PPARs agonists include RB394 and sEH IC. 50 =0.3μM, PPARγEC 50 =0.3μM, it has shown some efficacy in the treatment of diabetic nephropathy and steatohepatitis, but further development and exploration are still needed. Given that dual-target compounds of sEH inhibitors and PPARs agonists can not only lower blood glucose but also effectively treat diabetic inflammatory complications, non-alcoholic fatty liver disease, and neuropathic pain, reducing drug interactions that previously required multiple medications, the development of novel and more effective dual-target compounds of sEH inhibitors and PPARs agonists for the treatment of diabetes, non-alcoholic fatty liver disease, pain, and depression is urgent and necessary. Summary of the Invention

[0013] The purpose of this invention is to provide a compound, its preparation method, and its application in the preparation of sEH inhibitors and PPARs agonists. The compound provided by this invention has high activity against human sEH (HsEH) and PPARs, with few side effects, and can be used as a dual-target compound for the treatment of diabetes and its inflammatory complications, neuropathic pain, and depression.

[0014] This invention provides a compound having the structure shown in Formula II:

[0015]

[0016] Wherein, R1 is arginyl, aryl, alkyl-substituted aryl, haloaryl, haloalkyl-substituted aryl, haloalkoxy-substituted aryl, or haloaryloxy-substituted aryl; R3 is hydrogen, alkyl, alkoxy, hydroxyl, cyano, or carboxyl; R4 is hydrogen or alkyl; R5 is hydrogen, alkyl, alkoxy, hydroxyl, cyano, or carboxyl; A is cycloalkyl, heterocyclic, or aryl; and B is a single bond, cycloalkyl, heterocyclic, or aryl.

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

[0018] Y is a single bond, -CH2-, -O-, -S-, or -NH-; Z is =CH2, =O, =S, or =NH; n is an integer from 0 to 12.

[0019] This invention provides a compound having the structure shown in Formula II. The compound provided by this invention has a typical urea structure as the primary pharmacophore of soluble epoxide hydrolase (sEH), and a thiazolidinedione moiety as the primary pharmacophore of peroxisome proliferator-activated receptors (PPARs). The sEH inhibitor and PPARs agonist compound provided by this invention exhibits high inhibitory activity against human HsEH and high agonistic activity against PPARs, and can be used as an sEH inhibitor and PPARs agonist compound in the preparation of drugs for treating diseases mediated by soluble epoxide hydrolase and peroxisome proliferator-activated receptors. Attached Figure Description

[0020] Figure 1 The reaction route diagram is shown for sEH inhibitors with the structure shown in Formula II and PPARs agonist compounds. Detailed Implementation

[0021] This invention provides a compound having the structure shown in Formula II:

[0022]

[0023] Wherein, R1 is arginyl, aryl, alkyl-substituted aryl, haloaryl, haloalkyl-substituted aryl, haloalkoxy-substituted aryl, or haloaryloxy-substituted aryl; R3 is hydrogen, alkyl, alkoxy, hydroxyl, cyano, or carboxyl; R4 is hydrogen or alkyl; R5 is hydrogen, alkyl, alkoxy, hydroxyl, cyano, or carboxyl; A is cycloalkyl, heterocyclic, or aryl; and B is a single bond, cycloalkyl, heterocyclic, or aryl.

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

[0025] Y is a single bond, -CH2-, -O-, -S-, or -NH-; Z is =CH2, =O, =S, or =NH; n is an integer from 0 to 12.

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

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

[0028] In this invention, R1 is preferably ammonium alkyl, haloaryl, haloalkyl-substituted aryl, or haloalkoxy-substituted aryl; R3 is preferably hydrogen or alkyl; R4 is preferably hydrogen, methyl, or ethyl; R5 is preferably hydrogen or alkyl; A is preferably cyclohexyl or phenyl; B is preferably a single bond or phenyl; W is preferably a single bond or -O-; Y is preferably a single bond, -O-, or -NH-; Z is =O; n is preferably an integer from 0 to 2.

[0029] In this invention, R1 is preferably adamantyl alkyl group. R3 is preferably hydrogen or methyl; R4 is preferably hydrogen; R5 is preferably hydrogen or methyl.

[0030] In this invention, the compound preferably has any one of the following structures:

[0031]

[0032] This invention provides a method for preparing the compound described in the above technical solution.

[0033] Includes the following steps:

[0034] Compound a and compound h were subjected to a first substitution reaction to obtain compound i;

[0035] Compound i is subjected to a first hydrolysis reaction to obtain compound j;

[0036] Compound j was subjected to a second substitution reaction with compound aa to obtain compound k;

[0037] The compound k was subjected to a second hydrolysis reaction to obtain compound l;

[0038] Compounds l and w were subjected to a nucleophilic substitution reaction with compound af to obtain a compound having the structure shown in Formula II.

[0039] The structural formulas of compounds a, w, and af are as follows:

[0040]

[0041] In this case, Q in chemical a is H, hydroxyl, amino, thiol, carboxyl, or acyl chloride;

[0042] The structural formulas of compounds h, i, j, k, l, and aa are as follows:

[0043]

[0044] In compound h, X represents H, hydroxyl, halogen, and haloalkyl.

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

[0046] like Figure 1 The reaction route diagram shown illustrates that in this invention, compound a undergoes a nucleophilic substitution reaction with compound h to obtain compound i. In this invention, the nucleophilic substitution reaction is preferably carried out in the presence of triphenylphosphine and DIAD. In this invention, the molar ratio of compound a, compound h, triphenylphosphine, and DIAD is preferably 1:1:1.5:1.5. In this invention, the nucleophilic substitution reaction is preferably carried out under ice-salt bath conditions, and the reaction time is preferably 8-12 hours. The solvent for the nucleophilic substitution reaction is preferably tetrahydrofuran, and the reaction is purified by column chromatography.

[0047] In this invention, compound i is subjected to an ester hydrolysis reaction under alkaline conditions to obtain compound j. In this invention, the reagent providing the alkaline conditions is preferably LiOH, and the ester hydrolysis reaction is preferably carried out under THF / H2O conditions. In this invention, the temperature of the ester hydrolysis reaction is preferably room temperature, and the time is preferably 1.5–2.5 h. After the ester hydrolysis reaction, the resulting reaction solution is preferably subjected to vacuum distillation. Water and dichloromethane are added to the residue, and the pH of the system is adjusted to 2 with 6N HCl under ice-water bath conditions. Extraction is performed with dichloromethane (40 mL × 3), followed by sequential washing with water, washing with saturated brine, and drying with anhydrous sodium sulfate. The residue is then filtered, and the filtrate is concentrated under vacuum to obtain compound j.

[0048] This invention involves reacting compound j with compound aa via a nucleophilic substitution reaction to yield compound k. Preferably, the nucleophilic substitution reaction is carried out in the presence of K₂CO₃. The molar ratio of compound j, the nucleophile, and the base in the nucleophilic substitution reaction is preferably 1:1:3. The nucleophilic substitution reaction is preferably carried out at 80°C for 5-6 hours, and the solvent is preferably acetonitrile. The resulting product is purified by column chromatography after the nucleophilic substitution reaction.

[0049] After obtaining compound k, compound k is subjected to a second hydrolysis reaction to obtain compound l. The second hydrolysis reaction is a deprotection reaction under acidic conditions. In this invention, the reagent providing the acidic conditions is preferably trifluoroacetic acid or an EA solution of hydrogen chloride, and the deprotection reaction is preferably carried out under dichloromethane conditions. In this 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, the resulting reaction solution is preferably subjected to vacuum distillation. Water and dichloromethane are added to the residue, and the pH of the system is adjusted to 7 with solid sodium hydroxide under ice-water bath conditions. The organic layer is separated and removed, and the aqueous layer is extracted with dichloromethane (100 mL × 2). Then, it is washed successively with water, saturated brine, and dried with anhydrous sodium sulfate. After filtration, the filtrate is concentrated under vacuum to obtain compound l.

[0050] After obtaining compound 1, the present invention performs a nucleophilic substitution reaction on compound 1 and compound af to obtain an sEH inhibitor and PPARs agonist compound having the structure shown in Formula II. In the present invention, the nucleophilic substitution reaction is preferably carried out in the presence of triethylamine. In the present invention, the molar ratio of compound 1, compound af, 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 under ice bath conditions, the reaction time is preferably 10–50 min, more preferably 30 min, and the solvent is preferably DCM. After the nucleophilic substitution reaction, the mixture is purified by column chromatography.

[0051] This invention provides the application of the aforementioned compounds and their pharmaceutically acceptable deuterated derivatives, salts or hydrates, or compounds prepared by the preparation methods described above, in the preparation of peroxisome proliferator-activated receptor agonists and soluble epoxide hydrolase inhibitors.

[0052] In this invention, the peroxisome proliferator-activated receptor agonist and the soluble epoxide hydrolase inhibitor are used to treat soluble epoxides and diseases mediated by peroxisome proliferator-activated receptors; the soluble epoxides and diseases mediated by peroxisome proliferator-activated receptors 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.

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

[0054] This invention provides a sEH inhibitor and PPARs agonist compound. The sEH inhibitor and PPARs agonist compound provided by this invention has a typical urea structure as the primary pharmacophore of sEH and a thiazolidinedione moiety as the primary pharmacophore of PPARs. The sEH inhibitor and PPARs agonist compound provided by this invention exhibits high inhibitory activity against human HsEH and high agonistic activity against PPARs, and can be used as sEH inhibitors and PPARs agonists in the preparation of drugs for treating diseases mediated by soluble cyclooxygenase and peroxisome proliferator-activated receptors.

[0055] The present invention provides a compound containing an sEH inhibitor and a PPAR agonist, having the structure shown in Formula II. The sEH inhibitor portion of the present invention can stabilize endogenous epoxidized fatty acids with broad physiological activity, exhibiting a strong inhibitory effect on recombinant human sEH. It can exert its effects through multiple mechanisms, including regulating the production of various pro-inflammatory cytokines, reducing endoplasmic reticulum stress, preventing or reversing endothelial dysfunction, and stabilizing mitochondrial function. The PPAR agonist can synergistically inhibit the expression of cytokines—such as resistin, tumor necrosis factor α (TNFα), and interleukin-6—which promote insulin resistance. The PPAR agonist induces an increase in plasma adiponectin concentration. Adiponectin is a hormone secreted from adipose tissue and is present in low levels in the plasma of patients with type 2 diabetes. Adiponectin increases fatty acid oxidation in the liver and skeletal muscle. Therefore, the compounds involved in this invention can be used for soluble cyclooxide enzymes and peroxisome proliferator-activated receptor-mediated diseases 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.

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

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

[0058] Add trans-4-aminocyclohexanol hydrochloride (5.00 g, 32.98 mmol), sodium carbonate (10.49 g, 98.98 mmol), and water (25 mL) sequentially to a 100 mL three-necked flask. Cool to 0 °C in an ice bath, then add 5 mL of DCM solution containing Boc₂O (7.92 g, 36.28 mmol) dropwise over 3 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. After 4 hours, monitor with TLC (EA:PE = 1:3, phosphomolybdic acid colorimetric indicator) to confirm the reaction has occurred, and stop the reaction. Pour the reaction solution into 50 mL of water, extract with DCM (30 mL × 3), extract with EA (30 mL × 3), combine the organic layers, wash with water (30 mL), wash with saturated NaCl (30 mL), and dry to anhydrous magnesium sulfate. Filter under vacuum, wash with EA, and concentrate the filtrate to dryness under reduced pressure to obtain 8.0 g of crude white powder. The crude product was directly added to the next step without purification.

[0059] Example 2 Synthesis of 4-aminophenyl-4-nitrobenzene ester

[0060] To a 100 mL three-necked flask, add cis-4-Boc-aminocyclohexanol (7.10 g, 32.98 mmol), p-nitrobenzoic acid (5.51 g, 98.98 mmol), triphenylphosphine (12.98 g, 49.47 mol), and THF (20 mL). Cool to below -10 °C in an ice-salt bath, and then add DIAD (10 g, 49.47 mol) in THF solution (20 mL). After 2 hours, monitor the reaction by TLC. Once the reaction is complete, remove the solvent under reduced pressure to obtain 35.6 g of crude product. Purify the crude product by silica gel column chromatography. Mix 1.5 times the sample volume, pack 5 times the silica gel volume into a column, and use EA:PE = 1:10 as the eluent to obtain 5.53 g of white solid.

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

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

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

[0064] Add 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) sequentially to a 500 mL three-necked flask. Cool the flask to below -10 °C in an ice-salt bath. Add 5 mL of a THF solution containing DIAD (3.52 g, 17.42 mmol, 1.5 eq) dropwise at a rate of one drop every two seconds. After 72 hours, TLC monitoring showed that EA:PE = 1:1, indicating that the reaction was largely complete; therefore, the reaction was stopped. THF was removed by vacuum concentration, yielding 12.21 g of brownish-yellow oily substance. The crude product was purified by silica gel column chromatography with 1.5 times the sample volume mixed and packed into a 10-fold silica gel column. The eluent was EA:PE = 1:30, yielding 2.85 g of white solid, with a yield of 76.82%.

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

[0066] To a 100 mL round-bottom 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 sequentially, and the mixture was heated to reflux. A solid precipitated as the reaction proceeded. After 8 hours, TLC monitoring indicated the reaction was complete, and the reaction was stopped. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with a small amount of toluene to give 2.03 g of a white solid. ESI-MS (m / z): 424.1 [M+H] +

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

[0068] To a 500 mL three-necked flask, 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 the mixture was cooled to 0 °C in an ice bath before adding TFA (4 mL) dropwise. After 0.5 hours, TLC monitoring showed that the reaction was complete, and the reaction was stopped. TFA was removed from the reaction mixture by vacuum distillation. Water (30 mL) was added, and the mixture was extracted with DCM (30 mL × 3). The organic layers were combined and concentrated to dryness under reduced pressure. 1.17 g of crude brown solid was obtained. The crude product was used directly in the next step without purification.

[0069] Example 7 Synthesis of 1-[(1r,3R,5S,7R)-3,5-dimethyladamantane-1-yl]-3-((1r,4R)-4-{4-[(E)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)urea (SP-BO1)

[0070] Add memantine, dry dichloromethane, and 2 mL of BTC dichloromethane solution to a 50 mL single-necked flask. Cool to below -10 °C in an ice-salt bath and slowly add TEA DCM solution. Evaporate the solution to dryness, add 20 mL of DCM, then add 5-{(Z)-4-[(1r,4r)-4-aminocyclohexyl]oxybenzyl}thiazolidin-2,4-dione, and reflux. After 3 hours, monitor by TLC; the reaction is complete, and stop the reaction. Pour into 30 mL of water, filter to obtain a small amount of white solid with no fluorescence. Extract the filtrate three times with 30 mL of DCM, wash once with water, wash once with saturated saline, dry with anhydrous magnesium sulfate, and evaporate to dryness to obtain 1.2 g of white solid. Mix with 1.2 g of silica gel, pack 10 g of silica gel into a column, and eluent EA:PE = 1:7. Obtain 0.15 g of yellow solid. ESI-MS (m / z): 522.0 [MH] - .

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

[0072] 1-[(1r,3R,5S,7R)-3,5-dimethyladamantane-1-yl]-3-((1r,4R)-4-{4-[(E)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}cyclohexyl)urea, 10% Pd / C, was added to a 50 mL single-necked flask. The mixture was purged with hydrogen three times and Ar three times. The reaction was carried out at 30 °C for 3.5 hours until completion. The reaction was then stopped, filtered, and the filter cake was washed with a small amount of water and dried to give 0.15 g of a white solid. ESI-MS (m / z): 524.1 [MH] - . 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),7.13(d,J=8.4Hz,2H),6.90-6.83(m,2H),5.58(d,J=7.6Hz,1H),5.41(s,1 H),4.85(dd,J=9.1,4.3Hz,1H),4.25(tt,J=9.3,3.8Hz,1H),3.28(d,J=4.4Hz,1H),3.04(dd,J=14.2,9.1Hz,1H), 2.04(p,J=3.1Hz,1H),1.98(dd,J=12.9,4.1Hz,2H),1.87-1.78(m,2H),1.67(d,J=3.2Hz,2H),1.50(s,3H),1.36( ddd,J=12.8,9.8,3.2Hz,2H),1.32-1.24(m,2H),1.26-1.19(m,3H),1.19-1.12(m,1H),1.07(s,2H),0.80(s,6H).

[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 1.21 g (4.72 mmol, 1.5 eq) of 3-fluoro-4-trifluoromethoxyaniline, 0.95 g (18.70 mmol, 3 eq) of Et3N, and 10 mL of dry DCM to a 100 mL three-necked flask. Cool the flask to -15 °C in a cold trap, then add 15 mL of a DCM solution containing 0.48 g (1.60 mmol, 0.51 eq) dropwise over 3 minutes. After the addition is complete, allow the flask to warm to room temperature. TLC monitoring after 2 hours showed the reaction was complete, at which point the reaction was stopped.

[0075] Add 1.17 g (3.68 mmol, 1 eq) of 5-{(Z)-4-[(1r, 4r)-4-aminocyclohexyl]oxybenzyl}thiazolidin-2,4-dione, 0.95 g (18.7 mmol, 3 eq) of Et3N, 6 mL of DCM, and 20 mL of DCM solution of 3-fluoro-4-trifluoromethoxyaniline isocyanate to a 100 mL three-necked flask. React at room temperature. After 6 hours, TLC monitoring showed the reaction was complete, and the reaction was stopped. The DCM was removed by concentration under reduced pressure. Add 30 mL of 1N hydrochloric acid and stir for 5 minutes. Filter, and wash the filter cake with 20 mL of water to obtain 1.46 g of crude white solid. Purify the crude product by silica gel column chromatography. Mix 1.5 times the sample and pack 10 times the silica gel column with EA:PE = 1:7 as eluent to obtain 0.34 g of white solid. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 12.49 (s, 1H), 8.71 (s, 1H), 7.75 (s, 1H), 7.69 (d, J = 2.4Hz, 1H), 7.54 (d, J = 8.8Hz, 2H), 7.55-7.36 (m, 1H), 7.13-7.08(m,3H),6.31(d,J=7.6Hz,1H),4.50-4.44(m,1H),3.58-3.51(m,1H),2.08-2.05(m,2H),1.96-1.91(m,2H),1.54-1.34(m,4H). 13 C NMR (100MHz, DMSO-d6): δ (ppm) 168.4,167.9,159.7,155.4,154.6,152.9,141.8,1 32.6,125.7,124.7,120.6,116.7,114.0,106.2,106.0,74.9,47.7,30.3,30.1.ESI MS:m / z 540.0[M+H] + .

[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, add 1-((1r,4r)-4-{4-[(E)-(2,4-dioxathiazolidin-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), and stir at 30 °C. After 3 hours, TLC monitoring showed that the reaction was complete, and the reaction was terminated. Filter and concentrate under reduced pressure to give 40 mg of a white solid. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 12.01 (s, 1H), 8.73 (s, 1H), 7.68 (d, J = 2.4Hz, 1H), 7.65-7.40 (m, 1H), 7.38-7.09 (m, 3H), 6.88 (d, J = 8.6Hz, 2H), 6.3 0(d,J=7.6Hz,1H),4.88-4.84(m,1H),4.32-4.27(m,1H),3.56-3.49(m,1 H),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 (100MHz, 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 4-(4-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester

[0079] N-Boc-4-hydroxypiperidine (5.00 g, 0.25 mol), p-hydroxybenzaldehyde (15.18 g, 0.25 mol), triphenylphosphine (48.92 g, 0.37 mol), and THF (75 mL) were added sequentially to a 500 mL three-necked flask. The flask was cooled to below -10 °C in an ice-salt bath, and a THF solution (80 mL) of DIAD (37.74 mg, 0.37 mol) was added dropwise at a rate of one drop every two seconds. After 5 hours, the reaction was monitored by TLC and found to be complete. The reaction was then stopped. The THF was removed by concentration under reduced pressure, yielding 127.01 g of a brownish-yellow oily substance. The crude product was used directly for the next step without purification. 1H NMR (400MHz, CDCl3): δ (ppm) 9.88 (s, 1H), 7.82 (d, J = 2.0Hz, 2H), 7.01 (d, J = 2.0Hz, 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-oxy)benzaldehyde

[0081] 127.01 g of 4-(4-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester and 180 mL of DCM were added sequentially to a 500 mL three-necked flask. The mixture was cooled to 0 °C in an ice bath, and TFA (119.04 g, 1.04 mol) was added dropwise. After 37 hours, the reaction was monitored by TLC and found to be complete, at which point the reaction was stopped. The TFA in the reaction solution was removed by vacuum distillation. 50 mL of DCM was added, and the mixture was extracted with 1 N HCl (200 mL × 6). The aqueous layers were combined, and the pH was adjusted to 10 with NaOH solid. The mixture was then extracted with n-butanol (200 mL × 12). The organic layers were combined, concentrated to dryness under reduced pressure, and slurried with 12 mL of acetone. The mixture was filtered, and the filter cake was washed with 2 mL of acetone and dried to give 17.45 g of crude product, a brownish-red solid. The combined 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-oxy)benzylene]thiazolidin-2,4-dione

[0083] Add 4-(piperidin-4-oxy)benzaldehyde (4.00 g, 19.50 mmol), 2,4-thiazolidinedione (2.28 g, 19.50 mmol), pyridine (0.77 g, 9.75 mmol), glacial acetic acid (0.59 g, 9.75 mmol), and toluene (15 mL) sequentially to a 250 mL round-bottom flask, and heat to reflux. A solid precipitated as the reaction proceeded. After 8 hours, TLC monitoring showed the reaction was complete, and the reaction was stopped. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed 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-dimethyladamantane-1-yl[-4-{4-[(Z)-(2,4-dioxothiazolidin-5-ylidene)methyl]phenoxy}piperidine-1-carboxamide (SP-BO2)

[0085] Add memantine (16.51 g, 0.031 mol), Et3N (10.71 g, 0.11 mol), and dry DCM (50 mL) sequentially to a 250 mL three-necked flask. Cool the flask to -10 °C in an ice-salt bath. Add BTC (8.01 g, 0.027 mol) in DCM solution (50 mL) dropwise over 30 minutes. After the addition is complete, allow the flask to warm to room temperature naturally and continue the reaction for 4 hours. Stop the reaction and concentrate the solvent under reduced pressure to dryness.

[0086] Add (Z)-5-[4-(piperidin-4-oxy)benzylene]thiazolidin-2,4-dione (6.33 g, 0.021 mol), Et3N (6.33 g, 0.062 mol), and DCM (30 mL) sequentially to a 250 mL three-necked flask. Add the DCM solution (30 mL) of the above-mentioned memantine isocyanate dropwise over 30 minutes at room temperature, monitoring the addition 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 to anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 12.5 g of a yellow oily liquid. Purify the crude product by silica gel column chromatography, mixing 1.5 times the sample, packing a 5-fold silica gel column, and using EA:PE = 1:3 as the eluent to obtain 6.11 g of a pale yellow solid with a melting point of 83-83℃. 1 H NMR (400MHz, CDCl3): δ (ppm) 9.07 (s, 1H), 7.80 (s, 1H), 7.45 (d, J = 8.6Hz, 2H), 6.98 (d, J = 8.6Hz, 2H), 4.57 (s, 1H), 3.57 (d, J = 8.3Hz, 2H), 3.30-3.29 (m ,2H),2.16(d,J=10.0Hz,2H),1.98(d,J=4.2Hz,4H),1.83(s,5H),1.38(d, J=12.1Hz,2H),1.28(d,J=12.0Hz,2H),1.20-1.11(m,2H),0.85(s,6H).ESI MS:m / z 510.3[M+H] + .

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

[0088] N-[(1r,3R,5S,7r)-3,5-dimethyladamantane-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 added sequentially to a 50 mL single-necked flask, and the mixture was stirred at 30 °C. After 3 hours, the reaction was observed to be complete by TLC, and the reaction was terminated. The mixture was filtered and concentrated under reduced pressure to give 0.18 g of a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.38(s,1H),7.14(d,J=8.3Hz,2H),6.85(d,J=8.3Hz,2H),4.46(ddt,J=17.9,7.2, 3.7Hz,2H),4.26(s,1H),3.57(ddd,J=12.5,7.7,3.7Hz,2H),3.44(dd,J=14.2,4.0Hz,1H),3.24(ddd,J=13.0,7. 8,4.1Hz,2H),3.11(dd,J=14.2,9.4Hz,1H),2.14(p,J=3.3Hz,1H),1.92(ddd,J=11.9,8.0,3.7Hz,2H),1.85-1.7 1(m,3H),1.77(s,1H),1.38(d,J=12.4Hz,2H),1.27(dd,J=15.7,9.6Hz,4H),1.14(t,J=10.4Hz,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] Add p-trifluoromethoxyaniline (0.58 g, 3.28 mmol), Et3N (0.66 g, 6.56 mmol), and dry DCM (10 mL) sequentially to a 100 mL three-necked flask. Cool to -10 °C in an ice-salt bath, then add BTC (0.34 g, 1.12 mmol) in DCM solution (10 mL) dropwise over 3 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. After 2 hours, monitor the reaction by TLC. Once the reaction is complete, stop the reaction.

[0091] Add 5-{(Z)-4-[(1r,4r)-4-aminocyclohexyl]oxybenzyl}thiazolidin-2,4-dione (1.00 g, 3.28 mmol), Et3N (0.66 g, 6.56 mmol), DCM (6 mL), and a DCM solution of p-trifluoromethoxyaniline isocyanate (20 mL) sequentially to a 100 mL three-necked flask. React at room temperature for half an hour, then add 6 mL of DMSO. Heat the mixture to reflux. After 6 hours, monitor by TLC; the reaction is complete, and the reaction is stopped. Concentrate under reduced pressure to remove DCM, add 30 mL of 1N hydrochloric acid, stir for 5 minutes, filter, and wash the filter cake with 20 mL of water to obtain 1.46 g of crude white solid. Purify the crude product by silica gel column chromatography: mix 1.5 times the sample, pack 5 times the silica gel column, and use EA:PE = 1:5 as the eluent to obtain 0.46 g of white solid. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 12.48 (s, 1H), 8.75 (s, 1H), 7.73 (s, 1H), 7.56 (s, 4H), 7.23-7.15(m,4H),4.73(s,1H),3.82(s,2H),3.30(s,2H),2.00(s,2H),1.62(s,2H). 13 C NMR (100MHz, 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-dioxathiazolidin-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 sequentially, and the mixture was stirred at 30 °C. After 3 hours, the reaction was monitored by TLC and found to be complete, at which point the reaction was terminated. The mixture was filtered and concentrated under reduced pressure to give 0.18 g of a white solid. 1H NMR (400MHz, DMSO-d6): δ (ppm) 12.01 (s, 1H), 8.73 (s, 1H), 7.68 (d, J = 2.4Hz, 1H), 7.65-7.40 (m, 1H), 7.38-7.09 (m, 3H), 6.88 (d, J = 8.6Hz, 2H), 6.3 0(d,J=7.6Hz,1H),4.88-4.84(m,1H),4.32-4.27(m,1H),3.56-3.49(m,1 H),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 (100MHz, 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] Add 1.21 g (4.72 mmol, 1.5 eq) of 3-fluoro-4-trifluoromethoxyaniline, 0.95 g (18.70 mmol, 3 eq) of Et3N, and 10 mL of dry DCM to a 100 mL three-necked flask. Cool the flask to -15 °C and add 15 mL of a DCM solution containing 0.48 g (1.60 mmol, 0.51 eq) dropwise over 3 minutes. After the addition is complete, allow the flask to warm to room temperature. After 2 hours, monitor the reaction by TLC until it is complete, and then stop the reaction.

[0096] To a 100 mL three-necked flask, 5-{(Z)-4-[(1r,4r)-4-aminocyclohexyl]oxybenzyl}thiazolidin-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 solution of 3-fluoro-4-trifluoromethoxyaniline isocyanate (20 mL) were added sequentially. The reaction was carried out at room temperature, and after 6 hours, the reaction was monitored by TLC until it was complete, at which point the reaction was stopped. The DCM was removed by concentration under reduced pressure, and 30 mL of 1N hydrochloric acid was added and stirred for 5 minutes. The mixture was then filtered, and the filter cake was washed with 20 mL of water to obtain 1.46 g of crude white solid. The crude product was purified by silica gel column chromatography. The column was packed with 10x silica gel with 1.5x mixed sample and EA:PE = 1:7 as eluent, yielding 0.34 g of white solid, with a yield of 39.48%. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 12.49 (s, 1H), 8.71 (s, 1H), 7.75 (s, 1H), 7.69 (d, J = 2.4Hz, 1H), 7.54 (d, J = 8.8Hz, 2H), 7.55-7.36 (m, 1H), 7.13-7.08(m,3H),6.31(d,J=7.6Hz,1H),4.50-4.44(m,1H),3.58-3.51(m,1H),2.08-2.05(m,2H),1.96-1.91(m,2H),1.54-1.34(m,4H). 13 C NMR (100MHz, DMSO-d6): δ (ppm) 168.4,167.9,159.7,155.4,154.6,152.9,141.8,1 32.6,125.7,124.7,120.6,116.7,114.0,106.2,106.0,74.9,47.7,30.3,30.1.ESI MS:m / z 540.0[M+H] + .

[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, (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), and anhydrous methanol (10 mL) were added sequentially, and the mixture was stirred at 30 °C. After 3 hours, the reaction was observed to be complete by TLC, and the reaction was terminated. The mixture was filtered and concentrated under reduced pressure to give 1.04 g of a white solid. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 12.01 (s, 1H), 8.73 (s, 1H), 7.68 (d, J = 2.4Hz, 1H), 7.65-7.40 (m, 1H), 7.38-7.09 (m, 3H), 6.88 (d, J = 8.6Hz, 2H), 6.3 0(d,J=7.6Hz,1H),4.88-4.84(m,1H),4.32-4.27(m,1H),3.56-3.49(m,1 H),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 (100MHz, 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-oxy)benzyl]imidazoline-2,4-dione

[0100] Add 1.95 g (19.50 mmol) of 2,4-imidazolidinedione and 5 mL of water to a 100 mL round-bottom flask. Heat to 70 °C, adjust the pH to 7 with saturated sodium bicarbonate solution, add ethanolamine (2.38 g, 19.50 mmol), heat to 100 °C, and add dropwise 15 mL of EtOH solution of 4-(piperidin-4-oxy)benzaldehyde (4 g, 19.50 mmol). A solid precipitates as the reaction proceeds. After 16 hours, TLC monitoring indicates the reaction is complete, and the reaction is stopped. Cool the reaction solution to room temperature, filter, and wash the filter cake with a small amount of water to obtain 1.8 g of white solid. ESI MS: m / z 287.13 [M+H] + .

[0101] Example 18 Synthesis of N-[(1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl]-4-{4-[(Z)-(2,5-dioxyimidazoline-4-ylidene)methyl]phenoxy}piperidine-1-carboxamide (SP-BO3)

[0102] Add memantine (1.10 g, 3.46 mmol), Et3N (0.70 g, 6.92 mmol), and dry DCM (5 mL) to a 100 mL three-necked flask in sequence. Cool the flask to -10 °C in an ice-salt bath. Add BTC (0.51 g, 1.73 mmol) in DCM solution (4 mL) dropwise over 3 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. Continue the reaction for 4 hours. Stop the reaction and concentrate the solvent under reduced pressure to dryness.

[0103] Add (Z)-5-[4-(piperidin-4-oxy)benzylene]imidazoline-2,4-dione (0.89 g, 3.08 mmol), Et3N (0.70 g, 6.92 mmol), and DCM (10 mL) sequentially to a 100 mL three-necked flask. Add the DCM (10 mL) solution of the above-mentioned memantine isocyanate dropwise over 20 minutes at room temperature. Monitor the reaction by TLC until complete. Concentrate the reaction solution under reduced pressure to obtain 3.14 g of white solid. Purify the crude product by silica gel column chromatography. Mix 1.5 times the sample volume and pack 5 times the silica gel column. Elute with EA:PE = 1:3 to obtain 1.02 g of white solid. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 11.11 (s, 1H), 10.40 (s, 1H), 7.56 (d, J = 8.8Hz, 2 H),6.98(d,J=8.8Hz,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] Example 19 Synthesis of (Z)-4-[4-(2,5-dioxoimidazoline-4-ylidene)methyl]phenoxy)-N-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide (SP-BO4)

[0105] Add p-trifluoromethoxyaniline (0.41 g, 3.50 mmol), Et3N (0.70 g, 7.00 mmol), and dry DCM (10 mL) sequentially to a 100 mL three-necked flask. Cool to -10 °C in an ice-salt bath, then add BTC (0.33 g, 1.13 mmol) in DCM solution (10 mL) dropwise over 3 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. After 2 hours, monitor the reaction by TLC (EA:PE = 1:1, 2 drops of glacial acetic acid). The reaction is complete, and the reaction is stopped.

[0106] Add (Z)-5-[4-(piperidin-4-oxy)benzyl]imidazoline-2,4-dione (0.50 g, 1.75 mmol), Et3N (0.71 g, 7.00 mmol), DCM (5 mL), and a DCM solution of p-trifluoromethoxyaniline isocyanate (20 mL) sequentially to a 100 mL three-necked flask. React at room temperature for half an hour, then add 6 mL of DMSO. Heat the mixture to reflux. After 12 hours, monitor by TLC; the reaction is complete, and the reaction is stopped. Concentrate under reduced pressure to remove DCM, add 30 mL of 1N hydrochloric acid, stir for 5 minutes, filter, and wash the filter cake with 20 mL of water to obtain 0.65 g of crude white solid.

[0107] The crude product was purified by silica gel column chromatography. The sample was mixed with 1.5 times the volume of silica gel and packed into a 5-fold silica gel column. The eluent was EA:PE = 1:5, yielding 0.42 g of a white solid. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 11.25 (s, 1H), 10.42 (s, 1H), 7.59 (d, J = 8.8Hz, 2H), 7.41-7.39 (m, 2H), 7.37-7.13 (m, 1H), 7.13-7. 12(m,2H),7.03(d,J=8.8Hz,2H),6.39(s,1H),5.75(s,1H),3.81(d,J=49Hz,2H),3.44(d,J=49Hz,2H),2.01(s,2H),1.69(s,2H). 13 C NMR (100MHz, 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)phenylacetic acid ester

[0109] To a 500 mL three-necked flask, trans-4-Boc-aminocyclohexanol (9.27 g, 43.08 mmol, 1 eq), 4-hydroxyphenylacetic acid ester (6.55 g, 43.08 mmol, 1 eq), triphenylphosphine (16.94 g, 64.62 mmol, 1.5 eq), and THF (25 mL) were added sequentially. The flask was cooled to below -10 °C in an ice-salt bath. A THF solution of DIAD (13.07 g, 64.62 mmol, 1.5 eq) (12.5 mL) was then added dropwise at a rate of one drop every two seconds. After 72 hours, TLC monitoring showed the reaction was complete, and the reaction was stopped. The THF was removed by concentration under reduced pressure, yielding 35.57 g of a brownish-yellow oily substance. The crude product was purified by silica gel column chromatography. The column was packed with 10x silica gel using 1.5x stirred sample and EA:PE = 1:30 as eluent, yielding 2.33 g of a white solid.

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

[0111] Add 4-{(1r,4r)-4-[(tert-butyloxycarbonyl)amino]cyclohexyl}oxy)phenylacetate (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) sequentially to a 25 mL single-necked flask and stir at room temperature. After 50 min, monitor with TLC, stop the reaction, concentrate under reduced pressure to remove THF, extract with EA (30 mL), adjust pH to 4 with 1 N HCl, dry the organic layer with anhydrous magnesium sulfate (30 mL × 3), filter, concentrate under reduced pressure to dryness, and give 0.10 g of 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), K₂CO₃ (0.58 g, 4.20 mmol, 3 eq), and KI (0.023 g, 0.14 mmol, 0.1 eq) were added dropwise. Methyl bromoacetate (0.32 g, 2.10 mmol, 1.5 eq) was added dropwise, followed by Ar displacement three times. The mixture was heated to reflux. After 16 hours, the reaction was stopped by TLC monitoring. The mixture was concentrated to dryness under reduced pressure, and extracted with water (30 mL), followed by DCM extraction (30 mL × 3). The organic layers were combined, washed with water (30 mL), washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, 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 column was packed with 1.5 times the volume of sample and 3 times the volume of silica gel. The eluent was EA:PE = 1:5, yielding 0.40 g of a white solid, 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] 2-(4-{(1r,4r)-4-[(tert-butoxycarbonyl)amino]cyclohexyl)oxy}phenoxy)methyl acetate (0.30 g, 0.79 mmol), and DCM (10 mL) were added sequentially to a 25 mL single-necked flask. The mixture was cooled to 0 °C in an ice bath, and TFA (3 mL) was added dropwise. After 2 hours, the reaction was monitored by TLC and found to be complete. The reaction was then stopped. The TFA in the reaction solution was removed by vacuum distillation, yielding 0.21 g of crude brown oil.

[0116] Example 24 Synthesis of 2-[4-((1r,4r)-4-{3-[3-fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)methyl acetate (SP-CO3)

[0117] Add BTC (0.08 g, 0.27 mmol, 0.34 eq), Et3N (0.16 g, 1.58 mmol, 3 eq), and dry DCM (5 mL) sequentially to a 25 mL single-necked flask. Cool the flask to -80 °C in a cold trap. Add a 5 mL solution of 3-fluoro-4-trifluoromethoxyaniline (0.21 g, 0.79 mmol, 1 eq) in DCM dropwise over 3 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. Monitor the reaction by TLC after 10 minutes. Once the reaction is complete, stop the reaction.

[0118] A 10 mL solution of 3-fluoro-4-trifluoromethoxyaniline isocyanate in DCM and Et3N (0.16 g, 1.58 mmol, 3 eq) was added dropwise to a 25 mL three-necked flask. The mixture was kept on ice at 0 °C, and a 10 mL solution of 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)methyl acetate (0.22 g, 0.79 mmol, 1 eq) in DCM was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature. TLC monitoring showed the reaction was complete after 30 min, and the reaction was stopped. The DCM was removed by concentration under reduced pressure, yielding 0.44 g of crude white solid. The crude product was purified by silica gel column chromatography. The column was packed with 10x silica gel using 1.5x stirred sample and eluent of EA:PE = 1:5, yielding 0.10 g of white solid (25.6% yield). 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}cyclohexyl)oxy]phenoxy)acetic acid (SP-CO2)

[0120] To a 25 mL single-necked flask, methyl 2-[4-((1r,4r)-4-{3-[3-fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]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) were added sequentially, and the mixture was stirred at room temperature. After 50 min, the reaction was stopped by TLC monitoring. The mixture was concentrated under reduced pressure to remove THF, and EA (30 mL) was added. The mixture was extracted with water (20 mL × 2). The aqueous layer was adjusted to pH 2 with 1 N HCl and filtered to obtain 20.02 mg of a white solid. The yield was 29.06%. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 13.04 (s, 1H), 9.02 (s, 1H), 7.68 (dd, J = 13.4Hz, 2.2Hz, 1H), 7.38 (t, J = 8.8Hz, 1H), 7.11 (d, J = 8.8Hz, 1H), 6.86 (d, J = 8.0 Hz,2H),6.80(d,J=8.0Hz,2H),6.55(d,J=7.6Hz,1H),4.49(s,2H),3.51-3. 49(m,2H),1.99(d,J=9.6Hz,2H),1.89(d,J=9.6Hz,2H),1.46-1.23(m,4H). 13C NMR(101MHz,DMSO-d6)δ171.46,155.36,154.74,152.91,152.60,151.84,142.12,142.02,128.75,128.62,124.65 ,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[MH] - .

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

[0122] To a 25 mL single-necked flask, methyl 2-(4-{(1r,4r)-4-[(tert-butyloxycarbonyl)amino]cyclohexyl)oxy}phenoxy)acetate (4.00 g, 13.02 mmol, 1 eq), MeCN (20 mL), K₂CO₃ (5.40 g, 39.06 mmol, 3 eq), and KI (0.22 g, 1.30 mmol, 0.1 eq) were added dropwise. Ethyl chloroacetate (2.39 g, 19.53 mmol, 1.5 eq) was added dropwise, followed by Ar displacement three times, and the mixture was heated to reflux. After 16 hours, the reaction was stopped by TLC monitoring, concentrated to dryness under reduced pressure, and extracted with water (30 mL), DCM (30 mL × 3). The organic layers were combined, washed with water (30 mL), washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, 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 column was packed with 1.5 times the volume of sample and 3 times the volume of silica gel. The eluent was EA:PE = 1:5, yielding 4.06 g of a white solid.

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

[0124] To a 100 mL single-necked flask, ethyl acetate (4.06 g, 10.33 mmol) and DCM (20 mL) were added sequentially. The mixture was cooled to 0 °C in an ice bath, and TFA (6 mL) was added dropwise. After 6 hours, TLC monitoring showed that the reaction was complete, and the reaction was stopped. The DCM and TFA in the reaction solution were removed by vacuum distillation, yielding 4.40 g of crude brown oil. The crude product was used directly in the next step without purification.

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

[0126] Add BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) sequentially to a 25 mL single-necked flask. Cool the flask to -80 °C. Then, add a 15 mL solution of 3-fluoro-4-trifluoromethoxyaniline (0.21 g, 0.79 mmol, 1 eq) and Et3N (0.24 g, 2.37 mmol, 3 eq) in DCM dropwise over 30 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. Monitor the reaction by TLC after 10 minutes. Once the reaction is complete, stop the reaction.

[0127] A 25 mL solution of DCM in 3-fluoro-4-trifluoromethoxyaniline isocyanate and Et3N (0.24 g, 2.37 mmol, 3 eq) were added to a 100 mL three-necked flask. The mixture was kept on ice at 0 °C, and a 10 mL solution of DCM in ethyl acetate (0.23 g, 0.79 mmol, 1 eq) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature. TLC monitoring showed the reaction was complete after 30 min, and the reaction was stopped. The DCM was removed by concentration under reduced pressure, yielding 0.62 g of crude white solid. The crude product was purified by silica gel column chromatography. The column was packed with 12x silica gel using 1.5x stirred sample and eluent of EA:PE = 1:10, yielding 0.27 g of white solid (69.23% yield). 1 H NMR(400MHz, DMSO-d6)δ8.73(s,1H),7.68(dd,J=13.4,2.5Hz,1H),7.44-7.34(m,1H),7.09(ddd,J=9.0,2.6,1.3Hz,1H),6.92-6.79(m,4H),6.31(d, J=7.6Hz,1H),4.69(s,2H),4.16(q,J=7.1Hz,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=7.1Hz,3H). 13C NMR(101MHz,DMSO-d6)δ169.44,154.63,152.93,152.18,141.95,141.84,128.85,124.73,121.9 7,117.48,115.98,114.01,106.15,105.92,75.29,65.72,61.00,47.78,30.38,30.27,14.52.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] A 10 mL solution of DCM in 3-fluoro-4-trifluoromethoxyaniline isocyanate and Et3N (0.24 g, 2.37 mmol, 3 eq) were added to a 25 mL three-necked flask. The mixture was kept on ice at 0 °C, and a 10 mL solution of DCM in 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)-2-methylpropionate (0.24 g, 0.79 mmol, 1 eq) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature. TLC monitoring showed the reaction was complete after 30 min, and the reaction was stopped. The DCM was removed by concentration under reduced pressure, yielding 0.47 g of crude white solid. The crude product was purified by silica gel column chromatography. The column was packed with 10x silica gel using 1.5x stirred sample and eluent of EA:PE = 1:5, yielding 0.32 g of white solid (76.19% yield). 1 HNMR(400MHz,DMSO-d6)δ8.73(s,1H),7.68(dd,J=13.5,2.5Hz,1H),7.39(t,J =8.9Hz,1H),7.09(dt,J=9.3,1.9Hz,1H),6.89-6.81(m,2H),6.79-6.71(m,2H ),6.30(d,J=7.6Hz,1H),4.21(dt,J=9.9,5.6Hz,1H),3.70(s,3H),3.50(s,1H ),3.43-3.36(m,2H),2.01(d,J=15.5Hz,2H),1.95-1.87(m,2H),1.45(s,10H). 13C NMR(101MHz,DMSO-d6)δ174.26,154.63,153.28,148.83,141.94,141.84,128.85,124.72,121.97,121.7 6,119.42,116.85,114.01,106.16,105.92,79.60,75.05,52.69,47.79,30.42,30.31,25.37,15.62.ESI MS:m / z551.2[M+Na] + .

[0130] Example 30 Synthesis of 2-[4-((1r,4r)-4-{3-[3-fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)-2-methylpropionic acid (SP-C05)

[0131] Methyl 2-[4-((1r,4r)-4-{3-[3-fluoro-4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)-2-methylpropionate (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 added sequentially to a 25 mL single-necked flask and stirred at room temperature. After 3 h, the reaction was stopped by TLC monitoring. The THF was removed by concentration under reduced pressure, and DCM (30 mL) was added. The mixture was extracted with water (10 mL × 2). The aqueous layer was adjusted to pH 2 with 1 N HCl and filtered to give 0.15 g of white solid. The yield was 76.92%. 1 H NMR (400MHz, DMSO-d6) δ12.93(s,1H),8.78(s,1H),7.68(dd,J=13.5,2.5Hz,1H ),7.44-7.35(m,1H),7.09(ddd,J=9.1,2.6,1.3Hz,1H),6.90-6.82(m,2H),6.82 -6.75(m,2H),6.34(d,J=7.6Hz,1H),4.21(dq,J=9.6,5.6,4.7Hz,1H),3.57-3. 46(m,1H),2.05-1.97(m,2H),1.91(dd,J=12.8,4.2Hz,2H),1.50-1.26(m,10H). 13C NMR(101MHz,DMSO-d6)δ175.60,155.37,154.64,152.93,149.26,141.96,141.86,124.71,121.9 7,121.32,116.88,114.00,106.14,105.90,79.27,75.08,47.77,30.40,30.29,25.46.ESIMS:m / z 512.8[MH] - .

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

[0133] Add BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) sequentially to a 25 mL single-necked flask. Cool the flask to -80 °C. Then, add a 20 mL solution of p-trifluoromethoxyaniline (0.14 g, 0.79 mmol, 1 eq) and Et3N (0.24 g, 2.37 mmol, 3 eq) in DCM dropwise over 30 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. Monitor the reaction by TLC after 10 minutes. Once the reaction is complete, stop the reaction.

[0134] A 10 mL solution of DCM in p-trifluoromethoxyaniline isocyanate and Et3N (0.24 g, 2.37 mmol, 3 eq) were added to a 25 mL three-necked flask. The mixture was kept on ice at 0 °C, and a 10 mL solution of DCM in 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)methyl acetate (0.22 g, 0.79 mmol, 1 eq) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature. TLC monitoring was performed after 30 min, and the reaction was stopped when complete. The DCM was removed by concentration under reduced pressure, yielding 0.50 g of crude white solid. The crude product was purified by silica gel column chromatography. The column was packed with 10x silica gel using 1.5x stirred sample and eluent of EA:PE = 1:10, yielding 0.31 g of white solid.

[0135] 1H NMR (400MHz, DMSO-d6) δ8.51(s,1H),7.51-7.43(m,2H),7.21(d,J=8.2Hz,2H),6.91-6.80(m,4H),6.18(d,J=7.6Hz,1H),4.71(s,2H ),4.19(dt,J=9.8,5.7Hz,1H),3.69(s,3H),3.57-3.46(m,1H),2.00(dd,J=11.5,4.1Hz,2H),1.96-1.87(m,2H),1.49-1.26(m,4H). 13 C NMR(101MHz,DMSO-d6)δ169.93,154.87,152.21,152.17,142.43,140.29,12 2.09,119.01,117.50,115.95,75.34,65.62,52.19,47.71,30.48,30.29.ESI MS:m / z 505.0[M+Na] + .

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

[0137] To a 25 mL single-necked flask, methyl 2-[4-((1r,4r)-4-{3-[4-(trifluoromethoxy)phenyl]ureido}cyclohexyl)oxy]phenoxy)acetate (0.20 g, 0.41 mmol, 1 eq), THF (5 mL), H₂O (0.5 mL), and LiOH (30 mg, 1.20 mmol, 3 eq) were added sequentially and stirred at room temperature. After 3 h, the reaction was stopped by TLC monitoring. The mixture was concentrated under reduced pressure to remove THF, and extracted with DCM (30 mL) and water (10 mL × 2). The aqueous layer was adjusted to pH 2 with 1 N HCl and filtered to obtain 0.15 g of a white solid. The yield was 78.94%. 1 H NMR (400MHz, DMSO-d6) δ8.76(s,1H),7.51-7.44(m,2H),7.21(d,J=8.6Hz,2H),6.91-6.76(m,4H),6.40(d,J=7.6Hz,1H),4.52(s,2H) ,4.17(tt,J=9.7,4.0Hz,1H),3.55-3.45(m,1H),2.04-1.95(m,2H),1.94-1.86(m,2H),1.36(dddd,J=40.3,20.2,16.5,10.0Hz,5H). 13C NMR(101MHz,DMSO-d6)δ171.14,154.96,152.56,151.89,142.35,140.44,122.04,118.97,117.49,115.79,75.39,66.00,47.67,30.45,30.29.ESI MS:m / z 466.8[MH] - .

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

[0139] Add BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) sequentially to a 25 mL single-necked flask. Cool the flask to -80 °C. Then, add a 15 mL solution of p-trifluoromethoxyaniline (0.14 g, 0.79 mmol, 1 eq) and Et3N (0.24 g, 2.37 mmol, 3 eq) in DCM dropwise over 30 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. After 10 minutes, monitor the reaction by TLC (EA:PE = 1:3), indicating that the reaction is complete. Stop the reaction.

[0140] A 10 mL solution of DCM in p-trifluoromethoxyaniline isocyanate and Et3N (0.24 g, 2.37 mmol, 3 eq) were added to a 25 mL three-necked flask. The flask was kept on ice at 0 °C, and a 10 mL solution of DCM in ethyl acetate 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetate (0.23 g, 0.79 mmol, 1 eq) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature. TLC monitoring was performed after 30 min, and the reaction was stopped when complete. The DCM was removed by concentration under reduced pressure, yielding 0.93 g of crude white solid. The crude product was purified by silica gel column chromatography. The column was packed with 12x silica gel using 1.5x stirred sample and eluent of EA:PE = 1:10, yielding 0.24 g of white solid.

[0141] 1 H NMR (400MHz, DMSO-d6) δ8.52(s,1H),7.50-7.43(m,2H),7.22(d,J=8.6Hz,2H),6.92-6.80(m,4H),6.18(d,J=7.6Hz,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=13.7Hz,2H),1.48-1.24(m,5H),1.21(t,J=7.1Hz,4H). 13C NMR(101MHz,DMSO-d6)δ169.43,154.87,152.20,142.43,140.28,122.08,11 9.02,117.49,115.98,75.34,65.74,61.00,47.70,30.48,30.29,14.51.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] A 10 mL solution of DCM in p-trifluoromethoxyaniline isocyanate and Et3N (0.24 g, 2.37 mmol, 3 eq) were added to a 25 mL three-necked flask. The mixture was kept on ice at 0 °C, and a 10 mL solution of DCM in 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 was complete, the reaction was allowed to proceed at room temperature. TLC monitoring showed the reaction was complete after 30 min, and the reaction was stopped. The DCM was removed by concentration under reduced pressure, yielding 0.47 g of crude white solid. The crude product was purified by silica gel column chromatography. The column was packed with 10x silica gel using 1.5x stirred sample and eluent of EA:PE = 1:5, yielding 0.33 g of white solid (76.19% yield). 1 H NMR (400MHz, DMSO-d6) δ8.51 (s, 1H), 7.50-7.42 (m, 2H), 7.21 (d, J = 8.5Hz, 2H),6.88-6.81(m,2H),6.79-6.72(m,2H),6.18(d,J=7.6Hz,1H),4.21(tt ,J=9.7,3.7Hz,1H),3.70(s,3H),3.51(dtd,J=10.9,7.3,4.2Hz,1H),2.01 (dd,J=12.6,4.6Hz,2H),1.92(dd,J=13.0,4.3Hz,2H),1.51-1.25(m,11H). 13 C NMR(101MHz,DMSO-d6)δ174.25,154.88,153.32,148.84,142.45,140.29,122.0 7,121.78,119.03,116.88,79.62,75.12,52.68,47.72,30.52,30.33,25.38.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}cyclohexyl)oxy]phenoxy)-2-methylpropionic acid (SP-C11)

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

[0146] 1 H NMR (400MHz, DMSO-d6) δ8.54(s,1H),7.51-7.43(m,2H),7.22(d,J=8.6Hz,2H),6.90-6.72(m,4H),6.20(d,J=7.6Hz,1H ),4.21(td,J=9.6,4.8Hz,1H),3.57-3.45(m,1H),2.08-1.97(m,2H),1.91(dd,J=12.0,4.6Hz,2H),1.50-1.23(m,11H). 13 C NMR(101MHz,DMSO-d6)δ175.60,154.88,152.94,149.26,142.42,140.30,12 2.08,121.31,119.01,116.88,79.27,75.13,47.70,30.51,30.32,25.46.ESI MS:m / z 494.9[MH] - .

[0147] Example 36 Synthesis of methyl acetate 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantane-1-yl]ureido}cyclohexyl)oxy]phenoxy}acetate (SP-C15)

[0148] Add BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) sequentially to a 25 mL single-necked flask. Cool the flask to -80 °C. Then, add a 20 mL solution of a mixture of ammonium phosphate (0.14 g, 0.79 mmol, 1 eq) and Et3N (0.24 g, 2.37 mmol, 3 eq) in DCM dropwise over 30 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. Monitor the reaction by TLC after 10 minutes. Once the reaction is complete, stop the reaction.

[0149] Add 10 mL of DCM solution of p-methammonium isocyanate and Et3N (0.24 g, 2.37 mmol, 3 eq) to a 25 mL three-necked flask. Heat to 0 °C on ice and add 10 mL of DCM solution of methyl 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetate (0.22 g, 0.79 mmol, 1 eq). After addition, allow the reaction to proceed at room temperature. After 30 min, monitor the reaction by TLC. Once the reaction is complete, stop the reaction. Concentrate under reduced pressure to remove DCM, yielding 0.50 g of crude white solid. Purify the crude product by silica gel column chromatography. Mix 1.5 times the sample and pack a 10x silica gel column with EA:PE = 1:10 as eluent to obtain 0.33 g of white solid.

[0150] 1 H NMR (400MHz, DMSO-d6) δ6.89-6.79 (m, 4H), 5.58 (d, J = 7.6Hz, 1H), 5.41 (s, 1H), 4.70(s,2H),4.15(tt,J=10.0,4.0Hz,1H),3.69(s,3H),3.35(dt,J=7.3,3.6Hz ,1H),2.04(p,J=3.2Hz,1H),1.96(dt,J=13.4,3.9Hz,2H),1.86-1.77(m,2H),1 .67(d,J=3.1Hz,2H),1.49(s,4H),1.40-1.11(m,9H),1.07(s,2H),0.79(s,6H). 13 C NMR(101MHz,DMSO-d6)δ169.92,157.00,152.25,152.17,117.56,115.96,75.50,65.66, 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-dimethyladamantane-1-yl]ureido}cyclohexyl)oxy]phenoxy}acetic acid (SP-C14)

[0152] To a 25 mL single-necked flask, methyl 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantane-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 added sequentially and stirred at room temperature. After 3 h, the reaction was stopped by TLC monitoring. The THF was removed by concentration under reduced pressure, and DCM (30 mL) was added. The mixture was extracted with water (10 mL × 2). The aqueous layer was adjusted to pH 2 with 1 N HCl and filtered to obtain 0.15 g of white solid.

[0153] 1 H NMR (400MHz, DMSO-d6) δ6.85-6.78(m,2H),6.78-6.70(m,2H),5.77(d,J=7.6Hz,1H),5.5 9(s,1H),4.24(s,2H),4.11(tt,J=9.5,4.0Hz,1H),3.33(ddd,J=11.1,7.1,3.7Hz,1H),2 .04(p,J=3.2Hz,1H),2.00-1.90(m,2H),1.81(dq,J=11.8,3.8Hz,2H),1.67(d,J=3.1Hz, 2H),1.55-1.43(m,4H),1.42-1.25(m,4H),1.25-1.09(m,5H),1.07(s,2H),0.79(s,6H). 13 C NMR(101MHz,DMSO-d6)δ171.28,157.12,153.18,151.45,117.53,115.68,75.61,67 .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-dimethyladamantane-1-yl]ureido}cyclohexyl)oxy]phenoxy}ethyl acetate (SP-C16)

[0155] Add BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) sequentially to a 25 mL single-necked flask. Cool the flask to -80 °C. Then, add a DCM solution of ammonium phosphate (0.14 g, 0.79 mmol, 1 eq) and Et3N (0.24 g, 2.37 mmol, 3 eq) dropwise over 30 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. Monitor the reaction by TLC after 10 minutes. Once the reaction is complete, stop the reaction.

[0156] Add 10 mL of DCM solution of memantine isocyanate and Et3N (0.24 g, 2.37 mmol, 3 eq) to a 25 mL three-necked flask. Heat to 0 °C on ice and add 10 mL of DCM solution of ethyl acetate 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)acetate (0.23 g, 0.79 mmol, 1 eq). After addition, react at room temperature. After 30 min, monitor the reaction by TLC. Once the reaction is complete, stop the reaction. Concentrate under reduced pressure to remove DCM, yielding 0.93 g of crude white solid. Purify the crude product by silica gel column chromatography. Mix 1.5 times the sample and pack a 15 times silica gel column (to remove memantine that does not fluoresce and is converted to urea by itself). The eluent is EA:PE = 1:10, yielding 0.20 g of white solid.

[0157] 1 H NMR(400MHz, DMSO-d6)δ6.89-6.79(m,4H),5.58(d,J=7.6Hz,1H),5.41(s,1H),4.68(s,2H),4.16(q,J=7.1Hz,3H),3.35(dd,J=7.1,3.6Hz,1H), 2.04(p,J=3.2Hz,1H),2.01-1.90(m,2H),1.86-1.76(m,2H),1.67(d,J= 3.2Hz,2H),1.49(s,4H),1.40-1.11(m,11H),1.07(s,2H),0.79(s,6H). 13 C NMR(101MHz,DMSO-d6)δ169.43,156.99,152.21,152.17,117.51,115.97,75.46,65.73,61 .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] Example 39 Synthesis of methyl 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantane-1-yl]ureido}cyclohexyl)oxy]phenoxy}-2-methylpropionate (SP-C18)

[0159] Add BTC (0.08 g, 0.27 mmol, 0.34 eq) and dry DCM (5 mL) sequentially to a 25 mL single-necked flask. Cool the flask to -80 °C. Then, add a DCM solution of ammonium phosphate (0.14 g, 0.79 mmol, 1 eq) and Et3N (0.24 g, 2.37 mmol, 3 eq) dropwise over 30 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. Monitor the reaction by TLC after 10 minutes. Once the reaction is complete, stop the reaction.

[0160] Add 10 mL of DCM solution of memantine isocyanate and Et3N (0.24 g, 2.37 mmol, 3 eq) to a 25 mL three-necked flask. Heat to 0 °C on ice and add 10 mL of DCM solution of methyl 2-{4-[(1r,4r)-4-aminocyclohexyl]oxy}phenoxy)-2-methylpropionate (0.24 g, 0.79 mmol, 1 eq). After addition, react at room temperature. After 30 min, monitor the reaction by TLC. Once the reaction is complete, stop the reaction. Concentrate under reduced pressure to remove DCM, yielding 0.93 g of crude white solid. Purify the crude product by silica gel column chromatography. Mix 1.5 times the sample and pack a 15 times silica gel column with EA:PE = 1:10 as eluent to obtain 0.32 g of white solid.

[0161] 1 H NMR (400MHz, DMSO-d6) δ6.87-6.78(m,2H),6.78-6.69(m,2H),5.58(d,J=7.6Hz,1H),5.41(s,1H),4.22-4.11(m,1H),3.69(s,3H), 2.04(p,J=3.1Hz,1H),2.01-1.92(m,2H),1.86-1.77(m,2H),1.67(d,J=3.2Hz,2H),1.50-1.13(m,18H),1.07(s,2H),0.79(s,6H). 13 C NMR(101MHz,DMSO-d6)δ174.25,156.99,153.32,148.80,121.77,116.88,79.61,75.21,52 .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] Example 39 Synthesis of 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantane-1-yl]ureido}cyclohexyl)oxy]phenoxy}-2-methylpropionic acid (SP-C17)

[0163] Methyl 2-[4-((1R,4r)-4-{3-[(1R,3R,5S,7R)-3,5-dimethyladamantane-1-yl]ureido}cyclohexyl)oxy]phenoxy}-2-methylpropionate (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 added sequentially to a 25 mL single-necked flask and stirred at room temperature. After 3 h, the reaction was stopped by TLC monitoring. The THF was removed by concentration under reduced pressure, and DCM (30 mL) was added. The mixture was extracted with water (10 mL × 2). The aqueous layer was adjusted to pH 2 with 1 N HCl and filtered to obtain 0.10 g of white solid.

[0164] 1 H NMR (400MHz, DMSO-d6) δ6.79(s,4H),5.73(d,J=7.7Hz,1H),5.54(s,1H),4.14(td,J=9.6,4.8Hz,1H),3.33(ddd,J=10.8,7.0,3.6Hz,1H),2.04( p,J=3.2Hz,1H),2.01-1.91(m,2H),1.85-1.76(m,2H),1.67(d,J=3.2Hz ,2H),1.55-1.43(m,4H),1.43-1.10(m,14H),1.07(s,2H),0.79(s,6H). 13 C NMR(101MHz,DMSO-d6)δ175.96,157.08,152.49,149.72,121.01,116.83,79.75,75.30 ,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] Example 40 Synthesis of 4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl acetate

[0166] Add 1.69 g (4.84 mmol) of 4-(((1r, 4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)phenyl acetate and 12 mL of DCM to a 100 mL single-necked flask, and then add 6 mL of TFA dropwise at room temperature. After 3 hours, TLC monitoring showed that EA:PE = 1:1, indicating complete reaction, and the reaction was stopped. Remove TFA from the reaction solution by vacuum distillation. 2.06 g of crude brown oil was obtained. The crude product was dried in a 60 °C oven for 12 h and used directly in the next step without purification.

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

[0168] Add BTC (0.51 g, 1.17 mmol, 0.34 eq) and dry DCM (10 mL) sequentially to a 100 mL single-necked flask. Cool the flask to -78 °C in a cold trap, then add 3-fluoro-4-trifluoromethoxyaniline (1 g, 5.13 mmol, 1 eq), Et3N (1.65 g, 15.39 mmol, 3 eq), and a DCM solution (10 mL) dropwise over 30 minutes. After the addition is complete, bring the flask to room temperature and continue stirring for 4 hours. After 4 hours, monitor the reaction by TLC. Take one drop of the reaction solution into an EP tube, add memantine (EA:PE = 1:3), fumigate with iodine, and allow the reaction to complete.

[0169] A mixed solution of 4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl acetate·TFA (1.86 g, 5.13 mmol, 1 eq), Et3N (1.65 g, 15.39 mmol, 3 eq), and DCM (5 mL) was added to a 100 mL single-necked flask. The above reaction solution was added dropwise, and the reaction was carried out at room temperature. After 2 hours, the reaction was monitored by TLC (EA:PE = 1:3, AcOH 2d), indicating that the reaction was complete. The reaction was stopped. The sample was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 0.23 g of crude yellow oil. The sample was packed into a 5x silica gel column, mixed with 1.2x silica gel, and eluent (EA:PE = 1:10) to give 0.42 g of white solid, with a yield of 17.3%. 1H NMR (400MHz, DMSO-d6): δ (ppm) 8.727.69 (d, J = 2.5Hz, 1H), 7.65-7.38 (m, 1H), 7.36-7.35 (m, 1H), 7.11-6.94 (m, 4H), 6.30 (d, J=8.0Hz,1H),4.29(d,J=4.0Hz,1H),3.51(s,1H),2.23(s,3H),2.05(d,J=3.0Hz,2H),2.02-1.91(m,2H),1.48-1.34(m,4H). 13 C NMR (100MHz, 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)ureo)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 sequentially, and the reaction was carried out at room temperature. After 1.5 hours, TLC monitoring showed that the reaction was complete, and the reaction was stopped. The mixture was extracted with DCM (30 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. 0.21 g of crude brown solid was given. Yield: 96.33%.

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

[0173] Add cis-4-BOC-aminocyclohexanol (1.00 g, 4.64 mmol), methylparaben (0.7 g, 4.64 mmol), triphenylphosphine (1.8 g, 6.96 mmol), A4 molecular sieve (dried in an oven at 120 °C for 4 h), and THF (10 mL) sequentially to a 100 mL single-necked flask. Purge the solution three times with argon gas, then cool to below -10 °C in an ice-salt bath. Add 5 mL of a THF solution containing DIAD (1.4 g, 6.96 mmol) dropwise at a rate of one drop every two seconds. After 12 hours, TLC monitoring showed an EA:PE ratio of 1:1. Move the reaction vessel to 30 °C and add more 4A molecular sieve. After 6 hours, TLC monitoring showed an EA:PE ratio of 1:1, indicating the reaction was largely complete. Stop the reaction. THF was removed by vacuum concentration, yielding 5.2 g of brownish-yellow oily substance. No solid precipitate was observed after pulping. The sample was packed into a column with 4x silica gel, mixed with 1.2x silica gel, and eluent (EA:PE = 1:10), yielding 0.73 g of white solid product, with a yield of 45.1%.

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

[0175] Methyl benzoate (0.60 g, 2.09 mmol) and DCM (5 mL) were added sequentially to a 100 mL single-necked flask, followed by dropwise addition of TFA (4 mL) at room temperature. After 3 hours, TLC monitoring showed that EA:PE = 1:1, indicating complete reaction, and the reaction was stopped. TFA was removed from the reaction solution by vacuum distillation. 0.62 g of crude brown oil was obtained. The crude product was dried in a 60 °C oven for 12 h and used directly in the next step without purification.

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

[0177] Add BTC (0.23 g, 0.79 mmol) and dry DCM (15 mL) sequentially to a 100 mL single-necked flask. Cool the flask to -78 °C and add free 3-fluoro-4-trifluoromethoxyaniline (0.41 g, 2.32 mmol), Et3N (1.41 g, 13.92 mmol), and a DCM solution (10 mL) dropwise over 30 minutes. After the addition is complete, bring the flask to room temperature and continue stirring for 4 h. After 4 h, monitor the reaction by TLC. Take one drop of the reaction solution into an EP tube and add methyl 4-(((1r,4r)-4-aminocyclohexyl)oxy)benzoate, EA:PE = 1:3.

[0178] 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) was added to a 100 mL single-necked flask. The reaction was carried out at room temperature, and after 2 hours, the reaction was stopped by TLC monitoring (EA:PE = 1:3). The mixture was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 0.93 g of crude yellow oil. The solution was packed into a 7x silica gel column, mixed with 1.2x silica gel, and eluent (EA:PE = 1:5) to give 0.40 g of the product as a white solid, yield 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)ureo)cyclohexyl)oxy)benzoic acid (SP-C01c)

[0180] Methyl 4-(((1r, 4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)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) were added sequentially to a 100 mL single-necked flask and stirred at room temperature. After 3 h, TLC monitoring showed that (EA:PE = 1:1), the reaction was stopped, and the mixture was concentrated under reduced pressure to remove THF. DCM (50 mL) was added, and the mixture was extracted with water (15 mL × 2). The aqueous layer was adjusted to pH 2 with 1 N HCl, concentrated under reduced pressure until a small amount of solvent remained, filtered, and washed with 5 mL of water to give 0.53 g of a pale yellow solid. The combined yield of the three steps was 21.13%.

[0181] 1 H NMR (600MHz, DMSO-d6) δ10.19(s,1H),8.88(s,1H),8.35(s,3H),7.86(d,J=8.6Hz,2H),7.78(d,J=8.5Hz,1H),7.04(d,J=8.6Hz,5H),6.85(d,J=8. 3Hz,4H),4.39(tt,J=10.0,4.3Hz,1H),3.04(dt,J=10.8,5.5Hz,1H),2.1 5-2.09(m,2H),2.06-2.01(m,2H),1.61-1.50(m,2H),1.50-1.38(m,2H).

[0182] Example 47 Synthesis of 4-(((1R,4r)-4-(3-(((1R,3R,5S,7R)-3,5-dimethyladamantane-1-yl)ureo)cyclohexyl)oxy)phenyl acetate (SP-C01d)

[0183] Add BTC (0.02 g, 0.07 mmol, 0.34 eq) and dry DCM (5 mL) sequentially to a 100 mL single-necked flask. Cool the flask to -78 °C in a cold trap, then add memantine (0.04 g, 0.22 mmol, 1 eq), Et3N (0.07 g, 0.66 mmol, 3 eq), and 10 mL of DCM solution dropwise over 30 minutes. After the addition is complete, bring the flask to room temperature and continue stirring for 4 hours. Monitor the reaction by TLC after 4 hours. (Take one drop of the reaction solution into an EP tube, add 4-trifluoromethoxyaniline, EA:PE = 1:3), fumigate with iodine, and the reaction is complete.

[0184] A mixture of 4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl acetate·TFA (0.08 g, 0.22 mmol, 1 eq), Et3N (0.07 g, 0.66 mmol, 3 eq), and DCM (5 mL) was added dropwise to a 25 mL single-necked flask. The reaction mixture was then added dropwise, and the mixture was reacted at room temperature. After 2 hours, the reaction was monitored by TLC. Once the reaction was complete, the reaction was stopped. The mixture was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 0.10 g of crude yellow oil. The solution was packed into a 5x silica gel column, mixed with 1.2x silica gel, and eluent (EA:PE = 1:10) to give 32 mg of white solid, with a yield of 32.0%. 1 H NMR (400MHz, DMSO-d6): δ (ppm) 7.04-6.97 (d, 2H), 6.97-6.89 (d, 2H), 5.58 (d, J = 7.9Hz, 1H), 5.41 ( d,J=3.2Hz,1H),4.25(tt,J=9.9,3.9Hz,1H),3.35(dd,J=7.3,3.7Hz,1H),2.23(s,3H),2.02(ddt,J =24.4,8.4,3.5Hz,3H),1.87-1.80(m,2H),1.67(d,J=3.1Hz,2H),1.50(s,4H),1.37(ddd,J=15.2,9 .1,4.3Hz,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). 13C NMR (100MHz, 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] Add cis-4-BOC-aminocyclohexanol (1 g, 4.64 mmol, 1 eq), acetaminophen (0.70 g, 4.64 mmol, 1 eq), PPh3 (1.83 g, 6.96 mmol, 1.5 eq), type 4A molecular sieve (dried in an oven at 120 °C for 4 h), and THF (20 mL) sequentially to a 250 mL single-necked flask. Purge the solution three times with argon gas, cool to -10 °C in an ice-salt bath, and add 10 mL of a THF solution containing DIAD (1.21 g, 6.96 mmol, 1.5 eq) dropwise at a rate of one drop every two seconds. After 12 hours, TLC monitoring showed that EA:PE = 1:2, indicating the reaction was largely complete, and the reaction was stopped. The solution was concentrated under reduced pressure to remove THF, yielding 5.62 g of a brownish-yellow oily substance. Add 10 mL of ethanol and 5 mL of petroleum ether, stir for 2 h, slurry, and filter 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, tert-butyl ((1r,4r)-4-(4-acetylphenoxy)cyclohexyl)carbamate (0.90 g, 2.58 mmol) and DCM (6 mL) were added sequentially, followed by dropwise addition of TFA (4 mL) at room temperature. After 3 hours, TLC monitoring showed that EA:PE = 1:1, indicating complete reaction, and the reaction was stopped. TFA was removed from the reaction solution by vacuum distillation. 1.06 g of crude brown oil was obtained. This was dried in a 60 °C oven for 12 h. The crude product was used directly in the next step without purification.

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

[0190] Add BTC (0.08 g, 0.26 mmol, 0.34 eq) and dry DCM (10 mL) sequentially to a 50 mL single-necked flask. Cool the flask to -78 °C and add dropwise a DCM solution of 3-fluoro-4-trifluoromethoxyaniline (0.15 g, 0.77 mmol, 1 eq) and Et3N (0.47 g, 4.61 mmol, 3 eq) over 15 minutes. After the addition is complete, bring the flask to room temperature and continue stirring for 0.5 h. After 0.5 h, monitor the reaction by TLC. Take one drop of the reaction solution into an EP tube and add N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)acetamide·TFA, EA:PE = 1:1.

[0191] 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 to a 100 mL single-necked flask. The reaction was carried out at room temperature, and the reaction was stopped after 0.5 hours by TLC monitoring (EA:PE = 1:1). The sample was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 0.52 g of crude yellow oil. The sample was packed into a 4x silica gel column, mixed with 1.2x silica gel, and eluented with (EA:PE = 1:5, EA:PE = 1:3) to give 0.11 g of white solid, yield 33.4%. ESI-MS: m / z 470.2 [M+H] + 492.1 [M+Na] +

[0192] 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 9.75 (s, 1H), 8.74 (s, 1H), 7.67 (dd, J = 13.4, 2.4H z,1H),7.44(d,J=8.9Hz,2H),7.38(t,J=8.7Hz,1H),7.09(d,J=8.8Hz,1H),6.86(d ,J=8.9Hz,2H),6.29(d,J=7.6Hz,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) and dry tetrahydrofuran (15 mL) to a 100 mL flask. Heat to 0 °C on ice, then add SOCl2 (3.93 g, 33.01 mmol, 1.2 eq) dropwise and stir for 30 min. Transfer a portion of the solution to a 1.5 mL EP tube, add anhydrous methanol, monitor the reaction for completion by TLC, and concentrate to dryness under reduced pressure.

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

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

[0197] Add cis-4-BOC-aminocyclohexanol (2.00 g, 9.29 mmol, 1 eq), N-(4-hydroxyphenyl)-2-methylbutyramide (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), and THF (15 mL) sequentially to a 100 mL single-necked flask. Purge the solution three times with argon gas, cool to below -10 °C in an ice-salt bath, and then add DIAD (2.43 g, 13.9 mmol, 1.5 eq) in THF solution (5 mL) dropwise at a rate of one drop every two seconds. After the addition is complete, transfer the flask to room temperature. After 12 hours, TLC monitoring showed that EA:PE = 1:1, indicating that the reaction was largely complete, and the reaction was stopped. To remove some THF, the solid was concentrated under reduced pressure. 15 mL of anhydrous ethanol and 15 mL of diethyl ether were added and the mixture was stirred. The solid was filtered to obtain 2.24 g of light pink solid. The solid was monitored by TLC. 20 mL of DCM was added to dissolve the solid. The solid was washed with 16 mL of saturated Na2CO3. The organic layer was dried over anhydrous magnesium sulfate. The solid was filtered and concentrated under reduced pressure to dryness to obtain 1.94 g of pure white solid, with a yield of 53.6%.

[0198] Example 53 Synthesis of N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)-2-methylbutyramide

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

[0200] Example 54 Synthesis of N-(4-(((1R,4r)-4-(3-(((1R,3R,5S,7R)-3,5-dimethyladamantane-1-yl)ureo)cyclohexyl)oxy)phenyl)acetamide (SP-C01f)

[0201] Add BTC (0.14 g, 0.47 mmol) and dry DCM (10 mL) sequentially to a 100 mL single-necked flask. Cool the flask to -78 °C and add free memantine (0.25 g, 1.41 mmol), Et3N (0.85 g, 8.46 mmol), and DCM solution (10 mL) dropwise over 30 minutes. After the addition is complete, move the flask to room temperature and continue stirring for 4 h.

[0202] A mixed solution of A4 (0.35 g, 1.41 mmol), Et3N (0.28 g, 2.82 mmol), and DCM (5 mL) was added to a 100 mL single-necked flask and reacted at room temperature. After 2 hours, the reaction was stopped by TLC monitoring. The mixture was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 0.52 g of crude yellow oily product. The product was packed into a 4x silica gel column, mixed with 1.2x silica gel, and eluent (EA:PE = 1:5) to give 0.21 g of product, with a yield of 36.7%.

[0203] 1H-NMR (400MHz, DMSO-d6): δ (ppm) 9.73 (s, 1H), 7.43 (d, J = 8.96Hz, 2H), 6.84 (d, J = 8.96Hz, 2H) ,5.54(d,J=7.60Hz,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)ureo)cyclohexyl)oxy)benzene)-2-methylbutyramide (SP-C01g)

[0205] Add BTC (0.10 g, 0.35 mmol, 1 eq) and dry DCM (10 mL) sequentially to a 50 mL single-necked flask. Cool the flask to -78 °C and add dropwise a DCM solution of 3-fluoro-4-trifluoromethoxyaniline (0.2 g, 1.02 mmol, 1 eq) and Et3N (0.93 g, 9.22 mmol, 3 eq) over 30 minutes. After addition, bring the flask to room temperature and continue stirring for 0.5 h. Monitor the reaction by TLC. Take one drop of the reaction solution into an EP tube and add memantine.

[0206] A mixed solution of N-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenyl)-2-methylbutyramide·TFA (0.41 g, 1.02 mmol, 1 eq), Et3N (0.93 g, 9.22 mmol, 3 eq), and DCM (10 mL) was added to a 100 mL single-necked flask. The reaction was carried out at room temperature, and the reaction was stopped after 0.5 hours by TLC monitoring (EA:PE = 1:2, AcOH 1 d). Extract twice with 15 mL of water, wash once with 15 mL of saturated saline, dry with anhydrous magnesium sulfate, filter, concentrate under reduced pressure to dryness, and obtain 0.74 g of crude yellow oily product. Pack a column with 7x silica gel, mix with 1.2x silica gel, and elute with EA:PE = 1:5, EA:PE = 1:2 to obtain 0.13 g of yellow solid. The purity was insufficient, so the product was placed in a 25 mL single-necked flask, dissolved with 0.5 mL of DCM, and then precipitated with 4 mL of petroleum ether. A white solid precipitated, filtered, and 62 mg of product was obtained. The filtrate was recovered, yielding 11.9%. ESI-MS: m / z 512.3 [M+H] +

[0207] 1 H-NMR (400MHz, DMSO-d6): δ (ppm) 9.64 (s, 1H), 8.17 (s, 1H), 7.67 (dd, J = 13.4, 2.1Hz, 1H), 7.48 (d,J=8.8Hz,2H),7.38(t,J=8.9Hz,1H),7.10-7.08(m,1H),6.87(d,J=8.8Hz,2H),6.27(d,J=7 .4Hz,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=6.7Hz,3H),0.85(t,J=7.4Hz,3H).

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

[0209] Add 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) sequentially to a 100 mL three-necked flask. Cool to below -10 °C in an ice-salt bath, and add 20 mL of a THF solution containing DIAD (18.10 g, 0.069 mol, 1.5 eq) dropwise at a rate of one drop every two seconds. After 8 hours, monitor with TLC; EA:PE = 1:2, indicating the reaction is complete, and stop the reaction. Concentrate under reduced pressure to remove THF, yielding 12.21 g of a brownish-yellow oily substance. Add 50 mL of ethanol, stir for 2 hours, slurry, and filter to obtain 12.46 g of a yellow solid, yielding 80.58%.

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

[0211] To a 100 mL single-necked flask, tert-butyl carbamate (0.60 g, 2.09 mmol) and DCM (5 mL) were added sequentially, followed by dropwise addition of TFA (4 mL) at room temperature. After 3 hours, TLC monitoring showed that EA:PE = 1:1, indicating complete reaction, and the reaction was stopped. TFA was removed from the reaction solution by vacuum distillation. 0.62 g of crude brown oil was obtained. This crude product was dried in a 60 °C oven for 12 h and used directly in the next step without purification.

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

[0213] Add BTC (5.50 g, 18.53 mmol, 0.5 eq) and dry DCM (50 mL) sequentially to a 250 mL single-necked flask. Cool the flask to -80 °C in a cold trap. Add a 50 mL solution of DCM containing a mixture of memantine (6.56 g, 37.06 mmol, 1 eq) and Et3N (30.00 g, 296.48 mmol, 8 eq) dropwise over 4 hours. After the addition is complete, allow the flask to warm to room temperature naturally. After 30 minutes, monitor the reaction by TLC. If the reaction is complete, stop the reaction. Evaporate the reaction mixture to dryness. Add DCM (50 mL) and Et3N (30.00 g, 296.48 mmol, 8 eq). Cool the flask to 0 °C in an ice bath. Add a 50 mL solution of DCM containing I9 (8.89 g, 37.06 mmol, 1 eq) dropwise. After the addition is complete, allow the flask to warm to room temperature. After 30 minutes, monitor the reaction by TLC. If the reaction is complete, stop the reaction. DCM was removed by vacuum concentration, yielding 17.82 g of reddish-brown oily substance. The crude product was used directly 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-dimethyladamantane-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 THF solution of 1-((1r,4R)-4-(4-aminophenoxy)cyclohexyl)-3-((1r,3R,5S,7R)-3,5-dimethyladamantane-1-yl)urea (0.1 g, 0.24 mmol, 1 eq) in 5 mL. Monitor the reaction by TLC. Once the reaction is complete, stop the reaction and filter to give 72 mg of a white solid. The yield is 60.56%.

[0216] 1 H NMR(400MHz,Chloroform-d)δ7.37(d,J=8.8Hz,2H),7.21(s,1H),6.82(d,J=8.8Hz,2H),4.14-4.06(m,1H),3.56-3.51(m, 1H),2.38(q,J=7.6Hz,2H),2.17-1.99(m,6H),1.78(d,J=3.1Hz,2H),1.56-1.41(m,3H),1.39-1.08(m,12H),0.84(s,6H). 13 C NMR(101MHz,Chloroform-d)δ156.72,154.42,131.17,121.86,116.60,75.57 ,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] Add cis-4-BOC-aminocyclohexanol (1.00 g, 4.64 mmol), methylparaben (0.7 g, 4.64 mmol), triphenylphosphine (1.8 g, 6.96 mmol), A4 molecular sieve (dried in an oven at 120 °C for 4 h), and THF (10 mL) sequentially to a 100 mL single-necked flask. Purge the solution three times with argon gas, then cool to below -10 °C in an ice-salt bath. Add 5 mL of a THF solution containing DIAD (1.4 g, 6.96 mmol) dropwise at a rate of one drop every two seconds. After 12 hours, monitor the reaction by TLC. Move the flask to 30 °C and add more A4 molecular sieve. After 6 hours, monitor the reaction by TLC again; the reaction is mostly complete, and the reaction is stopped. THF was removed by vacuum concentration, yielding 5.2 g of brownish-yellow oily substance. No solid precipitate was observed after pulping. The sample was packed into a column with 4x silica gel, mixed with 1.2x silica gel, and eluent (EA:PE = 1:10), yielding 0.73 g of white solid product, with a yield of 45.1%.

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

[0220] Methyl 4-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)benzoate (0.60 g, 2.09 mmol) and DCM (5 mL) were added sequentially to a 100 mL single-necked flask. TFA (4 mL) was then added dropwise at room temperature. After 3 hours, TLC monitoring showed the reaction was complete, and the reaction was stopped. TFA was removed from the reaction solution by vacuum distillation. 0.62 g of crude brown oil was obtained. The crude product was dried in a 60 °C oven for 12 h and used directly in the next step without purification.

[0221] Example 62 Synthesis of methyl 4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)oxy)benzoate BTC (0.23 g, 0.79 mmol) and dry DCM (15 mL) were added sequentially to a 100 mL single-necked flask. The flask was cooled to -78 °C in a cold trap. A DCM solution (10 mL) of free p-trifluoromethoxyaniline (0.41 g, 2.32 mmol) and Et3N (1.41 g, 13.92 mmol) was added dropwise over 30 minutes. After the addition was complete, the flask was moved to room temperature and stirred for 4 h.

[0222] A mixed solution of I15·TFA (0.58 g, 1.59 mmol), Et3N (1.41 g, 13.92 mmol), and DCM (10 mL) was added to a 100 mL single-necked flask and reacted at room temperature. The reaction was stopped by TLC monitoring after 2 hours. The sample was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 0.93 g of crude yellow oil. The sample was packed into a 7x silica gel column, mixed with 1.2x silica gel, and eluent (EA:PE = 1:5) to give 0.40 g of the product as a white solid, yield 40.0%. ESI-MS: m / z 453.2 [M+H] +

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

[0224] Methyl 4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)oxy)benzoate (0.15 g, 0.33 mmol), THF (3 mL), H2O (2 mL), and LiOH (39.8 mg, 0.99 mmol) were added sequentially to a 25 mL single-necked flask. The mixture was stirred at room temperature. After 3 h, TLC monitoring showed that a small portion of the reaction had occurred. The temperature was raised to 30 °C, and 0.1 g of lithium hydroxide was added. After 2 h, TLC monitoring showed that a portion of the reaction had occurred. The temperature was raised to 50 °C, and 0.2 g of lithium hydroxide was added. After 2 h, TLC monitoring showed that the reaction had stopped. The pH was adjusted to 2 with 3N HCl, and the mixture was concentrated under reduced pressure until a small amount of solvent remained. The mixture was filtered, washed with 5 mL of water, and 70 mg of a pale yellow solid was obtained, with a yield of 48.6%.

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

[0226] At room temperature, add 0.17 g (0.39 mmol) of 4-(((1r,4r)-4-(3-(4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)oxy)benzoic acid and 10 mL of dry tetrahydrofuran to a 25 mL flask. Then add HATU (0.18 g, 0.46 mmol) and stir 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, and after 0.5 h, TLC was performed. The reaction was complete. The mixture was concentrated under reduced pressure to remove tetrahydrofuran. It was extracted twice with dichloromethane (12 mL) and water (10 mL), washed once with saturated brine (25 mL), dried over anhydrous magnesium sulfate, and filtered. The organic phase was concentrated under reduced pressure to obtain 0.20 g of a yellow oily substance. The mixture was packed into a 4x silica gel column, mixed with 1.2x silica gel, and eluted with EA:PE = 1:3. Column chromatography yielded 0.12 g of a pale yellow solid. The yield was 70.5%.

[0227] 1 H NMR(400MHz, DMSO-d6)δ8.81(s,1H),7.82(dd,J=9.4,2.7Hz,3H),7.54-7.45(m,2H),7.21(d,J=8.5Hz,2H),7.14(s,1H),7.02-6.94(m,2H),6.48(d, J=7.6Hz,1H),4.43(tt,J=9.8,4.0Hz,1H),3.54(ddt,J=14.2,10.6,5.3Hz ,1H),2.06(dd,J=12.6,4.3Hz,2H),2.01-1.89(m,2H),1.55-1.30(m,4H). 13 C NMR(101MHz,DMSO-d6)δ167.89,160.26,155.02,142.36,140.48,129.85,12 6.78,122.03,121.97,119.43,118.99,115.28,74.64,47.64,30.44,30.15.

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

[0229] Add 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) to a 25 mL flask and stir for 30 min. Add a THF solution of 1-((1r,4R)-4-(4-aminophenoxy)cyclohexyl)-3-((1r,3R,5S,7R)-3,5-dimethyladamantane-1-yl)urea (0.1 g, 0.24 mmol, 1 eq) in 5 mL. Monitor the reaction by TLC; EA:PE = 1:2. The reaction was complete. Stop the reaction and filter to give 80 mg of white solid. The yield was 71.32%.

[0230] 1 H NMR(400MHz,DMSO-d6)δ9.66(s,1H),7.48(d,J=8.8Hz,2H),6.85(d,J=8.8H z,2H),5.58(d,J=7.5Hz,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=10.5Hz,2H),1.82(d,J=10.5Hz,2H),1.68(s,2 H),1.62-1.55(m,2H),1.07-1.05(m,2H),0.83(t,J=7.4Hz,3H)0.80(s,6H).

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

[0232] Add BTC (0.08 g, 0.26 mmol) and dry DCM (10 mL) sequentially to a 50 mL single-necked flask. Cool the flask to -78 °C in a cold trap, and then add dropwise a DCM solution containing 3-fluoro-4-trifluoromethoxyaniline (0.15 g, 0.77 mmol) and Et3N (0.47 g, 4.61 mmol) over 15 minutes. After the addition is complete, bring the flask to room temperature and continue stirring for 0.5 h. After 0.5 h, monitor the solution by TLC; EA:PE = 1:1.

[0233] 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 to a 100 mL single-necked flask. The reaction was carried out at room temperature, and the reaction was stopped after TLC monitoring for 0.5 hours. The sample was extracted twice with 15 mL of water, washed once with 15 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 0.52 g of crude yellow oil. The sample was packed into a 4x silica gel column, mixed with 1.2x silica gel, and eluented with EA:PE = 1:5, EA:PE = 1:3 to give 0.21 g of 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)ureo)cyclohexyl)oxy)phenyl)amino)-3-oxopropionic acid (SP-CO1s)

[0235] Add monoethyl malonate (0.16 g, 0.12 mmol, 1 eq), dry tetrahydrofuran (5 mL), HATU (0.017 g, 0.29 mmol, 1.2 eq), and DIEA (0.09 g, 0.87 mmol, 6 eq) to a 25 mL flask and stir for 30 min. Add a THF (5 mL) solution of 1-((1r, 4r)-4-(4-aminophenoxy)cyclohexyl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)urea (0.05 g, 0.12 mmol, 1 eq), monitor by TLC (EA:PE = 1:1, AcOH 1 d), the reaction is complete, stop the reaction, and filter to give 42 mg of white solid. The yield is 64.67%. 1 H NMR (400MHz, DMSO-d6) δ9.68 (s, 1H), 8.73 (s, 1H), 7.68 (dd, J = 13.4, 2.5Hz, 1H), 7.50-7.43 (m,2H),7.39(t,J=8.9Hz,1H),7.10(dt,J=9.1,1.8Hz,1H),6.92-6.83(m,2H),6.30(d,J=7 .6Hz,1H),4.24(tt,J=9.6,4.0Hz,1H),3.63-3.46(m,1H),2.27(q,J=7.5Hz,2H),2.02(dd, J=12.7,4.4Hz,2H),1.92(dd,J=12.9,4.0Hz,2H),1.51-1.27(m,4H),1.07(t,J=7.5Hz,3H).

[0236] Example 68 Synthesis of methyl 4-(4-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)phenoxy)butyrate

[0237] 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 then add MeCN (15 mL) to a 25 mL single-necked flask. Add methyl 4-bromobutyrate (0.26 g, 1.46 mmol, 1.5 eq) dropwise, purging with Ar three times, and then heat to reflux. After 3 hours, TLC monitoring showed an EA:PE ratio of 1:3. The reaction was stopped, and the product was concentrated to dryness under reduced pressure. The solution was then extracted with water (20 mL) and DCM (20 mL x 2). The organic layers were combined, washed with water (10 mL), then with saturated brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 0.46 g of a brownish-black oily liquid. The crude product was purified by silica gel column chromatography. The column was packed with 1.5 times the volume of sample and 7 times the volume of silica gel, with an EA:PE ratio of 1:15 as the eluent, yielding 0.12 g of a white solid, with a yield of 30.07%.

[0238] Example 69 Synthesis of methyl 4-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenoxy)butyrate

[0239] Methyl 4-(4-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)oxy)phenoxy)butyrate (0.12 g, 0.29 mmol, 1 eq) and DCM (8 mL) were added sequentially to a 100 mL single-necked flask. The mixture was cooled to 0 °C in an ice bath, and TFA (0.5 mL) was added dropwise. After 2 hours, TLC monitoring showed that EA:PE = 1:3, indicating that the reaction was complete, and the reaction was stopped. The DCM and TFA in the reaction solution were removed by vacuum distillation to obtain 0.11 g of crude pale yellow solid. The crude product was used directly in the next step without purification. ESI MS: m / z 308.1 [M+H] + .

[0240] Example 70 Synthesis of 4-(4-(((1R,4r)-4-(3-(((1R,3R,5S,7R)-3,5-dimethyladamantane-1-yl)ureoyl)cyclohexyl)oxy)phenoxy)methyl butyrate (SP-C20)

[0241] Add BTC (0.97 g, 3.26 mmol, 0.5 eq) and dry DCM (10 mL) sequentially to a 250 mL single-necked flask. Cool the flask to -80 °C. Add a DCM solution of ammonium phosphate (1.15 g, 6.51 mmol, 1 eq) and Et3N (5.27 g, 52.08 mmol, 8 eq) dropwise over 30 min. After addition, allow the flask to warm to room temperature. After 30 min, monitor the reaction by TLC. If EA:PE = 1:3, the reaction is complete, and the reaction is stopped. The reaction mixture was evaporated to dryness, and DCM (15 mL) and Et3N (5.27 g, 52.08 mmol, 8 eq) were added. The mixture was kept in an ice bath at 0 °C, and a DCM solution (10 mL) of methyl 4-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenoxy)butyrate (2.00 g, 6.51 mmol, 1 eq) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature. TLC monitoring showed that EA:PE = 1:2, indicating complete reaction, and the reaction was stopped. The DCM was removed by concentration under reduced pressure, yielding 4.05 g of a yellow oil. This oil was mixed with 1.5 times the volume of silica gel, packed into a 4 times silica gel column (EA:PE = 1:7), yielding 1.05 g of a white solid. The yield was 31.48%. 1 H NMR (400MHz, DMSO-d6) δ6.94-6.82 (m, 4H), 5.65 (d, J = 7.6Hz, 1H), 5.49 (s, 1H ),4.19(tt,J=10.0,3.9Hz,1H),3.96(t,J=6.3Hz,2H),3.66(s,3H),2.51(t,J =7.3Hz,3H),2.10(p,J=3.2Hz,1H),2.03-1.93(m,4H),1.92-1.83(m,2H),1.7 3(d,J=3.1Hz,2H),1.55(s,4H),1.49-1.15(m,9H),1.13(s,2H),0.85(s,6H). 13 C NMR(101MHz,DMSO-d6)δ173.54,157.00,153.02,151.71,117.66,115.77,75.52,67.31,51 .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-dimethyladamantane-1-yl)ureo)cyclohexyl)oxy)phenoxy)butyric acid (SP-C21)

[0243] 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 sequentially to a 25 mL single-necked flask and stirred at room temperature. After 1.5 h, TLC monitoring showed that EA:PE = 1:3, at which point the reaction was stopped. The mixture was concentrated under reduced pressure to remove THF, and extracted with EA (20 mL). The aqueous layer was adjusted to pH 2 with 1 N HCl, and the mixture was filtered under reduced pressure to obtain 0.42 g of a pale yellow solid. The yield was 86.01%. 1 H NMR(400MHz,DMSO-d6)δ6.94-6.74(m,4H),4.16-4.10(m,1H),3.90(t,J=6.4Hz,4H),3.90 (t,J=6.4Hz,2H),3.33(tt,J=10.4,3.8Hz,1H),2.37(t,J=7.3Hz,2H),2.04(dt,J=6.8,3.3 Hz,1H),1.97(d,J=4.1Hz,1H),1.92(dt,J=14.1,6.1Hz,3H),1.82(dd,J=13.5,3.6Hz,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(101MHz,DMSO-d6)δ174.60,157.05,153.08,151.68,117.66,115.79,75.50,67.42,51.47,51.39 ,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 butyrate (SP-C23) of 4-(4-(((1r,4r)-4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureo)cyclohexyl)oxy)phenoxy)butyrate

[0245] Add BTC (0.03 g, 0.10 mmol, 0.34 eq) and dry DCM (5 mL) sequentially to a 25 mL single-necked flask. Cool the flask to -80 °C in a cold trap, then add dropwise a DCM solution of 4-trifluoromethoxyaniline (0.05 g, 0.29 mmol, 1 eq) and Et3N (0.09 g, 0.87 mmol, 3 eq) over 5 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. After 10 minutes, monitor the reaction by TLC. If EA:PE = 1:3, the reaction is complete, and the reaction is stopped. The reaction solution was evaporated to dryness, and DCM (10 mL) and Et3N (0.09 g, 0.87 mmol, 3 eq) were added. The mixture was kept in an ice bath at 0°C, and a DCM solution (5 mL) of methyl 4-(4-(((1r,4r)-4-aminocyclohexyl)oxy)phenoxy)butyrate (0.09 g, 0.29 mmol, 1 eq) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature. TLC monitoring showed that EA:PE = 1:2, indicating complete reaction, and the reaction was stopped. The DCM was removed by concentration under reduced pressure, yielding 0.15 g of crude white solid. The sample was mixed with 1.5 times silica gel and packed into a 4 times silica gel column (EA:PE = 1:7), yielding 0.10 g of white solid. The yield was 65.28%. 1 H NMR (400MHz, DMSO-d6) δ9.26 (s, 1H), 7.69 (dd, J=13.5, 2.5Hz, 1H), 7.37 (td, J=9.0, 1.2Hz,1H),7.12(ddd,J=9.0,2.6,1.4Hz,1H),6.91-6.79(m,4H),6.77(d,J=7.6Hz, 1H),4.17(tt,J=9.3,3.8Hz,1H),3.91(t,J=6.3Hz,2H),3.61(s,4H),3.57-3.45(m, 1H), 2.46 (t, J = 7.3Hz, 2H), 2.01-1.99 (m, 2H), 1.97-1.89 (m, 4H), 1.44-1.31 (m, 4H). 13 C NMR(101MHz,DMSO-d6)δ173.53,154.85,153.01,152.89,151.67,142.26,142.15,124.63, 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)ureo)cyclohexyl)oxy)phenoxy)butyric acid (SP-C24)

[0247] 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 sequentially to a 25 mL single-necked flask and stirred at room temperature. After 1.5 h, TLC monitoring showed that EA:PE = 1:3, at which point the reaction was stopped. The mixture was concentrated under reduced pressure to remove THF, and then extracted with EA (20 mL). The aqueous layer was adjusted to pH 2 with 1 N HCl, and the mixture was filtered under reduced pressure to obtain 0.47 g of a pale yellow solid. The yield was 96.21%. 1 H NMR (400MHz, DMSO-d6) δ12.11(s,1H),9.19(s,1H),7.68(dd,J=13.5,2.6Hz,1H),7.38 (td,J=8.9,1.2Hz,1H),7.10(ddd,J=9.0,2.6,1.3Hz,1H),6.91-6.79(m,4H),6.57(s, 1H),4.19(tt,J=9.3,3.8Hz,1H),3.90(t,J=6.4Hz,2H),3.54(ddt,J=11.1,7.4,3.9Hz ,1H),2.37(t,J=7.3Hz,2H),2.05-1.97(m,2H),1.96-1.85(m,4H),1.50-1.21(m,5H). 13 C NMR (101MHz, DMSO-d6) δ174.62,155.37,154.80,153.10,152.92,151.65,142.11,142.01,124. 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)cyclohexyl)oxy)benzylene)-2,4-dioxythiazolidin-3-yl)acetate

[0249] To a 100 mL round-bottom flask, tert-butyl ((1r,4r)-4-(4-formylphenoxy)cyclohexyl)carbamate (4.00 g, 12.53 mmol, 1 eq), methyl 2-(2,4-dioxythiazolin-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) were added sequentially, and the mixture was heated to reflux. A solid precipitated as the reaction proceeded. After 8 hours, TLC monitoring showed that EA:PE = 1:1, indicating complete reaction, and the reaction was stopped. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with a small amount of n-hexane to give 3.89 g of a white solid. No product spots were observed in the filtrate on TLC, resulting in a yield of 63.36%.

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

[0251] To a 100 mL single-necked flask, methyl 2-(5-((Z)-4-(((1r,4r)-4-(tert-butoxycarbonyl)amino)cyclohexyl)oxy)benzylene)-2,4-dioxythiazolidin-3-yl)acetate (3.89 g, 7.94 mmol, 1 eq) and DCM (8 mL) were added sequentially. The mixture was cooled to 0 °C in an ice bath, and TFA (2 mL) was added dropwise. After 4 hours, TLC monitoring showed that EA:PE = 1:3, indicating complete reaction, and the reaction was stopped. DCM and TFA were removed from the reaction solution by vacuum distillation, yielding 3.87 g of crude pale yellow solid. The crude product was used directly 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)ureo)cyclohexyl)oxy)benzyl)thiazolidin-3-yl)acetate (SP-D01)

[0253] Add BTC (0.03 g, 0.10 mmol, 0.34 eq) and dry DCM (5 mL) sequentially to a 25 mL single-necked flask. Cool the flask to -80 °C. Add 10 mL of a DCM solution containing 4-trifluoromethoxyaniline (0.05 g, 0.29 mmol, 1 eq) and Et3N (0.13 g, 1.30 mmol, 5 eq) dropwise over 5 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. After 10 minutes, monitor the reaction by TLC. If EA:PE = 1:3, the reaction is complete, and the reaction is stopped. The reaction solution was evaporated to dryness, and DCM (10 mL) and Et3N (0.13 g, 1.30 mmol, 5 eq) were added. The mixture was kept in an ice bath at 0 °C, and a solution of methyl 2-(5-((Z)-4-(((1r,4r)-4-aminocyclohexyl)oxy)benzylene)-2,4-dioxythiazolidin-3-yl)acetate (0.10 g, 0.26 mmol, 1 eq) in DCM (5 mL) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature. TLC monitoring was performed after 30 min. The reaction was complete after EA:PE = 1:1 and AcOH was added for 2 days. The reaction was then stopped. The DCM was removed by concentration under reduced pressure, yielding 0.23 g of crude white solid. The crude product was purified by silica gel column chromatography. The column was packed with 1.5 times the volume of sample and 5 times the volume of silica gel. The eluent was EA:PE = 1:10, yielding 0.10 g of white solid, with a yield of 66.67%. ESI MS: m / z 616.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ9.74(s,1H),7.96(s,1H),7.65-7.57(m,2H),7.54-7.45(m,2H),7.22(d,J=8.6Hz,2H),7.18-7.12(m,2H),6.44(d ,J=7.6Hz,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)ureo)cyclohexyl)oxy)benzyl)thiazolyl-3-yl)acetic acid

[0255] 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 added sequentially to a 25 mL single-necked flask and stirred at room temperature. After 1.5 h, TLC monitoring showed that EA:PE = 1:3, at which point the reaction was stopped. The mixture was concentrated under reduced pressure to remove THF, and the pH was adjusted to 4 with 1N HCl. The mixture was then extracted with EA (10 mL) and H2O (10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give 70 mg of a white solid. Yield: 92.98%. ESI MS: m / z 578.3 [MH] - .

[0256] Example 78 Synthesis of methyl acetate 2-(5-((Z)-4-(((1R,4r)-4-(3-((1R,3R,5S,7R)-3,5-dimethyladamantane-1-yl)ureoyl)cyclohexyl)oxy)benzylidene)-2,4-dioxythiazoline-3-yl)acetate

[0257] Add BTC (0.03 g, 0.10 mmol, 0.34 eq) and dry DCM (5 mL) sequentially to a 25 mL single-necked flask. Cool the flask to -80 °C in a cold trap. Add a 10 mL solution of DCM containing memantine (0.05 g, 0.28 mmol, 1 eq) and Et3N (0.28 g, 2.80 mmol, 10 eq) dropwise over 5 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. After 10 minutes, monitor the reaction by TLC. If the EA:PE ratio is 1:3, the reaction is complete, and the reaction is stopped. Evaporate the reaction solution to dryness. Add DCM (10 mL) and Et3N (0.28 g, 2.80 mmol, 10 eq). Cool the flask to 0 °C in an ice bath. Add a 5 mL solution of DCM containing N4 (0.10 g, 0.28 mmol, 1 eq) dropwise. After the addition is complete, allow the flask to react at room temperature. After 30 minutes, monitor the reaction by TLC. If the EA:PE ratio is 1:1 and the reaction proceeds with AcOH for 2 days, the reaction is complete, and the reaction is stopped. DCM was removed by vacuum concentration, yielding 0.31 g of crude white solid. The crude product was purified by silica gel column chromatography: 1.5 times the volume of sample was mixed, and the column was packed with 5 times the volume of silica gel. The eluent was EA:PE = 1:10, yielding 0.08 g of white solid, with a yield of 48.20%. ESI MS: m / z 594.66 [MH] - . 1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.65-7.56(m,2H),7.18-7.09(m,2H), 5.62(d,J=7.6Hz,1H),5.43(s,1H),4.51(s,2H),4.45(dd,J=8.9,4.7Hz,1H) ,3.72(s,3H),2.09-1.99(m,3H),1.89-1.81(m,2H),1.68(d,J=3.1Hz,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).

[0258] Example 79 Synthesis of (Z)5-(4-nitrobenzylidene)thiazolidin-2,4-dione

[0259] Add 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) sequentially to a 100 mL round-bottom flask, and heat to reflux. A solid precipitated as the reaction proceeded. After 8 hours, TLC monitoring showed EA:PE = 1:1, AcOH 1 day, indicating complete reaction, and the reaction was stopped. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with a small amount of n-hexane to obtain 5.06 g of a reddish-brown solid. The filtrate was evaporated to dryness and concentrated, then slurried with DCM (10 mL) and MeOH (1 mL) to obtain 3.06 g of a yellow solid, yield 98.19%. 1 ¹H NMR (400MHz, DMSO-d6): δ (ppm) 1 H NMR (400MHz, DMSO-d6) δ12.69(s,1H),8.31(d,J=8.5Hz,2H),7.83(d,J=8.5Hz,2H),7.81(s,1H).ESI MS:m / z 249.1[MH] - .

[0260] Example 80 Synthesis of (Z)-5-(4-aminobenzyl)thiazolidin-2,4-dione

[0261] To a 500 mL three-necked flask, add (Z)5-(4-nitrobenzyl)thiazolidin-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) sequentially, and heat to reflux. After 1.5 hours, TLC monitoring showed that EA:PE = 1:1 and AcOH 1 day, indicating complete reaction, and the reaction was stopped. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with a small amount of DCM. The filtrate was evaporated to dryness and concentrated to remove EtOH and some H2O. Extraction was performed using DCM:MeOH = 10:1 (60 mL × 4), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2.06 g of a reddish-brown solid, yield 72.38%. ESI MS: m / z 199.3 [MH] - .

[0262] Example 81 Synthesis of 1-((1r,3R,5S,7r)-3,5-dimethyladamantane-1-yl)-3-(4-((E)-(2,4-dioxythiazolinyl-5-ylidene)methyl)phenyl)urea (SP-E01)

[0263] Add BTC (0.05 g, 0.15 mmol, 0.34 eq) and dry DCM (5 mL) sequentially to a 25 mL single-necked flask. Cool the flask to -80 °C. Add a 10 mL solution of a mixture of memantine (0.08 g, 0.45 mmol, 1 eq) and Et3N (0.46 g, 4.50 mmol, 10 eq) in DCM dropwise over 5 minutes. After the addition is complete, allow the flask to warm to room temperature naturally. After 30 minutes, monitor the reaction by TLC. If the EA:PE ratio is 1:3, the reaction is complete, and the reaction is stopped. Evaporate the reaction solution to dryness, add DCM (10 mL), Et3N (0.46 g, 4.50 mmol, 10 eq), and heat to 0°C on ice. Add dropwise a solution of (Z)-5-(4-aminobenzyl)thiazolidin-2,4-dione (0.10 g, 0.45 mmol, 1 eq) in DCM (5 mL). After the addition is complete, react at room temperature. After 30 min, monitor by TLC (EA:PE = 1:1, AcOH 2d), indicating complete reaction. Stop the reaction. Extract with DCM (30 mL × 3) in 1N HCl (30 mL), combine the organic layers, wash with water (30 mL), wash with saturated brine (30 mL), dry to anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to obtain the final product. 0.37 g of crude yellow oily substance was obtained. The crude product was purified by silica gel column chromatography, with 1.5 times the sample volume mixed and 7 times the volume packed into a silica gel column. The eluent was EA:PE = 1:10, yielding 0.11 g of white solid, with a yield of 57.49%. ESI MS: m / z 423.9 [MH] - .

[0264] Example 82 Synthesis of (E)-1-(4-((2,4-dioxythiazolinyl-5-ylidene)methyl)phenyl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)urea (SP-E03)

[0265] Add BTC (0.05 g, 0.15 mmol, 0.34 eq) and dry DCM (5 mL) sequentially to a 25 mL single-necked flask. Cool the flask to -80 °C. Add 10 mL of a DCM solution containing 4-trifluoromethoxyaniline (0.08 g, 0.45 mmol, 1 eq) and Et3N (0.46 g, 4.50 mmol, 10 eq) dropwise over 5 minutes. After addition, allow the flask to warm to room temperature naturally. After 30 minutes, monitor the reaction by TLC. If EA:PE = 1:3, the reaction is complete, and the reaction is stopped. Evaporate the reaction solution to dryness, remove excess phosgene, add DCM (10 mL), Et3N (0.46 g, 4.50 mmol, 10 eq), and heat to 0°C on ice. Add dropwise a DCM solution (5 mL) of (Z)-5-(4-aminobenzyl)thiazolidin-2,4-dione (0.10 g, 0.45 mmol, 1 eq). After the addition is complete, react at room temperature. After 15 min, monitor with TLC. EA:PE = 1:1, AcOH 2d, the reaction is complete, and the reaction is stopped. Extract with DCM (30 mL × 3) in 1N HCl, combine the organic layers, wash with water (30 mL), wash with saturated brine (30 mL), dry to anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to obtain the final product. 0.31 g of crude yellow oily substance was obtained. The crude product was purified by silica gel column chromatography, with 1.5 times the sample volume mixed and 7 times the volume packed into a silica gel column. The eluent was EA:PE = 1:10, yielding 0.09 g of white solid, with a yield of 47.37%. ESI MS: m / z 421.8 [MH] - .

[0266] Test Example 1

[0267] 1. sEH inhibitory activity test

[0268] Detection Principle: The specific substrate (3-phenyl-oxy)-cyanoacetate-(6-methoxy-naphth-2-yl)methyl ester, i.e., PHOME, is itself non-fluorescent. However, under the action of sEH enzyme, it is hydrolyzed to produce the product 6-methoxy-2-naphthaldehyde. 6-methoxy-2-naphthaldehyde can emit fluorescence at a wavelength of 465 nm when excited by light at 330 nm. The intensity of the detected fluorescence signal is inversely proportional to the strength of the inhibitory effect on sEH enzyme. Based on the above principle, the inhibition rate of samples at different concentrations was calculated compared with the positive control group. The IC50 of the compound was calculated using SPSS 20 software based on the inhibition rate and concentration. 50 value.

[0269] 2. Preparation of reagents and drugs

[0270] 25mM Tris-HCl buffer (pH=7.4, containing 0.1mg / mL BSA): Take 12.5mL of 1M Tris-HCl buffer, add 5mg BSA, dilute with purified water and adjust the pH to 7.4 with hydrochloric acid, and bring the volume to 500mL.

[0271] PHOME solution: Dissolve 0.79 mg of PHOME in 106 μL of DMSO to obtain a 20 mM PHOME solution. Dilute to 1 / 3 mM with Tris-HCl buffer before use.

[0272] sEH solution: The sEH (5 mg / mL) stock solution was stored at -80°C and diluted to 4 μg / mL with 25 mM Tris-HCl buffer before use.

[0273] The sample powder to be tested is dissolved in DMSO to prepare a 20mM solution, stored at -20℃ for later use, and diluted with Tris-HCl buffer to the corresponding concentration before use.

[0274] 3. Experimental Grouping

[0275] Experimental design: solvent group, 100% activity group (A), inhibitor group (B), positive control group (C), as shown in Table 1.

[0276] Table 1 Experimental Grouping

[0277] hole buffer solution DMSO Inhibitors sEH Substrate Solvent group 168μL 2μL — — 30μL 100% Vitality Group (A) 148μL 2μL — 20μL 30μL Inhibitor group (B) 148μL — 2μL 20μL 30μL Positive control group (C) 148μL — 2μL 20μL 30μL

[0278] 4. Experimental Procedure

[0279] (a) Add 148 μL / well of Tris-HCl buffer to a 96-well black microplate;

[0280] (b) Add 2 μL of the test sample solution. Replace the solvent group and the 100% activity group with an equal volume of DMSO. Add the lead compound GL-B401 (structural formula: [insert structural formula here]) to the positive control group.

[0281] (c) The inhibitor group had a total of 5 concentrations, with final concentrations of 10 nM, 5 nM, 2.5 nM, 1.25 nM and 0.625 nM, respectively;

[0282] (d) Add 20 μL of s-EH solution (final concentration of 400 ng / mL), and replace the solvent group with an equal volume of Tris-HCl buffer;

[0283] (e) Add 30 μL of PHOME substrate to start the reaction (final concentration 50 μM) and incubate at 37 °C for 10 min;

[0284] (f) ELISA reader detects fluorescence signal data, with an excitation wavelength of 330 nm and an emission wavelength of 465 nm.

[0285] 5. Data Analysis

[0286] Each sample was prepared in triplicate, and the mean value of the three replicates was the fluorescence value (F) of the analyte. The inhibition rate % was calculated as [(AF - BF) / AF] × 100, where AF is the fluorescence value of the 100% activity group and BF is the fluorescence value of the inhibitor group. The IC50 of the compound was calculated using SPSS 20 software based on the inhibition rate and concentration. 50 value.

[0287] We used a biochemical approach to evaluate the activity of the compounds using cyano(6-methoxynaphthyl-2-yl)2-(3-phenylethyleneoxy-2-yl)acetic acid methyl ester (PHOME) as a substrate, and recombinant human sEH (HsEH) and murine sEH (MsEH) as the results. The results are shown in Table 2.

[0288] Table 2. Human(HsEH) and Murine(MsEH)sEH IC of the compounds 50

[0289]

[0290]

[0291] Test Example 2

[0292] 1. PPARγ agonist activity assay

[0293] Detection principle: When pM-hPPAR binds to an appropriate ligand, it is activated and binds to the GAL4 DNA binding site in plasmid pB4-RES-tk-luc, thereby initiating the expression of the downstream luciferase reporter gene. The presence of luciferase is used to determine whether the test compound is an agonist of PPAR.

[0294] 2. Test Results: SP-C01 for PPARγEC 50 =4.2μM, SP-A01 for PPARγEC 50 =6.77μM, SP-A07 for PPARγEC 50 =7.75μM, SP-B07 for PPARγEC 50 =1.43μM.

[0295] Table 3. PPARγ of the compounds in the examples

[0296]

[0297]

[0298] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. Other embodiments can be obtained based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A compound, characterized in that, has a structure shown in Formula II: wherein R1is memantine alkyl, R3is hydrogen or alkyl; R4is hydrogen or alkyl; R5is hydrogen or alkyl; A is cyclohexanediyl, and B is phenylene. W is -O-; Y is -O-; Z is =O; n is an integer from 0 to 12.

2. The compound of claim 1, wherein The R4 is hydrogen, methyl or ethyl; n is an integer from 0 to 2.

3. The compound of claim 1, wherein The R3 is hydrogen or methyl; the R5 is hydrogen or methyl.

4. The compound according to any one of claims 1 to 3, wherein has any one of the following structures:

5. Process for the preparation of a compound according to any one of claims 1 to 4, characterized in that, comprising the following steps: carrying out a first substitution reaction on the compound a and the compound h to obtain a compound i; carrying out a first hydrolysis reaction on the compound i to obtain a compound j; carrying out a second substitution reaction on the compound j and a compound aa to obtain a compound k; carrying out a second hydrolysis reaction on the compound k to obtain a compound l; carrying out a nucleophilic substitution reaction on the compound l, a compound w and a compound af to obtain a compound having a structure shown in Formula II; The structural formulae of the compound a, the compound w and the compound af are as follows: In the chemical a, Q is a hydroxyl group; The structural formulae of the compound h, the compound i, the compound j, the compound k, the compound l and the compound aa are as follows: In the compound h, X is a hydroxyl group.

6. Use of the compound of any one of claims 1 to 4 and pharmaceutically acceptable salts thereof or the compound prepared by the preparation method of claim 5 in the preparation of a peroxisome proliferator-activated receptor agonist and / or a soluble epoxide hydrolase inhibitor.

7. Use according to claim 6, characterized in that, The peroxisome proliferator-activated receptor agonist and / or the soluble epoxide hydrolase inhibitor are used for treating a soluble epoxide enzyme and a peroxisome proliferator-activated receptor mediated disease. The soluble epoxide enzyme and the peroxisome proliferator-activated receptor mediated disease is selected from an inflammatory disease, pain, sepsis, a cardiovascular disease, a neurodegenerative disease, diabetes, a diabetic complication, depression, liver fibrosis, renal failure, chronic obstructive pulmonary disease or pulmonary hypertension disease.

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

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