Piperidine derivatives and pharmaceutical compositions thereof, methods of preparation and use

Abstract

The present application discloses piperidine derivatives and their pharmaceutical compositions, preparation methods and uses. The piperidine derivative compounds are represented by formula (I), and the definitions of each substituent are described in the specification. The piperidine derivatives of the present application can be used as bifunctional selective ligands for the μ opioid peptide receptor (MOPR) and the κ opioid peptide receptor (KOPR), or bifunctional selective ligands for the μ opioid peptide receptor (MOPR) and the nociceptin / orphanin receptor (NOPR or ORL-1 receptor). Such compounds or pharmaceutical compositions thereof can be used to treat pain, anxiety, depression, alcohol addiction, and drug abuse / dependence. TIFF2024523683000118.tif62162

Description

Related Applications

[0001] This application claims priority from a Chinese patent application for invention filed on July 14, 2021, with the invention title "Piperidine derivatives and pharmaceutical compositions thereof, preparation methods and uses" and application number 202110797657.5, the entire contents of which are incorporated herein by reference. [Technical Field]

[0002] The present application relates to the field of medicinal chemistry, specifically to piperidine derivatives and their pharmaceutical compositions, preparation methods and uses. [Background technology]

[0003] Pain is one of the most common physiological sensations in people's daily lives, affecting more patients than those with diabetes, cardiovascular disease, and tumors combined. Pain has diverse pathogenic mechanisms and is associated with almost all diseases. There is a huge clinical demand for anti-inflammatory and analgesic drugs. Currently, opioid analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) dominate the pain treatment market, widely used in areas such as surgical analgesia, terminal cancer analgesia, and long-term chronic pain. Opioid analgesics are characterized by rapid onset and potent analgesic effects, making them the primary treatment for moderate to severe pain in clinical settings. However, their use is limited due to side effects such as dependence, respiratory depression, constipation, tolerance, and pruritus, leading to social problems such as drug addiction and death from overuse. Research and development of safe and effective analgesics without side effects is an urgent social need.

[0004] For many years, scientists have been trying to find new analgesics for clinical use that have the analgesic effects of opioid drugs but lack their side effects. Pharmacologists use a number of strategies to develop safe and effective drugs to treat pain and opioid dependence. Many new target mechanisms have been discovered and applied in the research and development of novel analgesics. Extensive research has shown that the analgesic effects of μ receptor agonists are related to G iIt has been shown that the G protein-biased μ opioid receptor agonists are regulated by the activation of the signaling pathway, and side effects such as dependence, respiratory depression, and constipation are regulated by the downstream β-arrestin signaling pathway. Therefore, G protein-biased μ opioid receptor agonists have become an important direction of research in this field in recent years. μ receptor-biased agonists selectively activate G i This activates the pathway without affecting the β-arrestin signaling pathway, making it possible to develop ideal opioid drugs.

[0005] WO2017 / 161017 discloses a benzimidazolone piperidine compound as a G protein-biased MOP receptor agonist, which shows good analgesic activity in rodent analgesic models and has less side effects than morphine.However, the compound itself may have deficiencies in drug discovery potential, and there are no further reports on clinical studies.

[0006] Selective KOP receptor agonists and DOP receptor agonists each have their own side effects, while avoiding the side effects mediated by MOP receptor agonists. KOP receptor agonists mediate side effects such as restlessness, sedation, and polyuria, but have been found to reduce the rewarding effects of addictive drugs, demonstrating their potential for the development of analgesics that overcome opioid drug dependence. Although DOP receptors produce convulsive effects after activation by agonists, they have been shown to have good analgesic effects for chronic pain. Unlike MOP receptor agonists, DOP receptors do not induce physiological dependence after activation and are less prone to abuse. They also possess anti-anxiety and antidepressant effects. However, to date, selective KOP receptor or DOP receptor ligand compounds have not been successful in clinical development due to limited analgesic efficacy.

[0007] The analgesic effect mediated by the NOP receptor is more complex than that of other opioid receptor family members. The nociceptin / orphanin FQ-NOP receptor system not only inhibits opioid receptor-mediated analgesia, but also mediates analgesia by reducing hyperalgesia. Studies have shown that NOP receptor agonists have the ability to suppress analgesia and modulate the dependence induced by NOP agonists. Non-human primate animal studies have demonstrated that selective NOP agonists do not cause respiratory depression or potential dependence. RO 64-6198 is the first reported small molecule selective NOP receptor agonist. Developed by Roche, it has demonstrated good analgesic effects in non-human primate and rodent animal models without the side effects mediated by conventional opioid drugs. In WO01 / 07050, SCHERING discloses piperidinyl derivative compounds, which are used as NOP receptor (ORL-1 receptor) agonists to treat cough. Because there is a strict interaction function between nociceptin / orphanin FQ receptors and conventional opioid receptors, in recent years, people's attention has shifted to the research of ligand compounds that act simultaneously on two targets.

[0008] BU08028 is a buprenorphine analogue, and this molecule has high affinity for the four typical opioid receptors. In vitro experiments have shown that BU08028 is a partial agonist of the MOP / NOP receptor, and compared with buprenorphine, BU08028 has stronger biological activity at the NOP receptor. In non-human primate in vivo experiments, compared with buprenorphine and remifentanil, BU08028 exhibits significantly higher analgesic and anxiolytic effects, less dependency, and more importantly, no significant physiological dependence. Nalorphine is a bifunctional opioid drug that acts as an MOP receptor antagonist and a KOP receptor agonist, and can inhibit the effects of morphine in vivo and exhibit analgesic activity itself. Bifunctional molecules with high activity at KOP receptors but low or moderate activity at MOP receptors have low dependency compared to simple MOP receptor agonists, but they themselves have side effects such as anxiety and hallucinations in patients. Cebranopadol is a bifunctional agonist at the MOP / NOP receptors. Preclinical data have shown that cebranopadol also has partial activating activity at the KOP receptor. Recent reports have shown that cebranopadol, compared to morphine, reduces tolerance, physiological dependence, and respiratory depression. Patent WO 2017 / 096323 discloses AT-121, a piperidinyl spiro compound with high affinity for both MOP and NOP receptors and is a partial agonist at these two receptors. In non-human primate animal experiments, this molecule demonstrated good analgesic and anti-obsession effects without side effects such as respiratory depression, opioid hypersensitivity, and drug dependence.

[0009] Existing reports indicate that different opioid receptors have their own pharmacological functional characteristics. Molecules with bifunctional or multifunctional opioid receptor activity exhibit unique pharmacological actions, producing favorable analgesic efficacy. They also effectively reduce the side effects of conventional opioid drugs such as morphine, such as respiratory depression, constipation, tolerance, and dependence. They also have antidepressant and anxiolytic effects and are potentially effective in treating alcohol addiction. However, research into these molecules is still in its early stages, with few successful cases. Meanwhile, there is an urgent need for analgesics without side effects. Therefore, more extensive research is needed in the field of novel analgesics with multifunctional or bifunctional opioid receptor activity. Summary of the Invention

[0010] The following is a summary of the subject matter described herein, which does not limit the scope of protection of the claims.

[0011] This application provides piperidine derivatives and their pharmaceutical compositions, preparation methods, and uses. These compounds have novel structures and high affinity and biological activity for MOP receptors, NOP receptors (ORL-1 receptors), and / or KOP receptors. They also exhibit high selectivity for bifunctional activity against MOP receptors and KOP receptors, or high selectivity for bifunctional activity against MOP receptors and NOP receptors (ORL-1 receptors). Some compounds also possess a high G protein bias, resulting in unique pharmacological mechanisms of action. They can be developed as novel opioid receptor drugs and used to treat acute and chronic pain, anxiety, depression, alcoholism, and drug abuse / dependence.

[0012] In an embodiment of the present application, the present application provides a compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof, [ka] During the ceremony, n is 0 or 1, m is 0 or 1; p is 0, 1 or 2; R 1 and R 2 are independently hydrogen, halogen, or C 1-3 Alkyl groups and C 1-3 alkoxy groups, R 1 and R 2 is not hydrogen at the same time, R 3 is an unsubstituted aryl group, a substituted aryl group, an unsubstituted heteroaryl group, a substituted heteroaryl group, an unsubstituted C 3-8 Cycloalkyl groups, substituted C 3-8 Cycloalkyl groups, unsubstituted C 4-6 Heterocycloalkyl groups and substituted C 4-6 heterocycloalkyl groups, R 4 is hydrogen, -C 1-3 alkyl group-unsubstituted heterocycloalkyl group, -C 1-3 Alkyl-substituted heterocycloalkyl groups, -C 1-3 Alkyl-substituted spiroheterocycloalkyl groups, -C 1-3 Alkyl group -C(O)NR 5 R 6 , -C 1-3 Alkyl group -NR 7 R 8 , -C 1-4 alkyl group-unsubstituted heteroaryl group and -C 1-4 alkyl-substituted heteroaryl groups; R 5 and R 6 are independently hydrogen or C 1-3 It may be an alkyl group, or R 5 and R 6 Let's go together 4-6 or R 5 and R 6 Let's go together 4-6 and R 7 and R 8 are independently hydrogen or C 1-3 It may be an alkyl group, or R 7and R 8 Let's go together 4-6 or R 7 and R 8 Let's go together 4-6 and R 4 is hydrogen, then m is 0 and n is 1.

[0013] On the other hand, the present application provides the above piperidine derivatives or stereoisomers thereof, pharmaceutically acceptable salts, solvates, deuterated compounds, metabolites or prodrugs thereof, and pharmaceutically acceptable carriers.

[0014] In a third aspect, the present application provides the biological activity of the above piperidine derivatives or pharmaceutical compositions thereof as MOP receptor and NOP receptor (ORL-1 receptor) agonists.

[0015] In a fourth aspect, the present application provides a method for preparing the above piperidine derivative, said method comprising the steps of: (1) A compound of formula (I-1) is subjected to a conjugate reaction with a compound of formula (I-2) to obtain a compound of formula (I-3). [ka] (2) The compound of formula (I-3) is deprotected to obtain the compound of formula (I-4), which is then conjugated with the compound of formula (I-5) to obtain the compound of formula (I). [ka] Or, (1') A compound of formula (I-7) is obtained by subjecting a compound of formula (I-6) to a conjugate reaction with a compound of formula (I-5). [ka] (2) The compound of formula (I-7) is subjected to a conjugate reaction with the compound of formula (I-2) to obtain the compound of formula (I). [ka] In the above preparation method, X1 and X2 each represent a leaving group such as bromine, or the compound of formula (I-5) is an aldehyde, a ketone, or a boronic acid, and Pr1 represents an amino-protecting group such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group, etc. [Brief explanation of the drawings]

[0016] The drawings are intended to provide an understanding of the technical solution of the present application, are a part of the specification, and are used to interpret the technical solution of the present application together with the embodiments of the present application, but are not intended to limit the technical solution of the present application. [Figure 1A] This is a graph showing the analgesic time-effect curve of the compound EX3 of the present application. The experimental results are shown as mean ± standard error. Compared with the blank control group, ###p < 0.001, and compared with the model group, *p < 0.05, ***p < 0.001. The differences between groups were compared using one-way ANOVA Dunnett's, and NS indicates no significance. [Figure 1B] This is an analgesic dose-effect diagram of the compound EX3 of the present application. The experimental results are shown as mean ± standard error. Compared with the blank control group, ###p < 0.001, and compared with the model group, *p < 0.05, ***p < 0.001. The differences between groups were compared using one-way ANOVA Dunnett's, and NS indicates no significance. [Figure 2] 1 shows the results of an experiment on von Frey hair and paw load-bearing of the compound EX3 of the present application. (A) is the time-dependent change curve of the mechanical pain threshold (Von Frey), (C) is the relative analgesia rate, (B) is the time-dependent change curve of the paw load-bearing difference value (Weight Bearing), and (D) is the relative analgesia rate. The experimental results are shown as mean ± standard error. Compared with the control group (G1), *p < 0.05 indicates a significant difference, and &&, $$, ##, **p < 0.01 indicate a highly significant difference. DETAILED DESCRIPTION OF THE INVENTION

[0017] In some embodiments, the present application provides a compound of formula (I), and stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs thereof, [ka] During the ceremony, n is 0 or 1, m is 0 or 1; p is 0, 1 or 2; R 1 and R 2 are independently hydrogen, halogen, or C 1-3 Alkyl groups and C 1-3 alkoxy groups, R 1 and R 2 is not hydrogen at the same time, R 3 is an unsubstituted aryl group, a substituted aryl group, an unsubstituted heteroaryl group, a substituted heteroaryl group, an unsubstituted C 3-8 Cycloalkyl groups, substituted C 3-8 Cycloalkyl groups, unsubstituted C 4-6 Heterocycloalkyl groups and substituted C 4-6 a heterocycloalkyl group, wherein the substituted aryl group, the substituted heteroaryl group, and the substituted C 3-8 Cycloalkyl group or substituted C 4-6 Heterocycloalkyl groups are substituted with halogen, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 substituted by 1 to 3 substituents independently selected from an alkoxy group, an aryl group, and a heteroaryl group; R 4 is hydrogen, -C 1-3 alkyl group-unsubstituted heterocycloalkyl group, -C 1-3 Alkyl-substituted heterocycloalkyl groups, -C 1-3 Alkyl-substituted spiroheterocycloalkyl groups, -C 1-3 Alkyl group -C(O)NR 5 R 6, -C 1-3 Alkyl group -NR 7 R 8 , -C 1-4 alkyl group-unsubstituted heteroaryl group and -C 1-4 alkyl-substituted heteroaryl groups; R 5 and R 6 are independently hydrogen or C 1-3 It may be an alkyl group, or R 5 and R 6 Let's go together 4-6 or R 5 and R 6 Let's go together 4-6 and R 7 and R 8 are independently hydrogen or C 1-3 It may be an alkyl group, or R 7 and R 8 Let's go together 4-6 or R 7 and R 8 Let's go together 4-6 and R 4 is hydrogen, then m is 0 and n is 1.

[0018] In some embodiments, in formula (I), n is 0, m is 0, and p is 0, 1, or 2.

[0019] In some embodiments, in formula (I), n is 1, m is 0, and p is 0, 1, or 2.

[0020] In some embodiments, in formula (I), n is 0, m is 1, and p is 0, 1, or 2.

[0021] In some embodiments, in Formula (I), R 1 and R 2 are independently hydrogen, halogen, or C 1-3 alkyl groups, R 1 and R2 is not hydrogen at the same time.

[0022] In some embodiments, in Formula (I), R 1 and R 2 are independently hydrogen, chlorine, fluorine, C 1-3 alkyl groups, R 1 and R 2 is not hydrogen at the same time.

[0023] In some embodiments, in Formula (I), R 1 and R 2 are each independently selected from hydrogen, chlorine, fluorine, and a methyl group; R 1 and R 2 is not hydrogen at the same time, and as an option, R 1 and R 2 are both chlorine, or R 1 is chlorine and R 2 is fluorine, or R 1 is fluorine and R 2 is chlorine, or R 1 and R 2 are both fluorine, or R 1 is fluorine, methyl group or chlorine, and R 2 is hydrogen, or R 1 is hydrogen and R 2 is chlorine or fluorine.

[0024] In some embodiments, in formula (I), the R 3 is selected from unsubstituted aryl groups, substituted aryl groups, unsubstituted heteroaryl groups, and substituted heteroaryl groups, wherein the unsubstituted aryl group is a phenyl group or a naphthyl group, the unsubstituted heteroaryl group is a furanyl group, a thienyl group, a pyridinyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, or a tetrazolyl group, and the substituted aryl group is selected from halogen, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC1-4 a phenyl group or a naphthyl group substituted with 1 to 3 groups independently selected from an alkoxy group, an aryl group, and a heteroaryl group, and the substituted heteroaryl group is selected from halogen, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 It is a furanyl group, a thienyl group, a pyridinyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, or a tetrazolyl group, each of which is substituted by 1 to 2 groups independently selected from an alkoxy group, an aryl group, and a heteroaryl group.

[0025] In some embodiments, in Formula (I), R 3 is a phenyl group, or a halogen, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy and haloC 1-4 a phenyl group substituted by 1 to 3 groups independently selected from alkoxy groups, or a phenyl group substituted by fluorine, chlorine, bromine, iodine, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy and haloC 1-4 It is a phenyl group substituted with 1 to 3 groups independently selected from alkoxy groups.

[0026] In some embodiments, in Formula (I), R 3is a phenyl group, a 3,4-dichlorophenyl group, a 3,4-difluorophenyl group, a 2-chloro-4-fluorophenyl group, a 2-fluoro-4-chlorophenyl group, a 4-trifluoromethylphenyl group, a 4-trifluoromethoxyphenyl group, a 2,4-dichlorophenyl group, a 2,6-dichlorophenyl group, a 2,4-difluorophenyl group, a 2-chloro-4-methylphenyl group, a 2-methyl-4-fluorophenyl group, a 2-methyl-4-chlorophenyl group, a 2-methoxy-4-chlorophenyl group, a 2,4-dimethylphenyl group, a 2,6-dimethylphenyl group, a 2,4,6-trimethylphenyl group, a 4-tert-butylphenyl group, a 2-chlorophenyl group, a 2-methylphenyl group, a 2-fluorophenyl group, a 2-methoxyphenyl group, a 4-chlorophenyl group, a 4-fluorophenyl group, or a 4-methoxyphenyl group.

[0027] In some embodiments, in Formula (I), R 3 is a furanyl group, a thienyl group, a pyridinyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, or a tetrazolyl group, and optionally is a fluorine, a chlorine, a bromine, an iodine, a C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy and haloC 1-4 substituted with 1 to 2 groups independently selected from alkoxy groups, and optionally R 3 is 5-trifluoromethylpyridin-2-yl, or 5-chlorothiophen-2-yl.

[0028] In some embodiments, in Formula (I), R 3 is unsubstituted C 3-8 Cycloalkyl group or substituted C 3-8 is a cycloalkyl group, 3-8 Cycloalkyl groups, substituted C 3-8 C in cycloalkyl groups 3-8The cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group, and the substituted C 3-8 Cycloalkyl groups are fluorine, chlorine, bromine, iodine, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group substituted by 1 to 3 groups independently selected from an alkoxy group and a phenyl group, and preferably the substituted C 3-8 The cycloalkyl group is a 4-tert-butylcyclohexyl group, a 4-isopropylcyclohexyl group, a 4-ethylcyclohexyl group, a 4-methylcyclohexyl group, a 4-trifluoromethylcyclohexyl group, a 2,3-dihydro-1H-inden-2-yl group, or a 2-chlorocyclohexyl group.

[0029] In some embodiments, in Formula (I), R 3 is a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4-tert-butylcyclohexyl group, a 4-isopropylcyclohexyl group, a 4-ethylcyclohexyl group, a 4-methylcyclohexyl group, a 4-trifluoromethylcyclohexyl group, a 2,3-dihydro-1H-inden-2-yl group, or a 2-chlorocyclohexyl group.

[0030] In some embodiments, in Formula (I), R 3 is unsubstituted C 4-6 Heterocycloalkyl group or substituted C 4-6 heterocycloalkyl group, wherein the unsubstituted C 4-6 Heterocycloalkyl group or substituted C 4-6 C in heterocycloalkyl groups 4-6 The heterocycloalkyl group is a tetrahydrofuranyl group, a tetrahydropyrrolyl group, a tetrahydrothienyl group, a piperidinyl group, a morpholino group, or a piperazinyl group, and the substituted C4-6 Heterocycloalkyl groups include fluorine, chlorine, bromine, iodine, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 a tetrahydrofuranyl group, a tetrahydropyrrolyl group, a tetrahydrothienyl group, a piperidinyl group, a morpholino group, or a piperazinyl group substituted by 1 to 3 groups independently selected from an alkoxy group and a phenyl group, and preferably the substituted C 4-6 The heterocycloalkyl group is N-isopropylpiperidin-4-yl.

[0031] In some embodiments, in Formula (I), R 4 is hydrogen, -C 1-3 alkyl group-at least one heterocycloalkyl group that is unsubstituted and selected from oxa and thia; 1-3 an alkyl group-substituted with at least one heterocycloalkyl group selected from oxa and thia; 1-3 Alkyl-substituted spiroheterocycloalkyl groups, -C 1-3 Alkyl group -C(O)NR 5 R 6 , -C 1-3 Alkyl group -NR 7 R 8 , -C 1-4 alkyl group-unsubstituted and at least one heteroaryl group selected from aza, oxa, and thia, and -C 1-4 alkyl-substituted and selected from at least one heteroaryl group selected from aza, oxa, and thia; R 5 and R 6 are independently hydrogen or C 1-3 Alternatively, R5 and R6 and the connected N together form C 4-6 or R 5 and R 6 And connected N together C 4-6 and R 7 and R 8 are independently hydrogen or C1-3 It may be an alkyl group, or R 7 and R 8 And connected N together C 4-6 or R 7 and R 8 And connected N together C 4-6 and R 4 is hydrogen, m is 0 and n is 1, and the substituted refers to substitution with one or more groups selected from the group consisting of a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C1-C4 alkanoyl group, a C1-C4 alkanoyloxy group, a hydroxyl group, a nitro group, a halogen atom, an oxo group, and a cyano group.

[0032] In some embodiments, in Formula (I), R 4 is selected from hydrogen, m is 0, and n is 1.

[0033] In some embodiments, in Formula (I), R 4 Ha-C 1-3 alkyl group-unsubstituted and at least one C selected from oxa and thia 2-6 Heterocycloalkyl groups, -C 1-3 alkyl-substituted and at least one C selected from oxa and thia 2-6 Heterocycloalkyl groups, -C 1-3 Alkyl-substituted spiroheterocycloalkyl groups, -C 1-3 Alkyl group -C(O)NR 5 R 6 , -C 1-3 Alkyl group -NR 7 R 8 , -C 1-4 alkyl group-unsubstituted and at least one C selected from aza, oxa and thia 3-6 Heteroaryl groups, and -C 1-4 alkyl group-substituted and at least one C selected from aza, oxa, and thia; 3-6 heteroaryl groups, R 5 and R6 are independently hydrogen or C 1-3 Alternatively, R5 and R6 and the connected N together form C 4-6 or R 5 and R 6 And connected N together C 4-6 and R 7 and R 8 are independently hydrogen or C 1-3 It may be an alkyl group, or R 7 and R 8 And connected N together C 4-6 or R 7 and R 8 And connected N together C 4-6 "Substituted" refers to being substituted with one or more groups selected from the group consisting of a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C1-C4 alkanoyl group, a C1-C4 alkanoyloxy group, a hydroxyl group, a nitro group, a halogen atom, an oxo group, and a cyano group.

[0034] In some embodiments, in Formula (I), R 4 is hydrogen, 2-(morpholino)ethyl, 2-(1,1-dioxothiomorpholine)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-(4-acetylpiperazin-1-yl)ethyl, 2-(3-oxopiperazin-1-yl)ethyl, 2-(pyrrolidin-1-yl)ethyl, 2-(piperidin-1-yl)ethyl, 2-(N,N'-dimethylamino)ethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, N,N'-dimethylacetamido, oxiran-2-ylmethyl, or 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl; R 4 is hydrogen, then m is 0 and n is 1.

[0035] In some embodiments, in Formula (I), R 4Ha-C 1-3 The alkyl group is a substituted spiroheterocycloalkyl group, and the substituted spiroheterocycloalkyl group may be an azaspiro[3.3]heptane, azaspiro[3.5]nonane, azaspiro[3.4]octane, azaspiro[5.5]undecane, or azaspiro[4.5]decane having zero or one oxa.

[0036] Furthermore, the compound represented by the formula (I) is the following compound, and its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite or prodrug. [ka] TIFF0007784037000008.tif232168TIFF0007784037000009.tif242169TIFF000 7784037000010.tif179168TIFF0007784037000011.tif126170TIFF00077840370 00012.tif177170TIFF0007784037000013.tif234170TIFF0007784037000014.t if174164TIFF0007784037000015.tif235165TIFF0007784037000016.tif119162

[0037] In some embodiments, the present application further discloses pharmaceutical compositions, the compositions comprising an effective dose of a piperidine derivative of general formula (I) according to the present application, and a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof, or further comprising one or more other therapeutic agents and a pharmaceutically acceptable carrier or excipient.

[0038] These pharmaceutically acceptable excipients include, for example, carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents (e.g., solid diluents such as fillers or bulking agents, and liquid diluents such as solvents and cosolvents), granulating agents, adhesives, flow aids, coating agents, controlled release agents (e.g., delayed or delayed release polymers or waxes), ), disintegrant, buffering agents, lubricants, preservatives, antifungal and antibacterial agents, Antioxidant, tension regulator The additives may be selected from thickeners, flavor enhancers, sweeteners, pigments, plasticizers, flavor masking agents, stabilizers or other excipients commonly used in pharmaceutical compositions.

[0039] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions and / or dosage forms are compatible, within the scope of sound medical judgment, with contact with the tissues of a subject (e.g., a human subject), without causing excessive toxicity, irritation, allergic response or other problem or complication, and are commensurate with a reasonable benefit / risk ratio. Each excipient is "acceptable" in the sense of compatibility with the other ingredients of the formulation.

[0040] Pharmaceutical compositions containing compounds of formula (I) can be formulated by known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

[0041] The pharmaceutical compositions may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intravaginal or transdermal administration.

[0042] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, or pastes such as buccal patches.

[0043] In some embodiments, the pharmaceutical composition further comprises one or more other therapeutic agents.

[0044] In some embodiments, the present application provides piperidine derivatives of general formula (I) according to the present application, and stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs thereof, for pharmaceutical use.

[0045] In some embodiments, the present application provides piperidine derivatives of general formula (I) according to the present application, and stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs thereof, for use in modulating the μ opioid peptide receptor (MOPR) and the κ opioid peptide receptor (KOPR), or the μ opioid peptide receptor (MOPR) and the nociceptin / orphanin receptor (NOPR or ORL-1 receptor).

[0046] In some embodiments, the present application provides piperidine derivatives represented by general formula (I) according to the present application, and stereoisomers, pharmaceutically acceptable salts, solvates, deuterated forms, metabolites, or prodrugs thereof, for use in the treatment of pain, anxiety, depression, alcohol addiction, and drug abuse / dependence.

[0047] In some embodiments, the present application further provides a method for treating pain, anxiety, depression, alcoholism, or drug abuse / dependence with a piperidine derivative represented by general formula (I), or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof, or a composition of the present application. The pain may be selected from acute pain, chronic pain, bone pain, joint pain, postoperative pain, muscle pain, dental pain, headache, inflammatory pain, neuropathic pain, and abdominal pain associated with Crohn's disease.

[0048] In some embodiments, the present application provides use of a piperidine derivative represented by general formula (I) according to the present application, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating pain, anxiety, depression, alcohol addiction, or drug abuse / dependence.

[0049] In some embodiments, the present application provides the above uses, wherein the pain may be selected from acute pain, chronic pain, bone pain, joint pain, post-operative pain, muscle pain, dental pain, headache, inflammatory pain, neuropathic pain, and abdominal pain associated with Crohn's disease.

[0050] In some embodiments, the present application provides a method for treating a disorder mediated by both the μ opioid peptide receptor (MOPR) and the kappa opioid peptide receptor (KOPR), or by both the μ opioid peptide receptor (MOPR) and the nociceptin / orphanin receptor (NOPR or ORL-1 receptor) in a patient, the method comprising administering to a patient in need thereof a piperidine derivative represented by general formula (I) according to the present application, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof, or a pharmaceutical composition thereof.

[0051] In some embodiments, the present application provides a method for treating or preventing pain, anxiety, depression, alcoholism, or drug abuse / dependence in a patient, the method comprising administering to a patient in need thereof a piperidine derivative of general formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof, or a pharmaceutical composition thereof. The pain may be selected from acute pain, chronic pain, bone pain, joint pain, postoperative pain, muscle pain, dental pain, headache, inflammatory pain, neuropathic pain, and abdominal pain associated with Crohn's disease.

[0052] In some embodiments, the present application provides a method for modulating the μ opioid peptide receptor (MOPR) and the κ opioid peptide receptor (KOPR), or the μ opioid peptide receptor (MOPR) and the nociceptin / orphanin receptor (NOPR or ORL-1 receptor), the method comprising administering a piperidine derivative represented by general formula (I) according to the present application or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof, or a pharmaceutical composition thereof.

[0053] In some embodiments, the present application provides a method for treating or preventing pain, anxiety, depression, alcohol addiction, or drug abuse / dependence in a patient by modulating the μ opioid peptide receptor (MOPR) and the κ opioid peptide receptor (KOPR), or the μ opioid peptide receptor (MOPR) and the nociceptin / orphanin receptor (NOPR or ORL-1 receptor), the method comprising administering to a patient in need thereof a piperidine derivative represented by general formula (I) or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof, or a pharmaceutical composition thereof. The pain may be selected from acute pain, chronic pain, bone pain, joint pain, postoperative pain, muscle pain, dental pain, headache, inflammatory pain, neuropathic pain, and abdominal pain associated with Crohn's disease.

[0054] In some embodiments, the present application provides a method for preparing the above-mentioned piperidine derivative, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof, comprising the steps of: (1) A compound of formula (I-1) is subjected to a conjugate reaction with a compound of formula (I-2) to obtain a compound of formula (I-3). [ka] (2) The compound of formula (I-3) is deprotected to obtain the compound of formula (I-4), which is then conjugated with the compound of formula (I-5) to obtain the compound of formula (I). [ka] Or, (1') A compound of formula (I-7) is obtained by subjecting a compound of formula (I-6) to a conjugate reaction with a compound of formula (I-5). [ka] (2) The compound of formula (I-7) is subjected to a conjugate reaction with the compound of formula (I-2) to obtain the compound of formula (I). [ka] In the above preparation methods, in formulas (I-2) and (I-5), X1 and X2 each represent a leaving group such as bromine, chlorine, or a sulfonate ester group, or the compound of formula (I-5) is an aldehyde, a ketone, or a boric acid; in formulas (I-1) and (I-3), Pr1 represents an amino-protecting group such as a tert-butoxycarbonyl group, a benzyloxycarbonyl group (CBz), or a fluorenylmethoxycarbonyl group (Fmoc); and the other groups in formulas (I-1) to (I-7) and formula (I) are as defined above.

[0055] Beneficial effects The compounds of the present invention have good opioid receptor activating activity, are suitable for pharmaceutical use, and have clinical application value.Furthermore, the synthesis process of the compounds of the present invention is simple, and therefore has good economic value.

[0056] Definitions and Explanations of Terms Unless otherwise specified, the definitions of groups and terms in the specification and claims, such as illustrative definitions, exemplary definitions, preferred definitions, definitions in tables, definitions of specific compounds in the examples, etc., can be combined in any combination, and such combinations and combined group definitions and compound structures should fall within the scope of the specification.

[0057] Carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen in the groups and compounds described herein includes any of their isotopes. Carbon, hydrogen, oxygen, sulfur, nitrogen, or halogen in the groups and compounds described herein may be optionally further substituted with one or more of their corresponding isotopes. Carbon isotopes are 12 C. 13 C and 14 C, isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and isotopes of oxygen include 16 O. 17 O and 18 O, and sulfur isotopes 32 S, 33 S, 34 S and 36Contains S, and nitrogen isotopes are 14 N and 15 Contains N, and the fluorine isotope is 19 Contains F, and the chlorine isotope is 35 Cl and 37 Contains Cl, and the bromine isotope is 79 Br and 81 Contains Br.

[0058] The term "alkyl group" refers to a linear or branched monovalent saturated hydrocarbon group having a main chain containing 1 to 10 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. The alkyl group may be further substituted with any substituent.

[0059] "Cycloalkyl group" refers to a monovalent saturated carbocyclic hydrocarbon group, which is monocyclic and typically has 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl groups. The cycloalkyl group may optionally be further substituted with any substituent.

[0060] "Heterocyclic alkane" refers to a saturated, monocyclic hydrocarbon group containing at least one heteroatom, the heteroatom being N, O, S, P, and their oxidized forms. Non-limiting examples include azacyclopropyl, oxacyclopropyl, thiacyclopropyl, azacyclobutyl, oxacyclobutyl, thiacyclobutyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, etc. The heterocyclic alkane may optionally be further substituted with any substituent.

[0061] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl groups. The aryl ring includes the above-described aryl ring fused to a heteroaryl group, heterocyclic group, or cycloalkyl ring, where the ring connected to the parent structure is an aryl ring. The aryl group may be substituted or unsubstituted. If substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably substituted with one or more substituents independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.

[0062] The term "heteroaryl group" refers to a heterocyclic aromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thienyl, pyridinyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl. The heteroaryl ring includes the above heteroaryl group fused to an aryl group, heterocyclic group, or cycloalkyl ring, and the ring connected to the parent structure is a heteroaryl ring.

[0063] "Pharmaceutically acceptable salts" refers to salts which retain the biological effectiveness and properties of the free acids or free bases and which are obtained by reaction of said free acids with non-toxic inorganic or organic bases, or by reaction of said free acids with non-toxic inorganic or organic acids.

[0064] The term "carrier" refers to a carrier or diluent that does not cause obvious irritation to the living body and does not eliminate the biological activity and properties of the compound being administered.

[0065] "Excipient" refers to an inert substance added to a pharmaceutical composition to be administered depending on the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, adhesives, disintegrating agents, etc.

[0066] The term "prodrug" refers to a compound that can be converted to a biologically active compound of the present application under physiological conditions or by solvolysis. The prodrugs of the present application are prepared by modifying the phenolic group in the compound, and the modification is removed by routine manipulation or in vivo to yield the parent compound. When the prodrugs of the present application are administered to a mammalian subject, the prodrugs are split to form free hydroxyl groups, respectively. Examples of prodrugs include, but are not limited to, phenolic hydroxyl groups and sodium phosphate salt derivatives of the present compounds.

[0067] An "effective dose" refers to that amount of a compound that elicits a physiological or medical response in a tissue, system, or subject, such that when administered to a subject, the compound produces or alleviates to a degree sufficient one or more symptoms of the disease or condition being treated to prevent it.

[0068] "Solvate" refers to a compound of the present application or a salt thereof, and further includes chemometric or non-chemometric solvents bound by intermolecular non-covalent interactions. When the solvent is water, it is a hydrate.

[0069] "Optionally" or "optionally" refers to a situation where the event or circumstance described below does not necessarily occur, and the statement includes cases where the event or circumstance occurs or does not occur. For example, "an alkyl group optionally substituted with F" refers to an alkyl group that may be substituted with F, but is not necessarily substituted with F, and the statement includes cases where the alkyl group is substituted with F and cases where the alkyl group is not substituted with F.

[0070] Other features and advantages of the present application will be set forth in the description which follows, and in part will be obvious from the description, or will be learned by the practice of the present application. The objectives and other advantages of the present application will be realized and obtained by the structure particularly pointed out in the written description, claims and drawings.

[0071] Specific Embodiments In order to make the purpose, technical solution and advantages of the present application clearer, the following detailed description of the embodiments of the present application is provided, and the features of the embodiments can be arbitrarily combined with each other unless there is a conflict.

[0072] The compounds of the general formula of the present application and their preparation methods and applications will be described in more detail below with reference to specific examples. The following examples are only for the purpose of explaining and interpreting the present application and should not be understood as limiting the scope of protection of the present application. Any technology realized based on the above content of the present application is included in the scope of protection of the present application.

[0073] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. The following abbreviations are used in this application: equiv. means equivalent ratio, sat. means saturated, M means mol / L, rt means room temperature, EtOH means ethanol, MeOH means methanol, DCM means dichloromethane, DCE means 1,2-dichloroethane, DMSO means dimethyl sulfoxide, DMF means N,N-dimethylformamide, EA means ethyl acetate, PE means petroleum ether, THF means tetrahydrofuran, TEA means triethylamine, TFA means trifluoroacetic acid, Ac OH represents acetic acid, CDI represents carbonyldiimidazole, Boc represents tert-butoxycarbonyl group (one of the amine protecting groups), NaBH(OAc)3 represents sodium triacetoxyborohydride, Boc2O represents di-tert-butyl dicarbonate, AIBN represents azobisisobutyronitrile, HMPA represents hexamethylphosphoric triamide, MsCl represents methanesulfonyl chloride, NBS represents N-bromosuccinimide, and TMS represents trimethylsilane.

[0074] Compounds are named according to conventional naming conventions in the art or by ChemDraw® software (PerkinElmer), and commercially available reagents take their manufacturer's catalog names.

[0075] 1H NMR data were collected and recorded at 400 MHz using a Bruker Ultrashield 400 nuclear magnetic resonance spectrometer. Chemical shift δ values ​​(ppm) are reported using CDCl3, CD3OD, DO, or DMSO-d6 as solvents and TMS (δ = 0) as the internal standard. Mass spectra were collected and recorded on a Shimadzu LCMS-2020 system and detected using a Shimadzu shim-pack VP-ODS (150 L*2.0, 4.6 μM) column. Mobile phase A was 0.1% trifluoroacetic acid in water, and mobile phase B was acetonitrile. High-performance liquid chromatography (HPLC) was performed on an Agilent Technologies 1260 Infinity liquid chromatograph and detected using a YMC Triart C18 EXRS (4.6*150 mm, 3 μm) column. Gradient elution conditions: 1.0 mL / min flow rate, 30% to 10% solvent A1 and 70% to 90% solvent B1, then 90% B1 and 10% A1, held for 0.5 min. Percentages are the volume percentage of a given solvent relative to the total solvent volume. Solvent A1 is a 0.1% aqueous solution of ammonia, and solvent B1 is acetonitrile. Percentages are the volume percentage of the solute in the solution. The injection volume is determined by the concentration of the reaction solution; typically, a 0.2 mg / mL sample has an on-column volume of 2 μL. The detection wavelength is 254 / 220 nm, and the column temperature is 30°C.

[0076] Example 1: Synthesis of 5,6-dichloro-1-(1-(3,4-dichlorobenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound EX1) [ka]

[0077] Synthesis of intermediate 1c: 4,5-dichloro-2-fluoronitrobenzene (1a) (10.00 g, 47.62 mmol), N-Boc-4-aminopiperidine (9.54 g, 47.62 mmol), and DMF (120 mL) were placed in a clean, dry, single-neck flask (250 mL). Anhydrous K2CO3 (9.87 g, 71.43 mmol) was added, and the mixture was heated to 60 °C and stirred for 2 hours. TLC showed that the reaction of the raw materials was almost complete. After the reaction was complete, the reaction mixture was cooled to room temperature and slowly poured into an ice-water mixture (500 mL) under stirring. A large amount of yellow solid precipitated. This was filtered, washed with a small amount of water, and dried to obtain 17.58 g of yellow solid product in 94.59% yield. 1 H NMR (400 MHz, chloroform-d) δ 8.30 (s, 1H), 8.01 (d, J = 7.4 Hz, 1H), 6.98 (s, 1H), 4.03 (d, J = 13.3 Hz, 2H), 3.68 - 3.53 (m, 1H), 3.06 (t, J = 12.3 Hz, 2H), 2.05 (d, J = 13.0 Hz, 2H), 1.59 - 1.48 (m, 2H), 1.48 (s, 9H).

[0078] Synthesis of intermediate 1d: tert-butyl 4-((4,5-dichloro-2-nitrophenyl)amino)piperidine-1-carboxylate (1c) (17.50 g, 44.84 mmol) was taken and placed in a single-neck flask (1 L). Anhydrous ethanol (450 mL) was added to the reaction flask and stirred at room temperature. Iron powder (15.03 g, 269.05 mmol) and saturated aqueous NH4Cl solution (45 mL) were added to the reaction system and heated to 80 °C. The reaction was continued for 1.5 hours with stirring. The TLC plate showed that the reaction of the raw materials was almost complete. The mixture was filtered through diatomaceous earth and the filter cake was washed with a small amount of anhydrous ethanol. The filtrate was evaporated under reduced pressure using a rotary evaporator to obtain a white solid. The solid was then extracted with ethyl acetate (350 mL). The crude product was dissolved in petroleum ether (200 mL), dispersed, pulped, filtered, and dried to give 14.23 g of an orange solid product, with a yield of 88.08%. 1 H NMR (400 MHz, chloroform-d) δ 6.78 (s, 1H), 6.66 (s, 1H), 4.04 (s, 2H), 3.52–3.16 (m, 4H), 2.95 (t, J = 12.5 Hz, 2H), 2.08–1.96 (m, 2H), 1.47 (d, J = 1.5 Hz, 9H), 1.43–1.30 (m, 2H).

[0079] Synthesis of intermediate 1e: tert-butyl 4-((2-amino-4,5-dichlorophenyl)amino)piperidine-1-carboxylate (1d) (14.20 g, 39.41 mmol) and anhydrous tetrahydrofuran (300 mL) were placed in a clean, dry three-necked flask (500 mL). The flask was purged with argon gas and cooled to 0 °C in an ice-water bath. A solution of N,N'-carbonyldiimidazole (8.31 g, 51.24 mmol) in dichloromethane (50 mL) was added dropwise. After the addition was completed, the ice-water bath was removed and the mixture was stirred at room temperature for 1 hour. The mixture was then heated to 35 °C and stirred for 18 hours. TLC showed that the reaction of the raw materials was almost complete. Saturated aqueous NaHCO3 solution (150 mL) was gradually added to the reaction mixture under stirring, and the mixture was extracted with ethyl acetate (250 mL x 3). The organic phase was dried over anhydrous Na2SO4 and then filtered. The filtrate was evaporated under reduced pressure using a rotary evaporator to obtain a gray-white solid crude product. Petroleum ether (250 mL) and ethyl acetate (2.5 mL) were added to the crude product, which was dispersed, pulped, filtered, and dried to obtain 14.50 g of a gray-white solid product with a yield of 95.22%. 1 H NMR (400 MHz, chloroform-d) δ 10.66 (s, 1H), 7.23 (s, 1H), 7.20 (s, 1H), 4.50–4.22 (m, 3H), 2.97–2.77 (m, 2H), 2.35–2.17 (m, 2H), 1.88–1.76 (m, 2H), 1.53 (s, 9H).

[0080] Synthesis of intermediate 1g: tert-butyl 4-(4,5-dichloro-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (1e) (5.00 g, 12.94 mmol) was taken in a dry three-necked round-bottom flask (250 mL), anhydrous tetrahydrofuran (130 mL) was added, and the flask was purged with argon gas. The flask was cooled to 0°C in an ice-water bath, and NaH (2.59 g, 64.72 mmol, 60% in mineral oil) was added to the reaction mixture in batches. After the addition was complete, the mixture was stirred for 30 minutes, and 4-(2-bromoethyl)morpholine hydrobromide (4.81 g, 17.47 mmol) was added to the reaction mixture gradually. After the addition, the mixture was stirred for 1 hour, the ice-water bath was removed, and the mixture was gradually heated to 35 ° C. The mixture was stirred for 18 hours, and TLC showed that the reaction of the raw materials was almost complete. The reaction was quenched by adding ice water dropwise to the reaction system while cooling and stirring in an ice-water bath. The mixture was extracted with ethyl acetate (150 mL × 3), the organic phase was dried over anhydrous Na2SO4, and then filtered. The filtrate was evaporated under reduced pressure using a rotary evaporator to obtain a crude off-white solid product. Petroleum ether (150 mL) was added to the crude product, and the mixture was dispersed, stirred, filtered, and dried to obtain 5.85 g of a white solid product with a yield of 90.49%. 1 H NMR (400 MHz, chloroform-d) δ 7.17 (s, 1H), 7.14 (s, 1H), 4.47 - 4.19 (m, 3H), 3.95 (t, J = 6.6 Hz, 2H), 3.74 - 3.60 (m, 4H), 2.85 (t, J = 12.5 Hz, 2H), 2.65 (t, J = 6.6 Hz, 2H), 2.59 - 2.44 (m, 4H), 2.24 (qd, J = 12.8, 4.5 Hz, 2H), 1.80 (d, J = 12.1 Hz, 2H), 1.51 (s, 9H). tert-Butyl 4-(5,6-dichloro-3-(2-morpholinoethyl)-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (1f) (5.85 g, 11.71 mmol) was placed in a dry, single-necked flask (100 mL). Anhydrous dichloromethane (60 mL) was added. Under cooling conditions in an ice-water bath, trifluoroacetic acid (15 mL) was added dropwise. After the addition was complete, the ice-water bath was removed and the mixture was stirred at room temperature for 3 hours. TLC showed that the reaction of the raw materials was almost complete. The solvent was evaporated under reduced pressure using a rotary evaporator to obtain a light brown oily crude product. Ether (150 mL) was added to the crude product, which was dispersed, stirred, filtered, and dried to obtain 6.01 g of a white solid product in a 99.95% yield. The white solid did not require further purification and was used directly in the next experiment.

[0081] Synthesis of compound EX1: 5,6-dichloro-1-(2-morpholinoethyl)-3-(piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one trifluoroacetate (1g) (100 mg, 195 μM) and anhydrous 1,2-dichloroethane (2 mL) were placed in a dry Schlenk tube. Dry triethylamine (19.7 mg, 195 μmol, 27 μL) was added and stirred for 5 min. 3,4-dichlorobenzaldehyde (51 mg, 292 μmol), acetic acid (14 mg, 234 μmol, 14 μL), NaBH(OAc) (1.17 mmol, 248 mg), and 4 Å molecular sieves (100 mg) were added to the reaction tube. The reaction was stirred at room temperature for 24 h under argon gas. The TLC plate showed that the reaction of the raw materials was nearly complete. The reaction was quenched by adding saturated aqueous sodium bicarbonate to the reaction flask, followed by extraction with dichloromethane three times. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure using a rotary evaporator to obtain the crude product. The crude product was purified by separation on a silica gel column (mobile phase: dichloromethane and methanol, 150:1 to 70:1 ratio) to obtain 55 mg of a white solid product in 50.6% yield. LC-MS (ESI) m / z: 557.10 (M+H). + ; 1H NMR (400 MHz, chloroform-d) δ 7.48 (s, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.30 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 4.34 - 4.22 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 3.51 (s, 2H), 3.01 (d, J = 11.2 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.39 (q, J = 11.1 Hz, 2H), 2.17 (t, J = 11.7 Hz, 2H), 1.78 (d, J = 11.7 Hz, 2H).

[0082] Example 2: Synthesis of 5,6-dichloro-1-(1-(3,4-difluorobenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX2) [ka] Using intermediate 1g and 3,4-difluorobenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 525.20 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.30 (s, 1H), 7.26 - 7.18 (m, 1H), 7.16 - 7.10 (m, 2H), 7.10 - 7.03 (m, 1H), 4.36 - 4.23 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 3.51 (s, 2H), 3.01 (d, J = 11.3 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.38 (q, J = 11.0, 10.5 Hz, 2H), 2.16 (t, J = 11.5 Hz, 2H), 1.78 (d, J = 11.7 Hz, 2H).

[0083] Example 3: Synthesis of 5,6-dichloro-1-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX3) [ka] Using intermediate 1g and 2-chloro-4-fluorobenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 541.10 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.52 (t, J = 7.3 Hz, 1H), 7.30 (s, 1H), 7.15 - 7.09 (m, 2H), 7.04 - 6.98 (m, 1H), 4.37 - 4.23 (m, 1H), 3.95 (t, J = 6.6 Hz, 2H), 3.73 - 3.57 (m, 6H), 3.05 (d, J = 11.0 Hz, 2H), 2.65 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.7 Hz, 4H), 2.47 - 2.33 (m, 2H), 2.28 (t, J = 11.6 Hz, 2H), 1.79 (d, J = 11.6 Hz, 2H).

[0084] Example 4: Synthesis of 5,6-dichloro-1-(2-morpholinoethyl)-3-(1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX4) [ka] Using intermediate 1g and 4-trifluoromethylbenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 557.20 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.60 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 7.30 (s, 1H), 7.13 (s, 1H), 4.36 - 4.24 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.67 (t, J = 4.7 Hz, 4H), 3.62 (s, 2H), 3.02 (d, J = 11.3 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.40 (q, J = 11.5 Hz, 2H), 2.19 (t, J = 11.5 Hz, 2H), 1.78 (d, J = 11.8 Hz, 2H).

[0085] Example 5: Synthesis of 5,6-dichloro-1-(2-morpholinoethyl)-3-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX5) [ka] Using Intermediate 1g and 4-trifluoromethoxybenzaldehyde as raw materials, synthesize the compound according to the synthesis method of Example 1. LC-MS (ESI) m / z: 573.20; 1H NMR (400 MHz, chloroform-d) δ 7.40 (d, J = 8.1 Hz, 2H), 7.31 (s, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.12 (s, 1H), 4.36 - 4.23 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 3.56 (s, 2H), 3.03 (d, J = 11.2 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.38 (q, J = 10.3 Hz, 2H), 2.17 (t, J = 11.3 Hz, 2H), 1.78 (d, J = 10.6 Hz, 2H).

[0086] Example 6: Synthesis of 5,6-dichloro-1-(1-(2,4-dichlorobenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX6) [ka] Using Intermediate 1g and 2,4-dichlorobenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 557.10 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.50 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.12 (s, 1H), 4.37 - 4.22 (m, 1H), 3.95 (t, J = 6.6 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 3.64 (s, 2H), 3.04 (d, J = 10.9 Hz, 2H), 2.65 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.40 (q, J = 11.9 Hz, 2H), 2.28 (t, J = 11.2 Hz, 2H), 1.78 (d, J = 10.9 Hz, 2H).

[0087] Example 7: Synthesis of 1-(1-(4-(tert-butyl)benzyl)piperidin-4-yl)-5,6-dichloro-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX7) [ka] Using intermediate 1g and 4-tert-butylbenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 545.30 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.39 - 7.32 (m, 3H), 7.29 (d, J = 8.1 Hz, 2H), 7.11 (s, 1H), 4.37 - 4.24 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.66 (t, J = 4.6 Hz, 4H), 3.55 (s, 2H), 3.06 (d, J = 11.2 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.45 - 2.28 (m, 2H), 2.15 (t, J = 11.1 Hz, 2H), 1.76 (d, J = 10.9 Hz, 2H), 1.33 (s, 9H).

[0088] Example 8: Synthesis of 1-(1-(4-(tert-butyl)cyclohexyl)piperidin-4-yl)-5,6-dichloro-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound EX8) [ka] Using intermediate 1g and 4-tert-butylcyclohexanone as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 537.30 (M+H) + ; 1 H NMR (400 MHz, chloroform-d) δ 7.26 (s, 1H), 7.12 (s, 1H), 4.31 - 4.18 (m, 1H), 3.94 (t, J = 6.7 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 3.26 (d, J = 11.4 Hz, 2H), 2.65 (t, J = 6.7 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.40 - 2.21 (m, 3H), 2.08 - 1.89 (m, 4H), 1.78 (d, J = 10.7 Hz, 2H), 1.51 - 1.28 (m, 6H), 1.17 - 1.05 (m, 1H), 0.89 (s, 9H).

[0089] Example 9: Synthesis of 5,6-dichloro-1-(1-cyclohexylpiperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX9) [ka] Using intermediate 1g and cyclohexanone as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 481.20 (M+H) + ; 1 H NMR (400 MHz, chloroform-d) δ 7.39 (s, 1H), 7.11 (s, 1H), 4.38 - 4.21 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 3.06 (d, J = 10.9 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.48 - 2.20 (m, 5H), 1.95 - 1.73 (m, 6H), 1.65 (d, J = 12.7 Hz, 1H), 1.34 - 1.18 (m, 4H), 1.19 - 1.03 (m, 1H).

[0090] Example 10: Synthesis of 5,6-dichloro-1-(1-cycloheptylpiperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX10) [ka] Using intermediate 1g and cycloheptanone as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 495.20 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.38 (s, 1H), 7.11 (s, 1H), 4.35 - 4.19 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 2.94 (d, J = 11.0 Hz, 2H), 2.70 - 2.58 (m, 3H), 2.52 (t, J = 4.6 Hz, 4H), 2.44 (t, J = 11.3 Hz, 2H), 2.28 (q, J = 11.6, 10.5 Hz, 2H), 1.92 - 1.82 (m, 2H), 1.78 (d, J = 10.0 Hz, 2H), 1.75 - 1.65 (m, 2H), 1.62 - 1.37 (m, 8H).

[0091] Example 11: Synthesis of 5,6-dichloro-1-(1-(cyclohexylmethyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX11) [ka] Using intermediate 1g and cyclohexylformaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 495.20 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.32 (s, 1H), 7.11 (s, 1H), 4.35 - 4.20 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 3.02 (d, J = 11.3 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.34 (q, J = 11.6, 10.0 Hz, 2H), 2.17 (d, J = 7.0 Hz, 2H), 2.06 (t, J = 11.2Hz, 2H), 1.88 - 1.63 (m, 7H), 1.49 (bs, 1H), 1.32 - 1.11 (m, 3H), 0.90 (q, J = 10.9, 10.2 Hz, 2H).

[0092] Example 12: Synthesis of 5,6-dichloro-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX12) [ka] Synthesis of compound EX12: 5,6-Dichloro-1-(2-morpholinoethyl)-3-(piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one trifluoroacetate (1g) (100 mg, 195 μM) and anhydrous 1,2-dichloroethane (2 mL) were placed in a dry Schlenk tube. Dry triethylamine (23 mg, 233 μmol, 32 μL) was added and stirred for 5 minutes. 4-Isopropylcyclohexanone (55 mg, 390 μmol), acetic acid (15 mg, 253 μmol, 14 μL), and NaBH(OAc)3 (165 mg, 779 μmol) were added to the reaction tube. Protected under argon gas, the reaction mixture was heated to 40 °C and stirred for 72 hours. The TLC plate showed that the reaction of the raw materials was almost complete. The reaction was quenched by adding saturated aqueous sodium bicarbonate to the reaction flask, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure using a rotary evaporator to obtain the crude product. The crude product was purified by separation using a silica gel column (the mobile phase was dichloromethane and methanol in a ratio of 150:1 to 70:1), and 86 mg of a white solid product was obtained, with a yield of 84.3%.

[0093] Example 12A: Synthesis of 5,6-dichloro-1-(1-(trans-4-isopropylcyclohexyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound EX12A) [ka] Compound EX12 of Example 12 was separated and purified from compound EX12 by high-performance liquid chromatography (Waters high-performance liquid chromatograph, column: YMC-Triart-C18 EXRS 20 mm x 100 mm x 5 μm, mobile phase: A = water + 0.1% by volume aqueous ammonia (25%), B = acetonitrile, gradient 70% to 90% B, 10 min), to obtain 15 mg of a white solid product, a yield of 14.71%. LC-MS (ESI) m / z: 523.20 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.36 (s, 1H), 7.11 (s, 1H), 4.33 - 4.20 (m, 1H), 3.94 (t, J = 6.7 Hz, 2H), 3.67 (d, J = 4.7 Hz, 4H), 3.15 (d, J = 11.1 Hz, 2H), 2.64 (t, J = 6.7 Hz, 2H), 2.52 (d, J = 4.6 Hz, 4H), 2.38 - 2.17 (m, 5H), 1.85 - 1.68 (m, 6H), 1.65 - 1.59 (m, 2H), 1.57 - 1.49 (m, 2H), 1.44 - 1.33 (m, 2H), 1.19 - 1.09 (m, 1H), 0.91 (s, 3H), 0.89 (s, 3H).

[0094] Example 12B: Synthesis of 5,6-dichloro-1-(1-(cis-4-isopropylcyclohexyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound EX12B) [ka] Compound EX12 of Example 12 was separated and purified from compound EX12 by high-performance liquid chromatography (Waters high-performance liquid chromatograph, column: YMC-Triart-C18 EXRS 20 mm x 100 mm x 5 μm, mobile phase: A = water + 0.1% by volume aqueous ammonia (25%), B = acetonitrile, gradient 70% to 90% B, 10 min), to obtain 44 mg of a white solid cis product, a yield of 43.14%. LC-MS (ESI) m / z: 523.20 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.36 (s, 1H), 7.11 (s, 1H), 4.32 - 4.21 (m, 1H), 3.94 (t, J = 6.7 Hz, 2H), 3.67 (d, J = 4.7 Hz, 4H), 3.15 (d, J = 11.1 Hz, 2H), 2.64 (t, J = 6.7 Hz, 2H), 2.52 (d, J = 4.7 Hz, 4H), 2.36 - 2.17 (m, 5H), 1.86 - 1.67 (m, 6H), 1.65 - 1.52 (m, 4H), 1.43 - 1.33 (m, 2H), 1.18 - 1.08 (m, 1H), 0.90 (s, 3H), 0.88 (s, 3H).

[0095] Example 13: Synthesis of 5,6-dichloro-1-(1-(4-chlorophenyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX13) [ka] Intermediate 1g (100 mg, 194 μmol) and anhydrous dichloromethane (2 mL) were placed in a dry Schlenk tube. Triethylamine (39 mg, 389 μmol, 54 μL) was added and stirred for 5 minutes. 4-Chlorophenylboronic acid (61 mg, 389 μmol), Cu(OAc)2 (35 mg, 194 μmol), and 4Å molecular sieves (100 mg) were added to the reaction tube and stirred at room temperature for 24 hours. TLC showed that the reaction of the raw materials was almost complete. Dichloromethane (10 mL) was added to the reaction tube and filtered through diatomaceous earth. The filtrate was evaporated under reduced pressure on a rotary evaporator to obtain the crude product. This was purified by silica gel column separation (mobile phase: dichloromethane / methanol, 110:1 to 100:1), yielding 40 mg of a white solid product in 40.3% yield. LC-MS(ESI) m / z:509.00 (M+H) + ; 1 H NMR (400 MHz, chloroform-d) δ 7.26 - 7.20 (m, 3H), 7.15 (s, 1H), 6.91 (d, J = 9.0 Hz, 2H), 4.49 - 4.37 (m, 1H), 3.97 (s, 2H), 3.78 (d, J = 12.5 Hz, 2H), 3.68 (s, 4H), 2.88 (t, J = 11.7 Hz, 2H), 2.68 (bs, 2H), 2.62 - 2.37 (m, 6H), 1.92 (d, J = 10.7 Hz, 2H).

[0096] Example 14: Synthesis of 1-(1-(4-(tert-butyl)phenyl)piperidin-4-yl)-5,6-dichloro-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX14) [ka] Using intermediate 1g and 4-tert-butylphenylboronic acid as raw materials, synthesize according to the synthesis method of Example 13. LC-MS (ESI) m / z: 531.10 (M+H) + ;1 H NMR (400 MHz, chloroform-d) δ 7.32 (d, J = 8.7 Hz, 2H), 7.27 (s, 1H), 7.14 (s, 1H), 6.94 (d, J = 8.7 Hz, 2H), 4.50 - 4.37 (m, 1H), 3.96 (t, J = 6.7 Hz, 2H), 3.81 (d, J = 11.9 Hz, 2H), 3.72 - 3.63 (m, 4H), 2.87 (t, J = 11.6 Hz, 2H), 2.66 (t, J = 6.6 Hz, 2H), 2.59 - 2.43 (m, 6H), 1.90 (d, J = 10.5 Hz, 2H), 1.31 (s, 9H).

[0097] Example 15: Synthesis of 5,6-dichloro-1-(2-morpholinoethyl)-3-(1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX15) [ka] Intermediate 1g (100 mg, 194 μmol) and anhydrous DMF (2 mL) were placed in a dry Schlenk tube. 2-Chloro-5-trifluoromethylpyridine (35 mg, 194 μmol) and K2CO3 (81 mg, 584 μmol) were added, and the mixture was heated to 60 °C and stirred for 5 hours. TLC showed that the reaction of the raw materials was almost complete. After cooling the reaction mixture to room temperature, a small amount of water was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then filtered. The filtrate was evaporated under reduced pressure on a rotary evaporator to obtain the crude product. The crude product was purified by silica gel column separation (mobile phase: petroleum ether / ethyl acetate, 5:1 to 1:1 ratio) to obtain 45 mg of a white solid product in 42.4% yield. LC-MS (ESI) m / z: 544.01 (M+H). + ; 1H NMR (400 MHz, chloroform-d) δ 8.43 (s, 1H), 7.67 (dd, J = 9.0, 2.5 Hz, 1H), 7.14 (s, 1H), 7.12 (s, 1H), 6.73 (d, J = 9.0 Hz, 1H), 4.70 - 4.60 (m, 2H), 4.58 - 4.46 (m, 1H), 3.95 (t, J = 6.5 Hz, 2H), 3.73 - 3.61 (m, 4H), 3.04 (td, J = 13.1, 2.6 Hz, 2H), 2.65 (t, J = 6.5 Hz, 2H), 2.59 - 2.45 (m, 4H), 2.37 (qd, J = 12.7, 4.3 Hz, 2H), 1.99 - 1.89 (m, 2H).

[0098] Example 16: Synthesis of 5,6-dichloro-1-(1-(4-chloro-2-fluorobenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX16) [ka] Using intermediate 1g and 2-fluoro-4-chlorobenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 541.20 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.40 (t, J = 8.1 Hz, 1H), 7.30 (s, 1H), 7.15 (dd, J = 8.3, 2.0 Hz, 1H), 7.12 (s, 1H), 7.09 (dd, J = 9.6, 2.1 Hz, 1H), 4.33 - 4.21 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.66 (t, J = 4.6 Hz, 4H), 3.61 (s, 2H), 3.04 (d, J = 11.1 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.46 - 2.29 (m, 2H), 2.23 (t, J = 11.7 Hz, 2H), 1.78 (d, J = 10.4 Hz, 2H).

[0099] Example 17: Synthesis of 5,6-dichloro-1-(1-(2,4-difluorobenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX17) [ka] Using intermediate 1g and 2,4-difluorobenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 525.30 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.47 - 7.35 (m, 1H), 7.31 (s, 1H), 7.12 (s, 1H), 6.89 (td, J = 8.4, 2.5 Hz, 1H), 6.81 (td, J = 9.4, 2.5 Hz, 1H), 4.34 - 4.21 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.66 (t, J = 4.6 Hz, 4H), 3.61 (s, 2H), 3.04 (d, J = 11.1 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.45 - 2.30 (m, 2H), 2.22 (t, J = 11.7 Hz, 2H), 1.78 (d, J = 11.3 Hz, 2H).

[0100] Example 18: Synthesis of 5,6-dichloro-1-(1-(2-chloro-4-methylphenylmethyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX18) [ka] Using Intermediate 1g and 2-chloro-4-methylbenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 538.30 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.40 (d, J = 7.6 Hz, 1H), 7.31 (s, 1H), 7.19 (s, 1H), 7.11 (s, 1H), 7.08 (d, J = 7.8 Hz, 1H), 4.37 - 4.23 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.73 - 3.59 (m, 6H), 3.07 (d, J = 11.0 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.7 Hz, 4H), 2.46 - 2.34 (m, 2H), 2.33 (s, 3H), 2.31 - 2.20 (m, 2H), 1.77 (d, J = 11.2 Hz, 2H).

[0101] Example 19: Synthesis of 5,6-dichloro-1-(1-(4-fluoro-2-methylbenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX19) [ka] Using intermediate 1g and 4-fluoro-2-methylbenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 521.30 (M+H) + ; 1 H NMR (400 MHz, chloroform-d) δ 7.28 - 7.21 (m, 2H), 7.12 (s, 1H), 6.93 - 6.81 (m, 2H), 4.36 - 4.22 (m, 1H), 3.94 (t, J = 6.7 Hz, 2H), 3.73 - 3.61 (m, 4H), 3.46 (s, 2H), 3.01 (d, J = 11.1 Hz, 2H), 2.64 (t, J = 6.8 Hz, 2H), 2.58 - 2.44 (m, 4H), 2.40 (s, 3H), 2.37 - 2.25 (m, 2H), 2.16 (t, J = 11.7 Hz, 2H), 1.76 (d, J = 12.7 Hz, 2H).

[0102] Example 20: Synthesis of 5,6-dichloro-1-(1-(4-ethylcyclohexyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX20) [ka] Using Intermediate 1g and 4-ethylcyclohexanone as starting materials, synthesize the compound according to the synthesis method of Example 1. LC-MS (ESI) m / z: 509.30 (cis-trans isomer mixture). 1 H NMR (400 MHz, chloroform-d) δ 7.38 (s, 1H), 7.11 (s, 1H), 4.39 - 4.20 (m, 1H), 3.95 (t, J = 6.7 Hz, 2H), 3.73 - 3.61 (m, 4H), 3.21 - 3.00 (m, 2H), 2.64 (t, J = 6.8 Hz, 2H), 2.59 - 2.47 (m, 4H), 2.47 - 2.15 (m, 5H), 2.00 - 1.72 (m, 4H), 1.68 - 1.53 (m, 4H), 1.51 - 1.41 (m, 2H), 1.40 - 1.29 (m, 2H), 1.28 - 1.15 (m, 1H), 0.88 (t, J = 7.4 Hz, 3H).

[0103] Example 21: Synthesis of 5,6-dichloro-1-(1-(4-methylcyclohexyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX21) [ka] Using Intermediate 1g and 4-methylcyclohexanone as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 495.30 (M+H) + (cis-trans isomer mixture, main product: by-product = 2:1) Main product:1 H NMR (400 MHz, chloroform-d) δ 7.39 (d, J = 9.8 Hz, 1H), 7.12 (s, 1H), 4.38 - 4.21 (m, 1H), 3.95 (t, J = 6.7 Hz, 2H), 3.73 - 3.62 (m, 4H), 3.13 (d, J = 7.7 Hz, 1H), 2.64 (t, J = 6.7 Hz, 2H), 2.60 - 2.46 (m, 4H), 2.45 - 2.21 (m, 5H), 1.91 - 1.73 (m, 4H), 1.67 - 1.43 (m, 6H), 1.30 (q, J = 12.1 Hz, 1H), 0.96 (d, J = 6.9 Hz, 3H).

[0104] Example 22: Synthesis of 5,6-dichloro-1-(2-morpholinoethyl)-3-(1-(4-(trifluoromethyl)cyclohexyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX22) [ka] Using Intermediate 1g and 4-trifluoromethylcyclohexanone as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 549.30 (M+H) + (cis-trans isomer mixture, main product: by-product = 2:1) Main product: 1H NMR (400 MHz, chloroform-d) δ 7.31 (s, 1H), 7.12 (s, 1H), 4.38 - 4.19 (m, 1H), 3.95 (t, J = 6.8 Hz, 2H), 3.75 - 3.59 (m, 4H), 3.17 (d, J = 11.2 Hz, 2H), 2.65 (t, J = 6.8 Hz, 2H), 2.59 - 2.48 (m, 4H), 2.44 - 2.28 (m, 3H), 2.25 - 2.12 (m, 2H), 2.11 - 1.99 (m, 2H), 1.98 - 1.86 (m, 3H), 1.81 (d, J = 12.1 Hz, 2H), 1.66 - 1.51 (m, 2H), 1.45 - 1.21 (m, 2H).

[0105] Example 23: Synthesis of 5,6-dichloro-1-(1'-isopropyl-[1,4'-bipiperidin]-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX23) [ka] Using Intermediate 1g and N-isopropyl-4-piperidone as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 524.40 (M+H) + ; 1 H NMR (400 MHz, chloroform-d) δ 7.37 (s, 1H), 7.11 (s, 1H), 4.29 (t, J = 12.7 Hz, 1H), 3.94 (t, J = 6.8 Hz, 2H), 3.79 - 3.58 (m, 5H), 3.12 - 2.93 (m, 4H), 2.76 (br s, 1H), 2.64 (t, J = 6.8 Hz, 2H), 2.57 - 2.48 (m, 4H), 2.48 - 2.23 (m, 6H), 2.17 (br s, 2H), 1.89 - 1.76 (m, 4H), 1.67 (br s, 2H), 1.07 (d, J = 6.3 Hz, 6H).

[0106] Example 24: Synthesis of 5,6-dichloro-1-(1-(4-fluorobenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX24) [ka] Using intermediate 1g and 4-fluorobenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 507.30 (M+H) + ; 1 H NMR (400 MHz, chloroform-d) δ 7.38 - 7.28 (m, 3H), 7.12 (s, 1H), 7.03 (t, J = 8.6 Hz, 2H), 4.38 - 4.23 (m, 1H), 3.94 (t, J = 6.7 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 3.53 (s, 2H), 3.02 (d, J = 11.2 Hz, 2H), 2.64 (t, J = 6.7 Hz, 2H), 2.52 (t, J = 4.7 Hz, 4H), 2.36 (q, J = 22.4, 10.0 Hz, 2H), 2.14 (t, J = 11.9 Hz, 2H), 1.77 (d, J = 11.0 Hz, 2H).

[0107] Example 25: Synthesis of 5,6-dichloro-1-(1-(4-chlorophenylmethyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX25) [ka] Using intermediate 1g and 4-chlorobenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 523.20 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.32 (s, 5H), 7.12 (s, 1H), 4.38 - 4.23 (m, 1H), 3.94 (t, J = 6.7 Hz, 2H), 3.73 - 3.62 (m, 4H), 3.55 (s, 2H), 3.13 - 2.92 (m, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.59 - 2.47 (m, 4H), 2.38 (br s, 2H), 2.26 - 2.07 (m, 2H), 1.78 (d, J = 12.3 Hz, 2H).

[0108] Example 26: Synthesis of 5,6-dichloro-1-(1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX26) [ka] Using intermediate 1g and 2-indanone as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 515.30 (M+H) + ; 1 H NMR (400 MHz, chloroform-d) δ 7.39 (s, 1H), 7.24 - 7.17 (m, 2H), 7.17 - 7.09 (m, 3H), 4.43 - 4.28 (m, 1H), 3.95 (t, J = 6.5 Hz, 2H), 3.73 - 3.61 (m, 4H), 3.35 - 3.23 (m, 1H), 3.23 - 3.04 (m, 4H), 2.95 (dd, J = 15.5, 8.5 Hz, 2H), 2.64 (t, J = 6.7 Hz, 2H), 2.58 - 2.47 (m, 4H), 2.39 (q, J = 12.5 Hz, 2H), 2.24 (t, J = 11.8 Hz, 2H), 1.84 (d, J = 11.9 Hz, 2H).

[0109] Example 27: Synthesis of 5,6-dichloro-1-(1-(2-chlorocyclohexyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX27) [ka] Using Intermediate 1g and 2-chlorocyclohexanone as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 515.30 (M+H) + ; 1 H NMR (400 MHz, chloroform-d)δ 7.37 (s, 1H), 7.11 (s, 1H), 4.62 (s, 1H), 4.39 - 4.25 (m, 1H), 3.95 (t, J = 6.7 Hz, 2H), 3.67 (t, J = 4.4 Hz, 4H), 3.28 (d, J = 9.9 Hz, 2H), 2.64 (t, J = 6.7 Hz, 2H), 2.57 - 2.43 (m, 6H), 2.41 - 2.21 (m, 3H), 2.07 (d, J = 10.7 Hz, 1H), 1.91 - 1.66 (m, 8H), 1.56 - 1.45 (m, 1H), 1.32 (br s, 1H).

[0110] Example 28: Synthesis of 5,6-dichloro-1-(1-(4-chloro-2-methylbenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX28) [ka] Using intermediate 1g and 4-chloro-2-methylbenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 537.20 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.24 (d, J = 8.8 Hz, 2H), 7.19 - 7.09 (m, 3H), 4.35 - 4.22 (m, 1H), 3.94 (t, J = 6.7 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 3.46 (s, 2H), 3.01 (d, J = 11.1 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.42 - 2.26 (m, 5H), 2.17 (t, J = 11.7 Hz, 2H), 1.76 (d, J = 11.6 Hz, 2H).

[0111] Example 29: Synthesis of 5,6-dichloro-1-(1-(4-chloro-2-methoxybenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX29) [ka] Using Intermediate 1g and 4-chloro-2-methoxybenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 553.20 (M+H) + ; 1 H NMR (400 MHz, chloroform-d) δ 7.35 (d, J = 7.1 Hz, 2H), 7.12 (s, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.87 (s, 1H), 4.36 - 4.23 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.83 (s, 3H), 3.66 (t, J = 4.6 Hz, 4H), 3.59 (s, 2H), 3.06 (d, J = 11.3 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.6Hz, 4H), 2.47 - 2.30 (m, 2H), 2.23 (t, J = 11.9 Hz, 2H), 1.77 (d, J = 11.3 Hz, 2H).

[0112] Example 30: Synthesis of 5,6-dichloro-1-(1-(2,4-dimethylbenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX30) [ka] Using intermediate 1g and 2,4-dimethylbenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 517.20 (M+H) + ; 1 H NMR (400 MHz, chloroform-d) δ 7.33 - 7.26 (m, 1H), 7.22 - 7.14 (m, 1H), 7.11 (s, 1H), 7.04 - 6.94 (m, 2H), 4.38 - 4.22 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.73 - 3.60 (m, 4H), 3.48 (s, 2H), 3.04 (d, J = 11.0 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.58 - 2.46 (m, 4H), 2.45 - 2.25 (m, 8H), 2.24 - 2.07 (m, 2H), 1.75 (d, J = 11.4 Hz, 2H).

[0113] Example 31: Synthesis of 5,6-dichloro-1-(2-morpholinoethyl)-3-(1-(2,4,6-trimethylbenzyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX31) [ka] Using intermediate 1g and 2,4,6-trimethylbenzaldehyde as raw materials, synthesize according to the synthesis method of Example 1. LC-MS (ESI) m / z: 531.30 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.20 (s, 1H), 7.10 (s, 1H), 6.86 (s, 2H), 4.36 - 4.20 (m, 1H), 3.93 (t, J = 6.7 Hz, 2H), 3.70 - 3.62 (m, 4H), 3.49 (s, 2H), 3.03 - 2.90 (m, 2H), 2.63 (t, J = 6.6 Hz, 2H), 2.56 - 2.48 (m, 4H), 2.39 (s, 6H), 2.32 - 2.18 (m, 7H), 1.78 - 1.66 (m, 2H).

[0114] Example 32: Synthesis of 5-chloro-1-(1-(2-chlorobenzyl)-4-yl)-3-(2-morpholinethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX32) [ka]

[0115] Synthesis of intermediate 32a: Using 5-chloro-2-fluoronitrobenzene and 1-N-Boc-4-aminopiperidine as raw materials, synthesize according to the synthesis method of intermediate 1f, obtain 835 mg of colorless waxy product, the yield is 63.2%. 1 H NMR (400 MHz, chloroform-d) δ 7.05 (s, 1H), 7.02 (s, 2H), 4.50 - 4.38 (m, 1H), 4.31 (br s, 2H), 3.97 (t, J = 6.4 Hz, 2H), 3.69 (t, J = 4.4 Hz, 4H), 2.85 (t, J = 13.4 Hz, 2H), 2.68 (d, J = 6.8 Hz, 2H), 2.55 (t, J = 4.5 Hz, 4H), 2.26 (qd, J = 12.5, 4.2 Hz, 2H), 1.80 (d, J = 12.8 Hz, 2H), 1.50 (s, 9H).

[0116] Synthesis of intermediate 32b: Using intermediate 32a, the Boc protecting group was removed by the action of trifluoroacetic acid at room temperature to obtain 720 mg of white trifluoroacetic acid salt solid, with a yield of 99.9%, which was used directly in the next reaction step without purification.

[0117] Synthesis of compound EX32: Using intermediate 32b and 2-chlorobenzyl bromide as raw materials, triethylamine was added in anhydrous dichloromethane to generate the target compound through a substitution reaction. The product was purified by column chromatography (mobile phase: dichloromethane / methanol, volume ratio of methanol: 1%) to obtain a white solid product (250 mg, yield: 97.8%). LC-MS (ESI) m / z: 490.20 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.53 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.30 - 7.24 (m, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 9.3 Hz, 1H), 7.06 - 6.99 (m, 2H), 4.42 - 4.29 (m, 1H), 3.96 (t, J = 6.9 Hz, 2H), 3.74 - 3.61 (m, 6H), 3.06 (d, J = 11.1 Hz, 2H), 2.66 (t, J = 6.9 Hz, 2H), 2.59 - 2.49 (m, 4H), 2.43 (q, J = 12.5 Hz, 2H), 2.28 (t, J = 11.8 Hz, 2H), 1.78 (d, J = 12.0 Hz, 2H).

[0118] Example 33: Synthesis of 5-chloro-1-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-6-fluoro-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX33) [ka]

[0119] Synthesis of intermediate 33a: Using 5-chloro-2,4-difluoronitrobenzene as raw material, the synthesis was carried out according to the synthesis method of intermediate 1e in Example 1, to obtain 3.24 g of a white solid, the yield was 72.80%. 1 H NMR (400 MHz, chloroform-d) δ 9.88 (s, 1H), 7.13 (d, J = 6.3 Hz, 1H), 6.96 (d, J = 9.2 Hz, 1H), 4.46–4.28 (m, 3H), 2.85 (t, J = 13.1 Hz, 2H), 2.25 (qd, J = 12.5, 4.6 Hz, 2H), 1.86–1.78 (m, 2H), 1.52 (s, 9H).

[0120] Synthesis of intermediate 33b: Using 33a as raw material, intermediate 33b was synthesized according to the synthesis method of intermediate 1f in Example 1, and 1.29 g of colorless oily product of intermediate 33b was obtained, with a yield of 98.78%. 1 H NMR (400 MHz, chloroform-d) δ 7.05 (d, J = 6.3 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 4.45 - 4.23 (m, 3H), 3.95 (t, J = 6.7 Hz, 2H), 3.73 - 3.63 (m, 4H), 2.90 - 2.77 (m, 2H), 2.65 (t, J = 6.7 Hz, 2H), 2.59 - 2.46 (m, 4H), 2.22 (qd, J = 12.7, 4.6 Hz, 2H), 1.86 - 1.74 (m, 2H), 1.50 (s, 9H).

[0121] Synthesis of Intermediate 33c: Intermediate 33b (1.30 g, 2.69 mmol) was placed in a dry, single-necked flask (50 mL), anhydrous dioxane (5 mL) was added, and the mixture was cooled in an ice-water bath. HCl / dioxane solution (4.0 M) was added dropwise. After the addition was complete, the ice-water bath was removed and the mixture was stirred at room temperature for 3 hours. TLC showed that the reaction of the raw materials was almost complete. The solvent was evaporated under reduced pressure using a rotary evaporator to give a light brown oily crude product. Methyl tert-butyl ether (50 mL) was added to the crude product, which was dispersed, stirred, filtered, and dried to give 1.13 g of a white solid product (Intermediate 33c) in 100% yield. The white solid was used directly in the next experiment without further purification.

[0122] Synthesis of compound EX33: Using intermediate 33c and 2-chloro-4-fluorobenzaldehyde as raw materials, the synthesis was carried out according to the synthesis method of Example 1 to obtain a white solid product (58 mg, yield 23.14%). LC-MS (ESI) m / z: 525.35 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.52 (t, J = 7.5 Hz, 1H), 7.16 - 7.06 (m, 2H), 7.06 - 6.97 (m, 2H), 4.39 - 4.25 (m, 1H), 3.95 (t, J = 6.7 Hz, 2H), 3.72 - 3.65 (m, 4H), 3.63 (s, 2H), 3.04 (d, J = 10.9 Hz, 2H), 2.65 (t, J = 6.7 Hz, 2H), 2.60 - 2.47 (m, 4H), 2.46 - 2.19 (m, 4H), 1.79 (d, J = 11.6 Hz, 2H).

[0123] Example 34: Synthesis of 5-chloro-6-fluoro-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX34) [ka] Synthesis of Compound EX34: Using Intermediate 33c and 4-isopropylcyclohexanone as raw materials, the compound was synthesized according to the synthesis method of Compound EX12 to obtain a white solid product (156 mg, yield 64.4%).

[0124] Example 34A: Synthesis of 5-chloro-6-fluoro-1-(1-(trans-4-isopropylcyclohexyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX34A) [ka] Synthesis of compound EX34A: Using intermediate 33c and 4-isopropylcyclohexanone as raw materials, compound EX34 was synthesized by referring to the synthesis method of compound EX12. The product was separated by high-performance liquid chromatography (Waters high-performance liquid chromatograph, column: YMC-Triart-C18 EXRS 20 mm x 100 mm x 5 μm, mobile phase: A = water + 0.1% vol. ammonia water (25%), B = acetonitrile, gradient 70% to 90% B, 10 min). A white solid product (16 mg, yield 6.61%) was obtained as a trans product. LC-MS (ESI) m / z: 507.38 (M+H). + ; 1H NMR (400 MHz, chloroform-d) δ 7.16 (d, J = 9.4 Hz, 1H), 7.02 (d, J = 6.2 Hz, 1H), 4.36 - 4.23 (m, 1H), 3.94 (t, J = 6.7 Hz, 2H), 3.67 (t, J = 4.7 Hz, 4H), 3.05 (d, J = 11.4 Hz, 2H), 2.64 (t, J = 6.7 Hz, 2H), 2.53 (t, J = 4.6 Hz, 4H), 2.44 - 2.20 (m, 5H), 1.91 (d, J = 11.7 Hz, 2H), 1.84 - 1.74 (m, 4H), 1.48 - 1.35 (m, 1H), 1.26 (q, J = 12.3 Hz, 2H), 1.08 - 0.95 (m, 3H), 0.87 (s, 3H), 0.85 (s, 3H).

[0125] Example 34B: Synthesis of 5-chloro-6-fluoro-1-(1-(cis-4-isopropylcyclohexyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX34B) [ka] Synthesis of compound EX34B: Using intermediate 33c and 4-isopropylcyclohexanone as raw materials, compound EX34 was synthesized by referring to the synthesis method of compound EX12. The compound was separated by high-performance liquid chromatography (Waters high-performance liquid chromatograph, column: YMC-Triart-C18 EXRS 20 mm x 100 mm x 5 μm, mobile phase: A = water + 0.1% vol. ammonia water (25%), B = acetonitrile, gradient 70% to 90% B, 10 min). A white solid product (48 mg, yield 19.84%) of the cis product was obtained. LC-MS (ESI) m / z: 507.38 (M+H). + ; 1H NMR (400 MHz, chloroform-d) δ 7.11 (d, J = 9.3 Hz, 1H), 7.03 (d, J = 6.2 Hz, 1H), 4.34 - 4.22 (m, 1H), 3.94 (t, J = 6.7 Hz, 2H), 3.68 (t, J = 4.7 Hz, 4H), 3.15 (d, J = 10.7 Hz, 2H), 2.64 (t, J = 6.7 Hz, 2H), 2.53 (t, J = 4.7 Hz, 4H), 2.36 - 2.13 (m, 5H), 1.83 - 1.75 (m, 2H), 1.73 - 1.59 (m, 5H), 1.57 - 1.45 (m, 2H), 1.44 - 1.32 (m, 2H), 1.18 - 1.08 (m, 1H), 0.90 (s, 3H), 0.89 (s, 3H).

[0126] Example 35: Synthesis of 5-chloro-3-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-6-fluoro-1-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX35) [ka]

[0127] Synthesis of Intermediate 35a: Using 4-chloro-2,5-difluoronitrobenzene as a raw material, the product was synthesized according to the synthesis method of Intermediate 1f in Example 1 to obtain the product (1.12 g, yield 85.8%). 1H NMR (400 MHz, chloroform-d) δ 7.09 (d, J = 5.5 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 4.48 - 4.17 (m, 3H), 3.95 (t, J = 6.8 Hz, 2H), 3.67 (t, J = 4.5 Hz, 4H), 2.88 - 2.76 (m, 2H), 2.65 (t, J = 6.8 Hz, 2H), 2.53 (t, J = 4.5 Hz, 4H), 2.25 (q, J = 12.3, 11.0 Hz, 2H), 1.80 (d, J = 12.1 Hz, 2H), 1.51 (s, 9H).

[0128] Synthesis of intermediate 35b: Using starting material 35a, referring to the synthesis of intermediate 33c in Example 33, a white solid product (1.13 g, yield 100%) was obtained. 1 H NMR (400 MHz, Methanol-d4) δ 7.47 (d, J = 6.2 Hz, 1H), 7.30 (d, J = 9.0 Hz, 1H), 4.59 - 4.48 (m, 1H), 4.30 (t, J = 6.0 Hz, 2H), 3.90 (br s, 4H), 3.66 - 3.50 (m, 5H), 3.45 (br s, 3H), 3.20 (td, J = 13.2, 3.0 Hz, 2H), 2.69 (qd, J = 13.5, 4.3 Hz, 2H), 2.16 - 2.03 (m, 2H).

[0129] Synthesis of compound EX35: Using intermediate 35b and 2-chloro-4-fluorobenzaldehyde as raw materials, the synthesis was carried out according to the synthesis method of Example 1 to obtain a white solid product (110 mg, yield 43.89%). LC-MS (ESI) m / z: 525.36 (M+H). + ; 1H NMR (400 MHz, chloroform-d) δ 7.53 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 6.1 Hz, 1H), 7.15 - 7.08 (m, 1H), 7.05 - 6.96 (m, 1H), 6.88 (d, J = 8.6 Hz, 1H), 4.39 - 4.24 (m, 1H), 3.95 (t, J = 6.7 Hz, 2H), 3.72 - 3.58 (m, 6H), 3.05 (d, J = 11.0 Hz, 2H), 2.65 (t, J = 6.7 Hz, 2H), 2.60 - 2.47 (m, 4H), 2.40 (qd, J = 12.3, 3.4 Hz, 2H), 2.28 (t, J = 11.7 Hz, 2H), 1.79 (d, J = 11.6 Hz, 2H).

[0130] Example 36: Synthesis of 5-chloro-6-fluoro-3(1-((4-isopropylcyclohexyl)piperidin-4-yl)-1-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX36) [ka] Synthesis of Compound EX36: Using Intermediate 35b and 4-isopropylcyclohexanone as raw materials, the compound was synthesized according to the synthesis method of Compound EX12 to obtain a white solid product (126 mg, yield 52.1%).

[0131] Example 36A: Synthesis of 5-chloro-6-fluoro-3(1-((trans-4-isopropylcyclohexyl)piperidin-4-yl)-1-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound EX36A) [ka] Synthesis of compound EX36A: Using intermediate 35b and 4-isopropylcyclohexanone as raw materials, compound EX36 was synthesized by referring to the synthesis method of compound EX12. The product was separated by high-performance liquid chromatography (Waters high-performance liquid chromatograph, column: YMC-Triart-C18 EXRS 20 mm x 100 mm x 5 μm, mobile phase: A = water + 0.1% vol. ammonia water (25%), B = acetonitrile, gradient 70% to 90% B, 10 min). A white solid product (16 mg, yield 6.61%) was obtained as a trans product. LC-MS (ESI) m / z: 507.54 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.31 (d, J = 6.2 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 4.36 - 4.24 (m, 1H), 3.94 (t, J = 6.7 Hz, 2H), 3.66 (t, J = 4.6 Hz, 4H), 3.06 (d, J = 11.1 Hz, 2H), 2.64 (t, J = 6.7 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.45 - 2.22 (m, 5H), 1.92 (d, J = 12.1 Hz, 2H), 1.86 - 1.73 (m, 4H), 1.49 - 1.35 (m, 1H), 1.27 (q, J = 12.4, 11.7 Hz, 2H), 1.09 - 0.94 (m, 3H), 0.87 (s, 3H), 0.86 (s, 3H).

[0132] Example 36B: Synthesis of 5-chloro-6-fluoro-3(1-((cis-4-isopropylcyclohexyl)piperidin-4-yl)-1-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound EX36B) [ka] Synthesis of compound EX36B: Using intermediate 35b and 4-isopropylcyclohexanone as raw materials, compound EX36 was synthesized by referring to the synthesis method of compound EX12. The compound was separated by high-performance liquid chromatography (Waters high-performance liquid chromatograph, column: YMC-Triart-C18 EXRS 20 mm x 100 mm x 5 μm, mobile phase: A = water + 0.1% vol. ammonia water (25%), B = acetonitrile, gradient 70% to 90% B, 10 min). A white solid product (46 mg, yield 19.02%) of the cis product was obtained. LC-MS (ESI) m / z: 507.52 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.27 (d, J = 6.1 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 4.34 - 4.21 (m, 1H), 3.94 (t, J = 6.7 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 3.15 (d, J = 11.5 Hz, 2H), 2.64 (t, J = 6.7 Hz, 2H), 2.52 (t, J = 4.5 Hz, 4H), 2.38 - 2.16 (m, 5H), 1.84 - 1.76 (m, 2H), 1.76 - 1.68 (m, 2H), 1.68 - 1.57 (m, 3H), 1.57 - 1.48 (m, 2H), 1.44 - 1.32 (m, 2H), 1.19 - 1.09 (m, 1H), 0.91 (s, 3H), 0.89 (s, 3H).

[0133] Example 37: Synthesis of 1-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-5,6-difluoro-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX37) [ka]

[0134] Synthesis of Intermediate 37a: Using 2-chloro-4,5-difluoronitrobenzene as a raw material, the intermediate was synthesized according to the synthesis method of Intermediate 1f in Example 1 to obtain the product (1.30 g, yield 98.5%). 1 H NMR (400 MHz, chloroform-d) δ 6.95 (dd, J = 10.2, 6.7 Hz, 1H), 6.89 (dd, J = 9.7, 6.9 Hz, 1H), 4.46 - 4.21 (m, 3H), 3.94 (t, J = 6.7 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 2.93 - 2.75 (m, 2H), 2.65 (t, J = 6.7 Hz, 2H), 2.53 (t, J = 4.6 Hz, 4H), 2.22 (qd, J = 12.6, 4.6 Hz, 2H), 1.86 - 1.74 (m, 2H), 1.50 (s, 9H).

[0135] Synthesis of Intermediate 37b: Using Intermediate 37a as a raw material, the synthesis was carried out with reference to the synthesis method of Intermediate 1g in Example 1 to obtain a white product (1.00 g, yield 100%). 1 H NMR (400 MHz, Deuterium Oxide) δ 7.22 (dd, J = 10.6, 6.8 Hz, 1H), 7.14 (dd, J = 10.1, 6.8 Hz, 1H), 4.47 - 4.32 (m, 1H), 4.22 (t, J = 5.9 Hz, 2H), 4.14 - 3.63 (m, 5H), 3.57 - 3.40 (m, 5H), 3.39 - 3.16 (m, 2H), 3.10 (td, J = 13.3, 3.0 Hz, 2H), 2.48 (qd, J = 13.5, 4.3 Hz, 2H), 2.03 (d, J = 13.7 Hz, 2H).

[0136] Synthesis of compound EX37: Using intermediate 37b and 2-chloro-4-fluorobenzaldehyde as raw materials, the synthesis was carried out according to the synthesis method of Example 1 to obtain a white solid product (106 mg, yield 48.26%). LC-MS (ESI) m / z: 509.38 (M+H).+ ; 1 H NMR (400 MHz, chloroform-d) δ 7.52 (t, J = 7.6 Hz, 1H), 7.16 - 7.05 (m, 2H), 7.05 - 6.96 (m, 1H), 6.93 - 6.83 (m, 1H), 4.40 - 4.24 (m, 1H), 3.95 (t, J = 6.7 Hz, 2H), 3.72 - 3.64 (m, 4H), 3.63 (s, 2H), 3.04 (d, J = 10.8 Hz, 2H), 2.65 (t, J = 6.8 Hz, 2H), 2.59 - 2.46 (m, 4H), 2.46 - 2.15 (m, 4H), 1.79 (d, J = 11.6 Hz, 2H).

[0137] Example 38: Synthesis of 5,6-difluoro-3(1-((4-isopropylcyclohexyl)piperidin-4-yl)-1-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX38) [ka] Synthesis of Compound EX38: Using Intermediate 37b and 4-isopropylcyclohexanone as raw materials, the compound was synthesized according to the synthesis method of Compound EX12 to obtain a white solid product (132 mg, yield 54.5%).

[0138] Example 38A: Synthesis of 5,6-difluoro-3(1-((trans-4-isopropylcyclohexyl)piperidin-4-yl)-1-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound EX38A) [ka] Synthesis of compound EX38A: Using intermediate 37b and 4-isopropylcyclohexanone as raw materials, compound EX38 was synthesized by referring to the synthesis method of compound EX12. The product was separated by high-performance liquid chromatography (Waters high-performance liquid chromatograph, column: YMC-Triart-C18 EXRS 20 mm x 100 mm x 5 μm, mobile phase: A = water + 0.1% vol. ammonia water (25%), B = acetonitrile, gradient 70% to 90% B, 10 min). A white solid product (15 mg, yield 6.16%) was obtained as a trans product. LC-MS (ESI) m / z: 491.52 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.18 (dd, J = 10.5, 6.8 Hz, 1H), 6.86 (dd, J = 9.9, 6.8 Hz, 1H), 4.35 - 4.24 (m, 1H), 3.94 (t, J = 6.8 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 3.05 (d, J = 11.0 Hz, 2H), 2.64 (t, J = 6.8 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.45 - 2.16 (m, 6H), 1.91 (d, J = 11.2Hz, 2H), 1.86 - 1.72 (m, 4H), 1.45 - 1.38 (m, 1H), 1.33 - 1.19 (m, 2H), 1.09 - 1.00 (m, 2H), 0.87 (s, 3H), 0.86 (s, 3H).

[0139] Example 38B: Synthesis of 5,6-difluoro-3(1-((cis-4-isopropylcyclohexyl)piperidin-4-yl)-1-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound EX38B) [ka] Synthesis of compound EX38B: Using intermediate 37b and 4-isopropylcyclohexanone as raw materials, compound EX38 was synthesized by referring to the synthesis method of compound EX12. The compound was separated by high-performance liquid chromatography (Waters high-performance liquid chromatograph, column: YMC-Triart-C18 EXRS 20 mm x 100 mm x 5 μm, mobile phase: A = water + 0.1% vol. ammonia water (25%), B = acetonitrile, gradient 70% to 90% B, 10 min). A white solid product (45 mg, 18.47% yield) was obtained as the cis-product. LC-MS (ESI) m / z: 491.52 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.14 (dd, J = 10.4, 6.8 Hz, 1H), 6.86 (dd, J = 9.9, 6.8 Hz, 1H), 4.33 - 4.23 (m, 1H), 3.94 (t, J = 6.8 Hz, 2H), 3.67 (t, J = 4.6 Hz, 4H), 3.15 (d, J = 11.4 Hz, 2H), 2.64 (t, J = 6.8 Hz, 2H), 2.52 (t, J = 4.5 Hz, 4H), 2.37 - 2.12 (m, 5H), 1.84 - 1.75 (m, 3H), 1.75 - 1.57 (m, 5H), 1.57 - 1.47 (m, 2H), 1.44 - 1.33 (m, 2H), 1.19 - 1.07 (m, 1H), 0.90 (s, 3H), 0.89 (s, 3H).

[0140] Example 39: Synthesis of 5,6-dichloro-1-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-3-(2-(1,1-dioxothiomorpholine)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX39) [ka] Synthesis of intermediate 39c: 4-(2-hydroxyethyl)thiomorpholine-1,1-dioxide (2.00 g, 11.16 mmol) and anhydrous dichloromethane (120 mL) were placed in a dry, single-necked flask (200 mL). Triethylamine (1.69 g, 2.33 mL, 16.74 mmol) was added to the reaction flask, and the reaction mixture was purged with argon gas to protect it. The mixture was cooled to 0°C in an ice-water bath, and methanesulfonyl chloride (1.53 g, 1.04 mL, 13.39 mmol) was added dropwise to the reaction mixture. After the addition was complete, the mixture was stirred at room temperature for 2 hours. TLC showed that the reaction of the raw materials was almost complete. The reaction was quenched by adding saturated aqueous NaHCO3, the liquid was separated, and the organic phase was washed with saturated aqueous NaCl, dried over anhydrous MgSO4, filtered, and rotary evaporated to give crude 39b (2.15 g, 74.88%) as a light brown oil, which was used directly in the next step reaction without further purification. tert-Butyl 4-(5,6-dichloro-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (1e) (500 mg, 1.29 mmol) and anhydrous DMF (8 mL) were placed in a dry two-necked flask (25 mL), purged with argon gas, and cooled to 0 °C in an ice-water bath. NaH (207 mg, 5.18 mmol, 60% in mineral oil) was added to the reaction flask and stirred in an ice-water bath for 30 minutes. A solution of 2-(1,1-dioxothiomorpholine)ethyl methanesulfonate (39b) (833 mg, 3.24 mmol) in anhydrous DMF (5 mL) was added dropwise to the reaction mixture and stirred for 1 hour at 0 °C. The temperature was then gradually increased to 45 °C and the reaction was continued for 12 hours. TLC showed that the reaction of the raw materials was almost complete. After the reaction was completed, the mixture was cooled to room temperature and slowly poured into ice water to precipitate a white solid. The solid was filtered, washed with water, and dried. The crude product was dispersed in petroleum ether, pulped, filtered, and dried to obtain a white solid product (632 mg, yield 89.2%). 1H NMR (400 MHz, chloroform-d) δ 7.19 (s, 1H), 7.03 (s, 1H), 4.45 - 4.24 (m, 3H), 3.95 (t, J = 6.2 Hz, 2H), 3.11 - 3.03 (m, 4H), 3.03 - 2.96 (m, 4H), 2.88 - 2.74 (m, 4H), 2.24 (qd, J = 12.6, 4.6 Hz, 2H), 1.85 - 1.73 (m, 2H), 1.51 (s, 9H).

[0141] Intermediate 39d was synthesized according to the synthesis method of intermediate 1f in Example 1 to obtain a white solid product (205 mg, yield 99.9%), which was directly used in the next reaction step without purification.

[0142] Synthesis of Compound EX39: Intermediate 39d (200 mg, 356 μmol) and anhydrous dichloromethane (3.5 mL) were placed in a dry round-bottom flask (50 mL). Triethylamine (216 mg, 2.14 mmol) was added to the reaction solution, stirred for 5 minutes, cooled to 0°C in an ice-water bath, and protected with argon gas. A solution of 2-chloro-4-fluorobenzyl bromide (87.6 mg, 392 μmol) in dichloromethane (1.5 mL) was added dropwise to the reaction mixture. After the addition was complete, the temperature was gradually raised to room temperature and the reaction was allowed to stir for 12 hours. The completion of the reaction was confirmed by TLC. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (25 mL x 3), washed with saturated saline, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated on a rotary evaporator to give a light brown crude product, which was purified and separated by silica gel column chromatography (mobile phase: DCM / MeOH, 150:1 to 100:1) to give a white solid product (165 mg, 78.51% yield). LC-MS (ESI) m / z: 589.20 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.51 (t, J = 7.4 Hz, 1H), 7.32 (s, 1H), 7.13 (dd, J = 8.6, 2.6 Hz, 1H), 7.07 - 6.95 (m, 2H), 4.35 - 4.19 (m, 1H), 3.95 (t, J = 6.2 Hz, 2H), 3.64 (s, 2H), 3.18 - 3.02 (m, 6H), 3.02 - 2.91 (m, 4H), 2.82 (t, J = 6.2 Hz, 2H), 2.48 - 2.33 (m, 2H), 2.33 - 2.19 (m, 2H), 1.86 - 1.62 (m, 3H).

[0143] Example 40: Synthesis of 5,6-dichloro-1-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX40) [ka]

[0144] Synthesis of Intermediate 40a: tert-butyl 4-(5,6-dichloro-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (3.00 g, 7.77 mmol), hexamethylphosphoric acid triamide (HMPA) (2.78 g, 15.53 mmol), and anhydrous tetrahydrofuran (80 mL) were placed in a clean, dry two-necked flask (200 mL). The flask was purged with argon gas and cooled to 0 °C in an ice-water bath. NaH (932 mg, 23.30 mmol, 60% in mineral oil) was added to the reaction mixture in batches. After stirring for 0.5 h, 1-chloro-2-bromoethane (4.46 g, 31.07 mmol, 2.68 mmol) was slowly added to the reaction mixture. mL) was added, and after the addition was complete, the ice-water bath was removed and the mixture was stirred at room temperature for 1 hour. The temperature was gradually increased to 80 ° C and refluxed for 8 hours. TLC plates showed that the reaction of the raw materials was almost complete. After the reaction was complete, the reaction system was cooled to room temperature, and ice water was added dropwise to the reaction system under stirring to quench the reaction. The mixture was extracted with ethyl acetate (150 mL × 3). The organic phase was washed with saturated aqueous NH4Cl and saturated aqueous NaCl, respectively, dried over anhydrous Na4SO2, filtered, and the solvent was evaporated using a rotary evaporator to obtain a light brown solid crude product. The crude product was dispersed in a mixed solvent of petroleum ether / ethyl acetate (1% ethyl acetate), stirred for 30 minutes, and then filtered to obtain a white solid product (2.91 g, yield 83.5%). 1 H NMR (400 MHz, chloroform-d) δ 7.19 (s, 1H), 7.17 (s, 1H), 4.47 - 4.22 (m, 3H), 4.16 (t, J = 6.1 Hz, 2H), 3.82 (t, J = 6.1 Hz, 2H), 2.96 - 2.73 (m, 2H), 2.24 (qd, J = 12.7, 4.6 Hz, 2H), 1.88 - 1.72 (m, 2H), 1.51 (s, 9H).

[0145] Synthesis of intermediate 40b: tert-butyl 4-(5,6-dichloro-3-(2-chloroethyl)-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (40a) (325 mg, 724 μmol) and CsCO (708 mg, 2.17 mmol) were placed in a clean, dry Schlenk tube (25 mL). Anhydrous dioxane (7.2 mL) was added and stirred at room temperature. N-methylpiperazine (290 mg, 321 μL, 2.90 mmol) was added. The mixture was purged with argon gas and heated to 105 °C under reflux for 12 hours. TLC showed that the reaction of the raw materials was almost complete. After the reaction was completed, the mixture was cooled to room temperature, an appropriate amount of water was added to the reaction flask, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was washed with saturated aqueous NaCl solution, dried over anhydrous NaSO, filtered, and the solvent was evaporated using a rotary evaporator to obtain a pale brown oily crude product. This was separated by silica gel column chromatography (mobile phase: DCM / MeOH, MeOH 0.5%-2%) to obtain a pale yellow waxy product (301 mg, yield 81.10%). 1 H NMR (400 MHz, chloroform-d) δ 7.16 (d, J = 0.8 Hz, 2H), 4.48 - 4.19 (m, 3H), 3.94 (t, J = 6.7 Hz, 2H), 2.93 - 2.76 (m, 2H), 2.73 - 2.50 (m, 6H), 2.50 - 2.30 (m, 4H), 2.28 (s, 4H), 2.28 - 2.16 (m, 3H), 1.85 - 1.75 (m, 2H), 1.51 (s, 9H).

[0146] Synthesis of intermediate 40c: Using 40b as raw material, it was synthesized according to the method of intermediate 1g in Example 1 to obtain a white solid product (273 mg, yield 100%), which was directly used in the next reaction step without purification.

[0147] Synthesis of compound EX40: Using 40c and 2-chloro-4-fluorobenzyl bromide as raw materials, the synthesis was carried out according to the synthesis method of Example 39 to obtain a white solid product (198 mg, yield 69.05%). LC-MS (ESI) m / z: 554.20 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.52 (t, J = 7.4 Hz, 1H), 7.30 (s, 1H), 7.17 - 7.09 (m, 2H), 7.01 (t, J = 8.3 Hz, 1H), 4.37 - 4.22 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.63 (s, 2H), 3.05 (d, J = 11.1 Hz, 2H), 2.72 - 2.54 (m, 6H), 2.55 - 2.32 (m, 6H), 2.33 - 2.20 (m, 5H), 1.78 (d, J = 10.8 Hz, 2H).

[0148] Example 41: Synthesis of 1-(2-(4-acetylpiperazin-1-yl)ethyl)-5,6-3-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX41) [ka]

[0149] Synthesis of intermediate 41a: Using 1-acetylpiperazine and 40a as raw materials, the intermediate 41a was synthesized according to the synthesis method of intermediate 40b in Example 40. A pale yellow waxy product (266 mg, yield 73.62%) was obtained. 1H NMR (400 MHz, chloroform-d) δ 7.16 (d, J = 0.8 Hz, 2H), 4.48 - 4.19 (m, 3H), 3.94 (t, J = 6.7 Hz, 2H), 2.93 - 2.76 (m, 2H), 2.73 - 2.50 (m, 6H), 2.50 - 2.30 (m, 4H), 2.28 (s, 4H), 2.28 - 2.16 (m, 3H), 1.85 - 1.75 (m, 2H), 1.51 (s, 9H).

[0150] Synthesis of compound EX41: Using 41a as the raw material, intermediate 41b (235 mg, yield 99.6%) was obtained by following the synthesis method of intermediate 40c in Example 40. Using intermediate 41b and 2-chloro-4-fluorobenzyl bromide as raw materials, the compound was synthesized by following the synthesis method of Example 39 to obtain a white solid product (116 mg, yield 46.75%). LC-MS (ESI) m / z: 584.20 (M+3H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.52 (t, J = 7.5 Hz, 1H), 7.30 (s, 1H), 7.15 - 7.07 (m, 2H), 7.05 - 6.96 (m, 1H), 4.35 - 4.23 (m, 1H), 3.96 (t, J = 6.4 Hz, 2H), 3.64 (s, 2H), 3.57 (t, J = 5.0 Hz, 2H), 3.42 (t, J = 5.0 Hz, 2H), 3.05 (d, J = 11.0 Hz, 2H), 2.67 (t, J = 6.4 Hz, 2H), 2.53 (t, J = 5.0 Hz, 2H), 2.48 (t, J = 5.0 Hz, 2H), 2.39 (qd, J = 12.4, 3.4 Hz, 2H), 2.27 (t, J = 11.7 Hz, 2H), 2.07 (s, 3H), 1.78 (d, J = 11.2 Hz, 2H).

[0151] Example 42: Synthesis of 5,6-1-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-3-(2-(3-oxopiperazin-1-yl)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX42) [ka]

[0152] Synthesis of intermediate 42a: Using 2-piperazinone and 40a as raw materials, the intermediate 42a was synthesized according to the synthesis method of intermediate 40b in Example 40. A colorless waxy product (167 mg, yield 48.8%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.18 (s, 1H), 7.07 (s, 1H), 6.43 (s, 1H), 4.47 - 4.19 (m, 3H), 3.97 (t, J = 6.4 Hz, 2H), 3.38 - 3.29 (m, 2H), 3.19 (s, 2H), 2.95 - 2.80 (m, 2H), 2.79 - 2.68 (m, 4H), 2.24 (qd, J = 12.6, 4.5 Hz, 2H), 1.87 - 1.73 (m, 2H), 1.51 (s, 9H).

[0153] Synthesis of Compound EX42: Using 42a as the raw material, intermediate 42b (150 mg, 100% yield) was obtained by following the synthesis method of intermediate 40c in Example 40. Using intermediate 42b and 2-chloro-4-fluorobenzyl bromide as raw materials, synthesis was performed by following the synthesis method of Example 39 to obtain a white solid product (88 mg, 56.02% yield). LC-MS (ESI) m / z: 554.20 (M+H). + ; 1H NMR (400 MHz, chloroform-d) δ 7.51 (t, J = 7.3 Hz, 1H), 7.30 (s, 1H), 7.12 (d, J = 8.5 Hz, 1H), 7.06 (s, 1H), 7.01 (t, J = 8.4 Hz, 1H), 6.42 (s, 1H), 4.34 - 4.22 (m, 1H), 3.96 (t, J = 6.5 Hz, 2H), 3.63 (s, 2H), 3.38 - 3.27 (m, 2H), 3.19 (s, 2H), 3.04 (d, J = 11.1 Hz, 2H), 2.81 - 2.66 (m, 4H), 2.38 (qd, J = 12.1, 3.5 Hz, 2H), 2.27 (t, J = 11.6 Hz, 2H), 1.78 (d, J = 11.4 Hz, 2H).

[0154] Example 43: Synthesis of 5,6-dichloro-1-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-3-(2-(pyrrolidin-1-yl)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX43) [ka]

[0155] Synthesis of intermediate 43a: Using pyrrole and 40a as raw materials, synthesize intermediate 43a according to the synthesis method of intermediate 40b in Example 40. A colorless oily product (485 mg, yield 90.1%) was obtained. 1H NMR (400 MHz, chloroform-d) δ 7.16 (s, 1H), 7.13 (s, 1H), 4.41 (tt, J = 12.5, 4.2 Hz, 1H), 4.31 (s, 2H), 3.97 (t, J = 7.2 Hz, 2H), 2.86 (d, J = 13.8 Hz, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.65 - 2.55 (m, 4H), 2.23 (qd, J = 12.7, 4.6 Hz, 2H), 1.82 - 1.76 (m, 6H), 1.51 (s, 9H).

[0156] Synthesis of compound EX43: Using 43a as the raw material, intermediate 43b (333 mg, yield 90.5%) was obtained by following the synthesis method of intermediate 40c in Example 40. Using intermediate 43b and 2-chloro-4-fluorobenzyl bromide as raw materials, the compound was synthesized by following the synthesis method of Example 39 to obtain a white solid product (182 mg, yield 51.40%). LC-MS (ESI) m / z: 525.20 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.52 (t, J = 7.5 Hz, 1H), 7.29 (s, 1H), 7.16 - 7.07 (m, 2H), 7.05 - 6.96 (m, 1H), 4.39 - 4.23 (m, 1H), 3.97 (t, J = 7.2 Hz, 2H), 3.63 (s, 2H), 3.04 (d, J = 10.9 Hz, 2H), 2.79 (t, J = 7.3 Hz, 2H), 2.69 - 2.51 (m, 4H), 2.38 (qd, J = 12.3, 3.3 Hz, 2H), 2.26 (t, J = 11.6 Hz, 2H), 1.86 - 1.72 (m, 6H).

[0157] Example 44: Synthesis of 5,6-dichloro-1-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-3-(2-(piperidin-1-yl)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX44) [ka]

[0158] Synthesis of intermediate 44a: Using piperidine and 40a as raw materials, synthesize intermediate 44a according to the synthesis method of intermediate 40b in Example 40. A colorless oily product (461 mg, yield 83.2%) was obtained. 1 H NMR (400 MHz, chloroform-d) δ 7.19 (s, 1H), 7.15 (s, 1H), 4.40 (tt, J = 12.5, 4.1 Hz, 1H), 4.31 (s, 2H), 3.93 (t, J = 6.9 Hz, 2H), 2.84 (t, J = 13.4 Hz, 2H), 2.59 (t, J = 6.9 Hz, 2H), 2.53 - 2.37 (m, 4H), 2.23 (qd, J = 12.7, 4.6 Hz, 2H), 1.79 (d, J = 11.8 Hz, 2H), 1.60 - 1.53 (m, 4H), 1.51 (s, 9H), 1.47 - 1.39 (m, 2H).

[0159] Synthesis of compound EX44: Using 44a as the raw material, intermediate 44b (303 mg, yield 96.2%) was obtained by following the synthesis method of intermediate 40c in Example 40. Using intermediate 44b and 2-chloro-4-fluorobenzyl bromide as raw materials, synthesis was performed by following the synthesis method of Example 39 to obtain a white solid product (110 mg, yield 27.1%). LC-MS (ESI) m / z: 539.20 (M+H). + ; 1H NMR (400 MHz, chloroform-d) δ 7.52 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.19 (s, 1H), 7.15 - 7.09 (m, 1H), 7.05 - 6.96 (m, 1H), 4.37 - 4.25 (m, 1H), 3.95 (t, J = 6.9 Hz, 2H), 3.63 (s, 2H), 3.04 (d, J = 11.0 Hz, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.54 - 2.43 (m, 4H), 2.43 - 2.31 (m, 2H), 2.27 (t, J = 11.6 Hz, 2H), 1.78 (d, J = 11.6 Hz, 2H), 1.64 - 1.51 (m, 4H), 1.50 - 1.38 (m, 2H).

[0160] Example 45: Synthesis of 5,6-dichloro-1-(1-(cyclopropylmethyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX45) [ka] Using Intermediate 1e and bromomethylcyclopropane as raw materials, the synthesis was carried out in accordance with the synthesis method of Example 39 to obtain a white solid product (88 mg, yield 50.0%). LC-MS (ESI) m / z: 453.20 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.42 (s, 1H), 7.12 (s, 1H), 4.42 - 4.27 (m, 1H), 3.95 (t, J = 6.6 Hz, 2H), 3.73 - 3.60 (m, 4H), 3.34 - 3.18 (m, 2H), 2.65 (t, J = 6.7 Hz, 2H), 2.59 - 2.46 (m, 4H), 2.47 - 2.26 (m, 4H), 2.24 - 2.10 (m, 2H), 1.87 - 1.75 (m, 2H), 0.99 - 0.84 (m, 1H), 0.62 - 0.49 (m, 2H), 0.21 - 0.06 (m, 2H).

[0161] Example 46: Synthesis of 5,6-dichloro-1-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-3-(2-(dimethylamino)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX46) [ka]

[0162] Synthesis of Intermediate 46a: Using N,N-dimethylbromoethyl hydrobromide and Intermediate 1e as raw materials, intermediate 46a was synthesized according to the synthesis method of Intermediate 1f to obtain a pink solid product (1.1 g, yield 93.2%). 1 H NMR (400 MHz, chloroform-d) δ 7.16 (s, 1H), 7.09 (s, 1H), 4.44-4.31 (m, 3H), 3.93-3.90 (t, J = 6.8 Hz, 2H), 2.87-2.81 (t, J = 12.4 Hz, 2H), 2.62-2.58 (t, J = 6.8 Hz, 2H), 2.31 (s, 6H), 2.28-2.17 (m, 2H), 1.81-1.78 (d, J = 10.4 Hz, 2H), 1.50 (s, 9H).

[0163] Synthesis of Compound EX46: Using 46a as the raw material, intermediate 46b (1.1 g, yield 98.9%) was obtained by following the synthesis method of intermediate 40c in Example 40. Using intermediate 46b and 2-chloro-4-fluorobenzyl bromide as raw materials, a white solid product (300 mg, yield 56.6%) was synthesized by following the synthesis method of Example 39. LC-MS (ESI) m / z: 499.20 (M+H) + ; 1 H NMR (400 MHz, chloroform-d) δ 7.53 (t, J = 7.5 Hz, 1H), 7.31 (s, 1H), 7.15 - 7.08 (m, 2H), 7.04 - 6.97 (m, 1H), 4.38 - 4.25 (m, 1H), 3.96 (t, J = 7.0 Hz, 2H), 3.64 (s, 2H), 3.05 (d, J = 10.9 Hz, 2H), 2.66 (t, J = 6.9 Hz, 2H), 2.46 - 2.32 (m, 8H), 2.28 (t, J = 11.7 Hz, 2H), 1.79 (d, J = 11.7 Hz, 2H).

[0164] Example 47: Synthesis of 6,7-dichloro-3-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-1-(2-morpholinoethyl)-3,4-dihydroquinazolin-2(1H)-one (compound EX47) [ka]

[0165] Synthesis of intermediate 47a: 4,5-Dichloro-2-nitrotoluene (5 g, 23.06 mmol) was placed in a clean, dry single-neck flask (500 mL). Carbon tetrachloride (230 mL), N-bromosuccinimide (NBS) (4.51 g, 25.36 mmol), and azobisisobutyronitrile (AIBN) (379 mg, 2.31 mmol) were added to the reaction flask, and the mixture was heated to 80°C and refluxed for 18 hours. TLC showed that the reaction of the raw materials was almost complete. Cool to room temperature, add saturated NaHCO3 aqueous solution to quench the reaction, extract with dichloromethane (100 mL x 3), wash with saturated NaCl aqueous solution, dry with anhydrous MgSO4, filter, and evaporate the solvent under reduced pressure using a rotary evaporator to obtain the crude product, which is purified by silica gel column chromatography (mobile phase is petroleum ether) to obtain 3.02 g of pale yellow solid product, the yield is 45.97%. Use it directly in the next step of the reaction.

[0166] Synthesis of intermediate 47b: N-BOC-4-aminopiperidine (2.32 g, 11.58 mmol) and anhydrous dichloromethane (60 mL) were placed in a clean, dry round-bottom flask (250 mL). Triethylamine (1.60 g, 2.20 mL, 15.79 mmol) was added. The reaction mixture was stirred at room temperature. 1-(bromomethyl)-4,5-dichloro-2-nitrobenzene (47a) (3.00 g, 10.53 mmol) in dichloromethane (40 mL) was added dropwise. The mixture was stirred at room temperature for 12 hours. TLC confirmed the completion of the reaction. After completion of the reaction, the solvent was evaporated under reduced pressure using a rotary evaporator. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether and ethyl acetate, proportional gradient 20:1 to 8:1) to give 2.77 g of a pale yellow oil product in 65.07% yield. 1H NMR (400 MHz, chloroform-d) δ 8.08 (s, 1H), 7.87 (s, 1H), 4.07 (s, 2H), 4.01 (s, 2H), 2.90–2.74 (m, 2H), 2.70–2.57 (m, 1H), 1.93–1.78 (m, 2H), 1.46 (s, 9H), 1.34–1.25 (m, 2H).

[0167] Synthesis of intermediate 47c: tert-butyl 4-((4,5-dichloro-2-nitrobenzenemethyl)amino)piperidine-1-carboxylate (47b) (2.50 g, 6.18 mmol) and absolute ethanol (60 mL) were placed in a single-neck flask (250 mL). The reaction mixture was stirred at room temperature. Iron powder (2.07 g, 37.10 mmol) and saturated aqueous NH4Cl solution (10 mL) were gradually added to the mixture, which was then heated to 80°C and stirred for 2 hours. The reaction mixture was then detected by TLC plate to be completely reacted. After completion of reaction, the reaction mixture is cooled to room temperature, filtered through diatomaceous earth, washed with absolute ethanol, the filtrate is collected, and the solution is evaporated under reduced pressure using a rotary evaporator to obtain a white solid. This solid is dissolved in ethyl acetate (100 mL), and a small amount of water (25 mL) is added, and a large amount of white solid precipitates. After filtering and drying, 2.00 g of white solid product is obtained, with a yield of 86.41%. Directly use it in the next step of reaction.

[0168] Synthesis of Intermediate 47d: Using Intermediate 47c as the raw material, the synthesis was carried out with reference to the synthesis method of Intermediate 1e in Example 1 to obtain a white solid product (590 mg, yield 64.52%). 1 H NMR (400 MHz, chloroform-d) δ 7.78 (s, 1H), 7.13 (s, 1H), 6.84 (s, 1H), 4.59–4.45 (m, 1H), 4.26 (s, 4H), 2.84 (s, 2H), 1.76–1.62 (m, 4H), 1.48 (s, 9H).

[0169] Synthesis of intermediate 47e: Using intermediate 47d as the raw material, intermediate 47e was synthesized according to the synthesis method of intermediate 1f in Example 1 to obtain a crude product, which was purified by alkaline aluminum oxide column chromatography (mobile phase: petroleum ether and ethyl acetate, proportional gradient 5:1 to 0:1) to obtain a white solid product (627 mg, yield 85.76%). 1 H NMR (400 MHz, chloroform-d) δ 7.13 (s, 2H), 4.51 - 4.38 (m, 1H), 4.24 (s, 2H), 4.16 (s, 2H), 3.96 (t, J = 7.1 Hz, 2H), 3.80 - 3.63 (m, 4H), 2.90 - 2.71 (m, 2H), 2.69 - 2.42 (m, 6H), 1.73 - 1.60 (m, 4H), 1.47 (s, 9H).

[0170] Synthesis of compound EX47: Using 47e as raw material, it was synthesized according to the synthesis method of intermediate 1g in Example 1 to obtain intermediate 47f as a white solid product (616 mg, yield 99.99%), which was directly used in the next reaction step. 1 H NMR (400 MHz, Methanol-d4) δ 7.42 (s, 1H), 7.25 (s, 1H), 4.54 - 4.42 (m, 1H), 4.40 (s, 2H), 4.30 (t, J = 5.8 Hz, 2H), 4.23 - 3.63 (m, 6H), 3.61 - 3.43 (m, 5H), 3.30 - 3.05 (m, 4H), 2.17 (qd, J = 13.2, 4.1 Hz, 2H), 2.05 - 1.91 (m, 2H).

[0171] Using Intermediate 47f and 2-chloro-4-fluorobenzyl bromide as raw materials, a white solid product (123 mg, yield 46.67%) was synthesized according to the synthesis method of Example 39. LC-MS (ESI) m / z: 555.20 (M+H) + ; 1H NMR (400 MHz, chloroform-d) δ 7.45 (t, J = 7.6 Hz, 1H), 7.17 - 7.05 (m, 3H), 6.97 (t, J = 8.2 Hz, 2H), 4.40 - 4.27 (m, 1H), 4.20 (s, 2H), 3.95 (t, J = 7.1 Hz, 2H), 3.77 - 3.67 (m, 4H), 3.58 (s, 2H), 2.98 (d, J = 11.0 Hz, 2H), 2.61 (t, J = 7.1 Hz, 2H), 2.59 - 2.50 (m, 4H), 2.24 (t, J = 11.7 Hz, 2H), 1.91 - 1.75 (m, 2H), 1.71 - 1.62 (m, 2H), 1.24 (t, J = 7.0 Hz, 1H).

[0172] Example 48: Synthesis of 5,6-dichloro-1-(2-(dimethylamino)ethyl)-3-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX48) [ka] Synthesis of Compound EX48: Using Intermediate 46b and 4-isopropylcyclohexanone as raw materials, the compound was synthesized according to the synthesis method of Compound EX12 to obtain a white solid product (1.53 g, yield 62.5%).

[0173] Example 48A: Synthesis of 5,6-dichloro-1-(2-(dimethylamino)ethyl)-3-(1-(trans-4-isopropylcyclohexyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound EX48A) [ka] Synthesis of compound EX48A: Using intermediate 46b and 4-isopropylcyclohexanone as raw materials, compound EX48 was synthesized by referring to the synthesis method of compound EX12. The compound was prepared and separated by high-performance liquid chromatography (Waters high-performance liquid chromatograph, column: YMC-Triart-C18 EXRS 20 mm x 100 mm x 5 μm, mobile phase: A = water + 0.1% vol. ammonia water (25%), B = acetonitrile, gradient 70% to 90% B, 10 min), to obtain a white solid product (169 mg, yield 6.91%). LC-MS (ESI) m / z: 481.30 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.41 (s, 1H), 7.08 (s, 1H), 4.36 - 4.26 (m, 1H), 3.92 (t, J = 7.0 Hz, 2H), 3.06 (d, J = 11.3 Hz, 2H), 2.60 (t, J = 6.9 Hz, 2H), 2.44 - 2.35 (m, 2H), 2.35 - 2.23 (m, 9H), 1.92 (d, J = 11.3 Hz, 2H), 1.84 - 1.76 (m, 4H), 1.74 - 1.69 (m, 2H), 1.47 - 1.37 (m, 1H), 1.26 (q, J = 11.9 Hz, 2H), 1.08 - 1.02 (m, 1H), 0.87 (s, 3H), 0.86 (s, 3H).

[0174] Example 48B: Synthesis of 5,6-dichloro-1-(2-(dimethylamino)ethyl)-3-(1-(cis-4-isopropylcyclohexyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound EX48B) [ka] Synthesis of compound EX48B: Using intermediate 46b and 4-isopropylcyclohexanone as raw materials, compound EX48 was synthesized by referring to the synthesis method of compound EX12. The compound was prepared and separated by high-performance liquid chromatography (Waters high-performance liquid chromatograph, column: YMC-Triart-C18 EXRS 20 mm x 100 mm x 5 μm, mobile phase: A = water + 0.1% vol. ammonia water (25%), B = acetonitrile, gradient 70% to 90% B, 10 min), to obtain a white solid product (411 mg, yield 16.80%). LC-MS (ESI) m / z: 481.30 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.35 (s, 1H), 7.08 (s, 1H), 4.35 - 4.22 (m, 1H), 3.92 (t, J = 7.0 Hz, 2H), 3.20 - 3.09 (m, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.36 - 2.26 (m, 8H), 2.26 - 2.16 (m, 2H), 1.85 - 1.67 (m, 5H), 1.67 - 1.57 (m, 3H), 1.57 - 1.48 (m, 2H), 1.43 - 1.33 (m, 2H), 1.18 - 1.10 (m, 1H), 0.91 (s, 3H), 0.89 (s, 3H).

[0175] Example 49: Synthesis of 1-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl)-5,6-dichloro-3-(1-(2-chloro-4-fluorophenylmethyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX49) [ka]

[0176] Synthesis of intermediate 49a: tert-butyl 4-(5,6-dichloro-3-(2-chloroethyl)-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (40a) (250 mg, 557 μmol) and CsCO (544 mg, 1.67 mmol) were placed in a clean, dry Schlenk tube (25 mL). Anhydrous dioxane (5.5 mL) was added and stirred at room temperature. 2-oxa-6-aza-spiro[3,3]heptane (138 mg, 1.39 mmol) was added. The mixture was purged with argon gas and heated to 105 °C under reflux for 12 hours. TLC showed that the reaction of the starting materials was almost complete. After the reaction was completed, the mixture was cooled to room temperature, an appropriate amount of water was added to the reaction flask, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated using a rotary evaporator to obtain a light brown oily crude product. This was separated by silica gel column chromatography (mobile phase: DCM / MeOH, MeOH 0.2% to 1%) to obtain 186 mg of a white solid product in 65.28% yield. LC-MS (ESI) m / z: 454.10 (M-56+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.16 (s, 1H), 7.09 (s, 1H), 4.71 (s, 4H), 4.47 - 4.20 (m, 3H), 3.78 (t, J = 6.6 Hz, 2H), 3.38 (s, 4H), 2.83 (t, J = 13.5 Hz, 2H), 2.70 (t, J = 6.5 Hz, 2H), 2.23 (qd, J = 12.7, 4.4 Hz, 2H), 1.79 (d, J = 12.1 Hz, 2H), 1.51 (s, 9H).

[0177] Synthesis of intermediate 49b: Using 49a (150 mg, 293 μmol) as the raw material, the synthesis was carried out according to the synthesis method of intermediate 1g to obtain a white solid product (154 mg, yield 99.95%), which was used directly in the next reaction step without purification.

[0178] Synthesis of compound EX49: Using 49b and 2-chloro-4-fluorobenzyl bromide as raw materials, the compound was synthesized according to the synthesis method of Example 39. The product was separated by silica gel column chromatography (mobile phase: DCM / MeOH, MeOH 0.2% to 1%) to obtain a white solid product (86 mg, yield 54.38%). LC-MS (ESI) m / z: 554.12 (M+H). + ; 1 H NMR (400 MHz, Methanol-d4) δ 7.66 (s, 1H), 7.59 (dd, J = 8.6, 6.3 Hz, 1H), 7.40 (s, 1H), 7.26 (dd, J = 8.7, 2.6 Hz, 1H), 7.13 (td, J = 8.4, 2.5 Hz, 1H), 4.33 (tt, J = 12.5, 4.4 Hz, 1H), 3.92 (t, J = 5.9 Hz, 2H), 3.71 (s, 2H), 3.63 (s, 4H), 3.22 (s, 4H), 3.12 (d, J = 11.1 Hz, 2H), 2.91 (t, J = 5.8 Hz, 2H), 2.48 (qd, J = 12.5, 3.6 Hz, 2H), 2.34 (t, J = 11.8 Hz, 2H), 1.79 (d, J = 11.4 Hz, 2H).

[0179] Example 50: Synthesis of 5,6-dichloro-1-(1-((5-chlorothiophen-2-yl)methyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX50) [ka] Using the intermediate 1g of Example 1 and 5-chlorothiophene-2-formaldehyde as raw materials, the product was synthesized according to the synthesis method of Example 1 to obtain a pale yellow solid product (289 mg, yield 93.3%). LC-MS (ESI) m / z: 530.30 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.31 (s, 1H), 7.13 (s, 1H), 6.75 (d, J = 3.1 Hz, 1H), 6.70 (d, J = 3.8 Hz, 1H), 4.36 - 4.24 (m, 1H), 3.95 (t, J = 6.6 Hz, 2H), 3.73 - 3.61 (m, 6H), 3.10 (d, J = 11.0 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.59 - 2.46 (m, 4H), 2.37 (qd, J = 12.5, 3.8 Hz, 2H), 2.20 (t, J = 11.7 Hz, 2H), 1.78 (d, J = 11.7 Hz, 2H).

[0180] Example 51: Synthesis of 6,7-dichloro-1-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-3,4-dihydroquinazolin-2(1H)-one (compound EX51) [ka]

[0181] Synthesis of intermediate 51a: 1-(bromomethyl)-4,5-dichloro-2-nitrobenzene (47a) (5.33 g, 18.71 mmol) and potassium phthalimide (3.30 g, 17.82 mmol) were placed in a clean, dry, single-neck flask (100 mL). Dry DMF (30 mL) was added and the mixture was heated to 125 °C and stirred for 12 hours. TLC showed complete reaction of the starting materials. After completion of the reaction, the reaction mixture was cooled to room temperature and slowly added to an ice-water mixture (120 mL) under stirring. A large amount of yellow solid precipitated. After stirring evenly, the mixture was filtered, washed with a small amount of water, and dried to obtain the yellow solid product (5.93 g, 94.8% yield). 1 H NMR (400 MHz, chloroform-d) δ 8.25 (s, 1H), 7.97–7.89 (m, 2H), 7.84–7.77 (m, 2H), 7.32 (s, 1H), 5.25 (s, 2H).

[0182] Synthesis of intermediate 51b: 2-(4,5-dichloro-2-nitrobenzenemethyl)isodihydroindole-1,3-diketone (51a) (2.5 g, 7.12 mmol) and absolute ethanol (71 mL) were placed in a single-neck flask (250 mL). The reaction mixture was stirred at room temperature, and iron powder (2.78 g, 49.84 mmol) and saturated aqueous NH4Cl solution (10 mL) were gradually added to the mixture. The mixture was heated to 55°C and stirred for 1 hour. The reaction mixture was then completely converted by TLC. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with absolute ethanol. The filtrate was collected and the solution was evaporated under reduced pressure on a rotary evaporator to obtain a yellow solid. The solid was dissolved in ethyl acetate (100 mL), a small amount of water (25 mL) was added, and the insoluble matter was filtered off. The liquid was separated, the organic phase was collected, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure on a rotary evaporator to obtain a crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether and ethyl acetate, proportional gradient 10:1 to 3:1) to obtain a pale yellow solid product (1.86 g, yield 81.4%). 1 H NMR (400 MHz, chloroform-d) δ 7.88–7.81 (m, 2H), 7.77–7.70 (m, 2H), 7.51 (s, 1H), 6.74 (s, 1H), 4.68 (s, 2H), 4.56 (s, 2H).

[0183] Synthesis of intermediate 51c: 2-(2-amino-4,5-dichlorobenzenemethyl)isodihydroindole-1,3-diketone (51b) (1.86 g, 5.79 mmol), 4-tert-butylpiperidone (1.38 g, 6.95 mmol), and anhydrous 1,2-dichloroethane (60 mL) were placed in a clean, dry round-bottom flask (100 mL). The reaction mixture was stirred at room temperature. Acetic acid (348 mg, 5.79 mmol, 331 μL) and NaBH(OAc) (3.07 g, 14.48 mmol) were added to the reaction mixture, which was then purged with argon gas and protected. The mixture was stirred at room temperature for 48 hours, at which point the reaction mixture was confirmed to be completely converted by TLC. After the reaction was completed, the reaction mixture was quenched by adding saturated aqueous NaHCO3 solution, extracted with dichloromethane (50 mL x 3), washed with saturated aqueous NaCl solution, dried over anhydrous MgSO4, filtered, and the solvent was evaporated under reduced pressure using a rotary evaporator to obtain the crude product, which was separated and purified by silica gel column chromatography (mobile phase: petroleum ether and ethyl acetate, proportional gradient 15:1 to 4:1) to obtain a pale yellow solid product (925 mg, yield 31.7%). 1 H NMR (400 MHz, chloroform-d) δ 7.89 - 7.80 (m, 2H), 7.78 - 7.69 (m, 2H), 7.54 (s, 1H), 6.63 (s, 1H), 5.38 (d, J = 6.1 Hz, 1H), 4.64 (s, 2H), 4.14 - 3.97 (m, 2H), 3.43 - 3.29 (m, 1H), 3.09 - 2.90 (m, 2H), 2.07 - 1.94 (m, 2H), 1.57 - 1.40 (m, 12H).

[0184] Synthesis of intermediate 51e: tert-butyl 4-((4,5-dichloro-2-((1,3-dicarbonylisodihydroindol-2-yl)methyl)phenyl)amino)piperidine-1-carboxylate (51c) (800 mg, 1.59 mmol) and ethanol (16 mL) were placed in a clean, dry single-neck flask (50 mL). Hydrazine hydrate (467 mg, 7.93 mmol, 453 μL, 85%) was added to the stirred reaction mixture, heated to 80°C, and refluxed for 2 hours. A large amount of solid precipitated, indicating complete reaction by TLC. After the reaction was completed, the reaction system was cooled to room temperature, filtered, and the filtrate was collected. The solvent was evaporated under reduced pressure using a rotary evaporator to give a pale yellow oily crude product, tert-butyl 4-((2-(aminomethyl)-4,5-dichlorophenyl)amino)piperidine-1-carboxylate (51d) (590 mg, 99.38% yield). The crude product (590 mg, 1.58 mmol) was dissolved in dry tetrahydrofuran (15 mL) and purged with argon gas for protection. A solution of N,N'-carbonyldiimidazole (358 mg, 2.21 mmol) in dichloromethane (6 mL) was added dropwise to the reaction system and stirred at room temperature for 18 hours. The reaction was found to be nearly complete by TLC plate. After the reaction was completed, the reaction mixture was quenched by adding saturated NaHCO3 solution dropwise, and extracted three times with ethyl acetate (25 mL x 3). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure using a rotary evaporator to obtain the crude product, which was separated and purified by alkaline aluminum oxide column chromatography (mobile phase: petroleum ether and ethyl acetate, proportional gradient 5:1 to 1:1) to obtain a white solid product (528 mg, yield 83.7%). 1H NMR (400 MHz, chloroform-d) δ 7.14 (s, 1H), 7.07 (s, 1H), 5.62 (s, 1H), 4.41 - 4.17 (m, 4H), 4.09 - 3.95 (m, 1H), 2.91 - 2.68 (m, 2H), 2.64 - 2.45 (m, 2H), 1.83 - 1.70 (m, 2H), 1.49 (s, 9H).

[0185] Synthesis of intermediate 51f: tert-butyl 4-(6,7-dichloro-2-carbonyl-3,4-dihydroquinazolin-1(2H)-yl)piperidine-1-carboxylate (51e) (220 mg, 549 μmol) and dry tetrahydrofuran (5.5 mL) were placed in a clean, dry three-necked flask (50 mL). The flask was purged with argon gas and cooled to 0°C in an ice-water bath. NaH (40 mg, 1.65 mmol, 60% in mineral oil) was added to the reaction mixture and stirred for 30 minutes. 4-(2-bromoethyl)morpholine hydrobromide (212 mg, 769 μmol) was added to the reaction mixture and stirred for 30 minutes. The ice-water bath was removed, and the mixture was gradually heated to 35°C and stirred for 18 hours. The reaction was found to be almost complete by TLC. After the reaction was completed, the reaction mixture was cooled in an ice-water bath and quenched by adding ice water dropwise. The mixture was then extracted three times with ethyl acetate (25 mL x 3). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure using a rotary evaporator to obtain the crude product. The crude product was purified by alkaline aluminum oxide column chromatography (mobile phase: petroleum ether and ethyl acetate, proportional gradient 5:1 to 1:1) to obtain a white solid product (192 mg, yield 68.0%). 1H NMR (400 MHz, chloroform-d) δ 7.14 (s, 1H), 7.03 (s, 1H), 4.41–4.15 (m, 4H), 4.04–3.92 (m, 1H), 3.73–3.62 (m, 4H), 3.50 (t, J = 6.6 Hz, 2H), 2.90–2.69 (m, 2H), 2.61–2.43 (m, 8H), 1.83–1.72 (m, 2H), 1.48 (s, 9H).

[0186] Synthesis of intermediate 51g: tert-butyl 4-(6,7-dichloro-3-(2-morpholinoethyl)-2-carbonyl-3,4-dihydroquinazolin-1(2H)-yl)piperidine-1-carboxylate (51f) (185 mg, 360 μmol) and dichloromethane (5 mL) were placed in a clean, dry round-bottom flask (25 mL). Trifluoroacetic acid (1 mL) was added dropwise with stirring at room temperature. The reaction was allowed to proceed for 2 hours. TLC showed that the reaction was nearly complete. The reaction mixture was then rotary evaporated under reduced pressure. Ether (10 mL) was added to the residue, which was dispersed, crushed, and filtered to give the product (190 mg, 99.99% yield) as a white solid. This product was used directly in the next step.

[0187] Synthesis of compound EX51: 6,7-dichloro-3-(2-morpholinoethyl)-1-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one trifluoroacetate (51g) (190 mg, 360 μmol) and dry dichloromethane (3.5 mL) were placed in a clean and dry Schlenk reaction flask (10 mL). Triethylamine (146 mg, 1.44 mmol, 200 μL) was added and stirred at room temperature for 5 minutes. 2-Chloro-4-fluorobenzyl bromide (97 mg, 433 μmol) was added to the reaction system and stirred at room temperature for 12 hours. The reaction was detected to be almost complete by TLC plate. After the reaction was completed, the reaction mixture was evaporated under reduced pressure using a rotary evaporator to obtain the crude product. The crude product was purified by alkaline aluminum oxide column chromatography (mobile phase: petroleum ether and ethyl acetate, proportional gradient 5:1 to 1:1) to obtain a white solid product (158 mg, yield 78.9%). LC-MS (ESI) m / z: 556.20 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.56 (t, J = 7.5 Hz, 1H), 7.17 - 7.05 (m, 3H), 6.98 (t, J = 8.6 Hz, 1H), 4.25 (s, 2H), 3.94 - 3.81 (m, 1H), 3.74 - 3.64 (m, 4H), 3.61 (s, 2H), 3.52 (t, J = 6.7 Hz, 2H), 3.01 (d, J = 11.2 Hz, 2H), 2.70 (q, J = 11.6, 10.9 Hz, 2H), 2.56 (t, J = 5.9 Hz, 2H), 2.53 - 2.44 (m, 4H), 2.24 (t, J = 11.8 Hz, 2H), 1.75 (d, J = 12.2 Hz, 2H).

[0188] Example 52: Synthesis of 6,7-dichloro-1-(1-(2-chloro-4-fluorophenyl)piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (compound EX52) [ka] Synthesis of compound EX52: Using intermediate 51e as raw material, dichloromethane as solvent and trifluoroacetic acid were added to obtain white solid 52a (218 mg, 100% yield), which was directly used in the next reaction step without further purification. Using 52a and 2-chlorobenzyl bromide as raw materials, the synthesis was carried out according to the synthesis method of Example 39 to obtain a white solid product (74 mg, yield 72.2%). LC-MS (ESI) m / z: 425.30 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.57 (d, J = 6.8 Hz, 1H), 7.35 (dd, J = 7.9, 1.4 Hz, 1H), 7.27 (t, J = 7.0 Hz, 2H), 7.23 - 7.15 (m, 2H), 7.13 (s, 1H), 5.31 (s, 1H), 4.23 (s, 2H), 4.05 - 3.87 (m, 1H), 3.68 (s, 2H), 3.05 (d, J = 10.5 Hz, 2H), 2.71 (q, J = 10.7 Hz, 2H), 2.25 (t, J = 11.1 Hz, 2H), 1.75 (d, J = 11.2 Hz, 2H).

[0189] Example 53: Synthesis of 5,6-dichloro-1-(1-(2-chlorobenzyl)piperidin-4-yl)-3-(2-(2-oxopyrrolidin-1-yl)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX53) [ka]

[0190] Synthesis of intermediate 53b: Using 1-(2-hydroxypyrrol)-2-one as raw material, 53a was synthesized according to the synthesis method of 39b, and 1.8 g of a pale yellow oily crude product was obtained, with a yield of 82.4%, which was used directly in the next reaction step without further purification. Using 53a and 1e as raw materials, 53b was synthesized according to the synthesis method of 39c to obtain 231 mg of a white solid product, with a yield of 35.88%. 1 H NMR (400 MHz, chloroform-d) δ 7.16 (s, 1H), 7.15 (s, 1H), 4.40 - 4.27 (m, 3H), 4.00 (t, J = 6.0 Hz, 2H), 3.58 (t, J = 6.0 Hz, 2H), 3.36 (t, J = 7.0 Hz, 2H), 2.84 (t, J = 12.7 Hz, 2H), 2.32 - 2.18 (m, 4H), 1.99 - 1.89 (m, 2H), 1.83 - 1.74 (m, 2H), 1.51 (s, 9H).

[0191] Synthesis of intermediate 53c: Using 53b as raw material, synthesize intermediate 53c according to the synthesis method of intermediate 1f in Example 1, obtain 215 mg of white solid product, yield 90.5%, which is used directly in the next reaction step without purification.

[0192] Synthesis of compound EX53: Using 53c and 2-chlorobenzyl bromide as raw materials, the synthesis was carried out according to the synthesis method of Example 39 to obtain a white solid product (68 mg, yield 78.4%). LC-MS (ESI) m / z: 522.30 (M+H). + ; 1H NMR (400 MHz, chloroform-d) δ 7.55 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.31 (s, 1H), 7.28 (d, J = 6.5 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.16 (s, 1H), 4.34 - 4.22 (m, 1H), 4.00 (t, J = 6.0 Hz, 2H), 3.69 (s, 2H), 3.58 (t, J = 6.0 Hz, 2H), 3.35 (t, J = 7.0 Hz, 2H), 3.08 (d, J = 11.1 Hz, 2H), 2.40 (qd, J = 12.0, 3.6 Hz, 2H), 2.33 - 2.20 (m, 4H), 1.99 - 1.87 (m, 2H), 1.77 (d, J = 10.0 Hz, 2H).

[0193] Example 54: Synthesis of 2-(5,6-dichloro-3-(1-(2-chloro-4-fluorobenzyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N,N-dimethylacetamide (Compound EX54) [ka]

[0194] Synthesis of Intermediate 54a: Using Intermediate 1e and 2-chloro-N,N-dimethylacetamide as raw materials, intermediate 54a was synthesized according to the synthesis method of Intermediate 1f in Example 1 to obtain a colorless oily product (610 mg, yield 99.9%). 1H NMR (400 MHz, chloroform-d) δ 7.17 (s, 1H), 7.05 (s, 1H), 4.62 (s, 2H), 4.44 - 4.34 (m, 1H), 4.31 (d, J = 13.6 Hz, 2H), 3.14 (s, 3H), 2.99 (s, 3H), 2.84 (t, J = 12.2 Hz, 2H), 2.25 (qd, J = 12.7, 4.6 Hz, 2H), 1.82 (d, J = 10.4 Hz, 2H), 1.51 (s, 9H).

[0195] Synthesis of intermediate 54b: Using intermediate 54a as raw material, it was synthesized according to the synthesis method of intermediate 1g in Example 1 to obtain a white solid product (628 mg, yield 100%), which was directly used in the next step of the experiment.

[0196] Synthesis of compound EX54: Using 54b and 2-chloro-4-fluorobenzyl bromide as raw materials, the synthesis was carried out according to the synthesis method of Example 39 to obtain a white solid product (299 mg, yield 94.1%). LC-MS (ESI) m / z: 514.20 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.52 (t, J = 7.5 Hz, 1H), 7.30 (s, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.05 (s, 1H), 7.01 (t, J = 8.7 Hz, 1H), 4.62 (s, 2H), 4.38 - 4.24 (m, 1H), 3.63 (s, 2H), 3.14 (s, 3H), 3.04 (d, J = 10.5 Hz, 2H), 2.99 (s, 3H), 2.39 (q, J = 12.6, 11.8 Hz, 2H), 2.27 (t, J = 11.7 Hz, 2H), 1.81 (d, J = 11.5 Hz, 2H).

[0197] Example 55: Synthesis of 2-(5,6-dichloro-3-(1-(4-fluorobenzyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N,N-dimethylacetamide (Compound EX55) [ka] Using 54b and 4-fluorobenzyl bromide as raw materials, the synthesis was carried out according to the synthesis method of Example 39 to obtain a white solid product (238 mg, yield 60.2%). LC-MS (ESI) m / z: 480.20 (M+H). + ; 1 H NMR (400 MHz, chloroform-d) δ 7.37 - 7.28 (m, 3H), 7.07 - 6.98 (m, 3H), 4.61 (s, 2H), 4.35 - 4.23 (m, 1H), 3.52 (s, 2H), 3.13 (s, 3H), 3.01 (d, J = 12.0 Hz, 2H), 2.98 (s, 3H), 2.37 (qd, J = 12.4, 3.8 Hz, 2H), 2.14 (t, J = 11.7 Hz, 2H), 1.79 (d, J = 11.4 Hz, 2H).

[0198] Example 56: Synthesis of 5,6-dichloro-1-(2-(dimethylamino)ethyl)-3-(1-(4-fluorobenzyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX56) [ka] Using 46b and 4-fluorobenzyl bromide as raw materials, the synthesis was carried out according to the synthesis method of Example 39 to obtain a white solid product (140 mg, yield 41.8%). LC-MS (ESI) m / z: 466.20 (M+H). + ; 1H NMR (400 MHz, chloroform-d) δ 7.36 - 7.28 (m, 3H), 7.09 (s, 1H), 7.02 (t, J = 8.7 Hz, 2H), 4.37 - 4.25 (m, 1H), 3.92 (t, J = 7.0 Hz, 2H), 3.52 (s, 2H), 3.02 (d, J = 11.6 Hz, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.42 - 2.32 (m, 2H), 2.31 (s, 6H), 2.14 (t, J = 11.2 Hz, 2H), 1.77 (d, J = 13.7 Hz, 2H).

[0199] Example 57: Synthesis of 5,6-dichloro-1-(1-(2-methylbenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX57) [ka] Using Intermediate 1g and 2-methylbenzaldehyde as raw materials, the synthesis was carried out in accordance with the synthesis method of Example 1 to obtain a white solid product (120 mg, yield 61.2%). LC-MS (ESI) m / z: 504.20 (M+H) + ; 1 H NMR (400 MHz, chloroform-d) δ 7.33 - 7.28 (m, 1H), 7.28 - 7.25 (m, 1H), 7.20 - 7.14 (m, 3H), 7.11 (s, 1H), 4.36 - 4.24 (m, 1H), 3.93 (t, J = 6.6 Hz, 2H), 3.66 (t, J = 4.6 Hz, 4H), 3.51 (s, 2H), 3.04 (d, J = 11.1 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.51 (t, J = 4.6 Hz, 4H), 2.41 (s, 3H), 2.39 - 2.27 (m, 2H), 2.18 (t, J = 11.4 Hz, 2H), 1.76 (d, J = 10.4 Hz, 2H).

[0200] Example 58: Synthesis of 5,6-dichloro-1-(1-(2-chlorobenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX58) [ka] Using Intermediate 1g and 2-chlorobenzyl bromide as raw materials, the synthesis was carried out in accordance with the synthesis method of Example 39 to obtain a white solid product (78 mg, yield 50.9%). LC-MS (ESI) m / z: 524.20 (M+H) + ; 1 H NMR (400 MHz, chloroform-d) δ 7.54 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.31 (s, 1H), 7.27 (t, J = 7.4 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.12 (s, 1H), 4.36 - 4.24 (m, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.69 (s, 2H), 3.66 (t, J = 4.6 Hz, 4H), 3.08 (d, J = 11.0 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.52 (t, J = 4.6 Hz, 4H), 2.41 (qd, J = 12.3, 3.5 Hz, 2H), 2.29 (t, J = 11.7 Hz, 2H), 1.78 (d, J = 11.5 Hz, 2H).

[0201] Example 59: Synthesis of 5,6-dichloro-1-(1-(2-fluorobenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX59) [ka] Using 1g and 2-fluorobenzyl bromide as raw materials, the synthesis was carried out in accordance with the synthesis method of Example 39 to obtain a white solid product (106 mg, yield 71.5%). LC-MS (ESI) m / z: 508.20 (M+H) + ; 1 H NMR (400 MHz, chloroform-d) δ 7.43 (td, J = 7.5, 1.9 Hz, 1H), 7.33 (s, 1H), 7.30 - 7.22 (m, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.12 (s, 1H), 7.05 (t, J = 9.1 Hz, 1H), 4.36 - 4.22 (m, 1H), 3.94 (t, J = 6.7 Hz, 2H), 3.73 - 3.56 (m, 6H), 3.07 (d, J = 11.4 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.53 (t, J = 4.6 Hz, 4H), 2.37 (qd, J = 12.4, 3.8 Hz, 2H), 2.23 (t, J = 11.3 Hz, 2H), 1.77 (d, J = 11.6 Hz, 2H).

[0202] Example 60: Synthesis of 5,6-dichloro-1-(1-(2-fluorobenzyl)piperidin-4-yl)-3-(oxiran-2-ylmethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX60) [ka]

[0203] Synthesis of intermediate 60a: Using intermediate 1e as raw material, remove the Boc protecting group with trifluoroacetic acid at room temperature to obtain 520 mg of white trifluoroacetic acid salt solid, with a yield of 99.8%, which was used directly in the next reaction step without further purification.

[0204] Synthesis of Intermediate 60b: Using Intermediate 60a and 2-fluorobenzyl bromide as raw materials, the synthesis was carried out according to the synthesis method of Example 39 to obtain 197 mg of white solid Intermediate 60b, with a yield of 99.9%. 1 H NMR (400 MHz, chloroform-d) δ 10.67 (s, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.35 (s, 1H), 7.31 - 7.25 (m, 1H), 7.20 (s, 1H), 7.15 (t, J = 7.3 Hz, 1H), 7.06 (t, J = 9.0 Hz, 1H), 4.35 - 4.20 (m, 1H), 3.70 (s, 2H), 3.11 (d, J = 11.1 Hz, 2H), 2.41 (q, J = 12.6 Hz, 2H), 2.26 (t, J = 11.9 Hz, 2H), 1.80 (d, J = 11.9 Hz, 2H).

[0205] Synthesis of Compound EX60: Using Intermediate 60b and bromomethylepoxyethane as raw materials, the compound was synthesized according to the synthesis method of Intermediate 1f to obtain a pale yellow solid product (48 mg, yield 42.0%). LC-MS (ESI) m / z: 451.10 (M+H). + ; 1H NMR (400 MHz, chloroform-d) δ 7.43 (t, J = 7.1 Hz, 1H), 7.34 (s, 1H), 7.30 - 7.23 (m, 2H), 7.15 (t, J = 7.3 Hz, 1H), 7.06 (t, J = 9.1 Hz, 1H), 4.41 (dd, J = 15.2, 2.6 Hz, 1H), 4.36 - 4.24 (m, 1H), 3.67 (s, 2H), 3.62 (dd, J = 15.3, 6.4 Hz, 1H), 3.27 - 3.17 (m, 1H), 3.08 (d, J = 10.7 Hz, 2H), 2.87 (t, J = 4.3 Hz, 1H), 2.65 (dd, J = 4.6, 2.6 Hz, 1H), 2.38 (q, J = 11.3, 10.8 Hz, 2H), 2.24 (t, J = 11.4 Hz, 2H), 1.85 - 1.71 (m, 2H).

[0206] Example 61: Synthesis of 3-(1-(2-chlorobenzyl)piperidin-4-yl)-5-fluoro-1-(2-morpholinethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX61) [ka]

[0207] Synthesis of intermediate 61a: Using 2,4-difluoronitrobenzene and 1-N-Boc-4-aminopiperidine as raw materials, synthesize according to the synthesis method of intermediate 1f, obtain 1.07 g of yellow waxy product, the yield is 80.0%. 1H NMR (400 MHz, chloroform-d) δ 6.97 - 6.90 (m, 1H), 6.88 (d, J = 9.1 Hz, 1H), 6.80 (t, J = 8.9 Hz, 1H), 4.50 - 4.17 (m, 3H), 3.99 (t, J = 6.9 Hz, 2H), 3.68 (t, J = 4.4 Hz, 4H), 2.85 (s, 2H), 2.67 (t, J = 7.2 Hz, 2H), 2.54 (t, J = 4.5 Hz, 4H), 2.26 (qd, J = 12.9, 4.3 Hz, 2H), 1.80 (d, J = 12.6 Hz, 2H), 1.50 (s, 9H).

[0208] Synthesis of intermediate 61b: Using intermediate 61a, the Boc protecting group was removed by the action of trifluoroacetic acid at room temperature to obtain 1.03 g of white trifluoroacetic acid salt solid, the yield was 99.9%, which was used directly in the next reaction step without purification.

[0209] Synthesis of compound EX61: Using intermediate 61b and 2-chlorobenzyl bromide as raw materials, synthesize the compound according to the synthesis method of Example 39. Obtain 226 mg of a pale yellow solid product, with a yield of 88.4%. LC-MS (ESI) m / z: 474.20 (M+H). + ; 1H NMR (400 MHz, chloroform-d) δ 7.56 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.31 - 7.23 (m, 1H), 7.19 (t, J = 7.7 Hz, 1H), 7.04 (d, J = 9.1 Hz, 1H), 6.95 - 6.88 (m, 1H), 6.79 (t, J = 8.9 Hz, 1H), 4.42 - 4.29 (m, 1H), 3.98 (t, J = 6.8 Hz, 2H), 3.74 - 3.59 (m, 6H), 3.07 (d, J = 11.0 Hz, 2H), 2.66 (t, J = 7.0 Hz, 2H), 2.59 - 2.50 (m, 4H), 2.44 (q, J = 12.8 Hz, 2H), 2.29 (t, J = 11.6 Hz, 2H), 1.79 (d, J = 11.7 Hz, 2H).

[0210] Example 62: Synthesis of 1-(1-(2-chlorobenzyl)piperidin-4-yl)-5-methyl-3-(2-morpholinethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX62) [ka]

[0211] Synthesis of intermediate 62a: Using 4-fluoro-3-nitrotoluene and 1-N-Boc-4-aminopiperidine as raw materials, synthesize according to the synthesis method of intermediate 1f, obtain 526 mg of colorless waxy product, the yield is 78.4%. 1H NMR (400 MHz, chloroform-d) δ 7.01 (d, J = 8.0 Hz, 1H), 6.90 - 6.82 (m, 2H), 4.51 - 4.39 (m, 1H), 4.30 (br s, 2H), 3.99 (t, J = 7.0 Hz, 2H), 3.69 (t, J = 4.5 Hz, 4H), 2.95 - 2.76 (m, 2H), 2.67 (t, J = 7.3 Hz, 2H), 2.55 (t, J = 4.4 Hz, 4H), 2.40 (s, 3H), 2.29 (qd, J = 12.4, 3.7 Hz, 2H), 1.80 (d, J = 13.1 Hz, 2H), 1.50 (s, 9H).

[0212] Synthesis of intermediate 62b: Using intermediate 62a, the Boc protecting group was removed by the action of trifluoroacetic acid at room temperature to obtain 459 mg of white trifluoroacetic acid salt solid, the yield was 99.8%, which was used directly in the next reaction step without purification.

[0213] Synthesis of compound EX62: Using intermediate 62b and 2-chlorobenzyl bromide as raw materials, the synthesis was carried out according to the synthesis method of Example 39 to obtain a white solid product (186 mg, yield 90.9%). LC-MS (ESI) m / z: 470.20 (M+H). + ; 1H NMR (400 MHz, chloroform-d) δ 7.54 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.91 - 6.81 (m, 2H), 4.42 - 4.29 (m, 1H), 3.98 (t, J = 7.1 Hz, 2H), 3.76 - 3.60 (m, 6H), 3.05 (d, J = 11.1 Hz, 2H), 2.67 (t, J = 7.2Hz, 2H), 2.55 (t, J = 4.6 Hz, 4H), 2.51 - 2.43 (m, 2H), 2.40 (s, 3H), 2.28 (t, J = 11.7 Hz, 2H), 1.78 (d, J = 11.8 Hz, 2H).

[0214] Example 63: Synthesis of 6,7-dichloro-1-(1-(2-fluorobenzyl)piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (compound EX63) [ka] Using 52a and 2-fluorobenzyl bromide as raw materials, the synthesis was carried out according to the synthesis method of Example 39 to obtain a white solid product (56 mg, yield 56.8%). LC-MS (ESI) m / z: 425.10 (M+H). + ; 1H NMR (400 MHz, chloroform-d) δ 7.45 (t, J = 7.5 Hz, 1H), 7.29 - 7.22 (m, 1H), 7.19 - 7.08 (m, 3H), 7.04 (t, J = 9.1 Hz, 1H), 5.48 (s, 1H), 4.22 (s, 2H), 3.99 - 3.85 (m, 1H), 3.67 (s, 2H), 3.05 (d, J = 10.9 Hz, 2H), 2.69 (q, J = 11.7, 10.9 Hz, 2H), 2.20 (t, J = 11.3 Hz, 2H), 1.74 (d, J = 11.7 Hz, 2H).

[0215] Example 64: Synthesis of 5,6-dichloro-1-(2-morpholinoethyl)-3-(1-phenylethylpiperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX64) [ka] Using Intermediate 1g and phenylacetaldehyde as raw materials, the synthesis was carried out in accordance with the synthesis method of Example 1 to obtain a white solid product (115 mg, yield 59%). HRMS (ESI): m / z calculated for C 26 H 33 Cl2N4O2([M+H] + ) 503.1975, found 503.1968; HPLC purity: 98.90%, t R = 5.10 min. 1H NMR (400 MHz, chloroform-d) δ 7.38 (s, 1H), 7.33 - 7.28 (m, 2H), 7.25 - 7.18 (m, 3H), 7.12 (s, 1H), 4.34 (tt, J = 12.5, 4.3 Hz, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.66 (t, J = 4.6 Hz, 4H), 3.17 (d, J = 11.2 Hz, 2H), 2.84 (dd, J = 10.4, 6.0 Hz, 2H), 2.71 - 2.61 (m, 4H), 2.52 (t, J = 4.6 Hz, 4H), 2.39 (qd, J = 12.4, 3.8 Hz, 2H), 2.22 (t, J = 11.5 Hz, 2H), 1.82 (d, J = 10.9 Hz, 2H).

[0216] Example 65: Synthesis of 5,6-dichloro-1-(1-(2,6-dichlorobenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX65) [ka] Using Intermediate 1g and 2,6-dichlorobenzaldehyde as raw materials, the synthesis was carried out in accordance with the synthesis method of Example 1 to obtain a white solid product (163 mg, yield 75%). HRMS (ESI): m / z calcd for C 25 H 29 Cl4N4O2([M+H] + ) 557.1039, found 557.1034; HPLC purity: 99.46%, t R = 5.89 min. 1H NMR (400 MHz, chloroform-d) δ 7.32 (d, J = 8.0 Hz, 2H), 7.26 (s, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.10 (s, 1H), 4.30 (tt, J = 12.3, 4.2 Hz, 1H), 3.94 (t, J = 6.6 Hz, 2H), 3.80 (s, 2H), 3.66 (t, J = 4.5 Hz, 4H), 3.07 (d, J = 11.1 Hz, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.51 (t, J = 4.6 Hz, 4H), 2.41 (t, J = 11.4 Hz, 2H), 2.31 (qd, J = 12.1, 3.5 Hz, 2H), 1.74 (d, J = 11.0 Hz, 2H).

[0217] Example 66: Synthesis of 5,6-dichloro-1-(1-(2,6-dimethylbenzyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (compound EX66) [ka] Using Intermediate 1g and 2,6-dimethylbenzaldehyde as raw materials, the synthesis was carried out in accordance with the synthesis method of Example 1 to obtain a white solid product (163 mg, yield 75%). HRMS (ESI): m / z calcd for C 27 H 35 Cl2N4O2([M+H] + ) 517.2132, found 517.2118; HPLC purity: 100%, t R = 6.60 min. 1H NMR (400 MHz, chloroform-d) δ 7.20 (s, 1H), 7.12 - 7.04 (m, 2H), 7.04 - 6.99 (m, 2H), 4.35 - 4.22 (m, 1H), 3.92 (t, J = 6.6 Hz, 2H), 3.65 (t, J = 4.6 Hz, 4H), 3.53 (s, 2H), 2.97 (d, J = 8.2 Hz, 2H), 2.63 (t, J = 6.6 Hz, 2H), 2.51 (t, J = 4.6 Hz, 4H), 2.42 (s, 6H), 2.35 - 2.19 (m, 4H), 1.73 (d, J = 9.2 Hz, 2H).

[0218] Example 67: 6,7-Dichloro-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-3-(2-morpholinethyl)-3,4-dihydroquinazolin-2(1H)-one [ka] Using intermediate 51g and 4-isopropylcyclohexanone as raw materials, 345 mg of compound EX67 was synthesized as a white solid with a yield of 46% according to the synthesis method of compound EX12. The compound is a mixture of cis-trans isomers with a ratio of approximately 5:2. HRMS (ESI): m / z calculated for C 28 H 43 Cl2N4O2([M+H] + ) 537.2758, found 537.2741; HPLC purity (mixture): 28.09%, t R1 = 7.48 min; 71.91%, t R2 = 8.61 min. Main product: 1H NMR (400 MHz, chloroform-d) δ 7.26 (s, 1H), 7.12 (s, 1H), 4.24 (s, 2H), 4.05 (m, 1H), 3.68 (t, J = 4.6 Hz, 4H), 3.51 (t, J = 6.7 Hz, 2H), 3.25 (d, J = 11.4 Hz, 2H), 2.77 - 2.61 (m, 2H), 2.60 - 2.44 (m, 7H), 2.34 (t, J = 11.3 Hz, 2H), 1.86 - 1.69 (m, 4H), 1.69 - 1.52 (m, 4H), 1.45 - 1.31 (m, 3H), 1.19 - 1.08 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H). By-products: 1 H NMR (400 MHz, chloroform-d) δ 7.35 (s, 1H), 7.12 (s, 1H), 4.24 (s, 2H), 4.21 - 4.12 (m, 1H), 3.68 (t, J = 4.6 Hz, 4H), 3.51 (t, J = 6.7 Hz, 2H), 3.25 (d, J = 11.4 Hz, 2H), 2.77 - 2.61 (m, 2H), 2.60 - 2.44 (m, 7H), 2.01 (d, J = 11.9 Hz, 2H), 1.86 - 1.69 (m, 4H), 1.69 - 1.52 (m, 4H), 1.19 - 1.08 (m, 1H), 1.08 - 0.95 (m, 3H), 0.86 (d, J = 7.0 Hz, 6H).

[0219] Example 68: 6,7-Dichloro-3-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-1-(2-morpholinethyl)-3,4-dihydroquinazolin-2(1H)-one [ka] Using intermediate 47f and 4-isopropylcyclohexyl as raw materials, compound EX68 (78 mg) was synthesized as a white solid in 38% yield, following the synthesis method of compound EX12. The compound is a mixture of cis-trans isomers in a ratio of approximately 3:1. HRMS (ESI): m / z calculated for C 28 H 43 Cl2N4O2([M+H] + ) 537.2758, found 537.2741; HPLC purity (220 nm): 23.07%, t R1 = 9.12 min ; 74.25%, t R1 = 10.33 min. Main product: 1 H NMR (400 MHz, chloroform-d) δ 7.13 (s, 1H), 7.11 (s, 1H), 4.30 (tt, J = 12.1, 4.1 Hz, 1H), 4.22 (s, 2H), 3.96 (t, J = 7.1 Hz, 2H), 3.73 (t, J = 4.6 Hz, 4H), 3.11 (d, J = 11.3 Hz, 2H), 2.62 (t, J = 7.1 Hz, 2H), 2.56 (t, J = 4.7 Hz, 4H), 2.33 - 2.25 (m, 1H), 2.25 - 2.15 (m, 2H), 1.97 - 1.77 (m, 3H), 1.77 - 1.65 (m, 4H), 1.65 - 1.49 (m, 4H), 1.46 - 1.32 (m, 2H), 1.18 - 1.08 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H). By-products: 1H NMR (400 MHz, chloroform-d) δ 7.11 (s, 1H), 7.10 (s, 1H), 4.30 (tt, J = 12.1, 4.1 Hz, 1H), 4.22 (s, 2H), 3.96 (t, J = 7.1 Hz, 2H), 3.73 (t, J = 4.6 Hz, 4H), 3.04 (d, J = 11.7 Hz, 2H), 2.62 (t, J = 7.1 Hz, 2H), 2.56 (t, J = 4.7 Hz, 4H), 2.42 - 2.33 (m, 2H), 2.33 - 2.25 (m, 1H), 1.97 - 1.77 (m, 3H), 1.77 - 1.65 (m, 4H), 1.65 - 1.49 (m, 4H), 1.46 - 1.32 (m, 2H), 1.18 - 1.08 (m, 1H), 0.86 (d, J = 6.8 Hz, 6H).

[0220] Example 69B: 1-(1-((1S,4S)-4-isopropylcyclohexyl)piperidin-4-yl)-5-methyl-3-(2-morpholinethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one [ka] Using intermediate 62b and 4-isopropylcyclohexyl as raw materials, compound EX69 was synthesized according to the synthesis method of compound EX12. After separation by high-performance liquid chromatography, 96 mg of the cis product EX69B was obtained as a white solid, with a separation yield of 19%. HRMS (ESI): m / z calculated for C 28 H 45 NO([M+H] + ) 469.3537, found 469.3542; HPLC purity (220 nM): 96.12%, t R = 4.87 min. 1H NMR (400 MHz, chloroform-d) δ 7.19 (d, J = 7.5 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.84 (s, 1H), 4.39 - 4.25 (m, 1H), 3.98 (t, J = 7.2 Hz, 2H), 3.70 (t, J = 4.6 Hz, 4H), 3.15 (d, J = 9.2 Hz, 2H), 2.67 (t, J = 7.2 Hz, 2H), 2.56 (t, J = 4.6 Hz, 4H), 2.48 - 2.29 (m, 6H), 2.29 - 2.15 (m, 2H), 1.85 - 1.76 (m, 2H), 1.76 - 1.68 (m, 2H), 1.68 - 1.58 (m, 3H), 1.58 - 1.47 (m, 2H), 1.44 - 1.32 (m, 2H), 1.18 - 1.09 (m, 1H), 0.89 (d, J = 6.6 Hz, 6H).

[0221] Example 70B: 5-chloro-1-(1-((1S,4S)-4-isopropylcyclohexyl)piperidin-4-yl)-3-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one [ka] Using intermediate 32b and 4-isopropylcyclohexyl as raw materials, compound EX70 was synthesized according to the synthesis method of compound EX12. After separation by high performance liquid chromatography, 106 mg of white solid cis product EX70B was obtained, with a separation yield of 17%. HRMS (ESI): m / z calculated for C 27 H 42 ClNO2([M+H] + ) 489.2991, found 489.2996; HPLC purity: 96.24%, t R = 5.53 min. 1H NMR (400 MHz, chloroform-d) δ 7.21 (d, J = 7.8 Hz, 1H), 7.09 - 6.96 (m, 2H), 4.32 (tt, J = 13.0, 4.3 Hz, 1H), 3.97 (t, J = 6.9 Hz, 2H), 3.69 (t, J = 4.6 Hz, 4H), 3.16 (d, J = 11.2 Hz, 2H), 2.66 (t, J = 6.8 Hz, 2H), 2.54 (t, J = 4.6 Hz, 4H), 2.47 - 2.30 (m, 3H), 2.30 - 2.17 (m, 2H), 1.87 - 1.76 (m, 2H), 1.76 - 1.66 (m, 2H), 1.66 - 1.58 (m, 3H), 1.58 - 1.48 (m, 2H), 1.45 - 1.33 (m, 2H), 1.19 - 1.09 (m, 1H), 0.90 (d, J = 6.6 Hz, 6H).

[0222] Example 71B: 5-fluoro-3-(1-((1S,4S)-4-isopropylcyclohexyl)piperidin-4-yl)-1-(2-morpholinoethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one [ka] Using intermediate 61b and 4-isopropylcyclohexyl as raw materials, compound EX71 was synthesized according to the synthesis method of compound EX12. After separation by high performance liquid chromatography, 76 mg of pale yellow solid cis product EX71B was obtained, with a separation yield of 12%. HRMS (ESI): m / z calculated for C 27 H 42 FN4O2([M+H] + ) 473.3286, found 473.3297; HPLC purity: >99%, t R = 4.18 min. 1H NMR (400 MHz, クロロホルム-d) δ 7.12 - 7.02 (m, 1H), 6.91 (dd, J = 8.6, 4.5 Hz, 1H), 6.78 (td, J = 9.1, 2.4 Hz, 1H), 4.31 (tt, J = 12.4, 4.3 Hz, 1H), 3.98 (t, J = 7.0 Hz, 2H), 3.68 (t, J = 4.6 Hz, 4H), 3.16 (d, J = 11.0 Hz, 2H), 2.66 (t, J = 7.0 Hz, 2H), 2.53 (t, J = 4.7 Hz, 4H), 2.44 - 2.27 (m, 3H), 2.22 (t, J = 11.7 Hz, 2H), 1.85 - 1.76 (m, 2H), 1.76 - 1.58 (m, 5H), 1.58 - 1.46 (m, 2H), 1.44 - 1.33 (m, 2H), 1.18 - 1.08 (m, 1H), 0.90 (d, J = 6.6 Hz, 6H).

[0223] Biological activity test Testing the affinity of compounds for MOP receptors, NOP receptors (ORL-1 receptors), KOP receptors, and DOP receptors: Compounds are dissolved in 100% DMSO (10 mM) as stock solutions. Compounds are diluted in 384-well round-bottom plates. Initial screening concentrations of compounds are 1 μM, 0.1 μM, in duplicate. The initial compound rescreening concentrations were 1 μM (MOP receptor), 10 μM (NOP receptor), or 100 μM (KOP and DOP receptors), diluted three-fold, with a 10-point gradient, in duplicate. The positive controls were DAMGO (MEC) (initial concentration 1 μM, diluted three-fold, with a 10-point gradient, in duplicate, for MOP receptor), Nociceptin (N / O FQ) (Sigma) (initial concentration 1 μM, diluted three-fold, with a 10-point gradient, in duplicate, for NOP receptor), Naltrexone hydrochloride (Sigma) (initial concentration 0.1 μM, diluted three-fold, with a 10-point gradient, in duplicate, for KOP receptor), and Naltrexone hydrochloride (initial concentration 10 μM, diluted three-fold, with a 10-point gradient, in duplicate, for DOP receptor). The working solution is 50 mM Tris pH 7.4, 5 mM MgCl2, the wash buffer is 50 mM Tris pH 7.4, stored at 4°C, and a 0.5% BSA solution (0.5 mL BSA added to 100 mL double distilled water, stored at 4°C). The reaction system was 500 μL. 100 μL of working solution and 5 μL of compound solution (1% DMSO, 99% water) were added to a 96-well deep well plate and shaken uniformly (5 min, 500 rpm). 299 μL of reaction solution and 1 μL of CHO-K1-containing MOP receptor membrane (PerkinElmer) (or HEK293-NOP receptor membrane or CHO-K1 DOP receptor membrane, PerkinElmer) were added to each well (for the KOP receptor test, 298 μL of reaction solution and 2 μL of CHO-K1-containing KOP receptor membrane, PerkinElmer) were added and shaken uniformly (5 min, 500 rpm). 100 μL of deuterated ligand [ 3 H]-DAMGO (PerkinElmer) (Fianl conc. 1 nM) (MOP receptor), [ 3H]-Nociceptin (PerkinElmer) (Final conc. 0.5 nM) (NOP receptor), [ 3 H]-U69593 (PerkinElmer) (Fianl conc. 1.5 nM) (KOP receptor), [ 3 Add [H]-DADLE (PerkinElmer) (Final concentration: 1 nM) (DOP receptor) and shake uniformly (5 min, 500 rpm). Incubate at 27°C for 1 hour. Preincubate a UNIFILTER-96 GF / C filter plate (0.5% PEI) at 4°C for 1 hour. Wash the UNIFILTER-96 GF / C filter plate (0.5% PEI) twice with 1 mL of wash buffer (per well). Transfer the cell membrane-containing mixture to a UNIFILTER-96 GF / C filter plate (0.5% PEI) and wash four times with 50 mL of wash buffer each time. Allow to dry (55°C, 10 min). Then, add 40 μL of scintillation fluid to each well, and read the scintillation points in a TopCount to determine membrane-bound radioactivity.

[0224] The binding rate (% Inhibition) of each test compound was measured at 10 concentrations, and the IC 50 The concentration at which 50% of binding is inhibited is determined by plotting the logarithm of the concentration on the X-axis and the response coefficient on the Y-axis. The data are processed using Xl-fit 5.3.1 software. The nonlinear regression equation is: Y = minimum + (maximum - minimum) / (1 + 10^(log(IC50-X) × Hill coefficient)) X = logarithm of compound concentration, Y = % Inhibition, Maximum and minimum values: Complex numbers are the same as Y units, LogIC50: The same as the logarithmic unit of the X-axis, Hill coefficient: Slope coefficient or Hill coefficient.

[0225] The binding ability of representative compounds of the present invention to receptor cell membranes was evaluated by radiolabeling [ 3H]-DAMGO (PerkinElmer), 3 H]-Nociceptin (PerkinElmer), [ 3 H]-U69,593 (PerkinElmer), [ 3 H]-DADLE (PerkinElmer) was used as a displaceable ligand, and K i The value is the formula K i = IC 50 / (1+L / K d ) and K d teeth[ 3 H]- is the binding affinity of the radioligand, and L is [ 3 3H]-radioliginate is used.

[0226] The affinity K of the compound measured in this application i Values ​​are shown in the table below, with " / " indicating no test data.

[0227] [Table 1] TIFF0007784037000103.tif226160

[0228] The compounds of the present application, such as EX3, EX6, EX16, EX17, EX54, EX58, and EX67, exhibit high selectivity and affinity for the MOP receptor and the KOP receptor. According to existing literature, bifunctional agonists that simultaneously act on the MOP receptor and the KOP receptor may reduce the side effects, such as dependency, of monoselective MOP receptor agonists. The euphoric effects of MOP receptor activation may offset the side effects, such as restlessness and aversion, of monoselective KOP receptor agonists, potentially achieving superior analgesic efficacy and minimal side effects. Compounds such as EX12B and EX48B exhibit high selectivity and affinity for the MOP receptor and the NOP receptor. These MOPr / NOPr bifunctional agonists enhance the analgesic effects of MOP receptor activation by activating the NOP receptor and reduce dependency by inhibiting dopamine release, potentially leading to the development of novel, non-addictive analgesics.

[0229] Testing the activation function (cAMP assay) of compounds against MOP receptor, NOP receptor (ORL-1 receptor), KOP receptor, and DOP receptor: Opioid receptors are G protein-coupled receptors, primarily G i After binding to a ligand and activating it, the G i The protein can inhibit adenylate cyclase activity, reducing intracellular cAMP levels. The cAMP kit (LANCE Ultra cAMP kit, PE) is used to measure the activating or inhibiting effects of compounds on four opioid receptors (MOPr, KOPr, DOPr, NOPr (ORL-1)). cAMP measurement is a competitive immunoassay method used to detect intracellular cAMP accumulation, and the detected signal value is negatively correlated with the cAMP concentration. Mix the standard according to the kit's instructions. Add 5 μL of standard, 5 μL of experimental buffer, 5 μL of 4x Eu-cAMP tracer working solution, and 5 μL of 4x ULight-anti-cAMP working solution to each well of a 384-well cell culture plate. Incubate at room temperature for 1 hour. Read the data using a microplate reader with an excitation wavelength of 330 nm and emission wavelengths of 620 nm and 665 nm. Calculate the signal ratio between 665 nm and 620 nm, and plot a standard curve based on the ratio and cAMP concentration. Stably expressing opioid receptor cell lines (CHO-hMOPr, CHO-hNOPr, HEK293-hKOPr, HEK293-hDOPr), cells were digested, centrifuged, resuspended in experimental buffer containing 0.5 mM IBMX, counted, and seeded into 384-well cell culture plates at a density of 3,000 cells / 5 μl per well. Compounds were diluted in experimental buffer to form 4x solutions. 2.5 μl of 4x compound was added to each well and incubated at 37°C for 10 min. 2.5 μl of 4x forskolin was then added and incubated at 37°C for 30 min. 5 μl of 4x Eu-cAMP tracer working solution and 5 μl of 4x ULight-anti-cAMP working solution were then added sequentially. The mixture was incubated at room temperature for 1 hour and read using a microplate reader. The excitation wavelength was 330 nm, and the emission wavelengths were 620 nm and 665 nm. The ratio of the 665 nm and 620 nm signals, i.e., Ratio (665 / 620), is calculated. Endorphin 1 was used for MOPr-positive compounds, nociceptin for NOPr (ORL-1)-positive compounds, dynorphin A 1-10 for KOPr-positive compounds, and DADLE for DOPr-positive compounds. The test compound detection concentration was 10 μM, diluted 3-fold, and tested in duplicate. The ratio (665 / 620) was plotted against compound concentration, and curve fitting and EC50 Do the calculations. Y=Bottom + (Top-Bottom) / (1+10^((LogEC50-X)*HillSlope)) X: logarithm of compound concentration, Y:% activity.

[0230] The compounds of the present application were tested by the above methods and are specifically shown in the table below, with "NA" indicating no test data.

[0231] [Table 2] TIFF0007784037000105.tif12168

[0232] According to the results of the cAMP activation function test of preferred compounds, compounds having biselectivity for MOP receptors and KOP receptors exhibit similarly good activation biological activity for MOP receptors and KOP receptors, and are MOP receptor / KOP receptor bifunctional agonists. Similarly, compounds having biselectivity for MOP receptors and KOP receptors also have good activation biological activity for these two opioid receptors.

[0233] In vivo pharmacodynamic testing: Formalin-induced inflammatory pain model The formalin-induced inflammatory pain pharmacodynamic animal model was established by Dubuisson and Dennis in 1977. Through long-term experimental validation, formalin diluted to a certain degree is injected subcutaneously into the footpad of a rat's hind paw using a microsyringe, producing continuous noxious stimulation and eliciting spontaneous pain behavior responses in the animals. Animals used: SPF male SD rats, 6-7 weeks old, weight range 160-180 g. Use as few animals as possible within the scope of research objectives and scientific standards.

[0234] Experimental Method: 1. Before the start of the experiment, all animals were housed in an animal room for one week to allow them to adapt to the environment. The room temperature was maintained at 22±2°C, and lighting was provided to avoid strong vocal and light stimuli. According to experimental needs, rats were randomly divided into groups, with 6-8 rats per group, and each group was numbered accordingly. All testing experiments were conducted between 8:00 AM and 12:00 PM. To allow the rats to adapt to the formalin testing environment, the rats were placed in experimental test boxes (transparent and visible) for 60 minutes each day for a total of three days. 2. Preparation of reagents: Prepare the analytical reagent formaldehyde solution into a 2% formalin solution in a sealed vial and use it (store it in a 4°C refrigerator after use). 3. Preparation of test compound solution. The solvent system is 5% DMSO + 10% Solutol + 85% saline, which can be adjusted to the actual required concentration according to the needs of the test experiment. 4. Dosage Form and Molding. The administration method in this experiment was subcutaneous injection. The rats were kept in the animal testing environment for six days, and the experiment was carried out while recording the rats' weight, room temperature, humidity, and other general control parameters. The rats were dosed according to their weight, and 15 minutes after administration, 50 μl of 2% formalin solution was injected subcutaneously into the instep of the rats' feet for molding. 5. Model evaluation. After formalin injection, the rats were placed in the test box, and the computer recorded the number of movements (paw lifts and paw licks of the injected paw) of the rats within 60 minutes after formalin injection, including the number of paw lifts in the early acute phase (phase I) and the late tonic phase (phase II) (phase I was from 0 to 9 minutes, and phase II was from 10 to 60 minutes) and the average cumulative number of paw lifts. Calculate the MPE% (Maximum Possible Effect, expressed as a percentage). %MPE = (1-number of exercises in the treatment group / number of exercises in the negative control group) x 100%

[0235] Data Statistics and Analysis: Data are presented as mean ± standard error. All data were analyzed using SPSS 13.0 statistical software. All data were tested for homogeneity of variance. Equal variance (p>0.05) was tested by one-way analysis of variance. Differences (p≦0.05) were tested by LSD multiple comparison analysis, with p≦0.05 indicating statistical differences. Heterogenous variance (p≦0.05) was tested by Kruskal-Wallis nonparametric test. Differences (p≦0.05) were tested by Mann-Whitney bimodal analysis, with p≦0.05 indicating statistical differences. Plots were generated using GraphPad Prism 8.0 (GraphPad Software, San Diego, California, USA) software.

[0236] As can be seen from the time-effect curve (Figure 1A), at a dose of 10 mg / kg, the time-effect curve for EX3 was nearly identical to that of the morphine group (mor) from 0 to 40 min. Thereafter, the time-effect curve became increasingly similar to that of the model group (model). This indicates that compound EX3 (10 mg / kg) had a good analgesic effect from 0 to 40 min, comparable to that of 3 mg / kg morphine. Statistical analysis of the maximum possible analgesic effect curve (Figure 1B) revealed that the model group had a significantly lower mean value than the blank control group (sham) (100 ± 3.3%), with a maximum possible effect of 0 ± 18.33%. The maximum possible analgesic effect of the 10 mg / kg compound EX3 group was 94.04 ± 5.81%, both of which were significantly higher than the model control group (p < 0.05). These experimental results suggest that compound EX3 has a good inhibitory effect on formalin-induced inflammatory pain.

[0237] In vivo pharmacodynamic testing: Nerve branch ligation injury model A spared nerve injury (SNI) animal model was developed to study the pharmacological mechanisms of neuropathic pain. This model was established using artificial surgery, producing a persistent and regenerative hyperalgesic response on the operated side, simulating typical clinical symptoms of neuropathic pain disorders. SNI model preparation: On day 0 of the experiment, rats were anesthetized using an isoflurane-infused anesthesia machine and secured to the operating table in a prone position. The lateral gluteal region was fully exposed. The left hind limb was shaved and disinfected with alcohol. Using surgical scissors, the skin was incised in the direction of the sciatic nerve parallel to the femur. The gluteal muscles and biceps femoris were bluntly dissected to expose the sciatic nerve trunk, carefully separating the surrounding adhesive tissue and fascia. Three branches of the sciatic nerve, namely the tibial nerve, common peroneal nerve, and sural nerve, were exposed. For the rats in the surgical group, the tibial nerve and common peroneal nerve were ligated with thread, and the tibial nerve and common peroneal nerve were sheared, respectively, to ensure the integrity of the sural nerve, and the muscle and epidermis were sutured layer by layer. After surgery, each rat was injected subcutaneously with 60,000 units of penicillin. They were kept in cages, and the administration experiment began 10 days after surgery. Main detection indicators and methods: Body weight. All animals were weighed weekly and detailed records were kept. For mechanical pain threshold measurements, animals were placed in specially designed pain detection multi-cell metal mesh cages and allowed to adapt to the environment for 10 minutes. After the animals had finished rearranging and exploring and adapted to the detection environment, electronic Von Frey Hairs (Bioseb) were used to stimulate the plantar surface of the little toe side of the hind paw of the SNI-operated side of the rat. Pressure was continuously increased until the rat elicited a clear paw flinching response. The Von Frey Hairs value at this time was recorded as the mechanical pain threshold, measured in grams. Two repeated measurements were performed, and the average value was taken as the final detection index. For paw load-bearing measurements, the weights of the two hind paws of the SNI model rats were not balanced. A paw support force measuring device (Dynamic Weight Bearing Test, BIO-DWB-DUAL, BIOSEB) was used to measure the load difference (left paw minus right paw) between the two hind paws of the animals. Two repeated measurements were performed, and the average value was taken as the load difference balance value between the two hind paws of the animals. The time points for testing the mechanical pain threshold and paw load-bearing were before molding, before administration, and 1, 2, and 4 hours after administration, for a total of five detection points.In this experiment, rats were randomly divided into five groups (8 rats per group) based on animal weight and baseline values ​​of mechanical pain threshold and paw load-bearing capacity before administration: a vehicle control group (5% DMSO + 10% Solutol HS15 + 85% saline), a positive control group (gabapentin, 100 mg / kg, dose converted to the clinical dose of gabapentin), and high, medium, and low dose groups of the test compound (10, 3, and 1 mg / kg). The positive control group used an oral dosage form consistent with clinical use, while all other experimental groups received subcutaneous abdominal injections. All experimental groups received a single dose. Experimental results were reported as the difference between mechanical pain threshold (von-Frey hair) and paw load-bearing capacity, and the corresponding analgesia rate was calculated. von-Frey hair relative analgesia rate (%) = (detection value - control group mean) / (SNI pre-surgery baseline value - control group mean) × 100. Paw weight-bearing relative analgesia rate (%) = (control mean value - detection value) / (control mean value - SNI pre-operative baseline value) × 100. Data were analyzed and plotted using GraphPad Prism 8.0 (GraphPad Software, San Diego, California, USA) software. As can be seen from the experimental results (Figure 2A and C), the von-Frey hair test results at 1 h post-administration showed that all three doses of compound EX3 elevated the animals' mechanical pain threshold to a certain extent, particularly at the mid- and high-dose levels, with a significant difference compared to the model group (p < 0.01). The mechanical pain thresholds of rats in the mid- and high-dose groups were 7.0 ± 0.1 g and 9.5 ± 0.2 g, respectively, with mean von-Frey hair relative analgesia rates of 12.93% and 49.02%, respectively. The analgesic effect of the high-dose group was superior to that of the positive control group (gabapentin, 100 mg / kg; mean von-Frey hair relative analgesia rate of 29.71%). Over time, the mechanical pain thresholds of rats in each test drug group decreased at 2 h, with a significant difference compared to the model group (p < 0.01). The mechanical pain threshold of rats in the high dose (10 mg / kg) group of compound EX3 was 8.3 ± 0.1 g, and the mean von-Frey hair relative analgesia rate was 33.99%, which is similar to that of the positive control group (the mean von-Frey hair relative analgesia rate of the positive control group was 36.26%).

[0238] The weight bearing balance of the two hind paws in the SNI model rats was not balanced. To further verify the analgesic effect of compound EX3 on SNI neuralgia in rats, the weight bearing difference (left paw minus right paw) of the animals was measured, and the average value was taken as the weight bearing balance value of the two hind paws of the animals. The test time points were the same as those for the von Frey hair test. As can be seen from the experimental results (Figure 2, B and D), after molding, the weight bearing balance value of the paws of the model animals increased significantly to 59.87 ± 1.60 g (compared to 3.88 ± 0.56 g before surgery). The drug significantly decreased the weight bearing balance value of the rats' hind paws, most significantly at the 1-hour time point. Each experimental group showed a significant difference compared with the model group (p<0.01). The rats in the high dose group (10 mg / kg) of compound EX3 had a hind paw weight differential equilibrium value of 46.82±1.68 g, and the average paw weight-bearing relative analgesia rate was 22.11%, which was close to the positive control gabapentin group (the average paw weight-bearing relative analgesia rate of rats in the positive control group was 20.85%). Over time, the analgesic effect of the drug became weaker and weaker, but still showed a significant difference compared with the model group (p<0.01). At 2 h, the paw load-bearing relative analgesia rate of the low and medium dose groups of compound EX3 remained at about 10%, while the hind paw load-bearing differential balance value of rats in the high dose group (10 mg / kg) was 46.54 ± 0.80 g, with an average paw load-bearing relative analgesia rate of 20.03%, maintaining a high level and slightly better than the positive control group (average paw load-bearing relative analgesia rate of 17.55%). At 4 h, the hind paw load-bearing differential balance value of rats in the high dose group of compound EX3 still showed a significant difference compared with the model group (p < 0.01), with an average paw load-bearing relative analgesia rate of 15.38%, slightly better than the positive control group (average paw load-bearing relative analgesia rate of 14.07%).

[0239] Evaluation of the SNI neuralgia model showed that compound EX3 could effectively suppress neuralgia in rats, with good dose-dependence, and the analgesic effect coincided with the drug metabolic cycle, with the drug exerting its maximum effect at 1 hour. The high-dose group (10 mg / kg) had a certain analgesic advantage over the positive control gabapentin (100 mg / kg), with a long duration of action and still maintaining good analgesic effect at 4 hours. Compound EX3 showed superior analgesic effect to the positive control gabapentin at a relatively low dose.

[0240] According to the above research results, the compound disclosed in the present application has biselectivity for MOP receptor and KOP receptor, and by acting on this bifunctional MOP receptor and KOP receptor, it can exert good analgesic effect, especially the inhibition of neuropathic pain is far superior to clinically used drug gabapentin.According to the reports of many existing documents, this effect cannot be achieved by single-selective MOP receptor agonist.

[0241] The compounds disclosed in the present application were preferably selected and subjected to in vivo pharmacodynamic evaluation using the above method, and the results showed that the compounds disclosed in the present application have good therapeutic effects on inflammatory pain and neuropathic pain. Continuous observation and data analysis during the experimental process showed that the compounds disclosed in the present application had less side effects such as constipation and itching than the positive control.

[0242] Although the examples set forth in this application are as described above, the above contents are merely embodiments for the convenience of understanding the application and are not intended to limit the application. Those skilled in the art may make any modifications and changes to the embodiments and details without departing from the spirit and scope of the application, and the scope of protection of the application is based on the appended claims. Some embodiments are given below. Item 1 A compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, solvate, deuterated product, metabolite or prodrug thereof, [ka] During the ceremony, n is 0 or 1, m is 0 or 1; p is 0, 1 or 2; R 1 and R 2 are independently hydrogen, halogen, or C 1-3 Alkyl groups and C 1-3 alkoxy groups, R 1 and R 2 is not hydrogen at the same time, R 3 is an unsubstituted aryl group, a substituted aryl group, an unsubstituted heteroaryl group, a substituted heteroaryl group, an unsubstituted C 3-8 Cycloalkyl groups, substituted C 3-8 Cycloalkyl groups, unsubstituted C 4-6 Heterocycloalkyl groups and substituted C 4-6 a heterocycloalkyl group, wherein the substituted aryl group, the substituted heteroaryl group, and the substituted C 3-8 Cycloalkyl group or substituted C 4-6 Heterocycloalkyl groups are substituted with halogen, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 substituted by 1 to 3 substituents independently selected from an alkoxy group, an aryl group, and a heteroaryl group; R 4 is hydrogen, -C 1-3 alkyl group-unsubstituted heterocycloalkyl group, -C 1-3 Alkyl-substituted heterocycloalkyl groups, -C 1-3 Alkyl-substituted spiroheterocycloalkyl groups, -C 1-3 Alkyl group -C(O)NR 5 R 6 、-C 1-3 Alkyl group -NR 7 R 8 、-C 1-4 alkyl group-unsubstituted heteroaryl group and -C 1-4 alkyl-substituted heteroaryl groups; R 5 and R 6 are independently hydrogen or C 1-3 It may be an alkyl group, or R 5 and R 6 Let's go together 4-6 or R 5 and R 6 Let's go together 4-6 and R 7 and R 8 are independently hydrogen or C 1-3 It may be an alkyl group, or R 7 and R 8 Let's go together 4-6 or R 7 and R 8 Let's go together 4-6 and R 4 is hydrogen, then m is 0 and n is 1, the compound, stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite or prodrug thereof Section 2 Item 1, wherein n is 0, m is 0, and p is 0, 1, or 2; or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof. Section 3 Item 1, wherein n is 1, m is 0, and p is 0, 1, or 2, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof. Section 4 Item 1, wherein n is 0, m is 1, and p is 0, 1, or 2; or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof. Section 5 R 1 and R 2 are independently hydrogen, halogen, or C 1-3 alkyl groups, R 1 and R 2 and is not simultaneously hydrogen, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite or prodrug thereof. Section 6 R 1 and R 2 are independently hydrogen, chlorine, fluorine, C 1-3 alkyl groups, R 1 and R 2 and R is not simultaneously hydrogen, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite or prodrug thereof. Section 7 R 1 and R 2 are each independently selected from hydrogen, chlorine, fluorine, and a methyl group; R 1 and R2 is not hydrogen at the same time, and as an option, R 1 and R 2 are both chlorine, or R 1 is chlorine and R 2 is fluorine, or R 1 is fluorine and R 2 is chlorine, or R 1 and R 2 are both fluorine, or R 1 is fluorine, methyl group or chlorine, and R 2 is hydrogen, or R 1 is hydrogen and R 2 Item 7. The compound according to item 6, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite or prodrug thereof, wherein is chlorine or fluorine. Section 8 R 3 is selected from unsubstituted aryl groups, substituted aryl groups, unsubstituted heteroaryl groups, and substituted heteroaryl groups, wherein the unsubstituted aryl group is a phenyl group or a naphthyl group, the unsubstituted heteroaryl group is a furanyl group, a thienyl group, a pyridinyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, or a tetrazolyl group, and the substituted aryl group is selected from halogen, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 a phenyl group or a naphthyl group substituted with 1 to 3 groups independently selected from an alkoxy group, an aryl group, and a heteroaryl group, and the substituted heteroaryl group is selected from halogen, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 Item 1, wherein the compound is a furanyl group, a thienyl group, a pyridinyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, or a tetrazolyl group, each of which is substituted by one or two groups independently selected from an alkoxy group, an aryl group, and a heteroaryl group, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated product, a metabolite, or a prodrug thereof. Section 9 R 3 is a phenyl group, or a halogen, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy and haloC 1-4 a phenyl group substituted by 1 to 3 groups independently selected from alkoxy groups, or a phenyl group substituted by fluorine, chlorine, bromine, iodine, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy and haloC 1-4 Item 9. The compound according to item 8, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof, wherein R is a phenyl group substituted by 1 to 3 groups independently selected from alkoxy groups. Section 10 R 3 is a phenyl group, a 3,4-dichlorophenyl group, a 3,4-difluorophenyl group, a 2-chloro-4-fluorophenyl group, a 2-fluoro-4-chlorophenyl group, a 4-trifluoromethylphenyl group, a 4-trifluoromethoxyphenyl group, a 2,4-dichlorophenyl group, a 2,6-dichlorophenyl group, a 2,4-difluorophenyl group, a 2-chloro-4-methylphenyl group, a 2-methyl-4-fluorophenyl group, a 2-methyl-4-chlorophenyl group, a 2-methoxy-4-chlorophenyl group, a 2,4-dimethylphenyl group, a 2,6-dimethylphenyl group, a 2,4,6-trimethylphenyl group, a 4-tert-butylphenyl group, a 2-chlorophenyl group, a 2-methylphenyl group, a 2-fluorophenyl group, a 2-methoxyphenyl group, a 4-chlorophenyl group, a 4-fluorophenyl group, or a 4-methoxyphenyl group, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated product, a metabolite, or a prodrug thereof. Section 11 R 3 is a furanyl group, a thienyl group, a pyridinyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, or a tetrazolyl group, and optionally is a fluorine, a chlorine, a bromine, an iodine, a C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy and haloC 1-4 substituted with 1 to 2 groups independently selected from alkoxy groups, and optionally R 3 Item 9. The compound according to item 8, wherein R is 5-trifluoromethylpyridin-2-yl or 5-chlorothiophen-2-yl, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite or prodrug thereof. Section 12 R 3 is unsubstituted C 3-8 Cycloalkyl group or substituted C 3-8 is a cycloalkyl group, 3-8 Cycloalkyl groups, substituted C 3-8 C in cycloalkyl groups 3-8 The cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group, and the substituted C 3-8 Cycloalkyl groups are fluorine, chlorine, bromine, iodine, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group substituted by 1 to 3 groups independently selected from an alkoxy group and a phenyl group, and preferably the substituted C 3-8 Item 1, wherein the cycloalkyl group is 4-tert-butylcyclohexyl, 4-isopropylcyclohexyl, 4-ethylcyclohexyl, 4-methylcyclohexyl, 4-trifluoromethylcyclohexyl, 2,3-dihydro-1H-inden-2-yl, or 2-chlorocyclohexyl, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof. Section 13 R 3 is a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4-tert-butylcyclohexyl group, a 4-isopropylcyclohexyl group, a 4-ethylcyclohexyl group, a 4-methylcyclohexyl group, a 4-trifluoromethylcyclohexyl group, a 2,3-dihydro-1H-inden-2-yl group, or a 2-chlorocyclohexyl group, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated product, a metabolite, or a prodrug thereof. Section 14 R 3 is unsubstituted C 4-6 Heterocycloalkyl group or substituted C 4-6 heterocycloalkyl group, wherein the unsubstituted C 4-6 Heterocycloalkyl group or substituted C 4-6 C in heterocycloalkyl groups 4-6 The heterocycloalkyl group is a tetrahydrofuranyl group, a tetrahydropyrrolyl group, a tetrahydrothienyl group, a piperidinyl group, a morpholino group, or a piperazinyl group, and the substituted C 4-6 Heterocycloalkyl groups include fluorine, chlorine, bromine, iodine, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 a tetrahydrofuranyl group, a tetrahydropyrrolyl group, a tetrahydrothienyl group, a piperidinyl group, a morpholino group, or a piperazinyl group substituted by 1 to 3 groups independently selected from an alkoxy group and a phenyl group, and preferably the substituted C 4-6 Item 1, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite or prodrug thereof, wherein the heterocycloalkyl group is N-isopropylpiperidin-4-yl. Section 15 R 4 is hydrogen, -C 1-3 alkyl group-at least one heterocycloalkyl group that is unsubstituted and selected from oxa and thia; 1-3 an alkyl group-substituted with at least one heterocycloalkyl group selected from oxa and thia; 1-3 Alkyl-substituted spiroheterocycloalkyl groups, -C 1-3 Alkyl group -C(O)NR 5 R 6 、-C 1-3 Alkyl group -NR 7 R 8 、-C 1-4 alkyl group-unsubstituted and at least one heteroaryl group selected from aza, oxa, and thia, and -C 1-4 alkyl-substituted and selected from at least one heteroaryl group selected from aza, oxa, and thia; R 5 and R 6 are independently hydrogen or C 1-3 Alternatively, R5 and R6 and the connected N together form C 4-6 or R 5 and R 6 And connected N together C 4-6 and R 7 and R 8 are independently hydrogen or C 1-3 It may be an alkyl group, or R 7 and R 8 And connected N together C 4-6 or R 7 and R 8 And connected N together C 4-6 and R 4 is hydrogen, m is 0, n is 1, and the term "substituted" refers to substitution with one or more groups selected from the group consisting of a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, a C1-C4 alkanoyl group, a C1-C4 alkanoyloxy group, a hydroxyl group, a nitro group, a halogen atom, an oxo group, and a cyano group; Preferably, the R 4 is hydrogen, 2-(morpholino)ethyl, 2-(1,1-dioxothiomorpholine)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-(4-acetylpiperazin-1-yl)ethyl, 2-(3-oxopiperazin-1-yl)ethyl, 2-(pyrrolidin-1-yl)ethyl, 2-(piperidin-1-yl)ethyl, 2-(N,N'-dimethylamino)ethyl, 2-(2-oxopyrrolidin-1-yl)ethyl, N,N'-dimethylacetamido, oxiran-2-ylmethyl, or 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl; R 4 is hydrogen, then m is 0 and n is 1; Item 15. The compound according to any one of Items 1 to 14, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof. Section 16 Item 1, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated product, metabolite, or prodrug thereof, which is one selected from the following compounds:

change

Claims

1. A compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate or a deuterated salt thereof, 【Chemistry 1】 During the ceremony, n is 1, m is 0, p is 0, 1 or 2; R 1 and R 2 are each independently selected from hydrogen, chlorine, fluorine, and a methyl group; R 1 and R 2 is not hydrogen at the same time, R 3 is an unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl group, or an unsubstituted fluorine, chlorine, bromine, iodine, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 A cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group substituted by 1 to 3 groups independently selected from an alkoxy group and a phenyl group, an unsubstituted phenyl group, or a fluorine, chlorine, bromine, iodine, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy and haloC 1-4 a phenyl group substituted by 1 to 3 groups independently selected from alkoxy groups, or an unsubstituted furanyl group, thienyl group, pyridinyl group, pyrrolyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, imidazolyl group, pyrazolyl group, triazolyl group, or tetrazolyl group, or a halogen, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 A furanyl group, a thienyl group, a pyridinyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, or a tetrazolyl group, which are substituted by one or two groups independently selected from an alkoxy group, an aryl group, and a heteroaryl group; an unsubstituted tetrahydrofuranyl group, a tetrahydropyrrolyl group, a tetrahydrothienyl group, a piperidinyl group, a morpholino group, or a piperazinyl group; or a fluorine, chlorine, bromine, iodine, C 1-4 Alkyl group, halo C 1-4 Alkyl group, C 1-4 Alkoxy group, haloC 1-4 selected from a tetrahydrofuranyl group, a tetrahydropyrrolyl group, a tetrahydrothienyl group, a piperidinyl group, a morpholino group, a piperazinyl group, or a 2,3-dihydro-1H-inden-2-yl group, each substituted by 1 to 3 groups independently selected from an alkoxy group and a phenyl group; R 4 is selected from hydrogen, a 2-(morpholino)ethyl group, a 2-(1,1-dioxothiomorpholine)ethyl group, a 2-(4-methylpiperazin-1-yl)ethyl group, a 2-(4-acetylpiperazin-1-yl)ethyl group, a 2-(3-oxopiperazin-1-yl)ethyl group, a 2-(pyrrolidin-1-yl)ethyl group, a 2-(piperidin-1-yl)ethyl group, a 2-(N,N'-dimethylamino)ethyl group, a 2-(2-oxopyrrolidin-1-yl)ethyl group, an N,N'-dimethylacetamido group, an oxiran-2-ylmethyl group, or a 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl group,

2. A compound represented by formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a deuterated derivative thereof, 【Chemistry 2】 During the ceremony, n is 0, m is 1, p is 0, 1 or 2; R 1 and R 2 are each independently selected from hydrogen, chlorine, fluorine, and a methyl group, and R 1 and R 2 are not both hydrogen; R 3 is an unsubstituted cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, or cyclooctyl group, or a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, or cyclooctyl group substituted by 1 to 3 groups independently selected from fluorine, chlorine, bromine, iodine, a C 1-4 alkyl group, a haloC 1-4 alkyl group, a C 1-4 alkoxy group, a haloC 1-4 alkoxy group, and a phenyl group, or an unsubstituted phenyl group, or a fluorine, chlorine, bromine, iodine, a C 1-4 alkyl group, a haloC 1-4 alkyl group, a C 1-4 alkoxy group, and a haloC 1-4 a phenyl group substituted by 1 to 3 groups independently selected from alkoxy groups, or an unsubstituted furanyl group, thienyl group, pyridinyl group, pyrrolyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, imidazolyl group, pyrazolyl group, triazolyl group, or tetrazolyl group, or a halogen, a C 1-4 alkyl group, a haloC 1-4 alkyl group, a C 1-4 alkoxy group, a haloC 1-4 a furanyl group, thienyl group, pyridinyl group, pyrrolyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, imidazoyl group, pyrazolyl group, triazolyl group, or tetrazolyl group substituted by 1 to 2 groups independently selected from alkoxy groups, aryl groups, and heteroaryl groups; an unsubstituted tetrahydrofuranyl group, tetrahydropyrrolyl group, tetrahydrothienyl group, piperidinyl group, morpholino group, or piperazinyl group; or a fluorine, chlorine, bromine, iodine, C 1-4 alkyl group, haloC 1-4 alkyl group, C 1-4 alkoxy group, haloC 1-4 selected from a tetrahydrofuranyl group, a tetrahydropyrrolyl group, a tetrahydrothienyl group, a piperidinyl group, a morpholino group, a piperazinyl group, or a 2,3-dihydro-1H-inden-2-yl group, each substituted by 1 to 3 groups independently selected from an alkoxy group and a phenyl group; R 4 is selected from a 2-(morpholino)ethyl group, a 2-(1,1-dioxothiomorpholine)ethyl group, a 2-(4-methylpiperazin-1-yl)ethyl group, a 2-(4-acetylpiperazin-1-yl)ethyl group, a 2-(3-oxopiperazin-1-yl)ethyl group, a 2-(pyrrolidin-1-yl)ethyl group, a 2-(piperidin-1-yl)ethyl group, a 2-(N,N'-dimethylamino)ethyl group, a 2-(2-oxopyrrolidin-1-yl)ethyl group, an N,N'-dimethylacetamido group, an oxiran-2-ylmethyl group, or a 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl group, or a stereoisomer, pharmaceutically acceptable salt, solvate, or deuterated compound thereof.

3. A compound represented by formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a deuterated derivative thereof, 【Transformation 3】 During the ceremony, n is 0 or 1, m is 0 or 1; p is 0, 1 or 2; R 1 and R 2 are each independently selected from hydrogen, chlorine, fluorine, and a methyl group, and R 1 and R 2 are not both hydrogen; R 3 is selected from a phenyl group, a 3,4-dichlorophenyl group, a 3,4-difluorophenyl group, a 2-chloro-4-fluorophenyl group, a 2-fluoro-4-chlorophenyl group, a 4-trifluoromethylphenyl group, a 4-trifluoromethoxyphenyl group, a 2,4-dichlorophenyl group, a 2,6-dichlorophenyl group, a 2,4-difluorophenyl group, a 2-chloro-4-methylphenyl group, a 2-methyl-4-fluorophenyl group, a 2-methyl-4-chlorophenyl group, a 2-methoxy-4-chlorophenyl group, a 2,4-dimethylphenyl group, a 2,6-dimethylphenyl group, a 2,4,6-trimethylphenyl group, a 4-tert-butylphenyl group, a 2-chlorophenyl group, a 2-methylphenyl group, a 2-fluorophenyl group, a 2-methoxyphenyl group, a 4-chlorophenyl group, a 4-fluorophenyl group, and a 4-methoxyphenyl group; R 4 is selected from hydrogen, a 2-(morpholino)ethyl group, a 2-(1,1-dioxothiomorpholine)ethyl group, a 2-(4-methylpiperazin-1-yl)ethyl group, a 2-(4-acetylpiperazin-1-yl)ethyl group, a 2-(3-oxopiperazin-1-yl)ethyl group, a 2-(pyrrolidin-1-yl)ethyl group, a 2-(piperidin-1-yl)ethyl group, a 2-(N,N'-dimethylamino)ethyl group, a 2-(2-oxopyrrolidin-1-yl)ethyl group, an N,N'-dimethylacetamido group, an oxiran-2-ylmethyl group, or a 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl group; is hydrogen, then m is 0 and n is 1, or a stereoisomer, pharmaceutically acceptable salt, solvate or deuterated form thereof.

4. A compound represented by formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate or a deuterated derivative thereof, 【Chemistry 4】 During the ceremony, n is 0 or 1, m is 0 or 1; p is 0, 1 or 2; R 1 and R 2 are each independently selected from hydrogen, chlorine, fluorine, and a methyl group, and R 1 and R 2 are not both hydrogen; R 3 is selected from a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a 4-tert-butylcyclohexyl group, a 4-isopropylcyclohexyl group, a 4-ethylcyclohexyl group, a 4-methylcyclohexyl group, a 4-trifluoromethylcyclohexyl group, a 2,3-dihydro-1H-inden-2-yl group, and a 2-chlorocyclohexyl group; R 4 is selected from hydrogen, a 2-(morpholino)ethyl group, a 2-(1,1-dioxothiomorpholine)ethyl group, a 2-(4-methylpiperazin-1-yl)ethyl group, a 2-(4-acetylpiperazin-1-yl)ethyl group, a 2-(3-oxopiperazin-1-yl)ethyl group, a 2-(pyrrolidin-1-yl)ethyl group, a 2-(piperidin-1-yl)ethyl group, a 2-(N,N'-dimethylamino)ethyl group, a 2-(2-oxopyrrolidin-1-yl)ethyl group, an N,N'-dimethylacetamido group, an oxiran-2-ylmethyl group, or a 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl group; is hydrogen, then m is 0 and n is 1, or a stereoisomer, pharmaceutically acceptable salt, solvate or deuterated form thereof.

5. A compound represented by formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate, or a deuterated derivative thereof, 【Transformation 5】 During the ceremony, n is 0 or 1, m is 0 or 1; p is 0, 1 or 2; R 1 and R 2 are each independently selected from hydrogen, chlorine, fluorine, and a methyl group, and R 1 and R 2 are not both hydrogen; R 3 is N-isopropylpiperidin-4-yl, R 4 is selected from hydrogen, a 2-(morpholino)ethyl group, a 2-(1,1-dioxothiomorpholine)ethyl group, a 2-(4-methylpiperazin-1-yl)ethyl group, a 2-(4-acetylpiperazin-1-yl)ethyl group, a 2-(3-oxopiperazin-1-yl)ethyl group, a 2-(pyrrolidin-1-yl)ethyl group, a 2-(piperidin-1-yl)ethyl group, a 2-(N,N'-dimethylamino)ethyl group, a 2-(2-oxopyrrolidin-1-yl)ethyl group, an N,N'-dimethylacetamido group, an oxiran-2-ylmethyl group, or a 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl group; is hydrogen, then m is 0 and n is 1, or a stereoisomer, pharmaceutically acceptable salt, solvate or deuterated form thereof.

6. A compound selected from one of the following compounds, or a stereoisomer, pharmaceutically acceptable salt, solvate or deuterated salt thereof: 【Transformation 6】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a stereoisomer thereof, a pharmaceutically acceptable salt, solvate or deuterated form thereof, and a pharmaceutically acceptable carrier.

8. Use of a compound according to any one of claims 1 to 6 or a stereoisomer, pharmaceutically acceptable salt, solvate or deuterated form thereof in the preparation of a medicament for treating pain, anxiety, depression, alcohol addiction, or drug abuse / dependence.

9. 9. The use according to claim 8, wherein the pain may be acute pain, chronic pain, bone pain, joint pain, post-operative pain, muscle pain, toothache, headache, inflammatory pain, neuropathic pain, and abdominal pain associated with Crohn's disease.

Images