Cyclohexyl-substituted piperidine derivative, pharmaceutical composition comprising same, and use thereof

Abstract

Disclosed in the present invention are a cyclohexyl-substituted piperidine derivative, a pharmaceutical composition comprising same, and a use thereof. The cyclohexyl-substituted piperidine derivative is a compound as represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The definition of substituents in general formula (I) is stated in detail in the description. The compound and the composition of the present invention can be used for treating a variety of diseases or disorders associated with an NOP receptor.

Description

A cyclohexyl-substituted piperidine derivative, a pharmaceutical composition containing the same, and its use

[0001] This application claims priority to the Chinese patent application filed on January 5, 2024, with application number CN202410019096X and invention name “A cyclohexyl-substituted piperidine derivative, a pharmaceutical composition containing the same and its use”, the content of which should be understood as incorporated into this application by reference. Technical Field

[0002] The present application relates to, but is not limited to, the field of medical technology. In particular, the present application relates to a cyclohexyl-substituted piperidine derivative, a pharmaceutical composition containing the same, and uses thereof. Background Art

[0003] Pain is a complex physiological and psychological phenomenon, one of the most common clinical symptoms, and has a significant impact on people's health and quality of life. Pain has diverse pathogenesis and accompanies nearly all diseases. There is a huge demand for analgesics in clinical practice. Currently, the most commonly used analgesics are nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, which are widely used for postoperative analgesia, advanced cancer analgesia, and long-term chronic pain. NSAIDs have anti-inflammatory and analgesic effects, relieving mild to moderate pain, but they can also cause side effects such as gastrointestinal irritation, liver and kidney damage, and neurological discomfort. Opioid analgesics, due to their rapid onset and potent analgesic effects, are the mainstay of clinical treatment for moderate to severe pain. However, side effects such as addiction, respiratory depression, constipation, tolerance, and pruritus limit their use and contribute to social problems such as drug dependence and fatalities from abuse. The development of safe, effective, and side-effect-free analgesics is a pressing social need. Currently, research on opioid receptor agonists primarily focuses on eliminating or mitigating opioid side effects.

[0004] The NOP (nociceptin / orphanin FQ peptide) receptor, also known as ORL-1 (opioid receptor-like receptor 1), is the fourth opioid receptor discovered in 1994, following the μ, κ, and δ receptors. The NOP receptor shares approximately 60% homology with other opioid receptors. The NOP receptor does not bind to classic opioid ligands (such as naloxone), and its endogenous ligand, nociceptin / orphanin FQ (N / O FQ), does not bind to other opioid receptors. NOP-mediated analgesia has fewer adverse reactions than other opioid receptors. The nociceptin / orphanin FQ-NOP receptor system can both inhibit opioid receptor-mediated analgesia and mediate analgesia by reducing hyperalgesia. Studies have shown that NOP receptor agonists have analgesic effects and modulate the addictive effects of MOP agonists. In non-human primate experiments, selective NOP agonists were found to not produce respiratory depression and potential addiction (ACS Chem Neurosci., 2013, 4(2), 214-224). In addition, preclinical research results indicate that NOP ligands may have the potential to relieve pain, relieve anxiety, treat depression, treat drug addiction, and act as diuretics.

[0005] Peptide NOP receptor ligands have failed to make progress in clinical trials due to poor pharmacokinetics and adverse reactions. Non-peptide small molecule NOP receptor ligands may be more suitable as therapeutic agents. Ro 64-6198 is the first reported small molecule NOP receptor selective agonist, developed by Roche. It has shown good analgesic effects in non-human primate model and rodent model experiments, and does not have classic opioid-mediated side effects. Tanabe Mitsubishi Pharma disclosed a class of benzimidazole compounds in WO2003082333A1, which are selective NOP receptor (ORL-1 receptor) agonists. Among them, MT-7716 can dose-dependently reduce the voluntary alcohol intake of rats and has entered clinical phase I trials for the treatment of alcohol dependence. Schering-Plough disclosed a class of piperidine derivative compounds in WO2001007050A1 as NOP receptor agonists for the treatment of cough.

[0006] Existing reports show that NOP agonists exhibit unique pharmacological effects, producing good analgesic effects while effectively reducing the side effects of traditional opioids such as morphine, such as respiratory depression, constipation, tolerance, and addiction. Drugs that selectively agonize NOP are expected to overcome the adverse reactions of traditional opioid analgesics, but research on NOP receptor agonists is currently in its early stages, and no NOP agonists have been approved for marketing. Therefore, the development of highly selective, safe, and effective NOP agonists has important clinical and social significance. Summary of the Invention

[0007] The present invention provides a cyclohexyl-substituted piperidine derivative, a pharmaceutical composition containing the compound, and uses thereof, which has better agonist activity and selectivity for NOP receptors, better pharmacodynamics and / or pharmacokinetic properties, good safety, and can be used to treat or prevent diseases related to NOP receptors.

[0008] To this end, the present invention adopts the following technical solutions:

[0009] In one aspect, the present invention provides a compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

[0010] in,

[0011] R 1 and R 2 Each independently selected from hydrogen, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, and provides: R 1 and R 2 Not simultaneously hydrogen;

[0012] R 3 Selected from -C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(NR a )R b 、-S(O)R c 、-S(O)2R c 、-NHS(O)2R c 、-NHC(O)R d 、-C(O)OR d , 5- to 10-membered heteroaryl, the 5- to 10-membered heteroaryl being optionally substituted by one or more R e replace;

[0013] R4 and R 5 Each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, or R 4 and R 5 and the carbon atom to which it is attached together form C 3-8 Cycloalkyl, or R 4 and R 5 and the carbon atoms to which they are attached together form a 3- to 8-membered heterocyclic group, R 4 and R 5 Can be the same or different, and specify R 4 and R 5 are not hydrogen at the same time, here, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl and 3 to 8 membered heterocyclyl are each optionally substituted with one or more R';

[0014] X 1 and X 2 Each independently selected from N and CR f ;

[0015] L 1 Selected from single bonds and -CR g R h -;

[0016] L 2 Selected from C 1-6 Alkylene, the C 1-6 The alkylene group is optionally replaced by one or more R m replace;

[0017] Y is selected from O and S;

[0018] R a and R b Each independently selected from hydrogen, hydroxy, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH, here, the C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH are each optionally substituted with one or more R', R a and R b Can be the same or different;

[0019] Each R c are independently selected from C1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -C6 -10 Aromatic hydrocarbons, here, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -C6 -10 The arenes are each optionally substituted with one or more R';

[0020] Each R d are independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, here, the C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 The cycloalkanes are each optionally substituted with one or more R';

[0021] R e 、R f Each independently selected from hydrogen, halogen, C 1-3 Alkyl, -OC 1-3 Alkanes, here, the C 1-3 Alkyl, -OC 1-3 The alkanes are each optionally substituted with one or more R';

[0022] R g 、R h and R m Each independently selected from hydrogen, halogen, C 1-3 Alkyl, here, the C 1-3 Alkyl is optionally substituted with one or more R';

[0023] Each R' is independently selected from H, F, Cl, Br and I;

[0024] n is an integer of 1, 2 or 3.

[0025] In one embodiment, R 1 and R 2 Each independently selected from hydrogen, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C1-3 Alkoxy, and provides: R 1 and R 2 are not hydrogen at the same time; in another embodiment, R 1 and R 2 Each independently selected from hydrogen, halogen, C 1-3 Alkyl, and provides: R 1 and R 2 are not hydrogen at the same time; in another embodiment, R 1 and R 2 are each independently halogen; in another embodiment, R 1 and R 2 are all fluorine or chlorine, or, R 1 R for chlorine 2 is fluorine, or R 1 R for fluorine 2 is chlorine; or, R 1 R for chlorine 2 It is a methoxy group.

[0026] In one embodiment, R 3 Selected from -C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(NR a )R b 、-S(O)R c 、-S(O)2R c 、-NHS(O)2R c 、-NHC(O)R d 、-C(O)OR d and 5- to 6-membered heteroaryl, the 5- to 6-membered heteroaryl being optionally substituted by one or more R e Replace; or, R 3 -C(O)NR a R b ; or, R 3 -S(O)2NR a R b ; or, R 3 -S(O)(NR a )R b ; or, R 3 -S(O)R c ; or, R 3 is -S(O)2R c ; or, R 3 -NHS(O)2R c ; or, R 3 -NHC(O)R d ; or, R3 -C(O)OR d ; or, R 3 is a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is optionally substituted by one or more R e replace.

[0027] In another embodiment, R 3 Selected from -C(O)N(CH3)2, -C(O)NH2, -C(O)NHOH, -S(O)2NH2, -S(O)2N(CH3)2, -S(O)(NH)CH3, -S(O)CH3, -S(O)CH2CH3, -S(O)2CH3, -S(O)2CH2CH3, - C(O)NHCH2CH2OH, -C(O)NHCH3, -C(O)NHCH2CH3, -NHC(O)CH3, -S(O)2CH(CH3)2, -NHC(O)CH2CH3, -C(O)OCH2CH3, -S(O)2-Ph, -S(O)2CH2-Ph, -NHS(O)2CH3, -NHS(O)2CH2CH3; or, R 3 Selected from C(O)NHCH3, -S(O)2N(CH3)2, -S(O)CH3, -S(O)2CH3, -S(O)2CH2CH3, -NHS(O)2CH3, -NHS(O)2CH2CH3, -NHC(O)CH3, -NHC(O)CH2CH3.

[0028] In one embodiment, R 4 and R 5 Each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, or R 4 and R 5 and the carbon atom to which it is attached together form C 3-6 Cycloalkyl, or R 4 and R 5 and the carbon atoms to which they are attached together form a 3- to 6-membered heterocyclic group, R 4 and R 5 Can be the same or different, and specify R 4 and R 5 are not hydrogen at the same time, here, the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and 3 to 6 membered heterocyclyl are each optionally substituted with one or more R; in another embodiment, R 4 is hydrogen, R 5 Selected from halogen, C 1-6 Alkyl, C1-6 Alkoxy, here, the C 1-6 Alkyl, C 1-6 Each alkoxy group is optionally substituted with one or more R'; in another embodiment, R 5 is hydrogen, R 4 Selected from halogen, C 1-6 Alkyl and C 1-6 Alkoxy, here, the C 1-6 Alkyl, C 1-6 Each alkoxy group is optionally substituted with one or more R'; in another embodiment, R 4 and R 5 are each independently halogen; in another embodiment, R 4 and R 5 Each individually is C 1-6 Alkyl, here, the C 1-6 Alkyl is optionally substituted with one or more R'; in another embodiment, R 4 、R 5 Each individually is C 1-6 Alkoxy, here, the C 1-6 Each alkoxy group is optionally substituted with one or more R'; in another embodiment, R 4 and R 5 and the carbon atom to which it is attached together form C 3-6 Cycloalkyl, here, the C 3-6 Cycloalkyl is optionally substituted with one or more R'; in another embodiment, R 4 and R 5 and the carbon atom to which they are attached together form a 3- to 6-membered heterocyclyl, wherein the 3- to 6-membered heterocyclyl is optionally substituted with one or more R'.

[0029] In another embodiment, R 4 and R 5 Each independently selected from hydrogen, halogen, C 1-6 Alkyl, or R 4 and R 5 and the carbon atom to which it is attached together form C 3-6 Cycloalkyl, or R 4 and R 5 and the carbon atoms to which they are attached together form a 3- to 6-membered heterocyclic group, R 4 and R 5 Can be the same or different, and specify R 4 and R 5 are not hydrogen at the same time; in another embodiment, R 4 and R 5 Each independently selected from hydrogen, halogen, C 1-3 Alkyl, or R 4and R 5 and the carbon atom to which it is attached together form C 3-4 Cycloalkyl, or R 4 and R 5 and the carbon atom to which it is attached together form a 3-4 membered heterocyclic group, R 4 and R 5 Can be the same or different, and specify R 4 and R 5 are not hydrogen at the same time; in another embodiment, R 4 and R 5 All are methyl, or, R 4 and R 5 One of them is isopropyl and the other is hydrogen, or R 4 and R 5 and the carbon atom to which it is attached together form a cyclopropyl group, or, R 4 and R 5 and the carbon atom to which it is attached together form a cyclobutyl group, or, R 4 and R 5 and the carbon atom to which it is attached together form an oxetane group.

[0030] In one embodiment, X 1 and X 2 are each independently selected from N and CH; in another embodiment, X 1 and X 2 are all N; in another embodiment, X 1 N, X 2 is CH; in another embodiment, X 2 N, X 1 is CH; in another embodiment, X 1 and X 2 All are CH.

[0031] In one embodiment, L 1 Selected from single bonds and -CR g R h -; In another embodiment, L 1 is selected from a single bond; in another embodiment, L 1 Selected from-CR g R h -; In another embodiment, L 1 Selected from -CH2-.

[0032] In another embodiment, L 1 is selected from a single bond and -CH2-.

[0033] In one embodiment, L 2 Selected from C 1-3 Alkylene, the C1-3 The alkylene group is optionally replaced by one or more R m In another embodiment, L 2 is selected from -CH2-, -CH2CH2- and -CH(CH3)-.

[0034] In one embodiment, Y is selected from O and S; in another embodiment, Y is O; in another embodiment, Y is S.

[0035] In one embodiment, R a and R b Each independently selected from hydrogen, hydroxy, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes and -(CH2) n -OH, here, the C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH are each optionally substituted with one or more R', R a and R b can be the same or different; in another embodiment, R a and R b One of them is selected from hydrogen, and the other is selected from hydroxyl, C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH, here, the C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH are each optionally substituted with one or more R'; in another embodiment, R a and R b One of the groups is selected from hydrogen and the other is selected from methyl, ethyl, cyclopropyl, cyclopropylmethyl, hydroxyl and hydroxyethyl; in another embodiment, R a and R b All C 1-3 Alkyl; in another embodiment, R a and R b It's all hydrogen.

[0036] In one embodiment, each R c are independently selected from C 1-3Alkyl, C 3-6 Cycloalkyl, phenyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -Benzene, here, the C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -benzene are each optionally substituted with one or more R'; in another embodiment, each R c Each is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, benzyl and phenyl.

[0037] In one embodiment, each R d are independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, here, the C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Each cycloalkane is optionally substituted with one or more R'; in another embodiment, each R d Each is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclopropylmethyl.

[0038] In one embodiment, R e 、R f Each independently selected from hydrogen, halogen, C 1-3 Alkyl, -OC 1-3 Alkanes, here, the C 1-3 Alkyl, -OC 1-3 Each alkane is optionally substituted with one or more R'; in another embodiment, R e and R f are each independently hydrogen; in another embodiment, R e and R f are each independently halogen; in another embodiment, R e and R f Each individually is C 1-3 Alkyl, the C 1-3 Alkyl is optionally substituted with one or more R'; in another embodiment, R e and R f Each individually -OC 1-3 Alkanes, the -OC 1-3 The alkane is optionally substituted with one or more R'.

[0039] In another embodiment, R e and R f Each is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl and trifluoromethoxy.

[0040] In one embodiment, R g 、R h and R m are each independently selected from hydrogen, fluoro and methyl; in another embodiment, R g 、R h and R m are each independently hydrogen; in another embodiment, R g 、R h and R m are each independently fluoro: In another embodiment, R g 、R h and R m Each independently is methyl.

[0041] In one embodiment, each R' is independently selected from H, F, Cl, and Br; in another embodiment, each R' is independently selected from H, F, and Cl.

[0042] In one embodiment, n is an integer of 1, 2, or 3; in another embodiment, n is 1; in another embodiment, n is 2; in another embodiment, n is 3.

[0043] In a preferred embodiment of the present invention, the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are further represented by general formula (II):

[0044] in:

[0045] In the general formula (II), R 1 ~R 5 、L 1 、L 2 , Y are as defined above.

[0046] In a preferred embodiment of the present invention, in the general formula (II),

[0047] R 1 and R 2 Each independently selected from hydrogen, halogen, C 1-3 Alkyl; and it is provided that R 1 and R 2 are not hydrogen at the same time; preferably, R 1 and R 2 are all halogen, and more preferably, R 1and R 2 are all fluorine or chlorine, or, R 1 R for chlorine 2 is fluorine, or R 1 R for fluorine 2 is chlorine; or, R 1 R for chlorine 2 is methoxy;

[0048] R 3 Selected from -C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(NR a )R b 、-S(O)R c 、-S(O)2R c 、-NHS(O)2R c 、-NHC(O)R d 、-C(O)OR d and 5- to 6-membered heteroaryl, the 5- to 6-membered heteroaryl being optionally substituted by one or more R e substituted; preferably, R 3 Selected from -C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(NR a )R b 、-S(O)R c 、-NHS(O)2R c 、-S(O)2R c ;

[0049] R 4 and R 5 Each independently selected from hydrogen, halogen, C 1-3 Alkyl, or R 4 and R 5 and the carbon atom to which it is attached together form C 3-6 Cycloalkyl, or R 4 and R 5 and the carbon atoms to which they are attached together form a 3- to 6-membered heterocyclic group, R 4 and R 5 Can be the same or different, and specify R 4 and R 5 are not hydrogen at the same time, here, the C 1-3 Alkyl, C 3-6 The cycloalkyl and 3 to 6 membered heterocyclyl groups are each optionally substituted with one or more R'; preferably, R 4 and R 5 All C1-3 Alkyl, or R 4 and R 5 One of them is C 1-3 alkyl, the other is hydrogen, or, R 4 and R 5 and the carbon atom to which it is attached together form a cyclopropyl group, or, R 4 and R 5 and the carbon atom to which it is attached together form a cyclobutyl group, or, R 4 and R 5 and the carbon atom to which it is attached together constitute an oxetane group;

[0050] L 1 is selected from a single bond and -CH2-;

[0051] L 2 Selected from C 1-3 Alkylene, the C 1-3 The alkylene group is optionally replaced by one or more R m Substitute, preferably, L 2 Selected from -CH2-, -CH2CH2-, -CH(CH3)-;

[0052] Y is selected from O;

[0053] R a and R b Each independently selected from hydrogen, hydroxy, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH, here, the C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH are each optionally substituted with one or more R', R a and R b Can be the same or different; preferably, R a and R b One of them is selected from hydrogen, and the other is selected from methyl, ethyl, cyclopropyl, cyclopropylmethyl, hydroxyl, hydroxyethyl, or, R a and R b are all methyl; or R a and R b are all hydrogen; further preferably, R a and R b One of them is selected from hydrogen, the other is selected from methyl, or R a and R b All are methyl;

[0054] Each R c are independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -Benzene, here, the C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -benzene are each optionally substituted with one or more R'; preferably, each R c are independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, benzyl and phenyl. c are independently selected from methyl and ethyl;

[0055] Each R d are independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, here, the C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Each cycloalkane is optionally substituted with one or more R'; in another embodiment, each R d Each is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclopropylmethyl.

[0056] R e is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl and trifluoromethoxy;

[0057] R m is selected from hydrogen, fluorine and methyl;

[0058] Each R' is independently selected from H, F, Cl and Br; preferably, each R' is independently selected from H, F and Cl;

[0059] n is an integer of 1, 2 or 3. Preferably, n is an integer of 1 or 2.

[0060] In a preferred embodiment of the present invention, the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are further represented by general formula (III):

[0061] in:

[0062] In the general formula (III), R 1 ~R 5 、L 2 As defined above.

[0063] In a preferred embodiment of the present invention, in the general formula (III),

[0064] R 1 and R 2 Each independently selected from hydrogen, halogen, C 1-3 Alkyl; and it is provided that R 1 and R 2 are not hydrogen at the same time; preferably, R 1 and R 2 are all halogen, and more preferably, R 1 and R 2 are all fluorine or chlorine, or, R 1 R for chlorine 2 is fluorine, or R 1 R for fluorine 2 is chlorine; or, R 1 R for chlorine 2 is methoxy;

[0065] R 3 Selected from -C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(NR a )R b 、-S(O)R c 、-S(O)2R c 、-NHS(O)2R c 、-NHC(O)R d 、-C(O)OR d and 5- to 6-membered heteroaryl, the 5- to 6-membered heteroaryl being optionally substituted by one or more R e substituted; preferably, R 3 Selected from -C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(NR a )R b 、-S(O)R c 、-NHS(O)2R c 、-S(O)2R c ;

[0066] R 4 and R 5 Each independently selected from hydrogen, halogen, C1-3 Alkyl, or R 4 and R 5 and the carbon atom to which it is attached together form C 3-6 Cycloalkyl, or R 4 and R 5 and the carbon atoms to which they are attached together form a 3- to 6-membered heterocyclic group, R 4 and R 5 Can be the same or different, and specify R 4 and R 5 are not hydrogen at the same time, here, the C 1-3 Alkyl, C 3-6 The cycloalkyl and 3 to 6 membered heterocyclyl groups are each optionally substituted with one or more R'; preferably, R 4 and R 5 All C 1-3 Alkyl, or R 4 and R 5 One of them is C 1-3 alkyl, the other is hydrogen, or, R 4 and R 5 and the carbon atom to which it is attached together form a cyclopropyl group, or, R 4 and R 5 and the carbon atom to which it is attached together form a cyclobutyl group, or, R 4 and R 5 and the carbon atom to which it is attached together constitute an oxetane group;

[0067] L 2 Selected from C 1-3 Alkylene, the C 1-3 The alkylene group is optionally replaced by one or more R m Substitute, preferably, L 2 Selected from -CH2-, -CH2CH2-, -CH(CH3)-;

[0068] R a and R b Each independently selected from hydrogen, hydroxy, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH, here, the C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH are each optionally substituted with one or more R', R a and R b Can be the same or different; preferably, Ra and R b One of them is selected from hydrogen, and the other is selected from methyl, ethyl, cyclopropyl, cyclopropylmethyl, hydroxyl, hydroxyethyl, or, R a and R b are all methyl; or R a and R b are all hydrogen; further preferably, R a and R b One of them is selected from hydrogen, the other is selected from methyl, or R a and R b All are methyl;

[0069] Each R c are independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -Benzene, here, the C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -benzene are each optionally substituted with one or more R'; preferably, each R c are independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, benzyl, and phenyl. c are independently selected from methyl and ethyl;

[0070] Each R d are independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, here, the C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Each cycloalkane is optionally substituted with one or more R'; in another embodiment, each R d Each is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclopropylmethyl.

[0071] R e is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl and trifluoromethoxy;

[0072] R m is selected from hydrogen, fluorine and methyl;

[0073] Each R' is independently selected from H, F, Cl and Br; preferably, each R' is independently selected from H, F and Cl;

[0074] n is an integer of 1, 2 or 3. Preferably, n is an integer of 1 or 2.

[0075] In a preferred embodiment of the present invention, the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are further represented by general formula (IV):

[0076] in:

[0077] In the general formula (IV), R 1 ~R 5 、L 2 As defined above.

[0078] In a preferred embodiment of the present invention, in the general formula (IV),

[0079] R 1 and R 2 Each independently selected from hydrogen, halogen, C 1-3 Alkyl; and it is provided that R 1 and R 2 are not hydrogen at the same time; preferably, R 1 and R 2 are all halogen, and more preferably, R 1 and R 2 are all fluorine or chlorine, or, R 1 R for chlorine 2 is fluorine, or R 1 R for fluorine 2 is chlorine; or, R 1 R for chlorine 2 is methoxy;

[0080] R 3 Selected from -C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(NR a )R b 、-S(O)R c 、-S(O)2R c 、-NHS(O)2R c 、-NHC(O)R d 、-C(O)OR d and 5- to 6-membered heteroaryl, the 5- to 6-membered heteroaryl being optionally substituted by one or more R e substituted; preferably, R 3 Selected from -C(O)NRa R b 、-S(O)2NR a R b 、-S(O)(NR a )R b 、-S(O)R c 、-NHS(O)2R c 、-S(O)2R c ;

[0081] R 4 and R 5 Each independently selected from hydrogen, halogen, C 1-3 Alkyl, or R 4 and R 5 and the carbon atom to which it is attached together form C 3-6 Cycloalkyl, or R 4 and R 5 and the carbon atoms to which they are attached together form a 3- to 6-membered heterocyclic group, R 4 and R 5 Can be the same or different, and specify R 4 and R 5 are not hydrogen at the same time, here, the C 1-3 Alkyl, C 3-6 The cycloalkyl and 3 to 6 membered heterocyclyl groups are each optionally substituted with one or more R'; preferably, R 4 and R 5 All C 1-3 Alkyl, or R 4 and R 5 One of them is C 1-3 alkyl, the other is hydrogen, or, R 4 and R 5 and the carbon atom to which it is attached together form a cyclopropyl group, or, R 4 and R 5 and the carbon atom to which it is attached together form a cyclobutyl group, or, R 4 and R 5 and the carbon atom to which it is attached together constitute an oxetane group;

[0082] L 2 Selected from C 1-3 Alkylene, the C 1-3 The alkylene group is optionally replaced by one or more R m Substitute, preferably, L 2 Selected from -CH2-, -CH2CH2-, -CH(CH3)-;

[0083] R a and R b Each independently selected from hydrogen, hydroxy, C 1-3 Alkyl, C 3-6Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH, here, the C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH are each optionally substituted with one or more R', R a and R b Can be the same or different; preferably, R a and R b One of them is selected from hydrogen, and the other is selected from methyl, ethyl, cyclopropyl, cyclopropylmethyl, hydroxyl, hydroxyethyl, or, R a and R b are all methyl; or R a and R b are all hydrogen; further preferably, R a and R b One of them is selected from hydrogen, the other is selected from methyl, or R a and R b All are methyl;

[0084] Each R c are independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -Benzene, here, the C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -benzene are each optionally substituted with one or more R'; preferably, each R c are independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, benzyl and phenyl. c are independently selected from methyl and ethyl;

[0085] Each R d are independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, here, the C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6Each cycloalkane is optionally substituted with one or more R'; in another embodiment, each R d Each is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclopropylmethyl.

[0086] R e is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl and trifluoromethoxy;

[0087] R m is selected from hydrogen, fluorine and methyl;

[0088] Each R' is independently selected from H, F, Cl and Br; preferably, each R' is independently selected from H, F and Cl;

[0089] n is an integer of 1, 2 or 3. Preferably, n is an integer of 1 or 2.

[0090] In a preferred embodiment of the present invention, the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are further represented by general formula (V):

[0091] in:

[0092] In the general formula (V), R 3 ~R 5 、L 2 As defined above.

[0093] In a preferred embodiment of the present invention, in the general formula (V),

[0094] R 3 Selected from -C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(NR a )R b 、-S(O)R c 、-S(O)2R c 、-NHS(O)2R c 、-NHC(O)R d 、-C(O)OR d and 5- to 6-membered heteroaryl, the 5- to 6-membered heteroaryl being optionally substituted by one or more R e substituted; preferably, R 3 Selected from -C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(NR a )R b 、-S(O)Rc 、-NHS(O)2R c 、-S(O)2R c ;

[0095] R 4 and R 5 Each independently selected from hydrogen, halogen, C 1-3 Alkyl, or R 4 and R 5 and the carbon atom to which it is attached together form C 3-6 Cycloalkyl, or R 4 and R 5 and the carbon atoms to which they are attached together form a 3- to 6-membered heterocyclic group, R 4 and R 5 Can be the same or different, and specify R 4 and R 5 are not hydrogen at the same time, here, the C 1-3 Alkyl, C 3-6 The cycloalkyl and 3 to 6 membered heterocyclyl groups are each optionally substituted with one or more R'; preferably, R 4 and R 5 All C 1-3 Alkyl, or R 4 and R 5 One of them is C 1-3 alkyl, the other is hydrogen, or, R 4 and R 5 and the carbon atom to which it is attached together form a cyclopropyl group, or, R 4 and R 5 and the carbon atom to which it is attached together form a cyclobutyl group, or, R 4 and R 5 and the carbon atom to which it is attached together constitute an oxetane group;

[0096] L 2 Selected from C 1-3 Alkylene, the C 1-3 The alkylene group is optionally replaced by one or more R m Substitute, preferably, L 2 Selected from -CH2-, -CH2CH2-, -CH(CH3)-;

[0097] R a and R b Each independently selected from hydrogen, hydroxy, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH, here, the C 1-6 Alkyl, C 3-6Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH are each optionally substituted with one or more R', R a and R b Can be the same or different; preferably, R a and R b One of them is selected from hydrogen, and the other is selected from methyl, ethyl, cyclopropyl, cyclopropylmethyl, hydroxyl, hydroxyethyl, or, R a and R b are all methyl; or R a and R b are all hydrogen; further preferably, R a and R b One of them is selected from hydrogen, the other is selected from methyl, or R a and R b All are methyl;

[0098] Each R c are independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -Benzene, here, the C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -benzene are each optionally substituted with one or more R'; preferably, each R c are independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, benzyl and phenyl. c are independently selected from methyl and ethyl;

[0099] Each R d are independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, here, the C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Each cycloalkane is optionally substituted with one or more R'; in another embodiment, each R d Each is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclopropylmethyl.

[0100] Re is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl and trifluoromethoxy;

[0101] R m is selected from hydrogen, fluorine and methyl;

[0102] Each R' is independently selected from H, F, Cl and Br; preferably, each R' is independently selected from H, F and Cl;

[0103] n is an integer of 1, 2 or 3. Preferably, n is an integer of 1 or 2.

[0104] In a preferred embodiment of the present invention, the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are further represented by general formula (VI):

[0105] in:

[0106] In the general formula (VI), R 3 ~R 5 、L 2 As defined above.

[0107] In a preferred embodiment of the present invention, in the general formula (VI),

[0108] R 3 Selected from -C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(NR a )R b 、-S(O)R c 、-S(O)2R c 、-NHS(O)2R c 、-NHC(O)R d 、-C(O)OR d and 5- to 6-membered heteroaryl, the 5- to 6-membered heteroaryl being optionally substituted by one or more R e substituted; preferably, R 3 Selected from -C(O)NR a R b 、-S(O)2NR a R b 、-S(O)(NR a )R b 、-S(O)R c 、-NHS(O)2R c 、-S(O)2R c ;

[0109] R 4 and R5 Each independently selected from hydrogen, halogen, C 1-3 Alkyl, or R 4 and R 5 and the carbon atom to which it is attached together form C 3-6 Cycloalkyl, or R 4 and R 5 and the carbon atoms to which they are attached together form a 3- to 6-membered heterocyclic group, R 4 and R 5 Can be the same or different, and specify R 4 and R 5 are not hydrogen at the same time, here, the C 1-3 Alkyl, C 3-6 The cycloalkyl and 3 to 6 membered heterocyclyl groups are each optionally substituted with one or more R'; preferably, R 4 and R 5 All C 1-3 Alkyl, or R 4 and R 5 One of them is C 1-3 alkyl, the other is hydrogen, or, R 4 and R 5 and the carbon atom to which it is attached together form a cyclopropyl group, or, R 4 and R 5 and the carbon atom to which it is attached together form a cyclobutyl group, or, R 4 and R 5 and the carbon atom to which it is attached together constitute an oxetane group;

[0110] L 2 Selected from C 1-3 Alkylene, the C 1-3 The alkylene group is optionally replaced by one or more R m Substitute, preferably, L 2 Selected from -CH2-, -CH2CH2-, -CH(CH3)-;

[0111] R a and R b Each independently selected from hydrogen, hydroxy, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH, here, the C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH are each optionally substituted with one or more R', R a and Rb Can be the same or different; preferably, R a and R b One of them is selected from hydrogen, and the other is selected from methyl, ethyl, cyclopropyl, cyclopropylmethyl, hydroxyl, hydroxyethyl, or, R a and R b are all methyl; or R a and R b are all hydrogen; further preferably, R a and R b One of them is selected from hydrogen, the other is selected from methyl, or R a and R b All are methyl;

[0112] Each R c are independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -Benzene, here, the C 1-3 Alkyl, C 3-6 Cycloalkyl, phenyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -benzene are each optionally substituted with one or more R'; preferably, each R c are independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, benzyl and phenyl. c are independently selected from methyl and ethyl;

[0113] Each R d are independently selected from C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, here, the C 1-3 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Each cycloalkane is optionally substituted with one or more R'; in another embodiment, each R d Each is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclopropylmethyl.

[0114] R e is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl and trifluoromethoxy;

[0115] R m is selected from hydrogen, fluorine and methyl;

[0116] Each R' is independently selected from H, F, Cl and Br; preferably, each R' is independently selected from H, F and Cl;

[0117] n is an integer of 1, 2 or 3. Preferably, n is an integer of 1 or 2.

[0118] In a preferred embodiment of the present invention, the compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof are further represented by general formula (VII):

[0119] in:

[0120] In the general formula (VII), R 4 、R 5 、R a 、R b 、L 1 、L 2 As defined above.

[0121] In a preferred embodiment of the present invention, in the general formula (VII),

[0122] R 4 and R 5 Each independently selected from hydrogen, halogen, C 1-3 Alkyl, or R 4 and R 5 and the carbon atom to which it is attached together form C 3-6 Cycloalkyl, or R 4 and R 5 and the carbon atoms to which they are attached together form a 3- to 6-membered heterocyclic group, R 4 and R 5 Can be the same or different, and specify R 4 and R 5 are not hydrogen at the same time, here, the C 1-3 Alkyl, C 3-6 The cycloalkyl and 3 to 6 membered heterocyclyl groups are each optionally substituted with one or more R'; preferably, R 4 and R 5 All C 1-3 Alkyl, or R 4 and R 5 One of them is C 1-3 alkyl, the other is hydrogen, or, R 4 and R 5 and the carbon atom to which it is attached together form a cyclopropyl group, or, R 4 and R 5 and the carbon atom to which it is attached together form a cyclobutyl group, or, R 4 and R 5and the carbon atom to which it is attached together constitute an oxetane group;

[0123] L 1 is selected from a single bond and -CH2-;

[0124] L 2 Selected from C 1-3 Alkylene, the C 1-3 The alkylene group is optionally replaced by one or more R m Substitute, preferably, L 2 Selected from -CH2-, -CH2CH2-, -CH(CH3)-;

[0125] R a and R b Each independently selected from hydrogen, hydroxy, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH, here, the C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) n -C 3-6 Cycloalkanes, -(CH2) n -OH are each optionally substituted with one or more R', R a and R b Can be the same or different; preferably, R a and R b One of them is selected from hydrogen, and the other is selected from methyl, ethyl, cyclopropyl, cyclopropylmethyl, hydroxyl, hydroxyethyl, or, R a and R b are all methyl; or R a and R b are all hydrogen; further preferably, R a and R b One of them is selected from hydrogen, the other is selected from methyl, or R a and R b All are methyl;

[0126] R m is selected from hydrogen, fluorine and methyl;

[0127] Each R' is independently selected from H, F, Cl and Br; preferably, each R' is independently selected from H, F and Cl;

[0128] n is an integer of 1, 2 or 3. Preferably, n is an integer of 1 or 2.

[0129] Preferred compounds of the present invention include, but are not limited to, the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0130] Optionally, selected from one of the following chemical formulas:

[0131] In another aspect, the present invention further provides a method for preparing the compound of the present invention, its stereoisomers or pharmaceutically acceptable salts thereof, the preparation method comprising the following steps:

[0132] (1) The compound of formula (I-1) undergoes a substitution reaction with the compound of formula (I-2) to obtain a compound of formula (I-3);

[0133] (2) The compound of formula (I-3) is subjected to a deprotection reaction to obtain the compound of formula (I-4), which is then subjected to a reductive amination reaction with the compound of formula (I-5) to obtain the compound of formula (I);

[0134] or,

[0135] (1') The compound of formula (I-6) is subjected to a reductive amination reaction with the compound of formula (I-5) to obtain a compound of formula (I-7);

[0136] (2') The compound of formula (I-7) undergoes a substitution reaction with the compound of formula (I-2) to obtain a compound of formula (I);

[0137] In the above preparation method, Y in formula (I-2) 1 represents a leaving group such as bromine, chloride, or sulfonate; in formulas (I-1) and (I-3), Pr represents an amino protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBz) or fluorenylmethyloxycarbonyl (Fmoc), etc.; the definitions of other groups in formulas (I-1) to (I-7) and formula (I) are as described above.

[0138] In another aspect, the present invention also provides a pharmaceutical composition comprising a compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In a specific embodiment, the compound of the present invention is provided in the pharmaceutical composition in an effective amount. In a specific embodiment, the compound of the present invention is provided in a therapeutically effective amount. In a specific embodiment, the compound of the present invention is provided in a prophylactically effective amount.

[0139] In another aspect, the present invention also provides use of the compound of the present invention, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing diseases associated with NOP receptors.

[0140] In another aspect, the present invention also provides a compound of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament.

[0141] In another aspect, the present invention also provides a compound of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating and / or preventing diseases associated with NOP receptors.

[0142] In another aspect, the present invention also provides a method for treating and / or preventing diseases associated with NOP receptors, which comprises administering a therapeutically effective amount of a compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to an individual in need thereof.

[0143] In a specific embodiment, the disease associated with the NOP receptor is selected from pain, cough, sleep disorders, hypertension, urinary incontinence, epilepsy, traumatic injury, eating disorders, anxiety, depression, alcohol addiction, drug withdrawal syndrome, memory loss caused by Alzheimer's disease or other dementias, preferably pain.

[0144] In a specific embodiment, the pain is selected from the group consisting of postoperative pain, cancer-induced pain, neuropathic pain, traumatic pain, and inflammation-induced pain.

[0145] Details

[0146] The following definitions are provided for the terms used to describe the present invention in the specification and claims of this application. For specific terms, if the meaning defined in this application is inconsistent with the meaning commonly understood by those skilled in the art, the meaning defined in this application shall prevail. If not defined in this application, the term shall have the meaning commonly understood by those skilled in the art.

[0147] The names of the compounds in this application correspond to their structural formulas. When the names of the compounds are inconsistent with the structural formulas, the structural formulas shall prevail, or the names of the compounds can be inferred based on the specific circumstances of the present invention and the knowledge of those skilled in the art.

[0148] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10"Aryl"; for example, naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, C6 aryl is particularly preferred. Aryl also includes ring systems in which the above-described aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system.

[0149] "5- to 10-membered heteroaryl" refers to a group of a 5-10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5- to 6-membered heteroaryl is particularly preferred, which is a 5-6-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms.

[0150] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepine, oxepinyl, and thiepine. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0151] "Halogen" refers to fluorine, chlorine, bromine and iodine atoms.

[0152] "Alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group.

[0153] “C 1-6 "Alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, also known as "lower alkyl". Examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl and t-butyl, n-pentyl, isopentyl, neopentyl, hexyl. The alkyl group in this application is preferably C 1-3 alkyl.

[0154] "Halogenated C 1-6 "Alkyl" refers to the above-mentioned "C 1-6 "alkyl" which is substituted by one or more halogen groups. In some embodiments, the halogenated C 1-3 Alkyl is particularly preferred. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, -CH3CH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, and the like.

[0155] “C 1-6 "Alkoxy" refers to a group -OR, wherein R is a substituted or unsubstituted C1-C6 alkyl. In some embodiments, C 1-3 Alkoxy is particularly preferred. In some embodiments, specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0156] “C 3-8 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-6 Cycloalkyl is preferred, more preferably C3 cycloalkyl. Cycloalkyl also includes ring systems in which the above cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0157] "3- to 8-membered heterocyclyl" refers to a group of a 3- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. In some embodiments, 3- to 6-membered heterocyclyl groups are particularly preferred, which are 3- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably, 3- to 4-membered heterocyclyl groups are 3- to 4-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl groups also include ring systems in which the above-mentioned heterocyclyl rings are fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary such heterocyclyl groups include, but are not limited to, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, dithianyl, and the like.

[0158] "Hydroxy" refers to -OH.

[0159] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0160] "Pharmaceutically acceptable salts" refer to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention, as defined above, which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts, which may be formed in the presence of acidic protons capable of reacting with inorganic or organic bases.

[0161] The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example: the term "optionally by one or more R m "Substituted" means that it may be substituted or not. When substituted, it means that any one or more hydrogen atoms on a specific atom are replaced by a substituent R m replace.

[0162] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1-2 R's, the group may optionally be substituted with up to two R's, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0163] Compared with the prior art, the present invention has one or more of the following beneficial effects:

[0164] The compounds provided by the present invention have excellent agonist activity and selectivity for NOP receptors and have great clinical application prospects in the treatment and / or prevention of NOP receptor-related diseases. In addition, the compounds of the present invention have significantly improved NOP agonist activity and / or pharmacokinetic properties compared to similar compounds reported in the literature. Moreover, the compounds of the present invention have no significant effect on the gastrointestinal motility function of rats.

[0165] Other features and advantages of the present application will be described in the following description, and in part will become apparent from the description, or will be understood by practicing the present application. Other advantages of the present application can be realized and obtained through the solutions described in the description. DETAILED DESCRIPTION

[0166] The following examples are provided to illustrate the present invention and its beneficial effects in detail, with the aim of helping readers better understand the essence and features of the present invention and not to limit the scope of the present invention. The following examples are provided only to illustrate the present invention and should not be construed as limiting the scope of the present invention.

[0167] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The units are given. NMR measurements were performed using a Bruker Ultrashield 400 MHz nuclear magnetic resonance instrument. The solvents used for the measurements were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CH3OD), and heavy water (D2O). The chemical shift δ values ​​(ppm) were reported using tetramethylsilane (TMS) as the internal standard.

[0168] LCMS was determined using Waters ACQUITY UPLC.

[0169] High performance liquid chromatography (HPLC) was measured by Waters preparative high performance liquid chromatograph using a YMC-Triart-C18 EXRS (20 mm×100 mm×5 μm) column.

[0170] The thin layer chromatography silica gel plate used was West Asia Reagent GF254 silica gel plate.

[0171] Column chromatography used 200-300 mesh silica gel from Qingdao Ocean Chemical Co., Ltd. as the carrier.

[0172] Unless otherwise specified, the 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. represents equivalent ratio; sat. represents saturated; M represents mol / L; rt represents room temperature; EtOH represents ethanol; MeOH represents methanol; DCM represents dichloromethane; DCE represents 1,2-dichloroethane; DMSO represents dimethyl sulfoxide; DMF represents N,N-dimethylformamide; EA represents ethyl acetate; PE represents petroleum ether; THF represents tetrahydrofuran; TEA represents triethylamine; TFA represents trifluoroacetic acid; AcOH represents acetic acid; CDI represents N, N'-carbonyldiimidazole; Boc represents tert-butyloxycarbonyl (a protecting group for amines); NaBH(OAc)3 represents sodium triacetoxyborohydride; Boc2O represents di-tert-butyl dicarbonate; MsCl represents methanesulfonyl chloride; Xantphos represents 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (a ligand for palladium catalysts); Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium; ddH2O represents double-distilled water; TLC: thin layer chromatography; HPLC: high performance liquid chromatography; 1H NMR: hydrogen nuclear magnetic resonance spectroscopy; LC-MS: liquid chromatography-mass spectrometry. Compounds are named according to conventional nomenclature in the art or using The software was named by PerkinElmer, and commercial reagents were named according to the supplier's catalog.

[0173] Example 1: Synthesis of 2-(5,6-difluoro-3-(1-(cis-4-isopropylcyclohexyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N,N-dimethylacetamide (1)

[0174] Synthesis of Intermediate 1c: To a clean, dry flask (250 mL) were added 2-bromo-4,5-difluoronitrobenzene (1a) (12.50 g, 52.52 mmol), Xantphos ligand (1.52 g, 2.63 mmol), and tris(dibenzylideneacetone)dipalladium (1.20 g, 1.31 mmol) in sequence. After replacing the nitrogen atmosphere, toluene (150 mL) was added. With stirring at room temperature, anhydrous cesium carbonate (23.96 g, 73.53 mmol) and 4-amino-1-tert-butyloxycarbonylpiperidine (1b) (12.62 g, 63.02 mmol) were added in sequence. The reaction was heated to 100°C and monitored by TLC until the reaction of starting material 1a was substantially complete. After cooling to room temperature, the reaction mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated, and the crude product was purified by column chromatography (mobile phase: petroleum ether and ethyl acetate, volume ratio: 5:1) to obtain 9.45 g of a yellow solid, with a yield of 50.40%. LC-MS (ESI) m / z: 358.16 (M+H)+ .

[0175] Synthesis of Intermediate 1d: Intermediate 1c (9.45 g, 26.44 mmol) was placed in a single-necked flask (500 mL). Anhydrous ethanol (270 mL) was added to the reaction flask. Under stirring at room temperature, iron powder (9.15 g, 163.86 mmol) and saturated aqueous NH4Cl solution (27 mL) were added to the reaction system. The temperature was raised to 80°C and monitored by TLC until the reaction of raw material 1c was essentially complete. The reaction solution was cooled to room temperature, filtered through celite, and the filter cake was washed with a small amount of anhydrous ethanol. The filtrate was concentrated, and the crude product was purified by column chromatography (mobile phase: petroleum ether and ethyl acetate, volume ratio: 5:1) to obtain 7.31 g of a gray solid, with a yield of 84.45%. LC-MS (ESI) m / z: 328.36 (M+H) + .

[0176] Synthesis of Intermediate 1e: Intermediate 1d (4.52 g, 13.80 mmol) and anhydrous tetrahydrofuran (60 mL) were placed in a clean, dry flask, the atmosphere was replaced with nitrogen, and N,N′-carbonyldiimidazole (3.12 g, 19.24 mmol) was added at 0°C. The mixture was stirred at room temperature for 12 hours. The reaction was terminated after completion of the reaction as confirmed by TLC. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: petroleum ether and ethyl acetate, volume ratio 1:1) to obtain 3.56 g of a yellow solid, with a yield of 73.06%. LC-MS (ESI) m / z: 354.22 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ11.03 (s, 1H), 7.44 (dd, J=9.9, 8.3Hz, 1H), 7.03 (dd, J=9.4, 8.1Hz, 1H), 4.28 (tt, J=12.2, 3 .9Hz, 1H), 4.08 (d, J=13.1Hz, 2H), 2.83 (s, 2H), 2.19 (qd, J=12.5, 4.4Hz, 2H), 1.66 (d, J=12.0Hz, 2H), 1.43 (s, 9H).

[0177] Synthesis of Intermediate 1g: To a clean, dry flask, add Intermediate 1e (2.76 g, 7.82 mmol) and THF (30 mL). The atmosphere was replaced with nitrogen. 60% (mass fraction) NaH (0.93 g, 23.46 mmol) was slowly added at 0°C and stirred for 0.5 h. 2-Chloro-N,N-dimethylacetamide (1f) (1.14 g, 9.38 mmol) was then added. Stirring continued at room temperature for 16 h. TLC confirmed the reaction was complete. Water was added dropwise at 0°C to quench the reaction. Extraction was performed with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated on a rotary evaporator under reduced pressure to remove the solvent, yielding 3.24 g of a white solid in a 94.60% yield. LC-MS (ESI) m / z: 439.13 (M+H). + .

[0178] Synthesis of Intermediate 1h: To a clean, dry flask, add Intermediate 1g (2.12g, 4.84mmol) and anhydrous dichloromethane (20mL). Trifluoroacetic acid (5mL) is added dropwise at 0°C. After the addition is complete, remove the ice-water bath and continue stirring at room temperature for 4 hours. TLC monitoring indicates that the starting material is substantially reacted. The solvent is removed under reduced pressure on a rotary evaporator to obtain a light brown oily crude product. Diethyl ether (50mL) is added to the crude product, dispersed, stirred, filtered, and dried to obtain 2.18g of a yellow solid (99.68% yield). The yellow solid is used directly in the next step without further purification.

[0179] Synthesis of Compound 1: To a clean, dry flask, add intermediate 1h (2.18 g, 4.84 mmol) and anhydrous 1,2-dichloroethane (10 mL). Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, 4-isopropylcyclohexanone (1i) (1.69 g, 12.10 mmol) was added. Acetic acid (0.38 g, 6.29 mmol) was added to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (3.08 g, 14.52 mmol) was added. The reaction was allowed to proceed at 40°C for 16 hours. Completion of the reaction was confirmed by TLC. The solvent was removed under reduced pressure on a rotary evaporator to obtain a yellow solid. The crude product was separated by preparative HPLC (YMC Triart C18 EXRS, 4.6×150 mm, 3 μm; mobile phase A: 0.1% aqueous ammonia; mobile phase B: 0.1% ammonia in acetonitrile, isocratic elution: 90% B / A (15 min); flow rate: 1.0 ml / min, peak elution time: 3.63 minutes) to obtain 200 mg of a white solid, in a yield of 8.93%. LC-MS (ESI) m / z: 463.36 (M+H). + ; 1H NMR (400MHz, DMSO-d6) δ7.44 (dd, J=11.0, 7.0Hz, 1H), 7.30 (dd, J=10.8, 7.1Hz, 1H), 4.69 (s, 2H), 4.18-3.97 (m, 0H), 3.07 (s, 4H), 2.83 ( s, 3H), 2.30 (dt, J=12.5, 8.9Hz, 3H), 2.11 (t, J=11.6Hz, 2H), 1.79-1.48 (m, 8H), 1.48-1.24 (m, 2H), 1.09 (s, 1H), 0.86 (d, J=6.6Hz, 6H).

[0180] Example 2: Synthesis of 2-(5,6-difluoro-3-(1-(cis-4-isopropylcyclohexyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-methylacetamide (2)

[0181] Synthesis of Intermediate 2b: To a clean, dry flask, intermediate 1e (1.20 g, 3.40 mmol), acetonitrile (15 mL), potassium carbonate (0.94 g, 6.81 mmol), and 2-chloro-N-methylacetamide (2a) (0.48 g, 4.42 mmol) were added sequentially. The mixture was refluxed and stirred at 70°C for 12 hours. Completion of the reaction was confirmed by TLC. The solvent was removed by rotary evaporation under reduced pressure. The residue was extracted three times with water and dichloromethane. The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was then evaporated under reduced pressure on a rotary evaporator to remove the solvent. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, 30:1 volume ratio) to obtain 1.24 g of a white solid, with a yield of 86.11%.

[0182] Synthesis of Intermediate 2c: To a clean, dry flask, intermediate 2b (0.80 g, 1.88 mmol) was added, along with anhydrous dichloromethane (9 mL). Trifluoroacetic acid (2.5 mL) was added dropwise at 0°C. After the addition was complete, the ice-water bath was removed and the reaction was stirred at room temperature for 3 hours. TLC monitoring confirmed that the reaction was essentially complete. The solvent was removed under reduced pressure on a rotary evaporator to obtain a crude product. Ether (50 mL) was added to the crude product, which was dispersed, stirred, filtered, and dried to obtain 0.81 g of a yellow solid (98.06% yield). The yellow solid was used directly in the next step without further purification.

[0183] Synthesis of Compound 2: To a clean, dry flask, add intermediate 2c (0.60 g, 1.37 mmol) and anhydrous 1,2-dichloroethane (8 mL). Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, 4-isopropylcyclohexanone (0.48 g, 3.42 mmol) was added. Acetic acid (0.12 g, 2.05 mmol) was added to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (0.87 g, 4.11 mmol) was added. The reaction was allowed to proceed at 40°C for 16 hours. Completion of the reaction was confirmed by TLC. The solvent was removed under reduced pressure on a rotary evaporator to obtain a yellow solid. The crude product was separated by preparative HPLC (YMC Triart C18 EXRS, 4.6×150 mm, 3 μm; mobile phase A: 0.1% aqueous ammonia; mobile phase B: 0.1% aqueous ammonia in acetonitrile, isocratic elution: 90% B / A (15 min); flow rate: 1.0 ml / min, peak elution time: 8.42 minutes) to obtain 203 mg of a white solid, a yield of 16.53%. LC-MS (ESI) m / z: 449.33 (M+H). + ; 1 H NMR (400MHz, DMSO-d6) δ8.08 (d, J=4.8Hz, 1H), 7.45 (dd, J=11.0, 6.9Hz, 1H), 7.28 (dd, J=10.7, 7.1Hz, 1H), 4.41 (s, 2H), 4.21-3.98 (m, 1H), 3.07 (d, J=11.1Hz, 2H), 2.60 (d, J= 4.5Hz, 3H), 2.37-2.21 (m, 3H), 2.10 (t, J=11.6Hz, 2H), 1.66 (d, J=11.5Hz, 4H), 1.54 (dq , J=14.2, 7.3, 6.7Hz, 3H), 1.48-1.28 (m, 4H), 1.16-1.03 (m, 1H), 0.86 (d, J=6.6Hz, 6H).

[0184] Example 3: Synthesis of 2-(3-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N,N-dimethylacetamide (4)

[0185] Intermediate 1h (0.46 g, 1.02 mmol) and 4,4-dimethylcyclohexanone (0.32 g, 2.55 mmol) were used as starting materials, following the method of Example 1 to obtain 320 mg of a white solid in a yield of 72.40%. LC-MS (ESI) m / z: 449.37 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ7.56 (t, J=9.0Hz, 1H), 7.39 (t, J=9.0Hz, 1H), 4.73 (s, 2H), 4.60 (d, J=12.7Hz, 1H), 3.60 (d, J=11.7Hz, 2H), 3.31-3.12 (m, 3H), 3.07(s, 3H), 2.83(s, 3H), 2.74-2.54(m, 2H), 2.07-1.76(m, 4H), 1.75-1.55 (m, 2H), 1.49 (d, J=13.1Hz, 2H), 1.26 (td, J=13.3, 3.5Hz, 2H), 0.92 (s, 6H).

[0186] Example 4: Synthesis of 2-(3-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-methylacetamide (5)

[0187] To a clean, dry flask, intermediate 2c (0.30 g, 0.68 mmol) and anhydrous 1,2-dichloroethane (4 mL) were added. Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, 4,4-dimethylcyclohexanone (0.22 g, 1.70 mmol) was added. Acetic acid was added to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (0.43 g, 2.04 mmol) was added. The reaction was allowed to proceed at 40°C for 16 hours, and completion of the reaction was confirmed by TLC. The solvent was removed under reduced pressure on a rotary evaporator, and the crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio 20:1) to obtain 230 mg of a white solid in a yield of 78.23%. LC-MS (ESI) m / z: 435.37 (M+H). + ; 1 H NMR (400MHz, DMSO-d6) δ8.11 (q, J=4.6Hz, 1H), 7.58 (t, J=8.9Hz, 1H), 7.35 ( t, J=8.9Hz, 1H), 4.52 (s, 1H), 4.44 (s, 2H), 3.50 (s, 2H), 3.08 (q, J=7.3Hz, 3H ), 2.61 (d, J=4.5Hz, 3H), 1.86 (d, J=36.9Hz, 4H), 1.60 (d, J=12.6Hz, 2H), 1. 48 (d, J=13.1Hz, 2H), 1.35-1.20 (m, 2H), 1.17 (t, J=7.3Hz, 2H), 0.91 (s, 6H).

[0188] Example 5: Synthesis of 2-(3-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-methylacetamide (6)

[0189] Intermediate 2c (0.30 g, 0.68 mmol) and 4,4-difluorocyclohexanone (0.23 g, 1.70 mmol) were used as starting materials, following the method of Example 4 to obtain 220 mg of a white solid in a yield of 73.09%. LC-MS (ESI) m / z: 443.22 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.08 (d, J=4.8Hz, 1H), 7.48 (dd, J=11.1, 6.9Hz, 1H), 7 .27(dd, J=10.7, 7.1Hz, 1H), 4.41(s, 2H), 4.22-3.98(m, 1H), 3.49-3.45(m, 1H) , 2.95 (d, J=6.8Hz, 2H), 2.60 (d, J=4.6Hz, 3H), 2.41-2.20 (m, 4H), 2.05 (d, J=10 .8Hz, 3H), 1.93-1.73 (m, 4H), 1.73-1.60 (m, 2H), 1.54 (q, J=13.3, 12.6Hz, 2H).

[0190] Example 6: Synthesis of 2-(3-(1-(4,4-difluorocyclohexyl)piperidin-4-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-ethylacetamide (7)

[0191] Synthesis of Intermediate 7a: To a clean, dry flask, add Intermediate 1e (1.20 g, 3.40 mmol), acetonitrile (15 mL), potassium carbonate (0.94 g, 6.81 mmol), and 2-chloro-N-ethylacetamide (0.54 g, 4.42 mmol). Reflux and stir at 70°C for 12 hours. Completion of the reaction was confirmed by TLC. The solvent was removed by rotary evaporation under reduced pressure. The residue was extracted three times with water and dichloromethane. The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was then evaporated under reduced pressure on a rotary evaporator to remove the solvent. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, 30:1 volume ratio) to obtain 1.30 g of a white solid, with a yield of 87.25%.

[0192] Synthesis of Intermediate 7b: To a clean, dry flask, intermediate 7a (0.80 g, 1.82 mmol) was added, along with anhydrous dichloromethane (9 mL). Trifluoroacetic acid (2.5 mL) was added dropwise at 0°C. After the addition was complete, the ice-water bath was removed and the reaction was stirred at room temperature for 3 hours. TLC monitoring confirmed that the reaction was essentially complete. The solvent was removed under reduced pressure on a rotary evaporator to obtain a crude product. Ether (5 mL) was added to the crude product, which was dispersed, stirred, filtered, and dried to obtain 0.82 g of a yellow solid (99.39% yield). The yellow solid was used directly in the next step without further purification.

[0193] Synthesis of Compound 7: To a clean, dry flask, intermediate 7b (0.82 g, 1.81 mmol) and anhydrous 1,2-dichloroethane (8 mL) were added. Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, 4,4-difluorocyclohexanone (607 mg, 4.53 mmol) was added. Acetic acid was added to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (1.15 g, 5.43 mmol) was added. The mixture was reacted at 40°C for 16 hours, and completion of the reaction was confirmed by TLC. The solvent was removed under reduced pressure on a rotary evaporator, and the crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio 20:1) to obtain 640 mg of a white solid in a 77% yield. LC-MS (ESI) m / z: 457.31 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.17 (t, J=5.4Hz, 1H), 7.48 (dd, J=11.0, 7.0Hz, 1H), 7.26 ( dd, J=10.7, 7.1Hz, 1H), 4.40 (s, 2H), 4.20-4.02 (m, 1H), 3.49-3.45 (m, 1H), 3.17-3. 02 (m, 2H), 2.95 (d, J = 6.8Hz, 2H), 2.28 (h, J = 10.6Hz, 4H), 2.05 (d, J = 11.3Hz, 2H), 1 .94-1.71 (m, 4H), 1.71-1.61 (m, 2H), 1.54 (q, J=12.1Hz, 2H), 1.03 (t, J=7.2Hz, 3H).

[0194] Example 7: Synthesis of 2-(3-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-ethylacetamide (8)

[0195] Intermediate 7b (0.60 g, 1.33 mmol) and 4,4-dimethylcyclohexanone (418 mg, 3.32 mmol) were used as starting materials, following the method of Example 6 to obtain 470 mg of a yellow solid in a yield of 78.73%. LC-MS (ESI) m / z: 449.39 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.18 (t, J=5.5Hz, 1H), 7.52 (dd, J=10.8, 7.2Hz, 1H), 7.29 (dd, J=10.4, 7.3Hz, 1H), 4.42 (s, 2H), 4.35-4.20 (m, 1H), 3.14-3.04 ( m, 2H), 2.85-2.56 (m, 3H), 2.45-2.23 (m, 3H), 1.83-1.64 (m, 4H), 1.47 (dd, J =23.1, 12.8Hz, 4H), 1.29-1.14 (m, 3H), 1.03 (t, J = 7.2Hz, 3H), 0.89 (s, 6H).

[0196] Example 8: Synthesis of 1-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (9)

[0197] Synthesis of intermediate 9a: To a clean, dry flask, add intermediate 1e (1.50 g, 4.25 mmol), acetonitrile (15 mL), potassium carbonate (1.17 g, 8.50 mmol), and 3-methyl-5-(chloromethyl)-1,2,4-oxadiazole (0.73 g, 5.53 mmol) in sequence. Reflux and stir at 70°C for 12 hours. TLC confirms the reaction is complete. After the reaction is completed, the reaction system is cooled to room temperature, filtered, and the filter cake is washed with a small amount of acetonitrile. The filtrate is then evaporated to remove the solvent under reduced pressure on a rotary evaporator. The crude product is purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio 20:1) to obtain 1.50 g of a yellow solid with a yield of 78.57%. LC-MS (ESI) m / z: 450.23 (M+H) + ;

[0198] Synthesis of Intermediate 9b: To a clean, dry flask, intermediate 9a (1.20 g, 2.67 mmol) was added, along with anhydrous dichloromethane (8 mL). Trifluoroacetic acid (2 mL) was added dropwise at 0°C. After the addition was complete, the ice-water bath was removed and the reaction was stirred at room temperature for 12 hours. TLC monitoring confirmed that the reaction was essentially complete. The solvent was removed under reduced pressure on a rotary evaporator to obtain a crude product. Ether (4 mL) was added to the crude product, which was dispersed, stirred, filtered, and dried to obtain 1.24 g of a white solid. This white solid was used directly in the next step without further purification.

[0199] Synthesis of Compound 9: To a clean, dry flask, add intermediate 9b (0.20 g, 0.43 mmol) and anhydrous 1,2-dichloroethane (4 mL). Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, 4,4-dimethylcyclohexanone (136 mg, 1.08 mmol) was added. Acetic acid (0.12 g, 2.05 mmol) was added to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (273 mg, 1.29 mmol) was added. The reaction was allowed to proceed at 40°C for 24 hours, and completion of the reaction was confirmed by TLC. Saturated aqueous sodium bicarbonate (5 mL) was added to the reaction mixture, stirred, and separated. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, 30:1 volume ratio) to obtain 130 mg of a white solid, with a yield of 65.83%. LC-MS (ESI) m / z: 460.58 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ7.57 (dd, J=11.0, 6.9Hz, 1H), 7.47 (dd, J=10.6, 7.0Hz, 1H), 5.39 (s, 2H), 4.23-3.97 (m, 1H), 2.96 (d, J=8.2Hz, 2H), 2.39-2.17 (m, 8H), 1.75-1.51 (m, 4H), 1.39 (d, J=11.8Hz, 4H), 1.29-1.09 (m, 2H), 0.87 (d, J=3.2Hz, 6H).

[0200] Example 9: Synthesis of 5,6-difluoro-1-(1-(cis-4-isopropylcyclohexyl)piperidin-4-yl)-3-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (10)

[0201] Intermediate 9b (0.80 g, 1.73 mmol) and 4-isopropylcyclohexanone (605 mg, 4.32 mmol) were used as starting materials, and the product was synthesized according to the method of Example 8. Preparative separation (isolation conditions were the same as those in Example 1) gave 200 mg of a white solid in a yield of 24.42%. LC-MS (ESI) m / z: 474.45 (M+H). + ; 1 H NMR (400MHz, DMSO-d6) δ7.54 (dd, J=11.0, 7.0Hz, 1H), 7.48 (dd, J=10.6, 7.1Hz, 1H), 5.40 (s, 2H), 4.19-4.04 (m, 1H), 3.07 (d, J=11.1Hz, 2H), 2.3 9-2.19 (m, 6H), 2.10 (t, J=11.5Hz, 2H), 1.68 (d, J=11.6Hz, 4H), 1.63-1. 48 (m, 3H), 1.47-1.27 (m, 4H), 1.15-1.03 (m, 1H), 0.86 (d, J=6.6Hz, 6H).

[0202] Example 10: Synthesis of N-cyclopropyl-2-(3-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (11)

[0203] Synthesis of Intermediate 11a: To a clean, dry flask, add Intermediate 1e (2.00 g, 5.66 mmol) and anhydrous dichloromethane (16 mL). Trifluoroacetic acid (4 mL) was added dropwise at 0°C. After the addition was complete, the ice-water bath was removed and the reaction was stirred at room temperature for 12 hours. TLC monitoring confirmed that the starting materials had essentially reacted. The solvent was removed under reduced pressure on a rotary evaporator to obtain a crude product. Methyl tert-butyl ether (5 mL) was added to the crude product, which was dispersed, stirred, filtered, and dried to obtain 2.06 g of a white solid (98.94% yield). The white solid was used directly in the next step without further purification.

[0204] Synthesis of Compound 11b: To a clean, dry flask, add intermediate 11a (2.06 g, 5.60 mmol) and anhydrous 1,2-dichloroethane (25 mL). Add triethylamine dropwise to adjust the pH to approximately 8. Stir for 10 minutes, then add 4,4-dimethylcyclohexanone (1.42 g, 11.20 mmol). Add acetic acid (0.51 g, 8.43 mmol) to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, add sodium triacetoxyborohydride (3.57 g, 16.86 mmol). React at 40°C for 24 hours. Completion of the reaction was confirmed by TLC. Saturated aqueous sodium bicarbonate (20 mL) was added to the reaction mixture, stirred, and separated. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol in a ratio of 15:1) to obtain 1.80 g of a white solid, with a yield of 88.39%. LC-MS (ESI) m / z: 364.26 (M+H). + ;

[0205] Synthesis of compound 11: To a clean, dry flask, intermediate 11b (0.20 g, 0.55 mmol), N,N-dimethylformamide (5 mL), cesium carbonate (358 mg, 1.10 mmol), and 2-chloro-N-cyclopropylacetamide (96 mg, 0.72 mmol) were added sequentially. Stir at 65°C for 12 hours, and the reaction was confirmed to be complete by TLC. The reaction system was cooled to room temperature, water (10 mL) was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined and the solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio 15:1) to obtain 200 mg of a yellow solid, with a yield of 79.05%. LC-MS (ESI) m / z: 461.61 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.28 (d, J=4.2Hz, 1H), 7.46 (dd, J=10.9, 6.9Hz, 1H), 7.27 (d d, J=10.7, 7.1Hz, 1H), 4.38 (s, 2H), 4.23-4.00 (m, 1H), 3.14-2.87 (m, 2H), 2.63 (tq, J =7.7, 4.2Hz, 2H), 2.43-2.11 (m, 4H), 1.78-1.50 (m, 4H), 1.41 (d, J = 12.5Hz, 4H), 1.29 -1.12 (m, 2H), 0.88 (d, J=2.7Hz, 6H), 0.62 (td, J=7.0, 4.7Hz, 2H), 0.51-0.35 (m, 2H).

[0206] Example 11: Synthesis of N-(cyclopropylmethyl)-2-(3-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (12)

[0207] Intermediate 11b (0.20 g, 0.55 mmol) and 2-chloro-N-(cyclopropylmethyl)acetamide (106 mg, 0.72 mmol) were used as starting materials, following the method of Example 10 to obtain 190 mg of a white solid in a yield of 72.80%. LC-MS (ESI) m / z: 475.31 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.28 (t, J=5.5Hz, 1H), 7.46 (dd, J=11.0, 7.0Hz, 1H), 7.26 (dd, J=10.7, 7.1Hz, 1H), 4.44 (s, 2H), 4.18-4.01 (m, 1H), 3.05-2 .79(m, 4H), 2.41-2.12(m, 5H), 1.76-1.51(m, 4H), 1.50-1.31(m, 4H), 1.2 7-1.09 (m, 2H), 0.99-0.78 (m, 7H), 0.48-0.30 (m, 2H), 0.26-0.02 (m, 2H).

[0208] Example 12: Synthesis of ethyl 2-(3-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetate (13)

[0209] Intermediate 11b (0.20 g, 0.55 mmol) and ethyl chloroacetate (88 mg, 0.72 mmol) were used as starting materials, and the synthesis method according to Example 10 was used to obtain 210 mg of a white solid with a yield of 85.02%. LC-MS (ESI) m / z: 450.27 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ7.50 (dd, J=11.0, 7.0Hz, 1H), 7.45 (dd, J=10.7, 7.1Hz, 1H), 4.68 (s, 2H), 4.14 (q, J=7.1Hz, 2H), 4.11-4.04 (m , 1H), 2.96 (d, J=8.1Hz, 2H), 2.40-2.15 (m, 5H), 1.73-1.51 (m, 4H), 1.40 (d, J=11.6Hz, 4H), 1.28-1.09 (m, 5H), 0.88 (d, J=2.9Hz, 6H).

[0210] Example 13: Synthesis of 2-(3-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide (14)

[0211] Synthesis of compound 14: To a clean, dry flask, intermediate 11b (0.20 g, 0.55 mmol), N,N-dimethylformamide (5 mL), cesium carbonate (358 mg, 1.10 mmol), and 2-bromoacetamide (98 mg, 0.72 mmol) were added sequentially. Stir at 65°C for 12 hours, and the reaction was confirmed to be complete by TLC. The reaction system was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with dichloromethane three times. The organic phases were combined and the solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio 15:1) to obtain 200 mg of a yellow solid, with a yield of 86.48%. LC-MS (ESI) m / z: 421.27 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ7.62 (s, 1H), 7.45 (dd, J=11.0, 7.0Hz, 1H), 7.27 (dd, J=10.7, 7.2Hz, 1H), 7.23 (s, 1H), 4.40 (s, 2H), 4.18-3. 97 (m, 1H), 2.96 (d, J=8.3Hz, 2H), 2.39-2.12 (m, 5H), 1.76-1.50 (m, 4H), 1.49-1.30 (m, 4H), 1.29-1.07 (m, 2H), 0.88 (d, J=2.8Hz, 6H).

[0212] Example 14: Synthesis of 2-(5,6-difluoro-2-oxo-3-(1-(spiro[2.5]octan-6-yl)piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-methylacetamide (15)

[0213] To a clean, dry flask, intermediate 2c (0.30 g, 0.68 mmol) and anhydrous 1,2-dichloroethane (4 mL) were added. Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, spiro[2.5]octan-6-one (0.21 g, 1.70 mmol) was added. Acetic acid was added to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (0.43 g, 2.04 mmol) was added. The mixture was reacted at 50°C for 24 hours, and completion of the reaction was confirmed by TLC. The solvent was removed under reduced pressure on a rotary evaporator, and the crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio 20:1) to obtain 180 mg of a white solid in a yield of 61.22%. LC-MS (ESI) m / z: 433.56 (M+H). + ; 1 H NMR (400MHz, CDCl3) δ7.56-7.38 (m, 1H), 6.92 (dd, J=9.4, 6.6Hz, 1H), 6.08 (s, 1H), 4.65-4.49 (m, 1H), 4.43 (s, 2H), 3.67-3.35 (m, 2H), 2.94 -2.55 (m, 6H), 2.08-1.91 (m, 4H), 1.91-1.75 (m, 4H), 1.60 (t, J=12.2Hz, 2H), 1.02 (d, J=13.3Hz, 2H), 0.44-0.31 (m, 2H), 0.30-0.13 (m, 2H).

[0214] Example 15: Synthesis of 2-(3-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-methylpropanamide (16)

[0215] Intermediate 11b (0.20 g, 0.55 mmol) and 2-chloro-N-methylpropionamide (88 mg, 0.72 mmol) were used as starting materials, and the synthesis method according to Example 10 was used to obtain 180 mg of a white solid in a yield of 72.87%. LC-MS (ESI) m / z: 449.62 (M+H) + ; 1H NMR (400MHz, DMSO-d6) δ8.02 (d, J=4.7Hz, 1H), 7.46 (dd, J=11.0, 7.1Hz, 1H), 7.26 ( dd, J=11.0, 7.2Hz, 1H), 4.98 (q, J=7.2Hz, 1H), 4.22-4.00 (m, 1H), 2.96 (d, J=8.1Hz , 2H), 2.58 (d, J=4.5Hz, 3H), 2.29 (t, J=14.4Hz, 5H), 1.75-1.54 (m, 4H), 1.50 (d, J= 7.2Hz, 3H), 1.47-1.33 (m, 4H), 1.19 (p, J=10.7, 9.2Hz, 2H), 0.88 (d, J=2.9Hz, 6H).

[0216] Example 16: Synthesis of 2-(3-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-(2-hydroxyethyl)acetamide (17)

[0217] Compound 13 (0.20 g, 0.45 mmol), ethanolamine (82 mg, 1.35 mmol) and methanol (2 mL) were added sequentially to a clean, dry flask, and the mixture was heated to 60°C and stirred overnight. TLC confirmed that the reaction was essentially complete. The reaction system was cooled to room temperature, and the solvent was removed under reduced pressure using a rotary evaporator. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio: 20:1) to obtain 130 mg of a white solid, with a yield of 63.40%. LC-MS (ESI) m / z: 465.58 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ8.21 (t, J=5.6Hz, 1H), 7.46 (dd, J=11.0, 6.9Hz, 1H), 7.25 (dd, J=10.7, 7.1Hz, 1H), 4.71 (t, J=5.4Hz, 1H), 4.44 (s, 2H), 4.08 (s, 1H), 3.42 (q, J=5.9Hz, 2H), 3.14 (q, J=5.9Hz, 2H), 2.96 (d, J=8.3Hz, 2H), 2.41-2.10 (m, 5H), 1. 74-1.51 (m, 4H), 1.40 (d, J=11.9Hz, 4H), 1.30-1.06 (m, 2H), 0.88 (d, J=2.8Hz, 6H).

[0218] Example 17: Synthesis of 1-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-3-((methylsulfonyl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (18)

[0219] Synthesis of Intermediate 18a: To a clean, dry flask, add Intermediate 1e (2.00 g, 5.67 mmol) and anhydrous DMF (25 mL). The atmosphere was replaced with nitrogen three times. In an ice bath, 60% sodium hydroxide (0.68 g, 17.01 mmol) was slowly added. The mixture was warmed to room temperature and stirred for 30 minutes. Chloromethyl methyl sulfide (1.10 g, 11.34 mmol) was then added. Stirring was continued at room temperature for 16 hours. Completion of the reaction was confirmed by TLC. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: petroleum ether and ethyl acetate, 1:1 volume ratio) to obtain 1.80 g of a yellow solid, with a yield of 76.72%.

[0220] Synthesis of Intermediate 18b: To a clean, dry flask, intermediate 18a (1.00 g, 2.42 mmol) and glacial acetic acid (15 mL) were added sequentially. Sodium perborate tetrahydrate (1.12 g, 7.26 mmol) was slowly added while stirring at room temperature. After stirring at room temperature for 16 hours, TLC confirmed that the starting materials had essentially reacted completely. Aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure on a rotary evaporator to yield 0.95 g of a yellow solid (88.02% yield).

[0221] Synthesis of Intermediate 18c: To a clean, dry flask, intermediate 18b (0.52 g, 1.17 mmol) was added, along with anhydrous dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added dropwise at 0°C. After the addition was complete, the ice-water bath was removed and the reaction was stirred at room temperature for 12 hours. TLC monitoring confirmed the substantial reaction of the starting materials. The solvent was removed under reduced pressure on a rotary evaporator to obtain a crude product. Methyl tert-butyl ether (5 mL) was added to the crude product, which was dispersed, stirred, filtered, and dried to obtain 520 mg of a white solid (96.58% yield). The white solid was used directly in the next step without further purification.

[0222] Synthesis of Compound 18: To a clean, dry flask, intermediate 18c (0.52 g, 1.13 mmol) and anhydrous 1,2-dichloroethane (5 mL) were added. Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, 4,4-dimethylcyclohexanone (214 mg, 1.69 mmol) was added. Acetic acid was added to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (599 mg, 2.83 mmol) was added. The reaction was allowed to proceed at 40°C for 24 hours, and completion of the reaction was confirmed by TLC. Saturated aqueous sodium bicarbonate (20 mL) was added to the reaction mixture, stirred, and separated. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, 40:1 volume ratio) to obtain 300 mg of a white solid in a yield of 58.18%. LC-MS (ESI) m / z: 456.50 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ7.60 (td, J=11.4, 7.0Hz, 2H), 5.40 (s, 2H), 4.72-4.45 ( m, 1H), 3.61 (d, J=11.9Hz, 2H), 3.28-3.11 (m, 3H), 3.06 (s, 3H), 2.62 (q, J=12.4 Hz, 2H), 2.03 (d, J=13.6Hz, 2H), 1.86 (d, J=11.9Hz, 2H), 1.64 (q, J=12.5Hz, 2H) , 1.50 (d, J=13.1Hz, 2H), 1.27 (dd, J=14.9, 11.5Hz, 2H), 0.92 (d, J=1.5Hz, 6H).

[0223] Example 18: Synthesis of 5,6-difluoro-1-((methylsulfonyl)methyl)-3-(1-(spiro[2.5]octan-6-yl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (20)

[0224] To a clean, dry flask, intermediate 18c (0.30 g, 0.65 mmol) and anhydrous 1,2-dichloroethane (4 mL) were added. Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, spiro[2.5]octan-6-one (202 mg, 1.63 mmol) was added. Acetic acid was added to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (413 mg, 1.95 mmol) was added. The reaction was allowed to proceed at 40°C for 24 hours, and completion of the reaction was confirmed by TLC. Saturated aqueous sodium bicarbonate (5 mL) was added to the reaction solution, stirred, and separated. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, 40:1 volume ratio) to obtain 120 mg of a white solid in a yield of 40.71%. LC-MS (ESI) m / z: 454.55 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ7.66 (s, 1H), 7.15 (dd, J=9.4, 6.6Hz, 1H), 5.01 (s, 2H), 4. 71-4.44(m, 1H), 3.72-3.43(m, 2H), 3.29-3.10(m, 1H), 2.98(s, 3H), 2.96-2.81( m, 3H), 2.20-2.06 (m, 2H), 1.99 (d, J = 11.9Hz, 2H), 1.89 (t, J = 13.0Hz, 2H), 1.64 ( t, J=12.0Hz, 3H), 1.04 (d, J=13.4Hz, 2H), 0.45-0.35 (m, 2H), 0.29-0.19 (m, 2H).

[0225] Example 19: Synthesis of 1-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-3-(2-(methylsulfonyl)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (21)

[0226] Intermediate 11b (0.20 g, 0.55 mmol) and 2-bromoethyl methyl sulfone (135 mg, 0.72 mmol) were used as starting materials, and the synthesis method according to Example 10 was used to obtain 220 mg of a white solid with a yield of 85.27%. LC-MS (ESI) m / z: 470.49 (M+H) + .

[0227] Example 20: Synthesis of N-(2-(3-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)acetamide (22)

[0228] Synthesis of Intermediate 22a: To a clean, dry flask, intermediate 14b (300 mg, 0.83 mmol), DMF (2 mL), potassium carbonate (229 mg, 1.66 mmol), and N-Boc-bromoethylamine (242 mg, 1.08 mmol) were added sequentially. The reaction was stirred at 50°C for 12 hours, and the reaction was confirmed to be complete by TLC. After the reaction, the reaction system was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the layers were separated. The organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure on a rotary evaporator to remove the solvent. The crude product was purified by column chromatography (mobile phase: petroleum ether and ethyl acetate, volume ratio 1:1) to obtain 377 mg of a yellow solid, with a yield of 89.65%. LC-MS (ESI) m / z: 507.46 (M+H) + .

[0229] Synthesis of Intermediate 22b: To a clean, dry flask, intermediate 22a (377 mg, 0.75 mmol) was added, along with anhydrous dichloromethane (4 mL). Trifluoroacetic acid (1 mL) was added dropwise at 0°C. After the addition was complete, the ice-water bath was removed and the reaction was stirred at room temperature for 12 hours. TLC monitoring confirmed the substantial reaction of the starting materials. The solvent was removed under reduced pressure on a rotary evaporator to obtain a crude product. Ether was added to the crude product, which was dispersed, stirred, filtered, and dried to obtain 390 mg of a yellow solid (100% yield). The product was used directly in the next step without further purification.

[0230] Synthesis of Compound 22: To a clean, dry flask, intermediate 22b (390 mg, 0.75 mmol) and anhydrous dichloromethane (4 mL) were added, followed by triethylamine (227 mg, 2.25 mmol). Acetyl chloride (71 mg, 0.90 mmol) was slowly added in an ice-water bath. Stirring was continued at room temperature for 3 hours. TLC confirmed the reaction was essentially complete. The solvent was removed under reduced pressure on a rotary evaporator, and the crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio 20:1) to obtain 64 mg of a white solid, a yield of 19.04%. LC-MS (ESI) m / z: 449.60 (M+H). + ; 1H NMR (400MHz, DMSO-d6) δ7.93 (t, J=5.9Hz, 1H), 7.44 (dd, J=11.0, 7.0Hz, 1H), 7.30 (dd, J=10.7, 7.1Hz, 1H), 4.19-3.95 (m, 1H), 3.81 (t, J=6.1Hz, 2H), 3.27(q, J=6.0Hz, 2H), 2.95(s, 1H), 2.41-2.08(m, 5H), 1.68(s, 3H), 1.67- 1.52 (m, 4H), 1.48-1.30 (m, 4H), 1.29-1.07 (m, 2H), 0.88 (d, J=2.9Hz, 6H).

[0231] Example 21: Synthesis of 2-(3-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N,N-dimethylacetamide (23)

[0232] Synthesis of Intermediate 23a: Intermediate 1d (2.00 g, 6.11 mmol) and anhydrous tetrahydrofuran (15 mL) were placed in a clean, dry flask. The atmosphere was replaced with nitrogen, and N,N'-thiocarbonyldiimidazole (TCDI) (1.52 g, 8.55 mmol) was added at 0°C. The mixture was stirred at room temperature for 18 hours. The reaction was terminated after completion of the reaction as confirmed by TLC. The reaction solution was concentrated under reduced pressure, saturated aqueous NaHCO₃ was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure on a rotary evaporator. The crude product was purified by column chromatography (mobile phase: petroleum ether and ethyl acetate, volume ratio: 1:1) to obtain 2.20 g of a yellow solid in a yield of 97.54%. LC-MS (ESI) m / z: 370.28 (M+H) + .

[0233] Synthesis of Intermediate 23b: To a clean, dry flask were added Intermediate 23a (1.00 g, 2.71 mmol), acetonitrile (10 mL), potassium carbonate (748 mg, 5.42 mmol), and 2-chloro-N,N-dimethylacetamide (428 mg, 3.52 mmol). The reaction was stirred at 70°C for 12 hours, and completion of the reaction was confirmed by TLC. After completion of the reaction, the reaction system was cooled to room temperature, filtered, and the filter cake was washed with a small amount of acetonitrile. The filtrate was concentrated under reduced pressure on a rotary evaporator, and the crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio 60:1) to obtain 1.20 g of a yellow solid, with a yield of 97.42%. LC-MS (ESI) m / z: 455.26 (M+H). + .

[0234] Synthesis of Intermediate 23c: To a clean, dry flask, intermediate 23b (1.20 g, 2.64 mmol) was added, along with anhydrous dichloromethane (8 mL). Trifluoroacetic acid (2 mL) was added dropwise at 0°C. After the addition was complete, the ice-water bath was removed and the reaction was stirred at room temperature for 12 hours. TLC analysis indicated that the reaction was essentially complete. The solvent was removed by rotary evaporation under reduced pressure to yield a light brown crude oil. Methyl tert-butyl ether was added to the crude product, the mixture was dispersed, stirred, filtered, and dried to yield 1.24 g of a white solid (100% yield). The white solid was used directly in the next step without further purification.

[0235] Synthesis of Compound 23: To a clean, dry flask, add intermediate 23c (1.24 g, 2.64 mmol) and anhydrous 1,2-dichloroethane (10 mL). Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, 4,4-dimethylcyclohexanone (678 mg, 5.38 mmol) was added. Acetic acid was added dropwise to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (1.71 g, 8.07 mmol) was added. The reaction was allowed to proceed at 40°C for 16 hours, and completion of the reaction was confirmed by TLC. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated on a rotary evaporator under reduced pressure. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, 40:1 volume ratio) to obtain 800 mg of a white solid, with a yield of 65.22%. LC-MS (ESI) m / z: 465.55 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ7.71 (s, 1H), 7.36 (dd, J=10.3, 7.2Hz, 1H), 4.71-4.56 (m, 1H), 4.38 (s, 2H), 3.70 (s, 2H), 3.16 (s, 3H), 2 .99 (s, 8H), 2.18-2.04 (m, 2H), 1.96 (d, J=11.8Hz, 2H), 1.83-1.51 (m, 4H), 1.34 (t, J=13.3Hz, 2H), 0.96 (s, 3H), 0.95 (s, 3H).

[0236] Example 22: Synthesis of 2-(3-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-methylacetamide (25)

[0237] Synthesis of Intermediate 25a: To a clean, dry flask were added Intermediate 23a (1.00 g, 2.71 mmol), acetonitrile (10 mL), potassium carbonate (748 mg, 5.42 mmol), and 2-chloro-N-methylacetamide (379 mg, 3.52 mmol). The reaction was stirred at 70°C for 12 hours, and completion of the reaction was confirmed by TLC. After completion, the reaction system was cooled to room temperature, filtered, and the filter cake was washed with a small amount of acetonitrile. The filtrate was concentrated under reduced pressure on a rotary evaporator. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, 40:1 volume ratio) to obtain 1.10 g of a yellow solid, with a yield of 92.13%.

[0238] Synthesis of Intermediate 25b: To a clean, dry flask, intermediate 25a (1.10 g, 2.50 mmol) was added, along with anhydrous dichloromethane (8 mL). Trifluoroacetic acid (2 mL) was added dropwise at 0°C. After the addition was complete, the ice-water bath was removed and the reaction was stirred at room temperature for 12 hours. TLC confirmed the substantial reaction. The solvent was removed under reduced pressure on a rotary evaporator to afford a light brown oily crude product. Methyl tert-butyl ether was added to the crude product, the mixture was dispersed, stirred, filtered, and dried to afford 1.14 g of a white solid (100% yield). The white solid was used directly in the next step without further purification.

[0239] Synthesis of Compound 25: To a clean, dry flask, intermediate 25b (1.14 g, 2.50 mmol) and anhydrous 1,2-dichloroethane (10 mL) were added. Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, 4,4-dimethylcyclohexanone (678 mg, 5.38 mmol) was added. Acetic acid was added dropwise to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (1.59 g, 7.50 mmol) was added. The reaction was allowed to proceed at 40°C for 16 hours, and completion of the reaction was confirmed by TLC. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated on a rotary evaporator under reduced pressure. The crude product was purified by column chromatography (mobile phase: dichloromethane:methanol, 40:1 ratio) to obtain 860 mg of a white solid in a yield of 76.38%. LC-MS (ESI) m / z: 451.54 (M+H). + ; 1H NMR (400MHz, CDCl3) δ7.91-7.59 (m, 2H), 7.38 (dd, J=10.2, 7.1Hz, 1H), 4.52-4.22 (m, 1H), 3.90 (s, 2H), 3.81-3.46 (m, 2H), 3.31-2.84 (m, 3H), 2.80 ( d, J=4.8Hz, 3H), 2.12-2.02(m, 2H), 2.00-1.88(m, 2H), 1.87-1.64(m, 4H), 1.59 (d, J=13.6Hz, 2H), 1.33 (t, J=13.3Hz, 2H), 0.96 (s, 3H), 0.94 (s, 3H).

[0240] Example 23: Synthesis of 2-(6,7-difluoro-1-(1-(cis-4-isopropylcyclohexyl)piperidin-4-yl)-2-oxo-1,4-dihydroquinazolin-3(2H)-yl)-N,N-dimethylacetamide (26)

[0241] Synthesis of Intermediate 26b: To a clean, dry flask, 4,5-difluoro-2-bromobenzonitrile (26a) (8.90 g, 40.83 mmol), Xantphos ligand (1.19 g, 2.06 mmol), and tris(dibenzylideneacetone)dipalladium (0.94 g, 1.03 mmol) were added sequentially. After replacing the nitrogen atmosphere, toluene (100 mL) was added. With stirring at room temperature, anhydrous cesium carbonate (18.62 g, 57.16 mmol) and 4-amino-1-tert-butyloxycarbonylpiperidine (1b) (9.81 g, 49.00 mmol) were added sequentially. The reaction was heated to 100°C and monitored by TLC until the reaction of the starting material 26a was substantially complete. After cooling to room temperature, the reaction mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated, and the crude product was purified by column chromatography (mobile phase: petroleum ether and ethyl acetate, volume ratio 6:1) to obtain 13.10 g of a yellow solid, with a yield of 95.13%. LC-MS (ESI) m / z: 338.09 (M+H) + .

[0242] Synthesis of intermediate 26c: To a clean, dry flask, intermediate 26b (13.10 g, 38.83 mmol) and THF (40 mL) were added sequentially, the nitrogen atmosphere was replaced, and a THF solution of BH3 (1.0 mmol / mL, 117 mL) was added dropwise at 0°C. The reaction solution was moved to room temperature and stirred for 16 hours. The reaction was confirmed to be complete by TLC. Methanol was added dropwise at 0°C to quench the reaction until no bubbles appeared. The solvent was removed by vacuum distillation, methanol (30 mL) and NaOH solution (1.0 mmol / mL, 78 mL) were added, and the mixture was stirred at room temperature for 1 hour. The methanol was evaporated and extracted with ethyl acetate. The organic phase was separated and concentrated under reduced pressure on a rotary evaporator to obtain 12.72 g of a brown oil with a yield of 95.93%. LC-MS (ESI) m / z: 342.36 (M+H) + .

[0243] Synthesis of Intermediate 26d: To a clean, dry flask, intermediate 26c (12.72 g, 37.26 mmol) and anhydrous tetrahydrofuran (60 mL) were added sequentially. The atmosphere was replaced with nitrogen, and N,N'-carbonyldiimidazole (8.46 g, 52.16 mmol) was added at 0°C. The mixture was stirred at room temperature for 16 hours. The reaction was terminated after completion of the reaction as confirmed by TLC. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: petroleum ether and ethyl acetate, volume ratio: 1:1) to obtain 10.27 g of a white solid, with a yield of 75.02%. LC-MS (ESI) m / z: 368.22 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ7.30 (dd, J=10.5, 8.8Hz, 1H), 7.21 (dd, J=13.2, 6.9Hz, 1H), 7.10 (s, 1H), 4.08 (s, 2H), 4.03 ( q, J=7.1Hz, 2H), 3.93-3.82 (m, 1H), 2.85 (s, 2H), 2.40 (qd, J=12.4, 4.3Hz, 2H), 1.66 (d, J=12.3Hz, 2H), 1.41 (s, 9H).

[0244] Synthesis of Intermediate 26e: To a clean, dry flask, add Intermediate 26d (5.51 g, 15.00 mmol) and THF (50 mL). The atmosphere was replaced with nitrogen. 60% NaH (1.20 g, 30.00 mmol) was slowly added at 0°C and stirred for 0.5 hours. 2-Chloro-N,N-dimethylacetamide (2.18 g, 18.00 mmol) was then added. The mixture was stirred at room temperature for 16 hours, and the reaction was confirmed to be complete by TLC. Water was added dropwise at 0°C to quench the reaction. The organic phase was extracted with ethyl acetate and dried over anhydrous Na2SO4 before being filtered. The filtrate was evaporated on a rotary evaporator to remove the solvent under reduced pressure to obtain 6.78 g of a yellow oil in a 99.85% yield. LC-MS (ESI) m / z: 453.35 (M+H) + .

[0245] Synthesis of Intermediate 26f: To a clean, dry flask, intermediate 26e (6.78 g, 14.98 mmol) was added, along with anhydrous dichloromethane (50 mL). Trifluoroacetic acid (10 mL) was added dropwise at 0°C. After the addition was complete, the ice-water bath was removed and the reaction was stirred at room temperature for 12 hours. TLC confirmed the reaction was essentially complete. The solvent was removed under reduced pressure on a rotary evaporator to afford a light brown oily crude product. Methyl tert-butyl ether was added to the crude product, the mixture was dispersed, stirred, filtered, and dried to afford 6.90 g of a yellow solid (98.85% yield). The yellow solid was used directly in the next step without further purification.

[0246] Synthesis of Compound 26: To a clean, dry flask, intermediate 26f (2.50 g, 5.36 mmol) and anhydrous 1,2-dichloroethane (20 mL) were added. Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, 4-isopropylcyclohexanone (1.88 g, 13.40 mmol) was added. Acetic acid was added to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (3.41 g, 16.08 mmol) was added. The mixture was reacted at 40°C for 16 hours, and completion of the reaction was confirmed by TLC. The solvent was removed under reduced pressure on a rotary evaporator, and the crude product was separated by preparative HPLC (separation conditions were the same as in Example 1) to obtain 650 mg of a white solid in a yield of 25.45%. LC-MS (ESI) m / z: 477.38 (M+H) + ; 1H NMR (600MHz, CDCl3) δ6.98 (dd, J=12.4, 6.7Hz, 1H), 6.90-6.77 (m, 1H), 4.32 (s, 2H), 4.15 (s , 2H), 3.97(tt, J=12.1, 3.9Hz, 1H), 3.21-3.07(m, 2H), 3.02(s, 3H), 2.97(s, 3H), 2.52(qd, J=12.4, 3.9Hz, 2H), 2.34-2.22 (m, 1H), 2.13 (t, J=11.6Hz, 2H), 1.85-1.70 (m, 2H), 1.70-1. 52 (m, 5H), 1.51-1.40 (m, 2H), 1.40-1.29 (m, 2H), 1.15-1.05 (m, 1H), 0.87 (d, J=6.6Hz, 6H).

[0247] Example 24: Synthesis of N-(2-(6,7-difluoro-2-oxo-1-(1-(spiro[2.5]octan-6-yl)piperidin-4-yl)-1,4-dihydroquinazolin-3(2H)-yl)ethyl)acetamide (30)

[0248] Synthesis of Intermediate 30a: To a clean, dry flask, add Intermediate 26d (3.00 g, 8.20 mmol) and THF (40 mL). The atmosphere was replaced with nitrogen. 60% sodium hydroxide (1.31 g, 32.80 mmol) was slowly added at 0°C and stirred for 0.5 hours. 2-Bromoethylamine hydrobromide (3.36 g, 16.40 mmol) pretreated with triethylamine was then added. Stir at room temperature for 16 hours, and the reaction was confirmed complete by TLC. The reaction was quenched by dropwise addition of water at 0°C and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated on a rotary evaporator to remove the solvent under reduced pressure. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, 10:1 volume ratio) to obtain 2.36 g of a white solid in a yield of 70.11%. LC-MS (ESI) m / z: 411.35 (M+H). + .

[0249] Synthesis of Intermediate 30b: To a clean, dry flask, add Intermediate 30a (2.00 g, 4.87 mmol) and anhydrous dichloromethane (20 mL). Triethylamine (1.48 g, 14.62 mmol) was then added slowly under an ice-water bath to the mixture. Acetyl chloride (459 mg, 5.84 mmol) was added. Stirring was continued at room temperature for 3 hours. TLC confirmed the reaction was essentially complete. The solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio 20:1) to obtain 1.20 g of a white solid, a yield of 54.54%. LC-MS (ESI) m / z: 453.36 (M+H). + .

[0250] Synthesis of Intermediate 30c: To a clean, dry flask, intermediate 30b (1.20 g, 2.65 mmol) was added, along with anhydrous dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added dropwise at 0°C. After the addition was complete, the ice-water bath was removed and the reaction was stirred at room temperature for 12 hours. TLC confirmed the reaction was essentially complete. The solvent was removed under reduced pressure on a rotary evaporator to afford a light brown oily crude product. Methyl tert-butyl ether was added to the crude product, the mixture was dispersed, stirred, filtered, and dried to afford 1.23 g of a white solid (99.51% yield). The white solid was used directly in the next step without further purification.

[0251] Synthesis of Compound 30: To a clean, dry flask, intermediate 30c (1.23 g, 2.64 mmol) and anhydrous 1,2-dichloroethane (10 mL) were added. Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, spiro[2.5]octan-6-one (656 mg, 5.28 mmol) was added. Acetic acid was added to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (1.68 g, 7.92 mmol) was added. The reaction was allowed to proceed at 40°C for 16 hours. Completion of the reaction was confirmed by TLC. The solvent was removed under reduced pressure on a rotary evaporator, and the crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio 20:1) to obtain 800 mg of a yellow solid in a yield of 65.79%. LC-MS (ESI) m / z: 461.45 (M+H). + ; 1H NMR (400MHz, CDCl3) δ7.14 (dd, J=12.2, 6.7Hz, 1H), 6.88 (dd, J=9.6, 8.2Hz, 1H), 6.59 (d, J=6.1Hz, 1H), 4. 21 (s, 2H), 4.14-3.95 (m, 1H), 3.52 (dd, J=6.9, 4.8Hz, 2H), 3.44 (q, J=5.6Hz, 2H), 3.31 (d, J=11.5Hz, 2H), 3.00-2.75(m, 3H), 2.68(t, J=11.8Hz, 2H), 2.00(d, J=11.8Hz, 2H), 1.94(s, 3H), 1.91-1.71(m, 4H), 1.54( qd, J=12.2, 3.5Hz, 2H), 0.97 (d, J=13.3Hz, 2H), 0.33 (dd, J=8.6, 5.7Hz, 2H), 0.20 (dd, J=8.8, 5.8Hz, 2H).

[0252] Example 25: Synthesis of N-(2-(6,7-difluoro-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-2-oxo-1,4-dihydroquinazolin-3(2H)-yl)ethyl)methanesulfonamide (31)

[0253] Synthesis of Intermediate 31a: To a clean, dry flask, add Intermediate 30a (1.18 g, 2.87 mmol) and anhydrous dichloromethane (10 mL). Triethylamine (580 mg, 5.75 mmol) was then added. Methanesulfonyl chloride (395 mg, 3.44 mmol) was slowly added under an ice-water bath. Stirring was continued at room temperature for 4 hours. TLC confirmed the reaction was essentially complete. Saturated sodium bicarbonate solution was slowly added to quench the reaction. Extraction was performed with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, 20:1 volume ratio) to obtain 1.30 g of a yellow oil in a 92.85% yield. LC-MS (ESI) m / z: 489.27 (M+H). + .

[0254] Synthesis of Intermediate 31b: To a clean, dry flask, intermediate 31a (1.30 g, 2.66 mmol) was added, along with anhydrous dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added dropwise at 0°C. After the addition was complete, the ice-water bath was removed and the reaction was stirred at room temperature for 12 hours. TLC confirmed the reaction was essentially complete. The solvent was removed under reduced pressure on a rotary evaporator to obtain a crude oil. Methyl tert-butyl ether was added to the crude product, the mixture was dispersed, stirred, filtered, and dried to obtain 1.30 g of a white solid (97.23% yield). The white solid was used directly in the next step without further purification.

[0255] Synthesis of Compound 31: To a clean, dry flask, intermediate 31b (1.30 g, 2.59 mmol) and anhydrous 1,2-dichloroethane (10 mL) were added. Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, 4-isopropylcyclohexanone (726 mg, 5.18 mmol) was added. Acetic acid was added to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (1.65 g, 7.77 mmol) was added. The reaction was allowed to proceed at 40°C for 16 hours, and completion of the reaction was confirmed by TLC. The solvent was removed under reduced pressure on a rotary evaporator. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio 20:1) and then subjected to preparative HPLC separation (separation conditions were the same as in Example 1) to obtain 150 mg of a white solid in an 11.30% yield. LC-MS (ESI) m / z: 513.38 (M+H). + ; 1 H NMR (400MHz, DMSO-d6) δ7.31 (t, J=9.5Hz, 1H), 7.17-7.03 (m, 2H), 4.28 (s, 2H), 3.7 6-3.60 (m, 1H), 3.34-3.21 (m, 3H), 3.18-3.06 (m, 2H), 3.01 (d, J=11.1Hz, 2H), 2.92 ( d, J=1.4Hz, 1H), 2.87 (s, 3H), 2.23 (s, 1H), 2.08 (t, J=11.5Hz, 2H), 1.76-1.59 (m, 4 H), 1.59-1.44 (m, 3H), 1.45-1.27 (m, 4H), 1.16-1.01 (m, 1H), 0.86 (d, J=6.6Hz, 6H).

[0256] Example 26: Synthesis of N-(2-(6,7-difluoro-1-(1-(cis-4-isopropylcyclohexyl)piperidin-4-yl)-2-oxo-1,4-dihydroquinazolin-3(2H)-yl)ethyl)ethanesulfonamide (32)

[0257] The intermediate 30a and ethylsulfonyl chloride were used as starting materials, and the synthesis method of Example 25 was followed. The final step was separated and purified (separation conditions were the same as in Example 1) to obtain 160 mg of a white solid, with a yield of 20.50%. LC-MS (ESI) m / z: 527.34 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ7.31 (t, J=9.6Hz, 1H), 7.18-7.05 (m, 2H), 4.28 (s, 2H), 3 .79-3.58(m, 1H), 3.33-3.21(m, 3H), 3.09(q, J=6.3Hz, 2H), 3.05-2.87(m, 5H), 2. 28-2.19 (m, 1H), 2.08 (t, J=11.6Hz, 2H), 1.76-1.60 (m, 4H), 1.60-1.47 (m, 3H), 1. 44-1.27 (m, 4H), 1.13 (t, J=7.3Hz, 3H), 1.10-1.03 (m, 1H), 0.86 (d, J=6.6Hz, 6H).

[0258] Example 27: Synthesis of N-(2-(1-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-6,7-difluoro-2-oxo-1,4-dihydroquinazolin-3(2H)-yl)ethyl)acetamide (33)

[0259] Intermediate 30c (1.23 g, 2.64 mmol) and 4,4-dimethylcyclohexanone (833 mg, 6.60 mmol) were used as starting materials, following the method of Example 24 to obtain 820 mg of a yellow solid in a yield of 67.16%. LC-MS (ESI) m / z: 463.57 (M+H) + ; 1 H NMR (600MHz, CDCl3) δ7.00 (s, 1H), 6.88 (dd, J=9.5, 8.2Hz, 1H), 6.49 (s, 1H), 4.1 9 (s, 2H), 4.02-3.76 (m, 1H), 3.54 (dd, J=6.9, 4.6Hz, 2H), 3.46 (dt, J=7.3, 4.9Hz , 2H), 3.24-2.94(m, 2H), 2.79-2.48(m, 2H), 2.48-2.17(m, 3H), 1.95(s, 3H), 1.8 9-1.72 (m, 4H), 1.46 (d, J=12.6Hz, 4H), 1.24-1.13 (m, 2H), 0.90 (d, J=4.1Hz, 6H).

[0260] Example 28: Synthesis of N-(2-(1-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-6,7-difluoro-2-oxo-1,4-dihydroquinazolin-3(2H)-yl)ethyl)ethanesulfonamide (34)

[0261] The intermediate 30a was synthesized from ethylsulfonyl chloride and 4,4-dimethylcyclohexanone according to the method of Example 25. The final step yielded 200 mg of a white solid in a 75.00% yield. LC-MS (ESI) m / z: 513.45 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ7.11 (s, 1H), 6.89 (t, J=8.8Hz, 1H), 5.21 (s, 1H), 4.26 (s, 2H ), 4.14 (s, 1H), 3.57 (t, J=5.7Hz, 2H), 3.35 (q, J=5.6Hz, 2H), 3.32-3.20 (m, 1H), 3. 01(q, J=7.4Hz, 2H), 2.93-2.69(m, 2H), 2.69-2.44(m, 2H), 2.05-1.65(m, 6H), 1.63 -1.42(m, 4H), 1.34(t, J=7.4Hz, 3H), 1.30-1.12(m, 2H), 0.92(s, 3H), 0.91(s, 3H).

[0262] Example 29: Synthesis of 1-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-3-((phenylsulfonyl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (36)

[0263] Synthesis of Intermediate 36a: To a clean, dry flask, add Intermediate 1e (500 mg, 1.41 mmol) and anhydrous DMF (7 mL). The atmosphere was purged with nitrogen three times. In an ice bath, 60% sodium hydroxide (170 mg, 4.26 mmol) was slowly added. The mixture was warmed to room temperature and stirred for 30 minutes. Chloromethylphenyl sulfide (125 mg, 2.13 mmol) was then added. Stirring was continued at room temperature for 16 hours. Completion of the reaction was confirmed by TLC. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporation under reduced pressure. The crude product was purified by column chromatography (mobile phase: petroleum ether and ethyl acetate, 1:1 volume ratio) to obtain 300 mg of a white solid in a 44.78% yield. LC-MS (ESI) m / z: 420.22 (M-tBu+H). + .

[0264] Synthesis of Intermediate 36b: To a clean, dry flask, intermediate 36a (300 mg, 0.61 mmol) and glacial acetic acid (3 mL) were added sequentially, and sodium perborate tetrahydrate (235 mg, 1.53 mmol) was slowly added while stirring at room temperature. After stirring at room temperature for 16 hours, TLC confirmed that the raw materials had essentially reacted completely. Aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then removed by rotary evaporation under reduced pressure to obtain 281 mg of a light yellow solid in a yield of 90.70%. LC-MS (ESI) m / z: 408.23 (M-Boc+H) + .

[0265] Synthesis of Intermediate 36c: To a clean, dry flask, intermediate 36b (280 mg, 0.55 mmol) was added, along with anhydrous dichloromethane (5 mL). Difluoroacetic acid (1 mL) was added dropwise at 0°C. After the addition was complete, the ice-water bath was removed and the reaction was stirred at room temperature for 12 hours. TLC monitoring confirmed that the starting materials had substantially reacted. The solvent was removed under reduced pressure on a rotary evaporator to obtain a crude product. Methyl tert-butyl ether (5 mL) was added to the crude product, which was dispersed, stirred, filtered, and dried to obtain 287 mg of a yellow solid (99.99% yield). The yellow solid was used directly in the next step without further purification.

[0266] Synthesis of Compound 36: To a clean, dry flask, intermediate 36c (203 mg, 0.39 mmol) and anhydrous 1,2-dichloroethane (5 mL) were added. Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, 4,4-dimethylcyclohexanone (123 mg, 0.96 mmol) was added. Acetic acid was added to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (298 mg, 1.17 mmol) was added. The reaction was allowed to proceed at 40°C for 24 hours, and completion of the reaction was confirmed by TLC. Saturated aqueous sodium bicarbonate (10 mL) was added to the reaction solution, stirred, and separated. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, 40:1 volume ratio) to obtain 115 mg of a white solid, with a yield of 57.07%. LC-MS (ESI) m / z: 518.53 (M+H) + ; 1H NMR (400MHz, CDCl3) δ7.81-7.74 (m, 2H), 7.67 (t, J=7.5Hz, 1H), 7.58 (dd, J=10.0, 6.7Hz, 1H), 7. 51 (t, J=7.7Hz, 2H), 7.04 (dd, J=9.5, 6.6Hz, 1H), 5.14 (s, 2H), 4.49-4.37 (m, 1H), 3.65 (d, J=10. 4Hz, 2H), 3.14 (t, J=12.3Hz, 1H), 3.05-2.79 (m, 4H), 1.95 (d, J=12.0Hz, 2H), 1.89-1.79 (m, 2H), 1.68-1.63 (m, 2H), 1.59 (d, J=13.8Hz, 2H), 1.32 (td, J=13.7, 3.5Hz, 2H), 0.95 (d, J=8.1Hz, 6H).

[0267] Example 30: Synthesis of 5,6-difluoro-1-((methylsulfonyl)methyl)-3-(1-(spiro[3.5]non-7-yl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (37)

[0268] To a clean, dry flask, intermediate 18c (0.95 g, 2.12 mmol) and anhydrous 1,2-dichloroethane (4 mL) were added. Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, spiro[3.5]nonan-7-one (0.44 g, 3.18 mmol) was added. Acetic acid was added to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (1.12 g, 5.30 mmol) was added. The reaction was allowed to proceed at 40°C for 24 hours, and completion of the reaction was confirmed by TLC. Saturated aqueous sodium bicarbonate (5 mL) was added to the reaction solution, stirred, and separated. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, 40:1 volume ratio) to obtain 220 mg of a white solid, with a yield of 21.30%. LC-MS (ESI) m / z: 468.33 (M+H) + ; 1H NMR (400MHz, CDCl3) δ7.71 (s, 1H), 7.15 (dd, J=9.3, 6.6Hz, 1H), 5.00 (s, 2H), 4.77-4.52 (m, 1H), 3.77-3.52 (m, 2H), 3.26-3.02 (m, 2H), 2.98 (s , 3H), 2.95-2.84(m, 2H), 2.07-1.92(m, 4H), 1.92-1.83(m, 2H), 1.82-1 .66 (m, 6H), 1.50 (q, J=12.2, 11.5Hz, 2H), 1.38 (q, J=13.1, 11.3Hz, 2H).

[0269] Example 31: Synthesis of 1-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-3-((methylsulfinyl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (19) and 1-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-3-((S-methylsulfonylimino)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (42)

[0270] Synthesis of intermediate 19b: To a clean, dry round-bottom flask were added intermediate 11b (200 mg, 0.55 mmol), acetonitrile (2.0 mL), K2CO3 (114 mg, 0.83 mmol), and chloromethyl methyl sulfide (64 mg, 0.66 mmol). The reaction mixture was stirred at 50°C for 2 hours. LCMS confirmed complete reaction of the starting material. Water (15 mL) and ethyl acetate (20 mL) were added to the reaction mixture for dilution, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4 and filtered, and the filtrate was evaporated under reduced pressure on a rotary evaporator to remove the solvent, yielding 210 mg of a brown crude product in a yield of 90.13%.

[0271] Synthesis of compound 19: To a clean, dry flask, intermediate 19b (200 mg, 0.47 mmol) and glacial acetic acid (3 mL) were added sequentially, and sodium perborate tetrahydrate (96 mg, 0.94 mmol) was slowly added while stirring at room temperature. After stirring at room temperature for 16 hours, TLC confirmed that the raw materials had essentially reacted completely. Aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was then removed by rotary evaporation under reduced pressure to obtain 150 mg of a yellow solid with a yield of 72.60%. LC-MS (ESI) m / z: 440.28 (M+H) + .

[0272] Synthesis of Intermediate 42a: Compound 19 (100 mg, 0.23 mmol) was added to a clean, dry flask. After nitrogen was replaced, anhydrous dichloromethane (1 mL), dimerized rhodium acetate (2.50 mg, 0.0057 mmol), trifluoroacetamide (52 mg, 0.46 mmol), magnesium oxide (37 mg, 0.92 mmol), and diacetoxyiodobenzene (113 mg, 0.35 mmol) were added. The mixture was stirred at room temperature for 16 hours. TLC monitoring confirmed that the starting materials had essentially reacted completely. The reaction solution was evaporated under reduced pressure on a rotary evaporator, and the crude product was purified by column chromatography (mobile phase: petroleum ether and ethyl acetate, volume ratio 1:4) to obtain 100 mg of a white solid in a yield of 79.37%. LC-MS (ESI) m / z: 551.32 (M+H). + .

[0273] Synthesis of Compound 42: To a clean, dry flask, add intermediate 42a (100 mg, 0.18 mmol), methanol (0.5 mL), and potassium carbonate (124 mg, 0.90 mmol). Stir at room temperature for 0.5 hours, and the reaction is confirmed to be complete by TLC. The reaction solution is filtered, and the filtrate is collected. The solvent is evaporated under reduced pressure on a rotary evaporator to obtain a light brown oily crude product. The crude product is purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio 30:1) to obtain 20 mg of a white solid, with a yield of 24.39%. LC-MS (ESI) m / z: 455.39 (M+H) + ; 1 H NMR (400MHz, DMSO-d6) δ7.58 (ddd, J=19.5, 10.8, 7.0Hz, 2H), 5.29-5.07 (m, 2H), 4.21-4.07 (m, 1H), 3.92 (s, 1H), 3.07-2.94 (m, 2H), 2.89 (s, 3H), 2.43-2.22 (m, 4H), 1.76-1.66 (m, 2H), 1.65-1.55 (m, 2H), 1.51-1.34 (m, 4H), 1.21-1.10 (m, 2H), 0.89 (d, J=2.6Hz, 6H).

[0274] Example 32: Synthesis of 2-(3-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethane-1-sulfonamide (43)

[0275] Synthesis of Intermediate 43c: To a clean, dry flask, anhydrous dichloromethane (30 mL), tert-butylamine (730 mg, 10.0 mmol), and triethylamine (3.54 g, 35.0 mmol) were added sequentially. The reaction system was cooled to 0°C, and 2-chloroethanesulfonyl chloride (1.63 g, 10.0 mmol) was added. Stirring was continued at 0°C for 2 h. TLC confirmed that the reaction was essentially complete. The reaction solution was diluted with dichloromethane and washed with saturated brine. The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated on a rotary evaporator under reduced pressure to remove the solvent, yielding 1.20 g of a colorless, transparent liquid in a yield of 73.62%.

[0276] Synthesis of Intermediate 43d: To a clean, dry flask were added Intermediate 11b (363 mg, 1.0 mmol), DMF (5 mL), potassium carbonate (207 mg, 1.5 mmol), and Intermediate 43c (196 mg, 1.2 mmol). The reaction system was heated to 70°C and stirred for 12 hours. TLC confirmed the substantial reaction of the starting materials. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, and filtered. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, which was purified by silica gel chromatography (mobile phase: dichloromethane and methanol, 30:1 volume ratio) to afford 460 mg of a white solid in an 87.29% yield. LC-MS (ESI) m / z: 527.39 (M+H). + .

[0277] Synthesis of Compound 43: Intermediate 43d (460 mg, 0.87 mmol) and dichloromethane (4 mL) were added sequentially to a clean, dry flask. The reaction system was cooled to 0°C, and trifluoroacetic acid (1 mL) was slowly added dropwise. After the addition was complete, the reaction solution was warmed to room temperature and stirred for 6 hours. TLC confirmed the near-complete reaction of the starting material. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. Saturated aqueous sodium carbonate solution was added to the crude product, and the product was extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and filtered. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio: 40:1 to 20:1) to obtain 280 mg of a white solid in a yield of 68.16%. LC-MS (ESI) m / z: 471.38 (M+H). + ; 1H NMR (400MHz, DMSO-d6) δ7.47 (dd, J=11.0, 7.0Hz, 1H), 7.39 (dd, J=10.7, 7.1H z, 1H), 6.96 (s, 2H), 4.18 (t, J=7.0Hz, 2H), 4.14-3.99 (m, 1H), 3.36 (t, J=7.0 Hz, 2H), 3.17 (d, J=5.2Hz, 1H), 3.07-2.81 (m, 2H), 2.29 (t, J=11.1Hz, 4H), 1. 76-1.51 (m, 4H), 1.48-1.35 (m, 4H), 1.28-1.13 (m, 2H), 0.88 (d, J=2.8Hz, 6H).

[0278] Example 33: Synthesis of 1-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-5,6-difluoro-3-(2-(S-methylsulfonylimino)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (44)

[0279] Synthesis of intermediate 44b: To a clean, dry round-bottom flask were added intermediate 11b (200 mg, 0.55 mmol), acetonitrile (2.0 mL), K2CO3 (114 mg, 0.83 mmol) and 2-chloroethyl methyl sulfide (73 mg, 0.66 mmol) in sequence. The reaction mixture was stirred at 50°C for 2 hours. LCMS confirmed the complete reaction of the starting material. Water (15 mL) and ethyl acetate (20 mL) were added to the reaction mixture for dilution, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4 and filtered, and the filtrate was distilled off under reduced pressure on a rotary evaporator to remove the solvent, affording 240 mg of a brown crude product in a 100% yield. LC-MS (ESI) m / z: 438.34 (M+H) + .

[0280] Synthesis of compound 44: To a clean, dry round-bottom flask were added intermediate 44b (240 mg, 0.55 mmol), methanol (2.0 mL), (NH4)2CO3 (79 mg, 0.82 mmol), and PhI(OAc)2 (406 mg, 1.26 mmol). The reaction mixture was stirred at 30°C for 2 hours. LCMS confirmed complete reaction. The solvent was removed by rotary evaporation under reduced pressure to afford the crude product, which was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio: 50:1 to 10:1) to afford 120 mg of a white solid in a 46.69% yield. LC-MS (ESI) m / z: 469.34 (M+H). + ; 1H NMR (400MHz, Methanol-d4) δ7.44 (dd, J=10.4, 7.1Hz, 1H), 7.37 (dd, J=9.9, 7.2Hz, 1H) , 4.59-4.52 (m, 1H), 4.47-4.34 (m, 2H), 3.71 (d, J=12.7Hz, 2H), 3.67-3.55 (m, 2H), 3.29 -3.21(m, 3H), 3.10(s, 3H), 2.89-2.79(m, 2H), 2.15-2.10(m, 2H), 2.03-1.98(m, 2H), 1 .82-1.72 (m, 2H), 1.64 (d, J=13.4Hz, 2H), 1.45-1.37 (m, 2H), 1.02 (s, 3H), 1.00 (s, 3H).

[0281] Example 34: Synthesis of 2-(5-chloro-3-(1-(4,4-dimethylcyclohexyl)piperidin-4-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-methylacetamide (47)

[0282] Synthesis of Intermediate 47b: To a clean, dry flask were added 1-chloro-2,4-difluoro-5-nitrobenzene (47a) (2.00 g, 10.33 mmol), acetonitrile (50 mL), N-Boc-4-aminopiperidine (2.07 g, 10.33 mmol), and potassium carbonate (2.14 g, 15.50 mmol). The reaction system was heated to 70°C and stirred for 12 h. TLC confirmed the substantial reaction of the starting materials. The reaction solution was cooled to room temperature, diluted with ice water, and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and filtered. The solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, which was purified by column chromatography (mobile phase: petroleum ether and ethyl acetate, volume ratio: 5:1) to afford 3.70 g of a yellow solid, in a yield of 95.81%. LC-MS (ESI) m / z: 374.25 (M+H). + .

[0283] Synthesis of intermediate 47c: Intermediate 47b (3.00 g, 8.03 mmol) was placed in a clean flask. Ethanol (80 mL) was added to the reaction flask. Iron powder (2.69 g, 48.18 mmol) and saturated aqueous NH4Cl solution (8 mL) were added to the reaction system while stirring at room temperature. The reaction system was heated to 80°C and stirred for 12 h. TLC was used to monitor the complete reaction of the starting materials. The reaction solution was cooled to room temperature, filtered through celite, and the filter cake was washed with a small amount of anhydrous ethanol. The filtrate was concentrated and the crude product was purified by column chromatography (mobile phase: petroleum ether and ethyl acetate, volume ratio: 5:1) to obtain 2.10 g of a white solid with a yield of 76.09%. LC-MS (ESI) m / z: 344.26 (M+H) + .

[0284] Synthesis of Intermediate 47d: Intermediate 47c (2.10 g, 6.11 mmol) and anhydrous tetrahydrofuran (30 mL) were placed in a clean, dry flask, the atmosphere was replaced with nitrogen, and N,N'-carbonyldiimidazole (1.19 g, 7.33 mmol) was added at 0°C. The mixture was stirred at room temperature for 12 hours, and the reaction was confirmed to be complete by TLC. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (mobile phase: petroleum ether and ethyl acetate, volume ratio 1:1) to obtain 2.00 g of a white solid, with a yield of 88.50%. LC-MS (ESI) m / z: 370.22 (M+H) + ; 1 H NMR (400MHz, CDCl3) δ9.40 (s, 1H), 7.11 (d, J = 6.0Hz, 1H), 6.94 (d, J = 8.5Hz, 1H), 4.41 (ddt, J = 12.6, 8.4, 4.1Hz , 1H), 4.33 (d, J=13.6Hz, 2H), 3.00-2.73 (m, 2H), 2.26 (qd, J=12.7, 4.6Hz, 2H), 1.90-1.74 (m, 2H), 1.52 (s, 9H).

[0285] Synthesis of Intermediate 47e: To a clean, dry flask, add Intermediate 47d (2.00 g, 5.41 mmol) and THF (10 mL). The atmosphere was replaced with nitrogen. 60% NaH (0.65 g, 16.23 mmol) was slowly added at 0°C and stirred for 0.5 h. 2-Chloro-N-methylacetamide (0.70 g, 6.49 mmol) was then added. The mixture was stirred at room temperature for 16 h, and the reaction was confirmed to be complete by TLC. Water was added dropwise at 0°C to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated on a rotary evaporator under reduced pressure to remove the solvent, yielding 2.16 g of a white solid in a 90.38% yield. LC-MS (ESI) m / z: 441.14 (M+H)+ .

[0286] Synthesis of Intermediate 47f: To a clean, dry flask, intermediate 47e (2.16 g, 4.90 mmol) was added, along with anhydrous dichloromethane (20 mL). Trifluoroacetic acid (5 mL) was added dropwise at 0°C. After the addition was complete, the ice-water bath was removed and the reaction was stirred at room temperature for 4 hours. TLC confirmed the substantial reaction of the starting material. The solvent was removed under reduced pressure on a rotary evaporator to afford a light brown oily crude product. Ether (50 mL) was added to the crude product, which was dispersed, stirred, filtered, and dried to afford 2.22 g of a yellow solid (100% yield). The yellow solid was used directly in the next step without further purification.

[0287] Synthesis of Compound 47: To a clean, dry flask, intermediate 47f (2.22 g, 4.90 mmol) and anhydrous 1,2-dichloroethane (10 mL) were added. Triethylamine was added dropwise to adjust the pH to approximately 8. After stirring for 10 minutes, 4,4-dimethylcyclohexanone (1.55 g, 12.25 mmol) was added. Acetic acid was added to adjust the pH to approximately 5. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (3.12 g, 14.70 mmol) was added. The reaction was allowed to proceed at 40°C for 16 hours, and completion of the reaction was confirmed by TLC. The solvent was removed under reduced pressure on a rotary evaporator, and the crude product was purified by column chromatography (mobile phase: dichloromethane and methanol, volume ratio 20:1) to obtain 1.40 g of a white solid in a yield of 63.35%. LC-MS (ESI) m / z: 451.32 (M+H). + ; 1 H NMR (400MHz, Chloroform-d) δ7.93 (s, 1H), 6.89 (d, J = 8.3Hz, 1H), 6.07 (s, 1H), 4.76-4.59 (m, 1H), 4.45 (s, 2H), 3.69 (d, J = 11.8Hz, 2H), 3.29-3.05 (m, 3H ), 3.04-2.91 (m, 2H), 2.83 (d, J = 4.8Hz, 3H), 2.08-1.96 (m, 4H), 1.72 (d, J = 12 .6Hz, 2H), 1.61 (d, J=13.7Hz, 2H), 1.41-1.28 (m, 2H), 0.96 (d, J=5.4Hz, 6H).

[0288] Biological activity test

[0289] Experimental Example 1: Test of the affinity of the compounds of the present invention for MOR, NOPr (ORL-1 receptor) and KOR:

[0290] Experimental Materials

[0291] (1) Main equipment: Electric constant temperature incubator (Shanghai YIHE), microplate counter (Universal Harvester, Perkin Elmer), microplate shaker (VWR), microtiter 384-well plate (Corning), 96-well plate (Perkin Elmer)

[0292] (2) Main reagents: cell membrane containing human MOR, KOR or NOPr (Perkin Elmer); DAMGO, [Tyrosyl-3,5- 3 H(N)](PerkinElmer) and DAMGO(MCE),[ 3 H]-U-69593 (PerkinElmer) and naltrexone hydrochloride (Sigma), [ 3 [H]-Nociceptin (PerkinElmer) and nociceptin (1-13) amide (Sigma); polyethyleneimine (PEI, Sigma), bovine serum albumin (BSA, Sigma), HEPES buffer (Sigma), ULTIMA GOLD scintillation fluid (Perkin Elmer), tris (hydroxymethyl)aminomethane (Tris-base, Sigma)

[0293] Experimental methods

[0294] (1) Solution preparation

[0295] Standard buffer: 50 mM HEPES pH 7.4 + 0.025% BSA

[0296] Wash buffer: 50 mM Tris pH 7.4

[0297] 0.5% PEI solution: 0.5 mL PEI + 100 mL ddH2O

[0298] Solvent system: DMSO:ddH2O=1:99 (volume ratio)

[0299] Test samples: compounds of the present invention, positive controls (DAMGO, naltrexone hydrochloride, Nociceptin (1-13) amide), vehicle controls

[0300] (2) Radioligand binding assay:

[0301] a. Add 5 μL of test samples of different concentrations and 100 μL of standard buffer to a 96-well plate and mix well (500 rpm / min, 5 min).

[0302] b. Add 1 μL of a suspension containing MOR, KOR, or NOPr membrane solution and 299 μL of standard buffer to each well; mix thoroughly (500 rpm / min, 5 min).

[0303] c. Add 100 μL of [ 3 H]-DAMGO to a final concentration of 1 nM (or 100 μL of [ 3 H]-U-69593 to a final concentration of 1.5 nM; or 100 μL of 3 H-Nociceptin was added to achieve a final concentration of 0.5 nM), centrifuged at 500 rpm / min for 5 min to mix, and then incubated at 27°C for 60 min;

[0304] d. Preincubate the UNIFILTER-96GF / B filter plate with 0.5% PEI at 4°C for 1 hour, and rinse the UNIFILTER-96GF / B filter plate (0.5% PEI) twice with 1 mL of washing buffer. Then transfer the mixture containing the cell membranes to the UNIFILTER-96GF / B filter plate (0.5% PEI) and wash it four times with 50 mL of washing buffer each time.

[0305] e. Dry at 55°C for 10 minutes.

[0306] f. Add 40 μL of ULTIMA GOLD scintillation fluid to each well and read the scintillation count using a Universal Harvester to determine the radioactivity bound to the membrane.

[0307] Each test compound was tested at 10 concentrations for its binding efficiency (% inhibition rate), and its IC 50 (Concentration at which 50% of binding is inhibited) is determined by plotting the logarithm of the concentration on the X-axis and the response counts on the Y-axis. Data were processed using Xl-fit 5.3.1 software. Nonlinear regression equation:

[0308] X = logarithm of compound concentration;

[0309] Y = percent inhibition (% inhibition);

[0310] Maximum and minimum values: Y values ​​at the top and bottom platforms of the curve;

[0311] LogIC 50 : The same logarithmic unit as the X-axis;

[0312] Hill coefficient: slope factor or Hill coefficient.

[0313] The ability of the representative compounds of the present application to bind to the receptor cell membrane is determined by radiolabeling [ 3H]-DAMGO (PerkinElmer), [ 3 H]-Nociceptin (PerkinElmer), [ 3 H]-U69593 (PerkinElmer) was used as an alternative ligand, and the Ki value was determined by the formula Ki = IC 50 / (1+L / Kd), where Kd is [ 3 H]-radioligand binding affinity, L is the binding affinity of the radioligand using [ 3 The experimental results are shown in Table 1 below, where " / " indicates no test data.

[0314] Table 1 Affinity K of the compounds of the present invention i Value and selectivity

[0315] Conclusion: The above affinity test results show that the compounds of the present invention exhibit high affinity and high selectivity for NOPr.

[0316] Experimental Example 2: Determination of the agonist function of the compounds of the present invention on MOR, NOPr, and KOR (cAMP method)

[0317] Opioid receptors are G protein-coupled receptors that mainly interact with G i When it is activated by binding to the ligand, it can be coupled to the protein through G i Proteins inhibit adenylate cyclase activity, thereby reducing intracellular cAMP levels. A cAMP assay (PerkinElmer) was used to assess the agonist or inhibitory effects of compounds on three opioid receptors (MOR, KOR, and NOPr). The cAMP assay is a competitive immunoassay used to measure intracellular cAMP accumulation. The measured signal is inversely correlated with cAMP concentration.

[0318] Experimental Materials

[0319] (1) Main equipment: EnVision multi-function plate reader (PerkinElmer), microplate 384-well plate (PerkinElmer)

[0320] (2) Main reagents: Fetal bovine serum (FBS, AUS Gene X), F12 culture medium (Hyclone), Penicillin-Streptomycin solution 100× (Gibco), Hygromycin B Gold (HB, Invivogen), Forskolin (adenylate cyclase activator, Selleck), Bovine serum albumin (BSA, PerkinElmer), IBMX (Sigma), cAMP kit (PerkinElmer), HEPES buffer (Gibco), HBSS buffer (Sigma), Endomorphin 1 (MCE), Dynorphin A1-10 (MCE), Nociceptin (MCE)

[0321] (3) Cell line: Human embryonic kidney 293 cells stably expressing human MOR, KOR, or NOPr (293-MOR, 293-KOR, 293-NOPr)

[0322] Experimental methods

[0323] (1) Cell culture and reagent preparation

[0324] Complete culture medium: DMEM + 10% FBS + 5% double antibody solution + 200 μg / mL HB

[0325] Buffer: 1×HBSS + 20 mM HEPES + 0.1% BSA + 500 μM IBMX

[0326] Solvent system: The test compound is dissolved in DMSO to form a stock solution of different concentrations and diluted with buffer before testing

[0327] Test compounds: compounds of the present invention, positive controls (Endomorphin 1, Dynorphin A1-10, Nociceptin), vehicle control (DMSO)

[0328] (2) cAMP test

[0329] a. Resuspend 293-MOR, 293-KOR, or 293-NOPr cells in buffer to a density of 20,000 cells / well and seed into a 384-well plate.

[0330] b. Prepare 8× drug-containing solution using buffer;

[0331] c. Add 2.5 μL of 8× drug solution to the cell plate and incubate at 37°C for 10 min;

[0332] d. Prepare 8× forskolin solution (8 μM) in assay buffer;

[0333] e. Add 2.5 μL of 8× forskolin solution to the cell plate and incubate at 37°C for 30 min.

[0334] f. Dilute the cAMP tracer (1:50) according to the cAMP kit instructions and add 10 μL to each well of the cell plate;

[0335] g. Dilute Ulight-anti-cAMP (1:50) according to the cAMP kit instructions and add 10 μL to each well of the cell plate;

[0336] h, incubate at room temperature for 1 h;

[0337] j. Read the absorbance at 665 nm and 615 nm on the EnVision multi-function plate reader

[0338] Data Analysis

[0339] (1) The relative activity of the test compound is calculated as follows:

[0340] % Activity = (Signal cmpd -Signal ave_VC )(Signal ave_PC -Signal ave_VC )×100

[0341] Signal cmpd : Absorbance signal of the test compound

[0342] Signal ave_VC : Absorbance signal of the normal group, without drug and Forskolin

[0343] Signal ave_PC : Absorbance signal of control group, without drug, with Forskolin

[0344] (2) Calculation of EC 50 And draw the effect dose curve of the test compound:

[0345] Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)*HillSlope))

[0346] X: logarithm of agonist concentration; Y: % activity.

[0347] According to the above method, the compounds of the present application were tested, "NA" indicates no test data, and the results are shown in Table 2 below:

[0348] Table 2 EC values ​​of the compounds of the present invention 50 value

[0349] Conclusion: The above cAMP agonist function test results show that the compounds of the present invention have high affinity for NOPr and also show good agonist biological activity (E max >80%), is a full agonist of NOPr, and has good selectivity.

[0350] Experimental Example 3: Pharmacodynamics test of the compound of the present invention in formalin-induced inflammatory pain model

[0351] 1. Experimental Principle

[0352] A 2% formalin solution was injected subcutaneously into the dorsal surface of the rat's left hind paw using a microinjection needle. This produced a sustained noxious stimulus, causing the animals to exhibit spontaneous pain behavioral responses (such as paw lifting and licking). During the experiment, the number of paw lifting and licking events was recorded using a locomotor activity analyzer to assess the severity of pain.

[0353] 2. Experimental instruments and reagents

[0354] Morphine: Shenyang No. 1 Pharmaceutical Co., Ltd., Northeast Pharmaceutical Group; DMSO: Hubei Xingfa Chemical Group Co., Ltd.; HS-15: Cencord; 0.9% NaCl injection: Wuhan Binhu Shuanghe Pharmaceutical Co., Ltd.; formaldehyde: Xilong Science Co., Ltd.; electronic balance: Shanghai Ranhao Electronics Co., Ltd. (JCS-51002C); spontaneous motion analyzer: Anhui Zhenghua Biological Instrument Equipment Co., Ltd. (ZH-PAN801).

[0355] 3. Solution preparation and administration

[0356] The test substance (compound of the present invention) was prepared in a vehicle formulation of 5% DMSO + 10% HS-15 + 85% 0.9% sodium chloride injection, with a 0.2 mg / mL drug solution prepared prior to administration at a volume of 5 mL / kg, administered as a single subcutaneous (sc) dose. The control substance, morphine, was prepared in a vehicle formulation of 0.9% sodium chloride injection, with a 0.6 mg / mL drug solution prepared prior to administration at a volume of 5 mL / kg, administered as a single subcutaneous dose.

[0357] 4. Experimental process

[0358] (1) Adaptive feeding

[0359] SPF male Sprague-Dawley rats were purchased from Hunan Slake Jingda Laboratory Animal Co., Ltd. (Laboratory Animal Production License No.: SCXK(Xiang)2019-0004). After acclimating for 4 days, the rats were transferred from the feeding room to the laboratory each morning. A training diaper was placed on the laboratory table, and a transparent white cylinder was placed on the training diaper. Each rat was weighed and placed in the transparent white cylinder for acclimation to the test environment for ≥1 hour, and for at least 3 consecutive days.

[0360] (2) Analgesic activity test of the test substance

[0361] After the rats have been continuously adapted to the experimental environment for 3 days, the tail roots of rats weighing 220-240g are numbered; rats that do not meet the weight standard are continued to be raised until the weight standard is met. 30min before the formal test, a metal sheet is affixed to the left hind foot of the rat, and the rats are placed in a transparent white cylinder for adaptation. 15min before the test, a single subcutaneous injection of the control substance Morphine (3mg / kg) and the representative compound of the present invention (test compound, animal grouping, administration method and administration dosage are shown in the table below) are given, and then formalin is used for modeling (the blank control group is not injected with formalin). After formalin modeling, the animal is immediately placed in an autonomous movement analyzer instrument, which automatically records the number of times the rat retracts its foot, lifts its foot, licks its foot, etc., and statistically analyzes the data from 0-60min after formalin injection.

[0362] (3) Detection indicators

[0363] After formalin was injected subcutaneously into the dorsal portion of the left hind paw of rats, the rats were placed in a test box. The number of movements (number of times the injected paw was lifted and licked) from 0 to 60 minutes after the formalin injection was recorded and analyzed, and the MPE% (Maximum Possible Effect, expressed as a percentage) was calculated.

[0364] MPE% = [(Vehicle-Sham) - (Administration group-Sham)] / (Vehicle-Sham) × 100%

[0365] Notes: ① MPE percentages for each group were calculated using the sham (model) group MPE = 100% and the vehicle (blank control) group MPE = 0%. ② The number of movements in the sham group was subtracted to eliminate the influence of background noise. ③ sham represents the mean of the sham group; (vehicle-sham) represents (mean of vehicle group minus mean of sham group).

[0366] (4) Data collection and statistical analysis

[0367] The results and data of the measurements and observations were entered into an Excel spreadsheet for statistical analysis. Each indicator was expressed as mean ± standard deviation, and one-way ANOVA was used to compare whether there were any statistical differences between the groups. A statistically significant difference was considered when p < 0.05.

[0368] 5. Test results

[0369] Table 3 Analgesic activity of the compounds of the present invention in the formalin-induced inflammatory pain model Note: **, P < 0.01; ***, P < 0.001; ****, P < 0.0001;

[0370] The above experimental results show that the representative compounds of the present invention have a good inhibitory effect on formalin-induced inflammatory pain.

[0371] Experimental Example 4: Effects of the compounds of the present invention on gastrointestinal motility in SD rats

[0372] 1. Experimental Principle

[0373] The speed at which digestive tract contents migrate is related to gastric emptying time, small intestinal motility, and the fluidity of digestive tract contents. Drugs that promote or inhibit gastrointestinal motility can alter gastrointestinal motility, thereby affecting the rate at which contents migrate through the intestine. Charcoal suspensions are not absorbed in the intestine. Using charcoal as an indicator, the effect of a test drug on gastrointestinal motility can be observed by measuring the distance it travels through the intestine over a given period of time.

[0374] 2. Experimental instruments and reagents

[0375] Morphine: Shenyang No. 1 Pharmaceutical Co., Ltd. of Northeast Pharmaceutical Group; DMSO: Hubei Xingfa Chemical Group Co., Ltd.; HS-15: Cencord; 0.9% NaCl injection: Wuhan Binhu Shuanghe Pharmaceutical Co., Ltd.; carbon powder: Jiangsu Kanghong Carbon Co., Ltd.; gum arabic: Tai'an Dingli Glue Co., Ltd.; electronic balance: Shanghai Ranhao Electronics Co., Ltd. (JCS-51002C).

[0376] 3. Solution preparation and administration

[0377] Preparation of 10% charcoal suspension: Weigh 1.5g of gum arabic, add 88.5mL of water, stir to dissolve, then add 10g of charcoal powder, stir thoroughly to make a uniform suspension and set aside.

[0378] The solvent formula of the compounds of the present invention is 5% DMSO + 10% HS-15 + 85% 0.9% sodium chloride injection, which are respectively prepared into 0.2, 0.6, and 2 mg / mL drug solutions before administration, with a dosing volume of 5 mL / kg and a single subcutaneous administration.

[0379] The solvent of the reference substance morphine was 0.9% sodium chloride injection, which was prepared into a 0.6 mg / mL drug solution before administration. The administration volume was 5 mL / kg, and it was administered subcutaneously as a single dose.

[0380] 4. Experimental process

[0381] (1) Adaptive feeding

[0382] SPF male Sprague-Dawley rats were purchased from Hunan Slake Jingda Laboratory Animal Co., Ltd. (Laboratory Animal Production License No.: SCXK(Xiang)2019-0004) and housed in groups of six. All experimental animals were housed in a cage for 5 days before the experiment to acclimate them to the breeding environment. The ambient temperature was maintained at 18-26°C, the humidity was 40-70%, and sufficient water and feed were provided. A 12-hour day and night cycle was maintained.

[0383] (2) Experimental operation

[0384] Grouping: All rats were fasted for 20 hours the day before the experiment and had free access to water. After randomization, the rats were numbered and divided into model group, positive control group, and low, medium, and high doses of the test substance, with 6 rats in each group.

[0385] Modeling and Dosing: The positive control group received morphine (3 mg / kg) and each dose group of the compound of the present invention subcutaneously. The model group received an equal volume of vehicle (dosing volume was 5 mL / kg). 15 minutes later, each group was gavaged with a 10% charcoal suspension (10 mL / kg). 60 minutes later, the rats were sacrificed, the abdominal cavity was opened, and the intestinal tract from the pylorus to the ileocecal region was excised and placed on a tray. The small intestine was straightened, and the distance traveled by the contents (charcoal) and the total length of the small intestine were accurately measured using a ruler to calculate the charcoal propulsion rate.

[0386] (3) Detection indicators

[0387] The charcoal powder migration distance and the total length of the small intestine in each group were used to calculate the charcoal powder propulsion rate, and the differences in the charcoal powder propulsion rates among the groups were compared to determine the effects of the drug on the gastrointestinal motility of rats.

[0388] Charcoal powder advancement rate (%) = [charcoal powder moving distance (cm) / total length of small intestine (cm)] × 100%.

[0389] (4) Data collection and statistical analysis

[0390] The measured data were entered into an Excel spreadsheet and statistically analyzed. Each index was expressed as mean ± standard deviation, and one-way ANOVA was used to compare whether there were any statistical differences between the groups. P < 0.05 was considered statistically significant.

[0391] 5. Conclusion

[0392] The positive control morphine (3 mg / kg) had a significant inhibitory effect on the gastrointestinal motility of rats. At a dose having the same analgesic activity as 3 mg / kg morphine, the example compounds of the present invention had no significant effect on the gastrointestinal motility of rats.

[0393] Although the embodiments disclosed in this application are as described above, the contents described are merely embodiments adopted to facilitate understanding of this application and are not intended to limit this application. Any person skilled in the art to which this application belongs may make any modifications and changes in the form and details of the implementation without departing from the spirit and scope disclosed in this application, but the scope of protection of this application shall still be based on the scope defined by the appended claims.

Claims

1. A compound represented by the general formula (I), its stereoisomers or its pharmaceutically acceptable salts; Wherein, R 1 and R 2 each independently selected from hydrogen, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, provided that R 1 and R 2 are not both hydrogen at the same time; R 3 selected from -C(O)NR a R b 、 -S(O)2NR a R b 、 -S(O)(NR a )R b 、 -S(O)R c 、 -S(O)2R c 、 -NHS(O)2R c 、 -NHC(O)R d 、 -C(O)OR d 、 a 5- to 10-membered heteroaryl group, wherein the 5- to 10-membered heteroaryl group is optionally substituted with one or more R e substituents; R 4 and R 5 each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, or R 4 and R 5 and the carbon atom to which they are attached together form a C 3-8 cycloalkyl, or R 4 and R 5 and the carbon atom to which they are attached together form a 3- to 8-membered heterocyclic group, R 4 and R 5 may be the same or different, provided that R 4 and R 5 are not both hydrogen at the same time, where the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and 3- to 8-membered heterocyclic group are each optionally substituted by one or more R'; X 1 and X 2 each independently selected from N and Cr f ; L 1 Selected from a single bond and -CR g R h -; L 2 selected from C 1-6 alkylene, said C 1-6 alkylene optionally being substituted by one or more R m substituents; Y is selected from O and S; R a and R b each independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, -(CH2) n -C 3-6 cycloalkane, -(CH2) n -OH, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, -(CH2) n -C 3-6 cycloalkane, -(CH2) n -OH are each optionally substituted by one or more R', and R a and R b may be the same or different; Each R c is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, -(CH2) n -C 3-6 cycloalkane, -(CH2) n -C6 -10 arene, where the C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, -(CH2) n -C 3-6 cycloalkane, -(CH2) n -C6 -10 arene is each optionally substituted by one or more R'; Each R d is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, -(CH2) n- C 3-6 cycloalkane, where the C 1-6 alkyl, C 3-6 cycloalkyl, -(CH2) n -C 3-6 cycloalkane is each optionally substituted by one or more R'; R e and R f each independently selected from hydrogen, halogen, C 1-3 alkyl, -O-C 1-3 alkane, where the C 1-3 alkyl, -O-C 1-3 alkane is each optionally substituted by one or more R'; R g 、R h and R m each independently selected from hydrogen, halogen, C 1-3 alkyl, where the C 1-3 alkyl is optionally substituted by one or more R'; each R' is independently selected from H, F, Cl, Br, and I; n is an integer of 1, 2, or 3.

2. The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein, R 1 and R 2 each independently selected from hydrogen, halogen, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, provided that: R 1 and R 2 are not both hydrogen; or, R 1 and R 2 each independently selected from hydrogen, halogen, C 1-3 alkyl, provided that: R 1 and R 2 are not both hydrogen; or, R 1 and R 2 each is independently halogen; or, R 1 and R 2 are both fluorine or chlorine, or, R 1 is chlorine and R 2 is fluorine, or, R 1 is fluorine and R 2 is chlorine; or, R 1 is chlorine and R 2 is methoxy.

3. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, R 3 selected from -C(O)NR a R b 、-S(O)2NR a R b 、-S(O)R c 、-S(O)2R c 、-NHS(O)2R c 、-NHC(O)R d 、-C(O)OR d and 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted by one or more R e ; or, R 3 is -C(O)NR a R b ; or, R 3 is -S(O)2NR a R b ; or, R 3 is -S(O)(NR a )R b ; or, R 3 is -S(O)R c ; or, R 3 is -S(O)2R c ; or, R 3 is -NHS(O)2R c ; or, R 3 is -NHC(O)R d ; or, R 3 is -C(O)OR d ; or, R 3 is 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is optionally substituted by one or more R e substituted.

4. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 3, wherein, R 3 selected from -C(O)N(CH3)2, -C(O)NH2, -C(O)NHOH, -S(O)2NH2, -S(O)2N(CH3)2, -S(O)(NH)CH3, -S(O)CH3, -S(O)CH2CH3, -S(O)2CH3, -S(O)2CH2CH3, -S(O)2CH(CH3)2, -C(O)NHCH2CH2OH, -C(O)NHCH3, -C(O)NHCH2CH3, -NHC(O)CH3, -NHC(O)CH2CH3, -C(O)OCH2CH3, -S(O)2-Ph, -S(O)2CH2-Ph, -NHS(O)2CH3, -NHS(O)2CH2CH3; or, R 3 selected from -C(O)NHCH3, -S(O)2N(CH3)2, -S(O)CH3, -S(O)2CH3, -S(O)2CH2CH3, -NHS(O)2CH3, -NHS(O)2CH2CH3, -NHC(O)CH3, -NHC(O)CH2CH3.

5. A compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein, R 4 and R 5 each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, or R 4 and R 5 and the carbon atom to which they are attached together form a C 3-6 cycloalkyl, or R 4 and R 5 and the carbon atom to which they are attached together form a 3- to 6-membered heterocyclic group, R 4 and R 5 may be the same or different, provided that R 4 and R 5 are not both hydrogen at the same time. Here, the C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl and 3- to 6-membered heterocyclic group are each optionally substituted by one or more R'; or, R 4 is hydrogen, R 5 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy. Here, the C 1-6 alkyl, C 1-6 alkoxy are each optionally substituted by one or more R'; or, R 5 is hydrogen, R 4 is selected from halogen, C 1-6 alkyl and C 1-6 alkoxy. Here, the C 1-6 alkyl, C 1-6 alkoxy are each optionally substituted by one or more R'; or, R 4 and R 5 are each independently halogen; or, R 4 and R 5 are each independently C 1-6 alkyl. Here, the C 1-6 alkyl is optionally substituted by one or more R'; or, R 4 , R 5 are each independently C 1-6 alkoxy. Here, the C 1-6 alkoxy are each optionally substituted by one or more R'; or, R 4 and R 5 and the carbon atom to which they are attached together form a C 3-6 cycloalkyl. Here, the C 3-6 cycloalkyl is optionally substituted by one or more R'; or, R 4 and R 5 Together with the attached carbon atom, they form a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is optionally substituted with one or more R'.

6. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 5, wherein, R 4 and R 5 each independently selected from hydrogen, halogen, C 1-6 alkyl, or R 4 and R 5 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, or R 4 and R 5 together with the carbon atom to which they are attached form a 3- to 6-membered heterocyclic group, R 4 and R 5 may be the same or different, provided that R 4 and R 5 are not both hydrogen at the same time; or, R 4 and R 5 each independently selected from hydrogen, halogen, C 1-3 alkyl, or R 4 and R 5 together with the carbon atom to which they are attached form a C 3-4 cycloalkyl, or R 4 and R 5 together with the carbon atom to which they are attached form a 3- to 4-membered heterocyclic group, R 4 and R 5 may be the same or different, provided that R 4 and R 5 are not both hydrogen at the same time; or, R 4 and R 5 are both methyl, or, R 4 and R 5 one of them is isopropyl and the other is hydrogen, or, R 4 and R 5 together with the carbon atom to which they are attached form cyclopropyl, or, R 4 and R 5 together with the carbon atom to which they are attached form cyclobutyl, or, R 4 and R 5 together with the carbon atom to which they are attached form oxetanyl.

7. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein, X 1 and X 2 are each independently selected from N and CH; or, X 1 and X 2 are both N; or, X 1 is N and X 2 is CH; or, X 2 is N and X 1 is CH; or, X 1 and X 2 are both CH.

8. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein, L 1 is a single bond; alternatively, L 1 is -CR g R h -; alternatively, L 1 is selected from -CH2-.

9. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein, L 2 selected from C 1-3 alkylene, said C 1-3 alkylene is optionally substituted by one or more R m substituents; or, L 2 is selected from -CH2-, -CH2CH2- and -CH(CH3)-.

10. A compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein, Y is O; or, Y is S; and / or R a and R b one of which is selected from hydrogen, and the other is selected from hydroxy, C 1-3 alkyl, C 3-6 cycloalkyl, -(CH2) n -C 3-6 cycloalkane, -(CH2) n -OH, wherein the C 1-3 alkyl, C 3-6 cycloalkyl, -(CH2) n -C 3-6 cycloalkane, -(CH2) n -OH are each optionally substituted by one or more R'; or, R a and R b one of which is selected from hydrogen, and the other is selected from methyl, ethyl, cyclopropyl, cyclopropylmethyl, hydroxy and hydroxyethyl; or, R a and R b are both C 1-3 alkyl; or, R a and R b are both hydrogen; and / or Each R c is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, benzyl and phenyl; and / or Each R d is independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl and cyclopropylmethyl; and / or R e and R f each independently is hydrogen; or, R e and R f each independently is a halogen; or, R e and R f each independently is a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted with one or more R'; or, R e and R f each independently is -O-C 1-3 alkane, and the -O-C 1-3 alkane is optionally substituted with one or more R'; or, R e and R f each independently is selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy, trifluoromethyl and trifluoromethoxy; and / or R g , R h and R m are each independently selected from hydrogen, fluorine and methyl; or, R g , R h and R m are each independently hydrogen; or, R g , R h and R m are each independently fluorine; or, R g , R h and R m each independently is methyl; and / or each R' is independently selected from H, F, Cl, and Br; or, each R' is independently selected from H, F, and Cl; and / or n is 1; or, n is 2; or, n is 3.

11. The compound, its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 10, which is selected from one of the following chemical structural formulas: Optionally, selected from one of the following chemical structural formulas:

12. The method for preparing the compound according to claim 1, its stereoisomer, or its pharmaceutically acceptable salt, said preparation method comprising the following steps: (1) The compound of formula (I-1) undergoes a substitution reaction with the compound of formula (I-2) to obtain the compound of formula (I-3); (2) The compound of formula (I-3) undergoes a deprotection reaction to obtain the compound of formula (I-4), and then a reductive amination reaction is carried out with the compound of formula (I-5) to obtain the compound of formula (I); Or, The compound of formula (I-6) undergoes a reductive amination reaction with the compound of formula (I-5) to obtain the compound of formula (I-7); The compound of formula (I-7) undergoes a substitution reaction with the compound of formula (I-2) to obtain the compound of formula (I); In the above preparation method, Y in formula (I-2) 1 represents a leaving group; Pr in formulas (I-1) and (I-3) represents an amino protecting group; the definitions of other groups in formulas (I-1) to (I-7) and formula (I) are as described in claim 1.

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, its stereoisomer, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

14. The compound according to any one of claims 1 to 11, its stereoisomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 13, for use as a medicine.

15. The compound according to any one of claims 1 to 11, its stereoisomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 13, for use in the treatment and / or prevention of diseases related to the NOP receptor.

16. Use of the compound according to any one of claims 1 to 11, its stereoisomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 13, in the manufacture of a medicament for the treatment and / or prevention of diseases related to the NOP receptor.

17. A method for treating and / or preventing diseases related to the NOP receptor, said method comprising administering to an individual in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 11, its stereoisomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 13.

18. The compound, its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition for use in the treatment and / or prevention of a disease associated with the NOP receptor as claimed in claim 15, or the use as claimed in claim 16, or the method as claimed in claim 17, wherein, The diseases related to the NOP receptor are selected from pain, cough, sleep disorder, hypertension, urinary incontinence, epilepsy, traumatic injury, eating disorder, anxiety, depression, alcohol addiction, drug withdrawal syndrome, memory loss caused by Alzheimer's disease or other dementia, preferably pain; optionally, the pain is selected from postoperative pain, pain caused by cancer, neuropathic pain, traumatic pain, and pain caused by inflammation.

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