Azetidine derivative as well as preparation method and medical application thereof

Abstract

The invention relates to an azetidine derivative, a preparation method thereof, an intermediate, a composition containing the azetidine derivative and application of the azetidine derivative in the field of medicine. Particularly, the invention relates to an azetidine derivative shown in a general formula I, a preparation method and an intermediate of the azetidine derivative, a pharmaceutical composition containing the azetidine derivative, and application of the azetidine derivative or the pharmaceutical composition of the azetidine derivative as an M4 receptor modulator in preparation of drugs for preventing and / or treating M4 receptor related diseases.

Description

Azacyclobutane derivatives, their preparation methods and pharmaceutical uses

[0001] This application claims Chinese patent application 202311178485.9, filed on September 13, 2023, and the application date... Priority is claimed for Chinese patent application 202410714094.2 dated June 4, 2024, the entire contents of which are incorporated herein by reference. For reference only.

[0002] This invention belongs to the pharmaceutical field, specifically relating to azacyclobutane derivatives, their preparation methods, intermediates, compositions containing them, and their applications in the pharmaceutical field.

[0003] Patients with schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, and various other neurodegenerative disorders often suffer from behavioral and cognitive impairments, leading to debilitating disruptions to their daily lives. Over the years, numerous pharmacological treatments have been discovered that offer some improvement in patients' behavior and cognitive function.

[0004] To discover new and improved pharmacological therapies, researchers began to consider muscarinic acetylcholine receptors (mAChRs) as a viable mechanism. Muscarinic acetylcholine receptors are G protein-coupled receptors (GPCRs) composed of five subtypes called M1, M2, M3, M4, and M5. Five mAChR subtypes (M1–M5) have been identified and are part of the G protein-coupled receptor (GPCR) superfamily. These subtypes are widely distributed throughout the peripheral and central nervous systems, with M1 and M4 subtypes primarily expressed in the CNS. The M4 receptor couples to Gi and is primarily expressed in the cerebral cortex, striatum, hypothalamus, and hippocampus (Lebois, et al., Neurop Harmacology 2018, 136, 362–373).

[0005] It is well known that cholinergic neurotransmission plays a crucial role in cognitive function. However, cholinergic receptor antagonists have been shown to cause severe memory impairment, while acetylcholinesterase inhibitors such as donepezil have demonstrated cognitive-enhancing effects in Alzheimer's disease. In schizophrenia, a high dopaminergic state in the striatum and nucleus accumbens is associated with psychosis. Most antipsychotics improve symptoms by antagonizing dopamine D2 receptors, and this is currently the target of antipsychotic drugs that block dopamine D2 receptors.

[0006] A clinical study of 345 Alzheimer's patients showed that the M1 / M4 agonist xanomeline, by activating muscarinic receptors, improved cognitive and psychiatric symptoms such as hallucinations, delusions, and vocalizations (Bodick, et al., Arch Neurol 1997, 54, 465-73). Furthermore, drugs acting on M receptors are also undergoing clinical trials for the treatment of schizophrenia; KarXT from Karuna Pharmaceuticals (with xanomeline as the active ingredient) has already achieved positive results in a Phase III clinical trial in the United States. Therefore, M1 / M4 agonists can improve cognitive and psychiatric symptoms.

[0007] Because the recognition sites of agonists for different M receptor subtypes are highly conserved in spatial structure, these drugs lack subtype selectivity, making them prone to toxic side effects and limiting their clinical use. For example, Xanomeline, the active ingredient in KarXT, is an M receptor agonist; its low subtype selectivity causes gastrointestinal discomfort and cardiovascular adverse reactions, leading some patients to discontinue treatment. In recent years, increasing research on allosteric modulators has revealed that key amino acids involved in receptor allosteric regulation have low conservation, providing a structural basis for the development of more selective allosteric modulator drugs. Allosteric modulators have proven to enhance ligand subtype selectivity for receptors and improve efficacy. M4 receptor positive allosteric modulators can improve M receptor subtype selectivity, reduce off-target side effects, and increase patient compliance. Furthermore, M4 receptor positive allosteric modulators enhance the binding activity of endogenous acetylcholine (ACh) to the M4 receptor by altering the conformation of the M4 receptor protein, producing an effect similar to that of M4 receptor agonists.

[0008] The recently developed M4-specific orthoallosteric modulator (PAM) enhances the effects of the endogenous agonist acetylcholine, revealing the role of these receptors in controlling dopamine release in the striatum and in key synapses in the hippocampus known to be important for cognition.

[0009] A recent study demonstrated that M4PAM reduced striatal dopamine release in wild-type mice after amphetamine treatment, but did not reduce striatal dopamine release in M4 knockout wild-type mice after amphetamine treatment (Byunetal., NeuropsychopHarmacology 2014, 39, 1578). Another study showed that M4PAM induced inhibition of glutamate excitatory synaptic transmission at the Schaeffer collateral-CA1 synapse in the hippocampus (Thorn, et al., Hippocampus 2017, 27, 794-810).

[0010] Furthermore, in vivo rodent studies have shown that M4PAM VU0467154 improves associative learning impairment in the touch screen pair-wise visual discrimination task induced by the non-competitive NMDA receptor antagonist MK-801. These effects are absent in M4 knockout mice, demonstrating the specificity of this phenotype for the M4 receptor (Bubser, et al., ACS Chemical Neuroscience 2014, 5, 920-942).

[0011] By using specific PAM to activate striatal and hippocampal M4 receptors, the hyperdopaminergic state of the striatum and overstimulation of the hippocampus can be reduced, providing a treatment for psychosis and cognitive impairment in schizophrenia.

[0012] Therefore, modulating M4 receptor activity is a promising therapeutic strategy for treating or preventing M4-mediated diseases or disorders, such as Alzheimer's disease, schizophrenia, psychosis, Parkinson's disease, pain, addiction, and Huntington's disease.

[0013] Summary of the Invention

[0014] It is essential to develop new compounds and formulations for the treatment or prevention of M4-mediated or M4-related diseases or disorders. Therefore, the object of this invention is to provide compounds useful for the treatment, prevention, or alleviation of such diseases.

[0015] The present invention aims to provide a nitrogen-containing heterocyclic butane derivative, its preparation method, intermediates, compositions comprising the derivative, and its application in the pharmaceutical field. The derivative and pharmaceutical composition can be used to prevent or treat M4-mediated or M4 receptor-related diseases.

[0016] On the one hand, the present invention provides a compound of Formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof.

[0017] in:

[0018] R1, R2, and R3 are each independently hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl.

[0019] Each R4 is independently a halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl.

[0020] E is -(CR) 10 R 11 )q-, -O-, or -NR 12 -;

[0021] Each R 10 R 11 Each can be independently deuterium, hydrogen, halogen, hydroxyl, mercapto, C1-C6 alkyl, or C1-C6 haloalkyl;

[0022] R 12 It is deuterium, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;

[0023] L is C 6-14 Aryl, 5-14 membered heteroaryl or 5-8 membered heterocyclic;

[0024] A does not exist or is C. 6-14 Aryl, 5-14 membered heteroaryl, 5-8 membered heterocyclic or C 6-10 Aryl 5-8 membered heterocyclic groups;

[0025] Each Ra is independently a halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, -N(R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6), -C(=O)-OR7, -C(=O)-R7 or -S(=O)2-R7;

[0026] R5 and R6 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl, or

[0027] R5 and R6, together with the nitrogen atom they are connected to, form 3-8 member nitrogen-containing heterocyclic groups;

[0028] R7 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0029] m can be 0, 1, 2, 3, or 4;

[0030] q can be 0, 1, 2, or 3;

[0031] n can be 0, 1, 2, 3, 4, or 5.

[0032] On the other hand, the present invention provides a compound of formula V, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof.

[0033] Each Ra is independently a C that is arbitrarily replaced. 6-14 Aryl, optionally substituted 5-14-membered heteroaryl, optionally substituted 5-8-membered heterocyclic group, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, -N(R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6), -C(=O)-OR7, -C(=O)-R7 or -S(=O)2-R7, preferably optionally substituted The 5-14 membered heteroaryl, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, -N(R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6), -C(=O)-OR7, -C(=O)-R7 or -S(=O)2-R7; the optional substituent is selected from halogen, hydroxyl, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl and C2-C6 alkynyl;

[0034] L does not exist or L is C. 6-14 Aryl, 5-14 membered heteroaryl, or 5-8 membered heterocyclic; L may be the same or different each time it appears;

[0035] p is 0, 1, 2 or 3, preferably 1 or 2;

[0036] R1, R2, and R3 are each independently hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl.

[0037] Each R4 is independently a halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl.

[0038] E is -(CR) 10 R 11 ) q -、-O- or -NR 12 -;

[0039] Each R 10 R 11 Each can be independently deuterium, hydrogen, halogen, hydroxyl, mercapto, C1-C6 alkyl, or C1-C6 haloalkyl;

[0040] R 12 It is deuterium, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;

[0041] A does not exist or is C. 6-14 Aryl, 5-14 membered heteroaryl, 5-8 membered heterocyclic or C 6-10 Aryl 5-8 membered heterocyclic group, where A can be the same or different each time it appears;

[0042] R5 and R6 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl, or

[0043] R5 and R6, together with the nitrogen atom they are connected to, form 3-8 member nitrogen-containing heterocyclic groups;

[0044] R7 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0045] m can be 0, 1, 2, 3, or 4;

[0046] q can be 0, 1, 2, or 3;

[0047] n can be 0, 1, 2, 3, 4, or 5.

[0048] On the other hand, the present invention provides a compound of formula V-1, its stereoisomers, deuterated derivatives or salts thereof:

[0049] R8 is selected from C1-C6 alkyl groups; L, A, Ra, n and E are as defined in formula V.

[0050] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of a compound of formulas I and V, a stereoisomer thereof, a deuterated form thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0051] On the other hand, the present invention provides the use of compounds of formulas I and V, their stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments, preferably in the preparation of medicaments for treating subjects with M4-mediated or M4-related diseases or disorders.

[0052] On the other hand, the present invention provides a method for preparing a compound of formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0053] The compound represented by formula IA or its salt may undergo a substitution reaction with a compound of formula IB or I-B' to produce the compound represented by formula I.

[0054] Wherein, R8 is a C1-C6 alkyl group; R1, R2, R3, R4, L, A, Ra, m, n and E are as defined in general formula I.

[0055] On the other hand, the present invention provides a method for preparing the compound of formula V, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0056] The compound shown in formula V-1 undergoes a substitution reaction with the compound shown in formula I-A' or its salt to produce the compound shown in formula V;

[0057] R8 is selected from C1-C6 alkyl groups; R1, R2, R3, R4, L, A, Ra, m, n, p and E are as defined in general formula V.

[0058] Detailed description of the invention

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions provided herein shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0060] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., "C". 1-20 Alkyl group. The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12Alkyl groups, more preferably alkyl groups having 1 to 8 carbon atoms (i.e., C14-C ... 1-8 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkyl groups, most preferably alkyl groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3 Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl, or heteroaryl. When the alkyl group is substituted, the substituent is not further substituted.

[0061] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group, as defined above, has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C). 2-6Alkenyl). Non-limiting examples include vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, etc. The alkenyl group can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, preferably one or more of the following groups independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl, or heteroaryl. When the alkenyl group is substituted, the substituent is not further substituted.

[0062] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group, as defined above, has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C64). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable linking point. The substituent is preferably one or more of the following groups, independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl, or heteroaryl. When the alkynyl group is substituted, the substituent is not further substituted.

[0063] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic cyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C64. 3-20 Cycloalkyl group. The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 carbon atoms (i.e., C12). 3-12 cycloalkyl groups, more preferably cycloalkyl groups having 3 to 8 carbon atoms (i.e., C14-C ... 3-8 Cycloalkyl groups, more preferably cycloalkyl groups having 3 to 6 carbon atoms (i.e., C14-C6 ... 3-6 Cycloalkyl groups, most preferably cycloalkyl groups having 3 to 5 carbon atoms (i.e., C14-C54-C ... 3-5 cycloalkyl groups, or cycloalkyl groups having 5 to 6 carbon atoms (i.e., C1646-C ... 3-5 (Cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl, etc. Non-limiting examples of polycyclic cycloalkyl groups include: spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0064] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocyclic group) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20 membered heterocyclic group), wherein one or more (e.g., 1, 2, 3, 4, or 5) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) n The heterocyclic group (where m and n are integers from 0 to 2) contains heteroatoms, but excludes the ring portions of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heterocyclic group preferably has 3 to 12 ring atoms (i.e., a 3-12 membered heterocyclic group), including 1 to 5 heteroatoms selected from N, O, and S atoms; more preferably, it has 3 to 8 ring atoms (i.e., a 3-8 membered heterocyclic group), including 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms; even more preferably, it has 3 to 6 ring atoms (i.e., a 3-6 membered heterocyclic group), including 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms; and most preferably, it has 5 to 6 ring atoms (i.e., a 5-6 membered heterocyclic group), including 1 to 4, 1 to 3, or 1 to 2 heteroatoms selected from N, O, and S atoms. Non-limiting examples of the monocyclic heterocyclic groups include: azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxocyclopentyl, 2,2-difluoro-1,3-dioxocyclopentyl, cyclopentanone, 2,2-difluorocyclopentanone, acrylonitrile, oxacyclopentyl, or azirropentyl, etc. Non-limiting examples of the polycyclic heterocyclic groups include: spiroheterocyclic, fused heterocyclic, and bridged heterocyclic groups.

[0065] The heterocyclic group can be fused to an aryl, heteroaryl, or cycloalkyl ring, for example, C 6-10 Aryl 5-8 membered heterocyclic groups, such as C 6-10 Aryl groups contain 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and are 5-8 membered heterocyclic groups, such as benzo5-6 membered nitrogen-containing heterocyclic groups or benzo5-6 membered oxygen-containing heterocyclic groups, such as indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, benzodioxanepentenyl, etc.

[0066] The heterocyclic group can be optionally substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl, or heteroaryl. When the heterocyclic group is substituted, the substituent is not further substituted.

[0067] The term "aryl" refers to an all-carbon monocyclic group (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms (i.e., C atoms). 6-14 Aryl group). The aryl group is preferably an aryl group having 6 to 10 carbon atoms (i.e., C64). 6-10 Aryl), further preferably phenyl or naphthyl, most preferably phenyl. The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracene, phenanthrene, etc.

[0068] The aryl group can be fused to a heteroaryl, heterocyclic, or cycloalkyl ring. The aryl group can be optionally substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl, or heteroaryl. When the aryl group is substituted, the substituent is not further substituted.

[0069] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., polycyclic heteroaryl) having a conjugated π-electron system, having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) nThe heteroatom (i.e., 5-14 membered heteroaryl) is selected from nitrogen, oxygen, or sulfur, but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., 5-10 membered heteroaryl). The monocyclic heteroaryl is preferably a heteroaryl having 5 to 6 ring atoms (i.e., 5-6 membered heteroaryl), and non-limiting examples include: furanyl, pyranyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridoneyl, pyrazinyl, pyrazinyl, etc. The polycyclic heteroaryl is preferably a 5-6 membered heteroaryl with a 5-6 membered heteroaryl or a 5-10 membered heteroaryl with a C- group. 6-10 Aryl or C 6-10 The aryl 5-10-membered heteroaryl group is preferred, with 5-6-membered heteroaryl 5-6-membered heteroaryl, 5-6-membered heteroaryl phenyl or phenyl 5-6-membered heteroaryl as further preferred. Non-limiting examples include: indolyl, inzolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, thiophene phenyl, quinazolinyl, benzothiazolyl, carbazole, thiophene pyridinyl, pyridinothiophene, pyridinopyrroleyl, etc.

[0070] The heteroaryl group can be fused to an aryl, heterocyclic, or cycloalkyl ring. The heteroaryl group can be optionally substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point. The substituent is preferably one or more of the following groups, independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl, or heteroaryl. When the heteroaryl group is substituted, the substituent is not further substituted.

[0071] The term "alkoxy" refers to -O- (alkyl) or -O- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C atoms). 1-10 Alkoxy group). The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C14). 1-8 Alkoxy groups, more preferably alkoxy groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkoxy groups, preferably alkoxy groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3Alkoxy groups. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any usable linking point. The substituent is preferably one or more of the following groups, independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl, or heteroaryl. When the alkoxy group is substituted, the substituent is not further substituted.

[0072] The term "alkylamine" refers to -NH- (alkyl), -N- (alkyl)2, -NH- (unsubstituted cycloalkyl), -N- (unsubstituted cycloalkyl)2, wherein alkyl and cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C atoms). 1-10 Alkylamine group). The alkylamine group is preferably an alkylamine group having 1 to 8 carbon atoms (i.e., C12). 1-8 Alkylamine group), more preferably alkylamine group having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkylamine group), preferably alkylamine group with 1 to 3 carbon atoms (i.e., C). 1-3 Alkylamine group. Non-limiting examples include: methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, cyclobutylamino, cyclopentamino, cyclohexylamino, dimethylamino, diethylamino, dipropylamino, etc. The alkylamino group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any usable linking point. The substituent is preferably one or more of the following groups, independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl, or heteroaryl. When the alkylamino group is substituted, the substituent is not further substituted.

[0073] The term "alkathioyl" refers to -S- (alkyl) or -S- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C atoms). 1-10 Alkylthio group). The alkylthio group is preferably an alkylthio group having 1 to 8 carbon atoms (i.e., C12). 1-8 Alkylthioyl), more preferably alkylthioyl groups having 1 to 6 carbon atoms (i.e., C14-C ... 1-6 Alkylthioyl), preferably alkylthioyl groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3Alkylthio (e.g., methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.). The alkylthio group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any usable linking point. The substituent is preferably one or more of the following groups, independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl, or heteroaryl. When the alkylthio group is substituted, the substituent is not further substituted.

[0074] The terms “halogen” or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine or bromine atoms.

[0075] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2-dichloro-2-fluoroethyl, 2, 2,2-Trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0076] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2 2-Dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0077] The term "thiol" refers to -SH.

[0078] The term "hydroxyl group" refers to -OH.

[0079] The term "nitro" refers to -NO2.

[0080] The term "amino" refers to -NH2.

[0081] The term "cyano" refers to -CN.

[0082] The term "oxo" or "oxo group" refers to =O.

[0083] The term "carbonyl" refers to C=O.

[0084] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0085] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0086] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood as representing each numerical value and range encompassed within a wider range.

[0087] In this article, "Z" and "-Z-" both refer to the same specific group and can be used interchangeably.

[0088] The expression "mn" used in this paper refers to the range from m to n, the subrange consisting of the individual point values ​​within it, and the individual point values ​​themselves. For example, the expression "C2-C8" or "C 2-8 "Covering a range of 2-8 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., and C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C..." 10 "or "C 3-10 "It should also be understood in a similar way, for example, it can cover any subrange and point value contained therein, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C..." 10 C7-C9, C7-C8, C8-C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C 10 For example, stating "C1-C6" or "C..." 1-6 "The term 'covers' the range of 1-6 carbon atoms and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, and C1, C2, C3, C4, C5, C6, etc. Similarly, the expression 'ternary to decaary' should be understood to include any subrange within this range and each point value, such as ternary to pentary, ternary to hexaary, ternary to octary, quaternary to pentary, quaternary to hexaary, quaternary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, octary to octary, quinary to decaary, etc., and tri-, quadri-, quinary, quinary, quinary, quinary, octary, quinary, octary, quinary, decaary, etc. Other similar expressions in this text should also be understood in a similar manner."

[0089] The different expressions used in this article, such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", and "X is A, B and C", all express the same meaning, that is, X can be any one or more of A, B, and C.

[0090] The terms “optional” or “optionally” mean that an event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally (al) alkyl-substituted cycloalkyl” means that an alkyl group may but is not required to be present, and this description includes cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

[0091] The terms "substitution" and "substituted" refer to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a chosen substituent from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound. When describing the absence of a substituent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When describing the optional substitution of each carbon atom in a group with a heteroatom, the condition is that the substitution does not exceed the normal valence of all atoms in the group in the present case and that a stable compound is formed.

[0092] If a substituent is described as "optionally...substituted," the substituent may be unsubstituted or substituted. If an atom or group is described as being optionally substituted by one or more of the substituents in the list, one or more hydrogen atoms on that atom or group may be replaced by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted. When the substituent is hydrogen, this may also indicate that the corresponding group is "unsubstituted" or "unsubstituted." Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable position of the substituent.

[0093] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0094] When any variable (e.g., R), and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear more than once in the composition or structure of a compound, their definition is independent for each occurrence in each case. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted by up to four R substituents, and the options for each R substituent in each case are independent of each other.

[0095] The compounds of this invention can exist in specific geometric or stereoisomeric forms. All such compounds of this invention, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, are within the scope of this invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of this invention. All such isomers and mixtures thereof are included within the scope of this invention. In some embodiments, the preferred compounds are those isomers exhibiting superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of this invention, or racemic mixtures or diastereomer mixtures, are also included within the scope of this invention. Purification and separation of such substances can be achieved using standard techniques known in the art.

[0096] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0097] The term "deuterated compound" refers to a compound in which one or more hydrogen atoms can be partially or completely replaced by deuterium atoms.

[0098] The compounds of this invention include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, respectively. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 Grade I, with deuterium as the preferred grade.

[0099] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0100] In the compounds of this invention, when a position is specifically designated as deuterium D, that position should be understood as having a deuterium abundance at least 1000 times greater than the native abundance (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the abundance of deuterium in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0101] The term "pharmaceutically acceptable" means that a substance is suitable for contact with a patient's tissues without causing undue toxicity, irritation, allergic reactions, etc., within the normal medical judgment, has a reasonable benefit-risk ratio, and is effective for its intended use.

[0102] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is safe and effective when used in mammals and has the intended biological activity.

[0103] The term "pharmaceutical composition" refers to a composition containing one or more compounds described in this invention, or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0104] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0105] The terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0106] As used herein, the term "treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or causing the symptom of a disease or symptom to cease; and extends to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, and an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or the use by a patient when experiencing one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

[0107] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom. The term "neuropsychiatric disorders" is a collective term for neurological and psychiatric disorders, encompassing both neurological and / or psychiatric conditions.

[0108] The term "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C ​​to 25°C.

[0109] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the terms "about" or "approximately" mean within an acceptable standard error of the average. Whenever a number with a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" means addition or subtraction.

[0110] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of the invention, so that other skilled in the art can modify and implement the invention in many forms to best suit the requirements of a particular application.

[0111] compound

[0112] This disclosure provides, in one aspect, a compound of Formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof.

[0113] Wherein: R1, R2, and R3 are each independently hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl;

[0114] Each R4 is independently a halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl.

[0115] E is -(CR) 10 R11 )q-, -O-, or -NR 12 -;

[0116] Each R 10 R 11 Each can be independently deuterium, hydrogen, halogen, hydroxyl, mercapto, C1-C6 alkyl, or C1-C6 haloalkyl;

[0117] R 12 It is deuterium, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;

[0118] L is C 6-14 Aryl, 5-14 membered heteroaryl or 5-8 membered heterocyclic;

[0119] A does not exist or is C. 6-14 Aryl, 5-14 membered heteroaryl, 5-8 membered heterocyclic or C 6-10 Aryl 5-8 membered heterocyclic groups;

[0120] Each Ra is independently a halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, -N(R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6), -C(=O)-OR7, -C(=O)-R7 or -S(=O)2-R7;

[0121] R5 and R6 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl, or

[0122] R5 and R6, together with the nitrogen atom they are connected to, form 3-8 member nitrogen-containing heterocyclic groups;

[0123] R7 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0124] m can be 0, 1, 2, 3, or 4;

[0125] q can be 0, 1, 2, or 3;

[0126] n can be 0, 1, 2, 3, 4, or 5.

[0127] In some embodiments, R1, R2, and R3 are each independently hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl.

[0128] Each R4 is independently a halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl.

[0129] E is -(CH2)q-, -O-, or -NH-;

[0130] L is C 6-14 Aryl, 5-14 membered heteroaryl or 5-8 membered heterocyclic;

[0131] A does not exist or is C. 6-14 Aryl, 5-14 membered heteroaryl, 5-8 membered heterocyclic or C 6-10 Aryl 5-8 membered heterocyclic groups;

[0132] Each Ra is independently a halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, -N(R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6), -C(=O)-OR7, -C(=O)-R7 or -S(=O)2-R7;

[0133] R5 and R6 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl, or

[0134] R5 and R6, together with the nitrogen atom they are connected to, form 3-8 member nitrogen-containing heterocyclic groups;

[0135] R7 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0136] m can be 0, 1, 2, 3, or 4;

[0137] q can be 0, 1, 2, or 3;

[0138] n can be 0, 1, 2, 3, 4, or 5.

[0139] In some embodiments, R1, R2, and R3 are each independently hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; preferably hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, or C2-C6 alkenyl; preferably hydrogen, halogen, C1-C6 alkyl, C1-C6 alkylthio, or C2-C6 alkenyl.

[0140] In some embodiments, R1 is a halogen, C1-C6 alkyl, C1-C6 alkylthio, or C2-C6 alkenyl, preferably a halogen, C1-C3 alkyl, or C2-C6 alkenyl. 1- C3 alkylthio or C2-C4 alkenyl, preferably halogen, methyl, methylthio, or vinyl, preferably chlorine, methyl, methylthio, or vinyl. In some embodiments, R1 is a halogen, such as chlorine.

[0141] In some embodiments, R2 is hydrogen. In some embodiments, R3 is hydrogen or a C1-C6 alkyl group, preferably a C1-C6 alkyl group, preferably a C1-C3 alkyl group, such as methyl.

[0142] In some embodiments, R1 is a halogen (e.g., chlorine), R2 is hydrogen, and R3 is a C1-C6 alkyl (e.g., C1-C3 alkyl, such as methyl).

[0143] In some embodiments, R1 is a halogen, C1-C6 alkyl, C1-C6 alkylthio, or C2-C6 alkenyl (e.g., halogen, C1-C3 alkyl, C2-C6 alkenyl). 1- C3 is alkylthio or C2-C4 is alkenyl (e.g., chloro, methyl, methylthio or vinyl), R2 is hydrogen, and R3 is hydrogen.

[0144] In some embodiments, R1 is a C1-C6 alkyl (e.g., C1-C3 alkyl, such as methyl), R2 is hydrogen, and R3 is a C1-C6 alkyl (e.g., C1-C3 alkyl, such as methyl).

[0145] In some embodiments, R4 is each independently a halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 1- C6 alkylthio group, C 1- C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl or C2-C6 alkynyl; preferably hydroxyl, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; preferably C1-C6 alkyl; preferably C1-C3 alkyl.

[0146] In some embodiments, E is -(CH2)q-, -O-, or -NH-, preferably -(CH2)q- or -O-, preferably -(CH2)q-, wherein q is 1 or 2, preferably 1.

[0147] In some implementations, -(CR 10 R 11 )q-, where q is 1 or 2.

[0148] In some implementations, -(CR 10 R 11 )q-, where q is 1.

[0149] In some implementation schemes, R 10 R 11 Each of the following is independently deuterium, hydrogen, halogen, hydroxyl, mercapto, C1-C6 alkyl or C1-C6 haloalkyl; preferably deuterium, hydrogen, halogen or C1-C6 alkyl; preferably hydrogen or halogen (e.g. fluorine).

[0150] In some implementation schemes, R 10 It is deuterium, hydrogen, halogen, hydroxyl, mercapto, C1-C6 alkyl or C1-C6 haloalkyl; preferably deuterium, hydrogen, halogen or C1-C6 alkyl; preferably hydrogen or halogen (e.g. fluorine).

[0151] In some implementation schemes, R 11 It is deuterium, hydrogen, halogen, hydroxyl, mercapto, C1-C6 alkyl or C1-C6 haloalkyl; preferably deuterium, hydrogen, halogen or C1-C6 alkyl; preferably hydrogen or halogen (e.g. fluorine).

[0152] In some implementation schemes, R 12 It is deuterium, hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; preferably deuterium, hydrogen or C1-C6 alkyl; preferably hydrogen or halogen (e.g. fluorine); preferably hydrogen.

[0153] In some implementation schemes, R 10 For halogens (e.g., fluorine), R 11 It is a halogen (e.g., fluorine).

[0154] In some implementations, L is C 6-14 Aryl, 5-14 membered heteroaryl or 5-8 membered heterocyclic; preferably C 6-14 Aryl group, 5-14 membered heteroaryl group containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, or 5-8 membered heterocyclic group (e.g., 5-8 membered nitrogen-containing heterocyclic group) containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; preferably C 6-14 Aryl or 5-14 heteroaryl groups containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur; preferably C 6-10The aryl group or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; preferably phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, or thiopheneyl; preferably phenyl, pyridyl, pyridazinyl, thiopheneyl, or pyrimidinyl.

[0155] In some embodiments, A is absent, and Ra, which is linked to A in the general formula, is directly linked to the L group. When A is present, in some embodiments, A is C. 6-14 Aryl, 5-14 membered heteroaryl, 5-8 membered heterocyclic or C 6-10 Aryl 5-8 membered heterocyclic group; preferably C 6-14 Aryl, 5-14 membered heteroaryl containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, 5-8 membered heterocyclic group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, or C 6-10 The aryl group contains 1-3 5-8 membered heterocyclic groups selected from nitrogen, oxygen, and sulfur; preferably C. 6-10 The aryl group, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, a 5-6 membered nitrogen-containing heterocyclic group, a 5-6 membered oxygen-containing heterocyclic group, a benzo5-6 membered oxygen-containing heterocyclic group, or a benzo5-6 membered nitrogen-containing heterocyclic group; preferably phenyl, piperazine, pyridinyl, quinolinyl, isoquinolinyl, morpholinyl, thiophene, indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, or benzodioxanepentenyl. In some embodiments, A is absent or is C. 6-10 The aryl group or a 5-10 heteroaryl group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, preferably phenyl or pyridyl.

[0156] In some implementations... for

[0157] In some implementations, L is C 6-14 Aryl or 5-14 heteroaryl groups containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, preferably C 6-10 The aryl group or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, preferably phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, or thiopheneyl; preferably phenyl, pyridyl, pyridazinyl, thiopheneyl, or pyrimidinyl; preferably...

[0158] In some embodiments, Ra is independently a halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, -N(R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6), -C(=O)-OR7, -C(=O)-R7 or -S(=O)2-R7; preferably halogen. The group can be halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -N(R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6) or -C(=O)-OR7; preferably halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -N(R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6) or -C(=O)-OR7.

[0159] In some embodiments, R5 and R6 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl, preferably H or C1-C3 alkyl. In some embodiments, R5 and R6 are linked together with their commonly attached nitrogen atom to form a 3- to 8-membered nitrogen-containing heterocyclic group, preferably a 5- to 6-membered nitrogen-containing heterocyclic group, such as pyrrole or piperidinyl.

[0160] In some embodiments, R7 is independently selected from C1-C6 alkyl or C1-C6 haloalkyl, preferably C1-C6 alkyl, and more preferably C1-C3 alkyl.

[0161] In some implementations, m is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, and preferably 0.

[0162] In some implementations, q is 0, 1, 2 or 3, preferably 1 or 2, and most preferably 1.

[0163] In some implementations, n is 0, 1, 2, 3, 4 or 5, preferably 0, 1, 2, 3 or 4, and preferably 0, 1 or 2.

[0164] In some embodiments, Formula I is further shown as Formula II.

[0165] In some embodiments, Formula I is further shown as in Formula III.

[0166] In some implementations, Equation I is further shown as Equation IX.

[0167] Wherein, Rb is deuterium, halogen, hydroxyl, mercapto, C1-C6 alkyl or C1-C6 haloalkyl; preferably halogen.

[0168] In some implementations, Equation I is shown as Equation X.

[0169] Each Rb is independently deuterium, halogen, hydroxyl, mercapto, C1-C6 alkyl or C1-C6 haloalkyl; preferably halogen.

[0170] In some embodiments, the compounds described herein are not the following compounds.

[0171] This disclosure also provides a compound of formula V, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof.

[0172] Each Ra is independently a C that is arbitrarily replaced. 6-14Aryl, optionally substituted 5-14-membered heteroaryl, optionally substituted 5-8-membered heterocyclic group, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamino, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, -N(R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6), -C(=O)-OR7, -C(=O)-R7 or -S(=O)2-R7, preferably optionally substituted 5-14-membered heteroaryl, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C1-C6 alkyl C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, -N(R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6), -C(=O) -OR7, -C(=O)-R7, or -S(=O)2-R7; the optional substituent is selected from halogen, hydroxyl, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl; L is absent or L is C 6-14 Aryl, 5-14-membered heteroaryl, or 5-8-membered heterocyclic; L may be the same or different each time it appears; p is 0, 1, 2, or 3, preferably 1 or 2; R1, R2, and R3 are each independently hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl.

[0173] Each R4 is independently a halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl.

[0174] E is -(CR) 10 R 11 ) q -、-O- or -NR 12 -;

[0175] Each R 10 R 11Each can be independently deuterium, hydrogen, halogen, hydroxyl, mercapto, C1-C6 alkyl, or C1-C6 haloalkyl;

[0176] R 12 It is deuterium, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;

[0177] A does not exist or is C. 6-14 Aryl, 5-14 membered heteroaryl, 5-8 membered heterocyclic or C 6-10 Aryl 5-8 membered heterocyclic group, where A can be the same or different each time it appears;

[0178] R5 and R6 are each independently H, C1-C6 alkyl, or C1-C6 haloalkyl, or

[0179] R5 and R6, together with the nitrogen atom they are connected to, form 3-8 member nitrogen-containing heterocyclic groups;

[0180] R7 is a C1-C6 alkyl or a C1-C6 haloalkyl;

[0181] m can be 0, 1, 2, 3, or 4;

[0182] q can be 0, 1, 2, or 3;

[0183] n can be 0, 1, 2, 3, 4, or 5.

[0184] In some implementations, L is not present.

[0185] In some implementations, L is C 6-14 Aryl, 5-14 membered heteroaryl or 5-8 membered heterocyclic.

[0186] In some implementations, A does not exist.

[0187] In some implementations, L is absent or is C. 6-14 Aryl, 5-14 membered heteroaryl or 5-8 membered heterocyclic; L may be the same or different each time it appears, and A does not exist.

[0188] In some implementations, Ra is independently the C that is optionally replaced. 6-14 The aryl group, optionally substituted 5-14-membered heteroaryl groups, and optionally substituted 5-8-membered heterocyclic groups, wherein the optionally substituted substituents are selected from halogens, hydroxyl groups, cyano groups, amino groups, nitro groups, oxo groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, C1-C6 alkylthio groups, C1-C6 alkylamine groups, C1-C6 haloalkoxy groups, C2-C6 alkenyl groups, and C2-C6 alkynyl groups.

[0189] In some implementations, Ra is independently the C that is optionally replaced. 6-14The aryl group and optionally substituted 5-14 heteroaryl groups, wherein the optionally substituted substituents are selected from halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, C1-C6 alkylthio groups, C1-C6 alkylamine groups, and C1-C6 haloalkoxy groups.

[0190] In some embodiments, Ra is an optionally substituted 5-14 membered heteroaryl group, wherein the optionally substituted substituent is selected from halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, and C1-C6 haloalkoxy groups.

[0191] In some embodiments, Ra is an optionally substituted pyridyl, optionally substituted pyrimidinyl, and optionally substituted pyrazinyl, preferably an optionally substituted pyridyl, wherein the optionally substituted substituent is selected from halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, and C1-C6 haloalkoxy groups.

[0192] In some embodiments, Ra is an optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, preferably an optionally substituted pyridyl, wherein the optionally substituted substituent is selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups.

[0193] In some embodiments, Ra is an optionally substituted phenyl group, wherein the optionally substituted substituent is selected from halogens, hydroxyl groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, and C1-C6 haloalkoxy groups.

[0194] In some embodiments, the compounds of the present invention are selected from the following compounds, their stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0195] intermediate

[0196] The present invention also provides a compound of formula V-1, its stereoisomers, deuterated derivatives or salts thereof:

[0197] Wherein, R8 is a C1-C6 alkyl group; L, A, Ra, n and E are as defined in formula V.

[0198] Preparation method

[0199] This invention also provides a method for preparing the compound of formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof. The preparation method utilizes commercially available raw materials synthesized using known reaction principles.

[0200] In some embodiments, the preparation method includes the following steps:

[0201] The compound shown in formula IA or its salt may undergo a substitution reaction with the compound shown in formula IB or I-B' to produce the compound shown in formula I;

[0202] R8 is selected from C1-C6 alkyl groups; R1, R2, R3, R4, L, A, Ra, m, n and E are as defined above.

[0203] In some embodiments, the substitution reaction conditions may be those conventional for such reactions in the art.

[0204] This invention also provides a method for preparing the compound of formula V, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof. The preparation method utilizes commercially available raw materials synthesized using known reaction principles.

[0205] In some embodiments, the preparation method includes the following steps:

[0206] The compound shown in formula V-1 undergoes a substitution reaction with the compound shown in formula I-A' or its salt to produce the compound shown in formula V;

[0207] R8 is selected from C1-C6 alkyl groups; R1, R2, R3, R4, L, A, Ra, m, n, p and E are as defined above.

[0208] In some embodiments, the substitution reaction conditions may be those conventional for such reactions in the art.

[0209] In some embodiments, methods for preparing compounds of formula V-1, their stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof include:

[0210] The compound shown in formula V-1-A undergoes a substitution reaction with the compound shown in formula V-1-B or its salt to produce the compound shown in formula V-1;

[0211] Wherein, R8 is a C1-C6 alkyl group; X1 is a halogen, preferably F; L, A, Ra, n and E are as defined above.

[0212] In some embodiments, the substitution reaction conditions may be those conventional for such reactions in the art.

[0213] Pharmaceutical Composition

[0214] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds shown, its stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0215] In some embodiments of the present invention, the above-described pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. The carrier refers to a carrier conventional in the pharmaceutical field, such as: diluents like water; binders like cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers like starch, etc.; disintegrants like calcium carbonate, sodium bicarbonate, etc.; lubricants like calcium stearate or magnesium stearate, etc. Additionally, other excipients such as sweeteners, flavorings, or colorings may be added to the composition.

[0216] In some embodiments of the invention, the pharmaceutical composition may be administered in any of the following ways: orally, by spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, non-enteric administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or by means of an external implantation device.

[0217] application

[0218] This invention further relates to the use of any of the compounds shown, their stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a medicament. In some embodiments, the medicament is a medicament for the prevention and / or treatment of M4-mediated or M4-related diseases or disorders.

[0219] The present invention also relates to a method for preventing and / or treating M4-mediated or M4-related diseases or disorders, comprising administering to a subject a therapeutically effective dose of any of the compounds shown, their stereoisomers, deuterated derivatives or pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof, or pharmaceutical compositions thereof.

[0220] In some embodiments, the M4-mediated or M4-related diseases or disorders are selected from one or more of the following: Alzheimer's disease, schizophrenia, pain, addiction, sleep disorders, cognitive impairment, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, Huntington's disease, dyskinesia, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, Down syndrome, cerebral amyloid angiopathy, dementia, Dutch amyloid hemorrhage, Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis, preferably one or more of Alzheimer's disease, schizophrenia, pain, addiction, and sleep disorders, preferably schizophrenia. Beneficial effects

[0221] This invention relates to a novel class of compounds that are M4 positive allosteric modulators, surprisingly exhibiting excellent effects and functions, and can be used for the prevention and / or treatment of M4-mediated or M4-related diseases or disorders, particularly for the prevention and / or treatment of diseases or disorders associated with M4 positive allosteric changes. In some embodiments, the compounds of this invention exhibit high allosteric activity against the M4 receptor. In some embodiments, the compounds of this invention also possess improved physicochemical properties (e.g., solubility, physical and / or chemical stability) and improved pharmacokinetic properties (e.g., resistance to cytochrome P450). 450 The compounds exhibit superior pharmaceutical properties, including lower isoenzyme inhibition, improved bioavailability, suitable half-life and duration of action, improved safety (lower toxicity and / or fewer side effects), good patient compliance, and / or less likelihood of developing tolerance. In some embodiments, the compounds of the present invention have stronger blood-brain barrier penetration and higher brain penetration capability. In some embodiments, the compounds of the present invention have improved safety, i.e., lower acute toxicity and peripheral adverse reactions. In some embodiments, the compounds of the present invention have improved safety windows (e.g., a larger safe dosage range, or a lower likelihood of side effects at the same dosage). Specifically, in vitro isotope binding assays and in vitro IP-1 assays of the present disclosure demonstrate that the compounds of the present invention are effective M4 positive allosteric modulators, producing M4 agonist-like efficacy with high selectivity, avoiding the off-target effects of M4 receptor agonists. Experimental results on the effects of MK-801-induced hyperactivity in mice indicate that the compounds of the present invention can effectively inhibit MK-801-induced hyperactivity in mice, showing potential for the treatment of schizophrenia. Pharmacokinetic studies in rats have shown that the compounds of this application have the potential to reduce the frequency of dosing, increase patient compliance, improve brain penetration, reduce peripheral drug exposure at the effective dose, and reduce the occurrence of peripheral adverse reactions.

[0222] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0223] Example

[0224] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products. Unless otherwise specified, all proportions or percentages used herein are by weight.

[0225] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS).

[0226] Example 1 Preparation of 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-(1-(2-chloropyridin-4-yl)azacyclobutane-3-yl)ethane-1-one

[0227] Step 1: Synthesis of I-1-1

[0228] 226 mg (0.8 mmol) of 2-chloro-7,8-dihydro-4-methyl-1,6-naphthyl-6(5H)-carboxylic acid tert-butyl ester was added to a single-necked flask equipped with a stir bar. 2 mL of a dioxane solution (4 mol / L) in hydrochloric acid was then added at room temperature, and the reaction was allowed to proceed at room temperature. After the reaction was complete as monitored by TLC, the solution was directly evaporated to dryness without purification, and the final quantification was performed.

[0229] Step 2: Synthesis of I-1-2

[0230] In a two-necked flask equipped with a stir bar, 92 μL (1 mmol) of 2-chloro-4-fluoropyridine, 243 mg (1 mmol) of methyl 2-(azacyclobutane-3-yl)acetate 2,2,2-trifluoroacetate, and 650 mg (1.99 mmol) of cesium carbonate were added. 4 mL of acetonitrile was added at room temperature, and the reaction was carried out at 65 °C. After the reaction was complete as monitored by TLC, it was cooled to room temperature, filtered through diatomaceous earth, and 210 mg of crude product was obtained without further purification. 1H NMR(300MHz, CDCl3)δ8.00(d,J=5.7Hz,1H),6.30–6.14(m,2H),4.19(t,J=8.1 Hz,2H),3.78–3.65(m,5H),3.20(tt,J=7.9,5.4Hz,1H),2.77(d,J=7.8Hz,2H).

[0231] Step 3: Synthesis of I-1

[0232] I-1-1 (quantitative), I-1-2 (190 mg, 0.79 mmol), and 1,5,7-triazidobicyclo(4.4.0)dec-5-ene (450 mg, 3.15 mmol) were added to a two-necked flask equipped with a stir bar. 8 mL of anhydrous tetrahydrofuran was added at room temperature, and the reaction was carried out at 70 °C. After the reaction was monitored by TLC until complete, the mixture was cooled to room temperature, concentrated, and then purified water, saturated sodium chloride solution, and saturated ammonium chloride solution were added sequentially. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (ethyl acetate) to obtain 50 mg of the product, namely the title compound (compound 1). 1 H NMR (300MHz, DMSO-d6) δ7.87(d,J=5.6Hz,1H),7.26(d,J=2.9Hz,1H),6.35–6.28(m,2H),4.55(d,J=7.1Hz,2H),4.09(td,J=8.2,2.5Hz,2H),3.74 (td,J=5.8,3.2Hz,2H),3.60(ddd,J=8.6,5.4,3.0Hz,2H),3.04(h,J=7.4,6.7Hz,1H),2.89(s,2H),2.73(d,J=0.6Hz,2H),2.25(d,J=9.3Hz,3H).

[0233] Example 2 Preparation of 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutan-3-yl)ethane-1-one

[0234] The synthesis method of Example 1 was followed, except that 2-chloro-4-fluoropyridine was replaced with 4-chloro-2-trifluoromethylpyridine (128 μL, 1 mmol), and compound I-2 was prepared by the same method. The product (compound 2) was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 80:1) to obtain 80 mg of product (compound 2). 1H NMR (300MHz, CDCl3) δ8.26(d,J=5.7Hz,1H),7.06(s,1H),6.56(d,J=2.5Hz,1H),6.31(dd,J=5.8,2.2Hz,1H),4.57(d,J=41.6Hz,2 H),4.26(t,J=8.1Hz,2H),3.80–3.65(m,4H),3.36–3.21(m,1H),3.01(dt,J=17.9,6.0Hz,2H),2.88(d,J=7.6Hz,2H),2.27(s,3H).

[0235] Example 3 Preparation of 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-(1-(pyrimidin-4-yl)azacyclobutane-3-yl)ethane-1-one

[0236] Step 1: Synthesis of I-3-1

[0237] 238 mg (0.85 mmol) of 2-chloro-7,8-dihydro-4-methyl-1,6-naphthyl-6(5H)-carboxylic acid tert-butyl ester was added to a single-necked flask equipped with a stir bar. 3 mL of a dioxane solution (4 mol / L) in hydrochloric acid was then added at room temperature, and the reaction was allowed to proceed at room temperature. After the reaction was complete as monitored by TLC, the solution was directly evaporated to dryness without purification, and quantified.

[0238] Step 2: Synthesis of I-3-2

[0239] In a two-necked flask equipped with a stir bar, 4-chloropyrimidine hydrochloride (151 mg, 1 mmol), methyl 2-(azacyclobutane-3-yl)acetate 2,2,2-trifluoroacetate (243 mg, 1 mmol), cesium fluoride (160 mg, 1.05 mmol), and cesium carbonate (1 g, 3.07 mmol) were added. 6 mL of tetrahydrofuran was added at room temperature, and the reaction was carried out at 50 °C. After the reaction was monitored by TLC until complete, the mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain 175 mg of an oily substance. 1 H NMR (300MHz, CDCl3) δ8.58(d,J=1.2Hz,1H),8.17(d,J=6.0Hz,1H),6.17(dd,J=6.0,1.3Hz,1H) ,4.28(t,J=8.5Hz,2H),3.88–3.68(m,5H),3.16(pt,J=8.1,5.4Hz,1H),2.74(d,J=7.8Hz,2H).

[0240] Step 3: Synthesis of I-3

[0241] I-3-1 (quantitative), I-3-2 (175 mg, 0.85 mmol), and 1,5,7-triazidobicyclo(4.4.0)dec-5-ene (470 mg, 3.38 mmol) were added to a two-necked flask equipped with a stir bar. 8 mL of anhydrous tetrahydrofuran was added at room temperature, and the reaction was carried out at 70 °C. After the reaction was monitored by TLC until complete, the mixture was cooled to room temperature, concentrated, and then purified water, saturated sodium chloride solution, and saturated ammonium chloride solution were added sequentially. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (ethyl acetate) to obtain 110 mg of the product (compound 3). 1 H NMR (300MHz, DMSO-d6) δ8.43(d,J=1.2Hz,1H),8.12(d,J=6.0Hz,1H),7.26(d,J=2.6Hz,1H),6.35(dd,J=6.0,1.3Hz,1H),4.56(d,J=6. 9Hz, 2H), 4.15 (ddd, J=10.3, 6.6, 2.4Hz, 2H), 3.86–3.62 (m, 4H), 3.05 (p, J=7.7, 6.9Hz, 1H), 2.98–2.76 (m, 4H), 2.26 (d, J=8.8Hz, 3H).

[0242] Example 4 Preparation of 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-(1-(2-(difluoromethyl)pyridin-4-yl)azacyclobutan-3-yl)ethane-1-one

[0243] The synthesis method of Example 3 was followed, except that 4-chloropyrimidine hydrochloride in step 2 was replaced with 4-bromo-2-(difluoromethyl)pyridine (208 mg, 1 mmol). Compound I-4 was prepared by the same method, and 76 mg of product (compound 4) was separated by silica gel column chromatography (dichloromethane:methanol = 100:1). 1H NMR (300MHz, DMSO-d6) δ8.15(d,J=5.6Hz,1H),7.27(d,J=2.0Hz,1H),6.82(d,J=55.3Hz,1H),6.55(t,J=2.2Hz,1H),6.43(dd,J=5.7,2.4Hz,1H ),4.56(d,J=6.2Hz,2H),4.20–4.04(m,2H),3.81–3.68(m,2H),3.68–3. 54(m,2H),3.15–2.99(m,1H),2.99–2.76(m,4H),2.26(d,J=7.7Hz,3H).

[0244] Example 5 Preparation of 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-(1-phenylazacyclobutane-3-yl)ethane-1-one

[0245] Step 1: Synthesis of I-5-1

[0246] 400 mg (1.41 mmol) of 2-chloro-7,8-dihydro-4-methyl-1,6-naphthyl-6(5H)-carboxylic acid tert-butyl ester was added to a single-necked flask equipped with a stir bar. 3 mL of a dioxane solution (4 mol / L) in hydrochloric acid was then added at room temperature, and the reaction was allowed to proceed at room temperature. After the reaction was complete as monitored by TLC, the solution was directly evaporated to dryness without purification, and the final quantification was performed.

[0247] Step 2: Synthesis of I-5-2

[0248] In a two-necked flask equipped with a stir bar, phenyltrifluoromethanesulfonate (226 mg, 1 mmol), methyl 2-(azacyclobutane-3-yl)acetate 2,2,2-trifluoroacetate (243 mg, 1 mmol), palladium acetate (20 mg, 0.12 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (64 mg, 0.10 mmol), and cesium carbonate (1 g, 3.07 mmol) were added. Under nitrogen protection, 8 mL of anhydrous toluene was added, and the reaction was carried out at 85 °C. After the reaction was monitored by TLC until complete, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain 60 mg of an oily substance. 1H NMR (300MHz, DMSO-d6) δ7.17–7.05(m,2H),6.63(tt,J=7.3,1.1Hz,1H),6.47–6.21(m,2H),3.91(t,J=7 .5Hz,2H),3.59(s,3H),3.43(dd,J=7.2,5.7Hz,2H),2.94(pt,J=7.6,5.7Hz,1H),2.70(d,J=7.7Hz,2H).

[0249] Step 3: Synthesis of I-5

[0250] I-5-1 (quantitative), I-5-2 (175 mg, 0.85 mmol), and 1,5,7-triazidobicyclo(4.4.0)dec-5-ene (470 mg, 3.38 mmol) were added to a two-necked flask equipped with a stir bar. 8 mL of anhydrous tetrahydrofuran was added at room temperature, and the reaction was carried out at 70 °C. After the reaction was monitored by TLC until complete, the mixture was cooled to room temperature, concentrated, and then successively extracted with purified water, saturated sodium chloride solution, and saturated ammonium chloride solution. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (ethyl acetate) to obtain 110 mg of the product (compound 5). 1 H NMR (300MHz, DMSO-d6) δ7.26(s,1H),7.21–7.02(m,2H),6.74–6.53(m,1H),6.45–6.27(m,2H),4.56(d,J=7.5Hz,2H),3.95(t,J=7.3 Hz,2H),3.75(td,J=5.8,3.3Hz,2H),3.45(ddd,J=7.7,5.5,2.1Hz,2H),3.07–2.96(m,1H),2.94–2.75(m,4H),2.25(d,J=8.2Hz,3H).

[0251] Example 6 Preparation of 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-(1-(2-methoxypyridin-4-yl)azacyclobutane-3-yl)ethane-1-one

[0252] The synthesis method of Example 1 was followed, except that 2-chloro-4-fluoropyridine in step 2 was replaced with 2-methoxy-4-fluoropyridine (111 μL, 1 mmol). The reaction was carried out at room temperature, and compound I-6 was prepared by the same method. The product (compound 6) was purified by reversed-phase column chromatography (methanol:water = 90:10) to obtain 38 mg of product (compound 6). 1H NMR (300MHz, DMSO-d6) δ7.77(d,J=5.8Hz,1H),7.28(d,J=2.5Hz,1H),6.07(dd,J=5.8,2.0Hz,1H),5.65(d,J=1.9 Hz,1H),4.59(d,J=7.3Hz,2H),4.16–3.96(m,2H),3.81(s,5H),3.57(ddd,J=8.2,5.4,2.7Hz,2H),3.08(q,J=7.0 Hz,1H),3.01–2.78(m,4H),2.29(d,J=9.6Hz,3H).

[0253] Example 7 Preparation of 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-(1-(2-(difluoromethoxy)pyridin-4-yl)azacyclobutane-3-yl)ethane-1-one

[0254] Step 1: Synthesis of I-7-1

[0255] 200 mg (0.71 mmol) of 2-chloro-7,8-dihydro-4-methyl-1,6-naphthyl-6(5H)-carboxylic acid tert-butyl ester was added to a single-necked flask equipped with a stir bar. 3 mL of a dioxane solution (4 mol / L) in hydrochloric acid was then added at room temperature, and the reaction was allowed to proceed at room temperature. After the reaction was complete as monitored by TLC, the solution was directly evaporated to dryness without purification, and the final quantification was performed.

[0256] Step 2: Synthesis of I-7-2

[0257] In a two-necked flask equipped with a stir bar, add 135 μL (1 mmol) of 4-bromo-2-(difluoromethoxy)pyridine, 2,2,2-trifluoroacetate of methyl 2-(azacyclobutane-3-yl)acetate (243 mg, 1 mmol), 85 mg (0.1 mmol) of (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II), 50 mg (0.1 mmol) of 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl, and 1 g (3.07 mmol). Under nitrogen protection, add 6 mL of anhydrous dioxane and react at 100 °C. After the reaction was monitored by TLC until it was complete, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 157 mg of orange powder. 1H NMR (300MHz, CDCl3) δ7.83(d,J=5.9Hz,1H),7.55(d,J=73.6Hz,1H),6.10(dd,J=5.9,2.1Hz,1H),5.78(d,J=2.0Hz,1H ),4.17(t,J=8.2Hz,2H),3.73(s,3H),3.68(dd,J=8.1,5.4Hz,2H),3.17(pt,J=8.0,5.4Hz,1H),2.75(d,J=7.8Hz,2H).

[0258] Step 3: Synthesis of I-7

[0259] I-7-1 (quantitative), I-7-2 (140 mg, 0.51 mmol), and 1,5,7-triazidobicyclo(4.4.0)dec-5-ene (210 mg, 1.51 mmol) were added to a two-necked flask equipped with a stir bar. 5 mL of anhydrous tetrahydrofuran was added at room temperature, and the reaction was carried out at 70 °C. After the reaction was monitored by TLC until complete, the mixture was cooled to room temperature, concentrated, and then purified by adding purified water, saturated sodium chloride solution, and saturated ammonium chloride solution sequentially. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reversed-phase column chromatography (methanol:water = 86:14) to obtain 40 mg of the product (compound 7). 1 H NMR (300MHz, CDCl3) δ7.80(d,J=5.8Hz,1H),7.55(d,J=73.7Hz,1H),7.07(d,J=1.0Hz, 1H),6.08(dd,J=5.8,2.0Hz,1H),5.75(d,J=2.0Hz,1H),4.57(d,J=42.3Hz,2H),4.20(t ,J=8.0Hz,2H),3.78(t,J=5.9Hz,2H),3.66(dd,J=8.1,5.3Hz,2H),3.25(ddt,J=10.5,7 .8,3.9Hz,1H),3.01(dt,J=17.8,6.0Hz,2H),2.87(dd,J=7.8,2.2Hz,2H),2.28(s,3H).

[0260] Example 8 Preparation of 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-(1-(2-fluoropyridin-4-yl)azacyclobutane-3-yl)ethane-1-one

[0261] The synthesis method of Example 7 was followed, except that 4-bromo-2-(difluoromethoxy)pyridine in step 2 was replaced with 4-bromo-2-fluoropyridine (102 μL, 1 mmol). Compound I-8 was prepared by the same method and purified by reversed-phase column chromatography (methanol:water = 90:10) to obtain 38 mg of product (compound 8). 1 H NMR (300MHz, CDCl3) δ7.94(dd,J=5.5,1.8Hz,1H),7.07(s,1H),6.73(dd,J=5.5,1.7Hz,1H),6.42(d,J=1.6Hz,1H),4.58(d,J=40.8Hz,2H),4 .27(t,J=8.1Hz,2H),3.94–3.64(m,4H),3.21(pt,J=7.6,5.3Hz,1H),3.01(dt,J=17.7,6.0Hz,2H),2.87(dd,J=7.8,2.3Hz,2H),2.28(s,3H).

[0262] Example 9 Preparation of 4-(3-(2-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-oxoethyl)azacyclobutane-1-yl)-N,N-diethyl-2-(trifluoromethyl)benzamide

[0263] Step 1: Synthesis of I-9-1

[0264] In a single-necked flask equipped with a stir bar, 316 mg (1 mmol) of 2-formic acid-5-iodotrifluorotoluene, 170 mg (1.55 mmol) of diethylamine hydrochloride, 340 mg (1.21 mmol) of N,N,N',N'-tetramethylchlorourea hexafluorophosphate, and 280 μL (3.5 mmol) of N-methylimidazole were added. 3 mL of anhydrous acetonitrile was added at room temperature, and the reaction was allowed to proceed at room temperature. After the reaction was complete as monitored by TLC, the mixture was evaporated to dryness, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (dichloromethane) to obtain 300 mg of an oily substance. 1 H NMR (300MHz, CDCl3) δ8.06(d,J=1.7Hz,1H),7.96(dd,J=8.2,1.7Hz,1H),7.12(d,J=8.0Hz,1H),3.89(dq,J=14 .1,7.2Hz,1H),3.30(dq,J=13.9,7.0Hz,1H),3.20–3.05(m,2H),1.27(t,J=7.2Hz,3H),1.09(t,J=7.1Hz,3H).

[0265] The remaining synthesis steps were performed according to the synthesis method of Example 7, except that 4-bromo-2-(difluoromethoxy)pyridine in step 2 of Example 7 was replaced with I-9-1 (300 mg, 0.99 mmol), and 180 mg of product (compound 9) was obtained by silica gel column chromatography (ethyl acetate). 1 H NMR (300MHz, DMSO-d6) δ7.26 (s, 1H), 7.16 (d, J = 8.2Hz, 1H), 6.75 –6.57(m,2H),4.56(d,J=6.6Hz,2H),4.08(td,J=7.6,2.5Hz,2H),3.75(td,J=7.8,6.8,3.2Hz,2H),3.56(td,J=7.2,6.6,3.5Hz,3H), 3.17(d,J=5.3Hz,1H),3.04(h,J=6.5Hz,3H),2.98–2.75(m,4H),2.26(d,J=7.4Hz,3H),1.09(t,J=7.0Hz,3H),0.97(t,J=7.0Hz,3H).

[0266] Example 10 Preparation of 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-(1-(2'-methyl-[2,4'-bipyridin]-4-yl)azacyclobutane-3-yl)ethane-1-one

[0267] Step 1: Synthesis of I-10-1

[0268] 300 mg (1.06 mmol) of 2-chloro-7,8-dihydro-4-methyl-1,6-naphthyl-6(5H)-carboxylic acid tert-butyl ester was added to a single-necked flask equipped with a stir bar. 3 mL of a dioxane solution (4 mol / L) in hydrochloric acid was then added at room temperature, and the reaction was allowed to proceed at room temperature. After the reaction was complete as monitored by TLC, the solution was directly evaporated to dryness without purification, and the final quantification was performed.

[0269] Step 2: Synthesis of I-10-2

[0270] 2-Bromo-4-fluoropyridine (118 μL, 1.14 mmol), pinacol ester of 2-chloropyridine-4-boronic acid (326 mg, 1.36 mmol), tetrakis(triphenylphosphine)palladium (127 mg, 0.11 mmol), and cesium carbonate (1.11 g, 3.42 mmol) were added to a two-necked flask equipped with a stir bar. Under nitrogen protection, 6 mL of a mixture of dioxane and water (5:1) was added, and the mixture was purged three times with nitrogen. The reaction was carried out at 110 °C. After the reaction was complete as monitored by TLC, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 130 mg of a white powder. 1 H NMR(300MHz,DMSO-d6)δ8.79(dd,J=8.9,5.6Hz,1H),8.57(dd,J=5.2,0.7Hz,1H), 8.27–8.18(m,2H),8.14(dd,J=5.2,1.6Hz,1H),7.49(ddd,J=8.7,5.6,2.4Hz,1H).

[0271] Step 3: Synthesis of I-10-3

[0272] In a two-necked flask equipped with a stir bar, 2'-chloro-4-fluoro-2,4'-bipyridine (250 mg, 1.20 mmol), trimethylcycloboroxane (1.01 mL, 3.59 mmol), palladium acetate (27 mg, 0.12 mmol), tricyclohexylphosphine (67 mg, 0.24 mmol), and potassium phosphate (764 mg, 3.60 mmol) were added. Under nitrogen protection, 6 mL of a mixture of dioxane and water (5:1) was added, and the mixture was purged three times with nitrogen. The reaction was carried out at 100 °C. After the reaction was complete as monitored by TLC, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (ethyl acetate:methanol = 300:1) to obtain 180 mg of a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.76(dd,J=9.0,5.6Hz,1H),8.59(dd,J=5.2,0.8Hz,1H),8.10(dd,J=10.8,2.4Hz ,1H),7.99(d,J=1.7Hz,1H),7.89(dd,J=5.2,1.7Hz,1H),7.44(ddd,J=8.7,5.6,2.4Hz,1H),2.57(s,3H).

[0273] Step 4: Synthesis of I-10-4

[0274] In a single-necked flask equipped with a stirrer, 4-fluoro-2'-methyl-2,4'-bipyridine (180 mg, 0.96 mmol), methyl 2-(azacyclobutan-3-yl)acetate 2,2,2-trifluoroacetate (268 mg, 1.10 mmol), and cesium carbonate (899 mg, 2.76 mmol) were added. DMSO was added at room temperature, and the reaction was carried out at 120 °C. After the reaction was monitored by TLC until complete, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 225 mg of a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.50(dd,J=5.3,0.8Hz,1H),8.24(d,J=5.6Hz,1H),7.93–7.87(m,1H),7.85–7.67(m,1H),6.99(d,J=2.1Hz,1H),6.39( dd,J=5.6,2.2Hz,1H),4.14(t,J=8.1Hz,2H),3.69(dd,J=8.2,5.6Hz,2H),3.62(s,3H),3.13–2.96(m,1H),2.78(d,J=7.8Hz,2H),2.54(s,3H).

[0275] Step 5: Synthesis of I-10

[0276] Following the synthesis method of step 3 in Example 7, except that I-7-2 in step 3 of Example 7 was replaced with I-10-4 (225 mg, 0.76 mmol), compound I-10 was prepared by the same method, and 106 mg of product (compound 10) was separated by silica gel column chromatography (dichloromethane:methanol = 20:1). 1 H NMR (300MHz, CDCl3) δ8.55 (dd, J=5.2, 0.8Hz, 1H), 8.31 (dd, J=5.7, 1.7Hz, 1H), 7.71 (d, J=1.7 Hz,1H),7.57(dt,J=4.4,2.2Hz,1H),7.06(s,1H),6.67(d,J=2.2Hz,1H),6.28(dd,J=5.7,2.2H z,1H),4.57(d,J=41.5Hz,2H),4.27(t,J=8.0Hz,2H),3.90–3.61(m,4H),3.27(dqd,J=14.2,6 .7, 2.9Hz, 1H), 3.00 (dt, J=17.6, 5.9Hz, 2H), 2.89 (d, J=7.7Hz, 2H), 2.62 (s, 3H), 2.26 (s, 3H).

[0277] Example 11 Preparation of 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-(1-(4-(piperidin-1-carbonyl)-3-(trifluoromethyl)phenyl)azacyclobutane-3-yl)ethane-1-one

[0278] Step 1: Synthesis of I-11-1

[0279] Add 1-Boc-piperidine (186 mg, 1.01 mmol) to a single-necked flask equipped with a stir bar, then add 4 mL of dichloromethane and 1.5 mL of trifluoroacetic acid sequentially at room temperature. After the reaction is complete as monitored by TLC, evaporate to dryness without purification.

[0280] Step 2: Synthesis of I-11-2

[0281] In a single-necked flask equipped with a stir bar, 316 mg (1 mmol) of 5-iodotrifluorotoluene-2-formic acid, piperidine trifluoroacetate (quantitative), 340 mg (1.21 mmol) of N,N,N',N'-tetramethylchlorourea hexafluorophosphate, and 280 μL (3.5 mmol) were added. 5 mL of anhydrous acetonitrile was added at room temperature, and the reaction was allowed to proceed at room temperature. After the reaction was monitored by TLC until complete, the mixture was evaporated to dryness, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (dichloromethane) to obtain 200 mg of a white powder. 1 H NMR (300MHz, CDCl3) δ8.06–7.94(m,2H),7.83(dd,J=8.5,2.0Hz,1H),3.38(q,J=7.1Hz,4H),1.24–1.12(m,6H).

[0282] The remaining synthesis steps were performed according to the synthesis method of Example 9, except that the intermediate N,N-diethyl-4-iodine-2-(trifluoromethyl)benzamide in step 1 of Example 9 was replaced with I-11-2 (332 mg, 0.87 mmol), and compound I-11 was prepared by the same method. The product (compound 11) was separated into 86 mg by silica gel column chromatography (ethyl acetate). 1H NMR (300MHz, CDCl3) δ7.15–7.04(m,2H),6.63(d,J=2.3Hz,1H),6.54(dd,J=8.3,2.3Hz,1H),4.59(d,J=41.5Hz,2H),4.19(t,J=7.6Hz,2H),3.79(t, J=5.9Hz,2H),3.63(dd,J=7.5,5.3Hz,2H),3.29–3.20(m,1H),3.16(t,J=5 .5Hz,2H),3.02(dt,J=17.4,5.9Hz,2H),2.88(dd,J=7.7,2.5Hz,2H),2.29 (s,3H),1.75–1.58(m,8H).

[0283] Example 12 Preparation of 4-(3-(2-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-oxoethyl)azacyclobutane-1-yl)-2-(trifluoromethoxy)benzylnitrile

[0284] The synthesis method of Example 7 was followed, except that 4-bromo-2-(difluoromethoxy)pyridine in step 2 was replaced with 2-trifluoromethoxy-4-bromobenzonitrile (266 mg, 1 mmol), and compound I-12 was prepared by the same method. 96 mg of product (compound 12) was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2). 1 H NMR (300MHz, DMSO-d6) δ7.64(d,J=8.5Hz,1H),7.26(d,J=2.4Hz,1H),6.55–6.33(m,2H),4.56(d,J=5.9Hz,2H),4.1 5(td,J=8.3,2.4Hz,2H),3.82–3.58(m,4H),3.07(dt,J=13.7,7.1Hz,1H),2.99–2.70(m,4H),2.26(d,J=8.3Hz,3H).

[0285] Example 13 Preparation of 4-(3-(2-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-oxoethyl)azacyclobutane-1-yl)-N,N-dimethyl-2-(trifluoromethyl)benzamide

[0286] The synthesis method of Example 9 was followed, except that diethylamine hydrochloride in step 1 was replaced with dimethylamine hydrochloride (100 mg, 1.23 mmol). Compound I-13 was prepared by the same method, and 96 mg of product (compound 13) was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2). 1 H NMR (300MHz, DMSO-d6) δ7.26(s,1H),7.16(d,J=8.3Hz,1H),6.70–6.50(m,2H),4.56(d,J=6.6Hz,2H),4.08(td,J=7.7,1.9Hz,2H),3.75(td ,J=6.0,2.9Hz,2H),3.57(dq,J=8.8,3.7Hz,2H),3.06(p,J=6.5Hz,1H),2.95(s,4H),2.93–2.77(m,3H),2.73(s,3H),2.26(d,J=7.5Hz,3H).

[0287] Example 14 Preparation of 4-(3-(2-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-oxoethyl)azacyclobutane-1-yl)-2-fluorobenzonitrile

[0288] The synthesis method of Example 7 was followed, except that 4-bromo-2-(difluoromethoxy)pyridine in step 2 was replaced with 2-fluoro-4-iodobenzonitrile (247 mg, 1 mmol). Compound I-14 was prepared by the same method and purified by reversed-phase column chromatography (methanol:water = 85:15) to obtain 50 mg of product (compound 14). 1 H NMR (300MHz, DMSO-d6) δ7.52(dd,J=8.6,7.7Hz,1H),7.26(d,J=2.8Hz,1H),6.36(dd,J=12.5,2.1Hz,1H),6.26(dd,J=8.6,2.1Hz,1H),4.55(d,J=7.1Hz,2H ),4.11(td,J=8.3,2.4Hz,2H),3.74(td,J=5.8,3.3Hz,2H),3.63(ddd,J=8.3, 5.4, ​​2.6Hz, 2H), 3.13–2.97 (m, 1H), 2.97–2.74 (m, 4H), 2.25 (d, J = 9.2Hz, 3H).

[0289] Example 15 Preparation of ethyl 4-(3-(2-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-oxoethyl)azacyclobutane-1-yl)-2-trifluoromethylbenzoate

[0290] The synthesis method of Example 7 was followed, except that 4-bromo-2-(difluoromethoxy)pyridine in step 2 was replaced with ethyl 4-bromo-2-(trifluoromethyl)benzoate (297 mg, 1 mmol). Compound I-15 was prepared by the same method, and 60 mg of product (compound 15) was separated by silica gel plate purification (petroleum ether: ethyl acetate = 1:1).

[0291] Example 16 Preparation of 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-(1-(pyridin-4-yl)azacyclobutan-3-yl)ethane-1-one

[0292] Step 1: Synthesis of I-16-1

[0293] 238 mg (0.85 mmol) of 2-chloro-7,8-dihydro-4-methyl-1,6-naphthyl-6(5H)-carboxylic acid tert-butyl ester was added to a single-necked flask equipped with a stir bar. 3 mL of a dioxane solution (4 mol / L) in hydrochloric acid was then added at room temperature, and the reaction was allowed to proceed at room temperature. After the reaction was complete as monitored by TLC, the solution was directly evaporated to dryness without purification, and quantified.

[0294] Step 2: Synthesis of I-16-2

[0295] In a two-necked flask equipped with a stir bar, 200 mg of 4-fluoropyridine hydrochloride (1.5 mmol), 365 mg of 2-(azacyclobutane-3-yl)methyl acetate 2,2,2-trifluoroacetate (1.5 mmol), and 1.3 g of cesium carbonate (3.07 mmol) were added. 6 mL of N,N-dimethylformamide was added at room temperature, and the reaction was carried out at 110 °C. After the reaction was complete as monitored by TLC, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (ethyl acetate) to obtain 190 mg of an oily substance. 1 H NMR (300MHz, CDCl3) δ8.27–8.18(m,2H),6.30–6.21(m,2H),4.16(t,J=8.0Hz ,2H),3.76–3.61(m,5H),3.16(pt,J=7.9,5.4Hz,1H),2.75(d,J=7.8Hz,2H).

[0296] Step 3: Synthesis of I-16

[0297] I-16-1 (quantitative), I-16-2 (175 mg, 0.85 mmol), and 1,5,7-triazidobicyclo(4.4.0)dec-5-ene (470 mg, 3.38 mmol) were added to a two-necked flask equipped with a stir bar. 8 mL of anhydrous tetrahydrofuran was added at room temperature, and the reaction was carried out at 70 °C. After the reaction was monitored by TLC until complete, the mixture was cooled to room temperature, concentrated, and then purified water, saturated sodium chloride solution, and saturated ammonium chloride solution were added sequentially. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain 130 mg of the product (compound 16).

[0298] Example 17 Preparation of 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-(1-(4-methoxy-3-(trifluoromethyl)phenyl)azacyclobutane-3-yl)ethane-1-one

[0299] The synthesis method of Example 7 was followed, except that 4-bromo-2-(difluoromethoxy)pyridine in step 2 was replaced with 4-bromo-2-(trifluoromethyl)anisole (255 mg, 1 mmol), and compound I-17 was prepared by the same method. 150 mg of product (compound 17) was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1). 1 H NMR (300MHz, DMSO-d6) δ7.26(s,1H),7.11(d,J=8.9Hz,1H),6.67(dd,J=8.9,2.8Hz,1H),6.57(d,J=2.8Hz,1H),4.56(d,J=6.9Hz,2H),3.9 6(t,J=7.3Hz,2H),3.83–3.65(m,5H),3.44(ddd,J=8.4,5.6,2.7Hz,2H),3.00(q,J=6.7Hz,1H),2.97–2.72(m,4H),2.25(d,J=7.4Hz,3H).

[0300] Example 18 Preparation of 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-(1-(3-fluoro-4-methoxyphenyl)azacyclobutane-3-yl)ethane-1-one

[0301] The synthesis method of Example 7 was followed, except that 4-bromo-2-(difluoromethoxy)pyridine in step 2 was replaced with 2-fluoro-4-iodoanisole (252 mg, 1 mmol), and compound I-18 was prepared by the same method. 100 mg of product (compound 18) was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1). 1 H NMR (300MHz, DMSO-d6) δ7.26(d,J=2.0Hz,1H),6.97(t,J=9.2Hz,1H),6.31(dd,J=13.4,2.6Hz,1H),6.14(ddd,J=8.7,2.7,1.2Hz,1H ),4.55(d,J=7.7Hz,2H),3.90(t,J=7.2Hz,2H),3.72(s,5H),3.45–3.37(m,2H),2.87(tt,J=25.4,6.5Hz,5H),2.25(d,J=8.8Hz,3H).

[0302] Example 19 Preparation of 6-(3-(2-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-oxoethyl)azacyclobutane-1-yl)nicotinonitrile

[0303] The synthesis method of Example 16 was followed, except that 4-fluoropyridine hydrochloride in step 2 was replaced with 4-cyano-2-fluoropyridine (122 mg, 1 mmol), and compound I-19 was prepared by the same method. 80 mg of product (compound 19) was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1). 1 H NMR (300MHz, DMSO-d6) δ8.42(d,J=2.2Hz,1H),7.78(dd,J=8.8,2.3Hz,1H),7.26(d,J=2.8Hz,1H),6.40(d,J=8.9Hz,1H),4.56(d ,J=7.0Hz,2H),4.39–4.00(m,2H),3.74(tq,J=5.5,3.0,2.5Hz,4H),3.11–2.99(m,1H),2.99–2.72(m,4H),2.25(d,J=8.8Hz,3H).

[0304] Example 20 Preparation of 4-(3-(2-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-oxoethyl)azacyclobutane-1-yl)-2-(trifluoromethyl)benzylnitrile

[0305] Step 1: Synthesis of I-20-1

[0306] 100 mg (0.36 mmol) of tert-butyl 2-chloro-7,8-dihydro-4-methyl-1,6-naphthyl-6(5H)-carboxylic acid was added to a single-necked flask equipped with a stir bar. 2 mL of a dioxane solution (4 mol / L) in hydrochloric acid was then added at room temperature, and the reaction was allowed to proceed at room temperature. After the reaction was complete as monitored by TLC, the solution was directly evaporated to dryness without purification, and quantified.

[0307] Step 2: Synthesis of I-20-2

[0308] In a two-necked flask equipped with a stir bar, 250 mg of 4-bromo-2-trifluoromethylbenzonitrile (1 mmol), 2,2,2-trifluoroacetate methyl 2-(azacyclobutane-3-yl)acetate (243 mg, 1 mmol), tris(dibenzylacetone)palladium (92 mg, 0.1 mmol), 62 mg of 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.1 mmol), and 288 mg of sodium tert-butoxide (3 mmol) were added. Under nitrogen protection, 6 mL of anhydrous dioxane was added, and the reaction was carried out at 100 °C. After the reaction was complete as monitored by TLC, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 40 mg of yellow powder.

[0309] Step 3: Synthesis of I-20-3

[0310] In a single-necked flask equipped with a stirrer, I-20-2 (750 mg, 2.51 mmol) and potassium trimethylsilanolate (1.3 g, 10.09 mmol) were added. 6 mL of anhydrous acetonitrile was added at room temperature, and the reaction was allowed to proceed at room temperature. After the reaction was complete as monitored by TLC, the mixture was concentrated, and purified water was added sequentially. The mixture was then extracted with ethyl acetate, and the ethyl acetate layer was discarded, retaining the aqueous layer. The aqueous layer was adjusted to pH 4 with 1 M HCl aqueous solution, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 396 mg of crude product, which required no further purification.

[0311] Step 4: Synthesis of I-20

[0312] In a single-necked flask equipped with a stir bar, I-20-1 (quantitative), I-20-3 (100 mg, 0.35 mmol), N,N,N',N'-tetramethylchlorourea hexafluorophosphate (120 mg, 0.43 mmol), and N-methylimidazole (116 μL, 1.41 mmol) were added. 3 mL of anhydrous acetonitrile was added at room temperature, and the reaction was allowed to proceed at room temperature. After the reaction was monitored by TLC until complete, the mixture was evaporated to dryness, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 120 mg of the product (compound 20).1 H NMR (300MHz, DMSO-d6) δ7.76(d,J=8.5Hz,1H),7.27(s,1H),6.73(s,1H),6.65(d,J=8.8Hz,1H),4.56(d,J=5.6Hz,2H),4.19 (t,J=8.5Hz,2H),3.73(dq,J=10.8,6.0,5.5Hz,4H),3.17–3.03(m,1H),2.87(dt,J=43.9,5.8Hz,4H),2.25(d,J=7.6Hz,3H).

[0313] Example 21 Preparation of 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-(1-(pyridin-2-yl)azacyclobutan-3-yl)ethane-1-one

[0314] Following the synthetic method of Example 16, except that 4-fluoropyridine hydrochloride in step 2 was replaced with 2-fluoropyridine (106 μL, 1.24 mmol), compound I-21 was prepared by the same method. 80 mg of product (compound 21) was obtained by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1). 1 H NMR (300MHz, DMSO-d6) δ8.04(d,J=4.9Hz,1H),7.47(t,J=7.8Hz,1H),7.26(s,1H),6.59(t,J=6.0Hz,1H),6.33(d,J=8.4Hz,1H),4.56(d,J=7.8Hz, 2H),4.06(t,J=7.8Hz,2H),3.76(d,J=6.2Hz,2H),3.59(d,J=14.0Hz,2H) ,3.11-2.97(m,1H),2.85(dt,J=32.7,5.9Hz,4H),2.26(d,J=8.0Hz,3H).

[0315] Example 22 Preparation of 2-(3-(2-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-oxoethyl)azacyclobutane-1-yl)-4-(4-(3-(2-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-oxoethyl)azacyclobutane-1-yl)pyridin-2-yl)benzonitrile

[0316] Step 1: Synthesis of I-22-1

[0317] 2-Bromo-4-fluoropyridine (118 μL, 1.14 mmol), pinacol 4-cyano-3-fluorophenylboronic acid (420 mg, 1.70 mmol), tetrakis(triphenylphosphine)palladium (127 mg, 0.11 mmol), and cesium carbonate (1.11 g, 3.42 mmol) were added to a two-necked flask equipped with a stir bar. Under nitrogen protection, 6 mL of a mixture of dioxane and water (5:1) was added, and the mixture was purged three times with nitrogen. The reaction was carried out at 110 °C. After the reaction was complete as monitored by TLC, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1) to obtain 224 mg of a white powder. 1 H NMR(300MHz, DMSO-d6)δ8.78(dd,J=9.0,5.6Hz,1H),8.26(dd,J=11.1,1.5Hz,1H),8.23–8.1 9(m,1H),8.19–8.14(m,1H),8.09(dd,J=8.2,6.8Hz,1H),7.45(ddd,J=8.6,5.6,2.4Hz,1H).

[0318] Step 2: Synthesis of I-22-2

[0319] In a single-necked flask equipped with a stirrer, 2-fluoro-4-(4-fluoropyridin-2-yl)benzonitrile (312 mg, 1.44 mmol), methyl 2-(azacyclobutane-3-yl)acetate 2,2,2-trifluoroacetate (268 mg, 1.10 mmol), and cesium carbonate (899 mg, 2.76 mmol) were added. DMSO was added at room temperature, and the reaction was carried out at 120 °C. After the reaction was monitored by TLC until complete, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain 222 mg of green powder. 1 H NMR (400MHz, CDCl3) δ8.30(d,J=5.8Hz,1H),7.46(d,J=8.1Hz,1H),7.15(dd,J=8.1,1.5Hz,1H),7.09(d,J =1.4Hz,1H),6.58(d,J=2.2Hz,1H),6.27(dd,J=5.8,2.3Hz,1H),4.48(t,J=8.1Hz,2H),4.24(t,J=8.1Hz, 2H),3.98(dd,J=8.2,5.4Hz,2H),3.79–3.74(m,2H),3.73(d,J=5.2Hz,6H),3.26–3.05(m,2H),2.76(dd,J=7.8,6.1Hz,4H).

[0320] Step 3: Synthesis of I-22

[0321] In a single-necked flask equipped with a stir bar, methyl 2-(1-(2-(4-cyano-3-(3-(2-methoxy-2-oxoethyl)azacyclobutane-1-yl)phenyl)pyridin-4-yl)azacyclobutane-3-yl)acetate (214 mg, 0.49 mmol), 2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride (136 mg, 0.62 mmol), and 1,5,7-triazidobicyclo(4.4.0)dec-5-ene (343 mg, 2.47 mmol) were added. Anhydrous tetrahydrofuran was added at room temperature, and the reaction was carried out at 70 °C. After the reaction was monitored by TLC until it was complete, the mixture was cooled to room temperature, concentrated, and then purified water, saturated sodium chloride solution, and saturated ammonium chloride solution were added sequentially. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (ethyl acetate) to obtain 171 mg of the product (compound 22). 1 H NMR (300MHz, CDCl3) δ8.21(dd,J=5.8,1.6Hz,1H),7.38(d,J=8.1Hz,1H),7.13–7.04(m,1H),6.99(dt ,J=5.0,2.5Hz,1H),6.84(d,J=3.8Hz,2H),6.50(t,J=2.6Hz,1H),6.20(dq,J=5.4,1.6Hz,1H),4.68(d ,J=14.2Hz,8H),4.45(td,J=8.1,2.5Hz,2H),4.29–4.18(m,2H),3.94(dt,J=5.5,3.0Hz,2H),3.72(dd t,J=12.0,9.1,4.6Hz,2H),3.35–3.11(m,2H),2.83–2.69(m,4H),2.46(d,J=3.1Hz,6H),2.20(s,6H).

[0322] Example 37 1-(2-chloro-4-methyl-7,8-dihydro-1,6-naphthid-6(5H)-yl)-2-fluoro-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutane-3-yl)ethane-1-one

[0323] Step 1: Synthesis of I-37-1

[0324] 1-tert-Butoxycarbonyl-3-azacyclobutanone (778 mg, 4.54 mmol), triethyl 2-fluoro-2-phosphorylacetate (838 μL, 4.13 mmol), and DBU (925 μL, 6.19 mmol) were added to a two-necked flask equipped with a stir bar. Anhydrous dichloromethane was added at room temperature, and the reaction was allowed to proceed at room temperature. After the reaction was monitored by TLC until complete, the mixture was cooled to room temperature, quenched with saturated ammonium chloride solution, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 549 mg of an oily substance. 1H NMR (300MHz, CDCl3) δ4.74 (td, J=4.5, 4.1, 2.8Hz, 2H), 4.65 (td, J=5.0, 4.3, 2.8Hz, 2H), 4.29 (q, J=7.1Hz, 2H), 1.46 (s, 9H), 1.33 (t, J=7.1Hz, 3H).

[0325] Step 2: Synthesis of I-37-2

[0326] 549 mg (2.12 mmol) of 3-(2-ethoxy-1-fluoro-2-oxoethylene)azacyclobutane-1-carboxylic acid tert-butyl ester (Pd / C, catalytic amount) was added to a single-necked flask equipped with a stirrer. Methanol was added at room temperature, and the mixture was purged three times with hydrogen gas. The reaction was allowed to proceed at room temperature. After the reaction was completed by TLC, the mixture was filtered, and the organic phase was concentrated to obtain the crude product. The crude product was dissolved in DCM and reacted slowly with trifluoroacetic acid (5 eq) at room temperature. After the reaction was completed by TLC, the organic phase was concentrated, and an oily substance (quantitative) was separated, requiring no further purification.

[0327] Step 3: Synthesis of I-37-3

[0328] In a single-necked flask equipped with a stirrer, 2,2,2-trifluoroacetate of 2-(azacyclobutan-3-yl)-2-fluoroethyl acetate (quantitative), 4-chloro-2-(trifluoromethyl)pyridine (233 μL, 1.82 mmol), and potassium carbonate (753 mg, 5.45 mmol) were added. DMSO was added at room temperature, and the reaction was carried out at 120 °C. After the reaction was monitored by TLC until complete, it was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 1311 mg of a clear oil. 1H NMR (300MHz, CDCl3) δ8.29(d,J=5.7Hz,1H),6.59(d,J=2.3Hz,1H),6.35(dd,J=5.7,2.3Hz,1H),5.07(dd,J=48.6,5.6Hz,1 H),4.29(q,J=7.1Hz,2H),4.22–4.12(m,1H),4.12–3.91(m,3H),3.36(dtq,J=22.5,8.4,5.7Hz,1H),1.32(t,J=7.1Hz,3H).

[0329] Step 4: Synthesis of I-37-4

[0330] 500 mg (1.77 mmol) of 2-chloro-4-methyl-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid tert-butyl ester was added to a single-necked flask equipped with a stir bar, followed by 3 mL of 1,4-dioxane hydrochloride at room temperature. The reaction was allowed to proceed at room temperature. After the reaction was completed as monitored by TLC, the organic phase was concentrated, and a white solid (quantitative) was obtained, requiring no further purification.

[0331] Step 5: Synthesis of I-37

[0332] In a single-necked flask equipped with a stirrer, ethyl 2-fluoro-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutan-3-yl)acetate (1049 mg, 3.42 mmol), 2-chloro-4-methyl-5,6,7,8-tetrahydro-1,6-naphthylpyridine hydrochloride (750 mg, 3.42 mmol), and 1,5,7-triazidobicyclo(4.4.0)dec-5-ene (3335 mg, 23.96 mmol) were added. Anhydrous tetrahydrofuran was added at room temperature, and the reaction was carried out at 70 °C. After the reaction was monitored by TLC until complete, the mixture was cooled to room temperature, concentrated, and then extracted successively with purified water, saturated sodium chloride solution, and saturated ammonium chloride solution. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography (ethyl acetate) to obtain 178 mg of the product (compound 37).

[0333] Examples 23-36

[0334] Biological testing evaluation

[0335] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0336] The CVL-231 structure mentioned in this disclosure is shown below, and it was prepared according to the method of Example 11 in PCT / IB2017 / 053565.

[0337] Test Example 1: In vitro positive allosteric regulation assay of M4 receptor

[0338] 1.1 In vitro isotope binding assay

[0339] 1.1.1 Preparation of cell receptor membrane

[0340] Cells were removed from the -80°C freezer and thawed naturally. They were then centrifuged at 1000g at 4°C for 10 minutes. The pellet was collected, and the supernatant was discarded. Buffer was added to the pellet. The cells were mixed for 20-30 seconds, then centrifuged at 48000g at 4°C for 25 minutes. The supernatant was carefully discarded, and buffer was added again, mixed, and centrifuged at 48000g at 4°C for 25 minutes. The pellet was then stored at -80°C.

[0341] 1.1.2 Preparation of test sample

[0342] Before preparing the test sample, label each 2mL EP tube with a different concentration for each sample. Calculate the theoretical sample weight based on the designed concentration and required volume. Generally, 5.0 × 10⁻⁶. -3 M is the initial dosage, dissolved in DMSO, and then sequentially diluted with DMSO to 5.0 × 10⁻⁶. -4 M~5.0×10 -9 M. Dilute the diluted DMSO solution with buffer solution to the working concentration. The final concentration of DMSO in the working solution is 1% (the final concentration of DMSO in the reaction system is 0.2%). If the test sample does not dissolve well or is not uniformly suspended, HCl (1M, 50μL) can be added appropriately, or appropriate suspension or sonication can be performed. After preparation, the test sample should be stored at 4℃ and discarded after the experiment. After the experiment, any remaining test sample should be returned to the test sample manager.

[0343] 1.1.3 Test Procedure

[0344] Step 1: Prepare the membrane into a membrane suspension of a certain concentration using a buffer solution.

[0345] Step 2: Add 50 μL of buffer to the total binding tube (TB) and 50 μL of atropine to the nonspecific binding tube (NB) (final concentration 1.0 × 10⁻⁶). -5 M), 50 μL of the ortho-agonist acetylcholine (8 concentration gradients) was added to the test compound tube (CB), and 50 μL of allosteric modifier was added to all tubes.

[0346] Step 3: Add 50 μL of buffer to each reaction tube.

[0347] Step 4: Add 50 μL of the corresponding radioactive ligand to each reaction tube.

[0348] Step 5: Add 50 μL of the membrane preparation to each reaction tube.

[0349] Step 6: Incubate each reaction tube at the corresponding temperature and time. After the reaction is complete, the bound ligands are rapidly filtered under reduced pressure. The filter plate is saturated with 0.5% PEI solution 1 hour in advance, thoroughly washed with ice-cold Tris-HCl buffer, dried at 60°C for 30 minutes, and 40 μL of scintillation solution is added.

[0350] Step 7: Let stand overnight, then place the filter plate into the liquid scintillation counter for counting.

[0351] 1.2 In vitro inositol 1-phosphate (IP-1) assay method

[0352] (1) Prepare the reaction buffer (1 x Stimulation buffer) required for the experiment: Dilute the 5 x Stimulation buffer in the Cisbio IP-one kit with double distilled water (ddH2O) at a ratio of 1:4 and set aside.

[0353] (2) Compound preparation: Dilute the compound to a 5 mM stock solution with DMSO, then dilute it 3.16 times to 10 gradients, and then dilute the prepared compound to the corresponding concentration (4x) with 1 x Stimulation buffer for later use.

[0354] (3) Cell preparation: CHO-M4 cells on the culture dish were digested with trypsin, and the cells were washed with culture medium and collected into 5 mL centrifuge tubes. The cells were centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. 3 mL of PBS was added, and the cells were gently mixed by pipetting. The cells were centrifuged again at 1000 rpm for 5 minutes, and the supernatant was discarded. The cells were resuspended in 1 x Stimulation buffer, counted using a Countstar cell counter, and the cell density was adjusted to 2.14 x 10⁻⁶ cells / mL. 6 Quantity / mL, for later use.

[0355] (4) Cell addition: Add the cell suspension to the experimental plate at 7 μL / well (i.e., about 15,000 cells / well).

[0356] (5) Addition of 1 x Stimulation buffer and addition of compound:

[0357] Allosteric regulation mode: Add the compound diluted with 1 x Stimulation buffer to the above experimental plate, 3.5 μL / well.

[0358] (6) Reaction incubation: After slow shaking, place the experimental plate at 37°C for 20 minutes.

[0359] (7) Compound addition with EC 20 Addition of agonists:

[0360] Activation mode: Add the compound diluted with 1 x Stimulation buffer to the above experimental plate, 3.5 μL / well.

[0361] Allosteric regulation mode: EC 20 A 4x Acetylcholine chloride solution was added to the experimental plate at a rate of 3.5 μL / well.

[0362] (8) Reaction incubation: After slow shaking, place the experimental plate at 37°C for 60 minutes.

[0363] (9) Add detection reagents: Dilute IP1-d2 and Anti-IP1 cryptate 1:20 with Lysis & detection buffer from the Cisbio IP-one detection kit, and add 3 μL of each diluted IP1-d2 and Anti-IP1 cryptate to the experimental plate. After shaking, let the experimental plate stand at room temperature for 60 minutes.

[0364] (10) Experimental readings: Read the plate on the Envision and detect the readings of the 665nm and 615nm channels. Calculate the ratio of the 665nm / 615nm readings.

[0365] 1.3 Test Results

[0366] As shown in Table 1, the results of in vitro isotope binding assay and in vitro IP-1 assay both indicate that the compounds of the present invention are effective positive allosteric modulators of the M4 receptor. For example, the in vitro activities of the representative compounds, such as Examples 1, 4, 7, 11, 22, and 25, are comparable to those of CVL-231, indicating that this series of compounds has the potential to treat schizophrenia.

[0367] Table 1. In vitro activity detection of compounds of the present invention

[0368] Note: " / " indicates that it was not detected.

[0369] Test Example 2: Effect of compound on MK-801-induced hyperactivity behavior in mice

[0370] 2.1.1 Test Methods

[0371] Thirty minutes after administering the test substance (or control substance) by gavage, MK-801 was injected intraperitoneally at a dose of 0.3 mg / kg (administration volume of 10 mL / kg body weight). The mice were then placed in a self-activity box for video recording for 60 minutes. After the recording was completed, the video was analyzed to evaluate the mice's activity.

[0372] 2.1.2 Experimental Data

[0373] The experimental results are shown in Table 2. The experiments demonstrate that CVL-231, along with the compounds in Exemplary Embodiments 1 and 4 of this invention, inhibits highly active ED in mice. 50 The concentrations were 26.70, 41.57, and 58.23 mg / kg, respectively, indicating that the compound of the present invention has a good ability to inhibit MK-801-induced hyperactive behavior in mice and has the potential to treat schizophrenia.

[0374] Table 2 Animal efficacy data of the compounds of this invention

[0375] Test Example 3: Rat Pharmacokinetic Test

[0376] Using CVL-231 as a control, a rat oral / tail vein injection model was used to compare the half-life, brain penetration, and other pharmacokinetic parameters of the compound and the control drug to evaluate their in vivo pharmacokinetic characteristics.

[0377] 3.1 Test Methods

[0378] Preparation of intravenous administration solution: Prepare a 0.2 mg / mL solution of the compound using a 20% hydroxypropyl-β-cyclodextrin solution. The administration volume is 0.5 mL / 100 g body weight, which translates to a dose of 1 mg / kg body weight based on the concentration conversion.

[0379] Preparation of the oral administration solution: Use 0.5% methylcellulose aqueous solution to aid suspension and dispersion, preparing a suspension of 1 mg / mL. The administration volume is 1 mL / 100g body weight, which, according to the concentration conversion, is 10 mg / kg body weight.

[0380] Three rats were used in each group, and the above-mentioned doses were administered orally by gavage and via tail vein, respectively. Blood samples were collected from the orbital cavity at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 10 h after administration to prepare plasma samples. The best results were obtained by LC / MS / MS.

[0381] 3.2 Test Results

[0382] The experimental results are shown in Table 3. Rat pharmacokinetic studies showed that the compounds in Examples 1, 2, 3, and 4 exhibited [specific effects / results]. 1 / 2 Compared to CVL-231, all showed significant improvements, indicating potential advantages such as reducing the frequency of medication and increasing patient compliance. Furthermore, compounds in Examples 1, 2, and 4 improved brain penetration compared to CVL-231, reducing peripheral drug exposure at the effective dose, suggesting a reduction in peripheral adverse reactions.

[0383] Table 3 Pharmacokinetic tests of the compounds of this invention

[0384] In summary, the compounds of this invention have suitable t 1 / 2 It has the potential to reduce the frequency of medication and increase patient compliance; and it has a high brain penetration rate, which can reduce the amount of drug exposed in the periphery at the effective dose and reduce the occurrence of peripheral adverse reactions.

[0385] Those skilled in the art will recognize that many modifications and variations can be made to the invention without departing from its spirit and scope. The specific embodiments described herein are provided by way of example only and are not intended to limit the scope in any way. The true scope and spirit of the invention are shown in the appended claims, and the description and embodiments are merely exemplary.

Claims

A compound of general formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof: in: R1, R2, and R3 are each independently hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; each R4 is independently halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; E is -(CR 10 R 11 ) q -、-O- or -NR 12 -; Each R 10 R 11 Each is independently a deuterium, hydrogen, halogen, hydroxyl, mercapto, C1-C6 alkyl, or C1-C6 haloalkyl; R 12 It is deuterium, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; L is C 6-14 Aryl, 5-14 membered heteroaryl or 5-8 membered heterocyclic; A is absent or is C 6-14 Aryl, 5-14 membered heteroaryl, 5-8 membered heterocyclic or C 6-10 Aryl 5-8 membered heterocyclic groups; each Ra is independently a halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, -N(R5)(R6), -N(R5)(C(=O)R6), -C(= O)-N(R5)(R6), -C(=O)-OR7, -C(=O)-R7 or -S(=O)2-R7; R5 and R6 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl, or R5 and R6 are linked together with the nitrogen atom they are connected to to form a 3-8 member nitrogen-containing heterocyclic group; R7 is C1-C6 alkyl or C1-C6 haloalkyl; m is 0, 1, 2, 3 or 4; q is 0, 1, 2 or 3; n is 0, 1, 2, 3, 4 or 5. The compound of general formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof according to claim 1, is characterized in that... R1, R2, and R3 are each independently hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; each R4 is independently halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; E is -(CH2)q-, -O-, or -NH-; L is C 6-14 Aryl, 5-14 membered heteroaryl or 5-8 membered heterocyclic; A is absent or is C 6-14 Aryl, 5-14 membered heteroaryl, 5-8 membered heterocyclic or C 6-10 Aryl 5-8 membered heterocyclic groups; each Ra is independently a halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, -N(R5)(R6), -N(R5)(C(=O)R6), -C( =O)-N(R5)(R6), -C(=O)-OR7, -C(=O)-R7 or -S(=O)2-R7; R5 and R6 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl, or R5 and R6 are linked with the nitrogen atom they are connected to to form a 3-8 member nitrogen-containing heterocyclic group; R7 is C1-C6 alkyl or C1-C6 haloalkyl; m is 0, 1, 2, 3 or 4; q is 0, 1, 2 or 3; n is 0, 1, 2, 3, 4 or 5. The compound of general formula I, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof according to claim 1 or 2, is characterized in that... It satisfies one or more of the following conditions: (1) R1, R2, and R3 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio or C2-C6 alkenyl; preferably hydrogen, halogen, C1-C6 alkyl, C1-C6 alkylthio or C2-C6 alkenyl; (2) Each R4 is each independently hydroxyl, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; preferably C1-C6 alkyl; more preferably C1-C3 alkyl; (3) E is -(CR 10 R 11 )q-, -O-, or -NR 12 -, preferably -(CH2)q-, -(CHF)q-, -O- or -NH-, more preferably -(CH2)q-, -(CHF)q- or -O-, and even more preferably -(CH2)q-; (4)L is C 6-14 Aryl, 5-14 membered heteroaryl containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, or 5-8 membered heterocyclic group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; preferably C 6-14 Aryl or 5-14 heteroaryl groups containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur; preferably C 6-10 Aryl or a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; preferably phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, or thiopheneyl; preferably phenyl, pyridyl, pyridazinyl, thiopheneyl, or pyrimidinyl; (5) A is absent or is C. 6-14 Aryl, 5-14 membered heteroaryl containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, 5-8 membered heterocyclic group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, or C 6-10 The aryl group contains 1-3 5-8 membered heterocyclic groups selected from nitrogen, oxygen, and sulfur; preferably C. 6-10 Aryl, 5-10 membered heteroaryl, 5-6 membered nitrogen-containing heterocyclic group, 5-6 membered oxygen-containing heterocyclic group, benzo5-6 membered oxygen-containing heterocyclic group or benzo5-6 membered nitrogen-containing heterocyclic group; preferably phenyl, piperazine, pyridinyl, quinolinyl, isoquinolinyl, morpholinyl, thiophene, indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl or benzodioxanepentenyl; preferably phenyl or pyridinyl; (6) each Ra is independently halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -N(R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5) (R6) or -C(=O)-OR7; preferably halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -N(R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6) or -C(=O)-OR7; (7) R5 and R6 are each independently hydrogen or C1-C3 alkyl, or R5 and R6 are linked together with the nitrogen atom they are connected to to form a 5-6 member nitrogen-containing heterocyclic group; (8) R7 is C1-C6 alkyl, preferably C1-C3 alkyl; (9) m is 0, 1 or 2, preferably 0; (10) q is 1 or 2, preferably 1; (11) n is 0, 1, 2, 3 or 4, preferably 0, 1 or 2; (12) R 10 R 11 Each is independently deuterium, hydrogen, halogen, hydroxyl, mercapto, C1-C6 alkyl or C1-C6 haloalkyl; (13)R 12 It is deuterium, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. The compound of formula I according to any one of claims 1-3, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, is characterized in that... General formula I is further shown in general formula II: Preferably, it is shown in Formula III: The compound of formula I according to any one of claims 1-3, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, is characterized in that... General formula I is further shown as general formula IX or general formula X: The preferred formula is shown in equation X: Each Rb is independently deuterium, halogen, hydroxyl, mercapto, C1-C6 alkyl, or C1-C6 haloalkyl. The compound of formula I according to any one of claims 1-5, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, is characterized in that... The compound is selected from the following compounds: A compound of formula V, its stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof: in, p is 0, 1, 2, or 3, preferably 1 or 2; each Ra is independently a C that is optionally substituted. 6-14 Aryl, optionally substituted 5-14-membered heteroaryl, optionally substituted 5-8-membered heterocyclic group, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, -N( R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6), -C(=O)-OR7, -C(=O)-R7 or -S(=O)2-R7; preferably optionally substituted 5-14 heteroaryl, halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C 1- C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, -N(R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6), -C(=O)-OR7, -C(=O)-R7 or -S(=O)2-R7; the optional substituent is selected from halogen, hydroxyl, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl and C2-C6 alkynyl; L is absent or L is C 6-14 Aryl, 5-14 membered heteroaryl, or 5-8 membered heterocyclic; L may be the same or different each time it appears; R1, R2, and R3 are each independently hydrogen, halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; each R4 is independently halogen, hydroxyl, mercapto, cyano, amino, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, or C2-C6 alkynyl; E is -(CR 10 R 11 ) q -、-O- or -NR 12 -; Each R 10 R 11 Each is independently a deuterium, hydrogen, halogen, hydroxyl, mercapto, C1-C6 alkyl, or C1-C6 haloalkyl; R 12 It is deuterium, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; A is absent or is C 6-14 Aryl, 5-14 membered heteroaryl, 5-8 membered heterocyclic or C 6-10 Aryl 5-8 membered heterocyclic group; A may be the same or different each time it appears; R5 and R6 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl, or R5 and R6 are linked together with the nitrogen atom they are connected to to form a 3-8 membered nitrogen-containing heterocyclic group; R7 is C1-C6 alkyl or C1-C6 haloalkyl; m is 0, 1, 2, 3 or 4; q is 0, 1, 2 or 3; n is 0, 1, 2, 3, 4 or 5. The compound of general formula V according to claim 7, its stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, is characterized in that, L is C 6-14 Aryl, 5-14 membered heteroaryl, or 5-8 membered heterocyclic; each Ra is independently a halogen, hydroxyl, mercapto, cyano, amino, nitro, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylamine, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, -N(R5)(R 6) -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6), -C(=O)-OR7, -C(=O)-R7 or -S(=O)2-R7; R5 and R6 are each independently H, C1-C6 alkyl or C1-C6 haloalkyl, or R5 and R6 are linked together with the nitrogen atom they are connected to to form a 3-8 member nitrogen-containing heterocyclic group; R7 is C1-C6 alkyl or C1-C6 haloalkyl; The compound of formula V according to claim 7 or 8, its stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, is characterized in that, The compound is selected from the following compounds: A compound of formula V-1, its stereoisomers, deuterated derivatives, or salts thereof: in, R8 is selected from C1-C6 alkyl groups; L, A, Ra, n and E are as defined in any one of claims 7-9. A method for preparing the compound, its stereoisomer, deuterated product, or pharmaceutically acceptable salt thereof as described in any one of claims 1-6, characterized in that, The steps include: the compound represented by formula IA or its salt reacts with the compound represented by formula IB or formula I-B' to produce the compound represented by formula I; Wherein, R8 is a C1-C6 alkyl group; R1, R2, R3, R4, L, A, Ra, m, n and E are as defined in any one of claims 1-6. A method for preparing the compound, its stereoisomer, deuterated product, or pharmaceutically acceptable salt thereof as described in any one of claims 7-9, characterized in that, Includes the following steps: The compound shown in formula V-1 undergoes a substitution reaction with the compound shown in formula I-A' or its salt to produce the compound shown in formula V; Wherein, R8 is selected from C1-C6 alkyl groups; R1, R2, R3, R4, L, A, Ra, m, n, p and E are as defined in any one of claims 7-9. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1-9, its stereoisomer, deuterated form or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. The use of the compound, its stereoisomer, deuterated form or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 13 in the preparation of a medicament, preferably the medicament being a medicament for the prevention and / or treatment of M4-mediated or M4-related diseases or disorders. According to the use of claim 14, the M4-mediated or M4-related disease or disorder is selected from one or more of Alzheimer's disease, schizophrenia, pain, addiction, sleep disorder, cognitive impairment, Parkinson's disease, Parkinson's disease-levodopa-induced dyskinesia, Huntington's disease, dyskinesia, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, Down syndrome, cerebral amyloid angiopathy, dementia, Dutch amyloid hemorrhage, Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis; preferably selected from one or more of Alzheimer's disease, schizophrenia, pain, addiction, and sleep disorder; more preferably schizophrenia.

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