Substituted azetidine derivative, preparation method therefor, and medical use thereof

Abstract

The present invention relates to the field of medicine, relates to a substituted azetidine derivative, a preparation method therefor, and a medical use thereof, and specifically relates to a compound represented by general formula I or a pharmaceutically acceptable salt or stereoisomer thereof, a pharmaceutical composition comprising the compound, and a use thereof in the field of medicine. The present invention also relates to a method for preparing the compound, and an intermediate.

Description

Substituted azacyclic butane derivatives, their preparation methods and pharmaceutical uses

[0001] This application claims priority to Chinese Patent Application No. 202410956574.X, filed on July 17, 2024; Chinese Patent Application No. 202411591957.8, filed on November 8, 2024; and Chinese Patent Application No. 202510315349.2, filed on March 18, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention pertains to the pharmaceutical field, specifically relating to substituted azacyclobutane derivatives, their stereoisomers or pharmaceutically acceptable salts thereof, compositions comprising the compounds and their applications in the pharmaceutical field, as well as methods for preparing the compounds and intermediates. Background Technology

[0003] Muscarinic acetylcholine receptors (mAChRs) are G protein-coupled receptors (GPCRs) composed of five subtypes: 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 mainly expressed in the cerebral cortex, striatum, hypothalamus, and hippocampus (Lebois, et al., Neurop Harmacology 2018, 136, 362–373).

[0004] Cholinergic neurotransmission plays a crucial role in cognitive function. 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.

[0005] Positive allosteric modulators (PAMs) of the M receptor have become a research hotspot in the field of mental illness in recent years. 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 the M receptor are also undergoing clinical trials for the treatment of schizophrenia. KarXT from Karuna Pharmaceuticals (with xanomeline as its active ingredient) has already entered Phase III clinical trials in the United States and achieved positive results. Therefore, M1 / M4 agonists hold promise for improving cognitive and psychiatric symptoms.

[0006] Because the recognition sites of agonists for different M receptor subtypes are highly conserved in their spatial structure, these drugs lack subtype selectivity, which makes them prone to toxic side effects and limits their clinical use. For example, Xanomeline, the active ingredient of KarXT, is an M receptor agonist. Its low subtype selectivity causes gastrointestinal discomfort and cardiovascular adverse reactions, leading some patients to choose to discontinue treatment.

[0007] In recent years, an increasing number of studies on allosteric modulators have revealed that the key amino acids involved in receptor allosteric regulation have low conservation, which provides a structural basis for the development of more selective allosteric modulator drugs. It has been proven that allosteric modulators can enhance the subtype selectivity of ligands to receptors and improve drug efficacy.

[0008] M4 receptor orthoallosteric modulators can improve M receptor subtype selectivity, reduce off-target adverse reactions and side effects, and increase patient compliance. Furthermore, by altering the conformation of the M4 receptor protein, these modulators enhance the binding activity of endogenous acetylcholine (Ach) to the M4 receptor, producing an effect similar to that of M4 receptor agonists. This reveals the role of these receptors in controlling dopamine release in the striatum and their function in key synapses in the hippocampus known to be important for cognition.

[0009] A recent study demonstrated that M4 PAM reduced striatal dopamine release after amphetamine treatment in wild-type mice, but did not reduce striatal dopamine release after amphetamine treatment in M4 knockout wild-type mice (Byunetal., NeuropsychopHarmacology 2014, 39, 1578). Another study showed that M4 PAM induced inhibition of glutamate-excitatory synaptic transmission at the Schaeffer collateral-CA1 synapse in the hippocampus (Thorn, et al., Hippocampus 2017, 27, 794-810). Furthermore, in vivo rodent studies showed that M4 PAM VU0467154 improved associative learning impairment in the touch screen pair-wise visual discrimination task induced by the non-competitive NMDA receptor antagonist MK-801. These effects were not present in M4 knockout mice, demonstrating the specificity of this phenotype for the M4 receptor (Bubser, et al., ACS Chemical Neuroscience 2014, 5, 920-942).

[0010] By activating M4 receptors in the striatum and hippocampus using specific PAMs, the hyperdopaminergic state of the striatum and overstimulation of the hippocampus can be reduced, providing a therapeutic approach for psychosis and cognitive impairment in schizophrenia. 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. Thus, developing new compounds and formulations for the treatment or prevention of M4-mediated diseases or disorders is essential.

[0011] Invention Overview

[0012] The purpose of this invention is to provide compounds for treating, preventing, or alleviating such diseases, which have good M4 receptor positive allosteric regulatory activity and drug-like properties, particularly improved brain penetration and pharmacokinetic properties, and are expected to effectively reduce the adverse effects caused by activation of extra-brain muscarinic receptors.

[0013] The following is only a summary of some aspects of the invention, and is not intended to limit it. In the event of any discrepancy between the disclosure in this specification and the cited documents, the disclosure in this specification shall prevail.

[0014] This invention aims to provide a substituted azacyclic butane derivative, its stereoisomers or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, methods for their preparation, and intermediates thereof. The derivatives and pharmaceutical compositions can be used for the prevention or treatment of diseases related to the M4 receptor.

[0015] On the one hand, the present invention provides a compound represented by Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0016] R1, R2, and R3 are each independently selected from H, deuterium, halogen, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted hydroxy C1-C6 alkyl, optionally substituted C2-C6 alkenyl, and optionally substituted C2-C6 alkynyl, wherein the optional substituents are independently selected from deuterium and halogen.

[0017] Each R4, when present, is independently selected from deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, and hydroxyl, wherein the optional substituents are independently selected from deuterium and halogens.

[0018] R5 and R6 are each independently selected from hydrogen, deuterium, halogens, and OR. 10 And optionally substituted C1-C6 alkyl groups, provided that at least one of R5 and R6 is deuterium, halogen, or OR. 10 The optional substituents are independently selected from deuterium and halogens;

[0019] R 10 The substituent is H, an optionally substituted C1-C6 alkyl group, or an optionally substituted C3-C8 cycloalkyl group, wherein the optional substituent is independently selected from deuterium and halogens;

[0020] R 11 For H or deuterium;

[0021] L is selected from any one or more R. 1-1 Replacement C 6-14 aryl, optionally with one or more R 1-1 Substituted 5-14 heteroaryl groups and optionally one or more R 1-1 Substituted 5-14 membered heterocyclic groups;

[0022] Each R 1-1 It is independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, nitro, C1-C6 alkylthio, hydroxyl and cyano;

[0023] A is absent or selected from 5-14 heteroaryl groups, C 6-14 Aryl and 5-14 membered heterocyclic groups;

[0024] Each Ra group, when present, is independently selected from deuterium, optionally by one or more R groups. 1-2 Substituted C1-C6 alkyl groups, optionally with one or more R 1-2 Substituted C1-C6 alkoxy groups, optionally with one or more R 1-2 Substituted C1-C6 alkylthio, halogen, cyano, hydroxyl, nitro, amino, oxo, optionally with one or more R 1-2 Substituted C3-C6 cycloalkyl groups, -N(R8)(R9), -N(R8)(C(=O)R9), -C(=O)-N(R8)(R9), -C(=O)-OR7, -C(=O)-R7, -S(=O)2-R7, -NR 13 -(CH2) r -CR 14 =CRbRc, -CHR 13 -(CH2) r -CR 14 =CRbRc, -O-NR 13 -(CH2) r -CR 14 =CRbRc and -O-CHR 13 -(CH2) r -CR 14 =CRbRc;

[0025] Each R 1-2 Independently selected from deuterium, halogen, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, -N(R8)(R9), -N(R8)(C(=O)R9), -C(=O)-N(R8)(R9), -C(=O)-OR7, -C(=O)-R7 and -S(=O)2-R7;

[0026] R7 is a C1-C6 alkyl group; R8 and R9 are each independently selected from H, deuterium, C1-C6 alkyl groups optionally substituted with one or more Rb groups, C3-C8 cycloalkyl groups optionally substituted with one or more Rb groups, C1-C6 alkoxy groups optionally substituted with one or more Rb groups, and C1-C6 alkylthio groups optionally substituted with one or more Rb groups.

[0027] Each Rb is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, -N(CH3)2, -NHCH3 and hydroxyl;

[0028] Rc is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy;

[0029] R 13 and R 14 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C2-C6 alkenyl;

[0030] Or R 13 and R 14 The carbon or nitrogen atoms connected to it link to form 3-8 membered carbon rings or heterocycles;

[0031] Alternatively, R8 and R9 can be linked to their connected nitrogen atoms to form optional R... 1-3 Substituted 3- to 8-membered nitrogen-containing heterocyclic groups;

[0032] Each R 1-3 Independently selected from deuterium, hydrogen, halogen, hydroxyl, nitro, amino, C1-C6 alkylthio, C1-C6 deuterated alkylthio, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy;

[0033] m can be 0, 1, 2, 3, or 4;

[0034] p is 0, 1, 2 or 3;

[0035] n is any integer from 0 to 5;

[0036] r is any integer from 0 to 5.

[0037] More preferably, in the compound represented by Formula I above, R5 and R6 are each independently selected from hydrogen, deuterium, halogen, and OR. 10 The condition is that at least one of R5 and R6 is deuterium, halogen, or OR. 10 .

[0038] More preferably, in the compound represented by Formula I above, R5 and R6 are each independently selected from hydrogen, deuterium, halogen, and OR. 10 The condition is that one or both of R5 and R6 are deuterium, halogen, or OR. 10 Furthermore, R5 and R6 are not the same.

[0039] More preferably, in the compound shown in Formula I above, R5 and R6 are each independently selected from hydrogen, deuterium and fluorine, provided that one or both of R5 and R6 are deuterium or fluorine, and R5 and R6 are not the same.

[0040] Even more preferably, in the compound shown in Formula I above, R5 is a halogen and R6 is selected from hydrogen and deuterium.

[0041] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by Formula I as described above, its stereoisomers or pharmaceutically acceptable salts thereof, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or combination thereof.

[0042] On the other hand, the present invention provides the use of a compound of Formula I, its stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of a medicament, preferably in the preparation of a medicament for treating M4-mediated or M4-related diseases or disorders in patients. The M4-mediated or M4-related diseases or disorders are selected from one or more of 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 hereditary 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 disorders, with schizophrenia being the most preferred.

[0043] On the other hand, the present invention provides a compound of formula V, its stereoisomer or salt thereof:

[0044] Among them, R 12 It is a C1-C6 alkyl group; R5, R6, R 11 L, A, Ra and n are defined as in Equation I.

[0045] On the other hand, the present invention provides a method for preparing the compound of formula I above, comprising the following steps:

[0046] The compound represented by formula VC or its salt reacts with the compound represented by formula V in a substitution reaction to produce the compound represented by formula I.

[0047] Among them, R 12 It is a C1-C6 alkyl group; R1, R2, R3, R4, m, p, R5, R6, R 11 L, A, Ra and n are defined as in Equation I.

[0048] Terms and Definitions

[0049] Unless otherwise stated or there is a clear conflict in the context, 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 discrepancy, 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.

[0050] The term “optional” or “optionally” means that the event or situation described below may, but not necessarily, occur, and the description includes both the cases in which the event or situation occurs and the cases in which it does not occur.

[0051] The term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted," meaning that the structure or group is unsubstituted or substituted by one or more substituents as described in this invention, wherein the substitution occurs at a reasonable position permissible by any valence on the given structure or group. If the substitution occurs on a structure or group that is not allowed to be substituted, then the substituent is absent. For example, "optionally substituted..." means that the group is unsubstituted or substituted by one or more specified or unspecified substituents, such as substituted by 1-3 substituents, substituted by 2 substituents, or substituted by 1 substituent. Unless otherwise specified, as used herein, the connection point of a substituent may arise from any suitable position of the substituent. When the bond of a substituent is shown as a bond connecting two atoms through a ring, such a substituent may be bonded to any cyclic atom in the substituted ring.

[0052] Generally, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced by a specific substituent. Unless otherwise indicated, a substituent may be substituted at any of the reasonable substituted positions in the group. When more than one position in a given structural formula can be substituted by one or more specific substituents selected from the group, the substituents may be substituted at the reasonable positions in the structural formula, either in the same or different ways.

[0053] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptions used in this invention as “each independently” or “independently” should be interpreted broadly. This can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0054] When the lower and upper limits of a numerical range are disclosed, any 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 value and range encompassed within a wider range. When any variable (e.g., Ra), 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, its definition is independent in each instance. For example, if a group is substituted by 0, 1, 2, or 3 Ra substituents, the group may optionally be substituted by up to three Ra substituents, and the options for each Ra substituent in each instance are independent of each other; that is, each Ra substituent may be the same or different.

[0055] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or range of groups. In particular, this invention includes every independent sub-combination of the members of these types and ranges. For example, the expression mn used herein refers to the range from m to n, as well as the subrange consisting of the individual point values ​​therein, and the individual point values ​​themselves.

[0056] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group with a conjugated electronic system. The term "aryl" can be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of aryl groups include 6- to 14-membered aryl groups (i.e., C6-14-membered aryl groups). 6-14 aryl), 6-10 aryl (i.e., C 6-10 Aryl groups, specifically including phenyl, naphthyl, etc. The aryl groups may optionally be substituted by one or more substituents described in this invention.

[0057] The term "heteroaryl" refers to a heteroaromatic system having a conjugated electronic system comprising 1 to 5 heteroatoms (e.g., 1, 2, 3, 4, or 5) and 5 to 14 ring atoms (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14), wherein the heteroatoms are selected from one or more of oxygen, sulfur, and nitrogen. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". Examples of heteroaryl groups include 5-14 member nitrogen-containing heteroaryl groups, 5-10 member heteroaryl groups, 5-6 member nitrogen-containing heteroaryl groups, 5-10 member monocyclic or polycyclic heteroaryl groups, and 5-6 member heteroaryl groups, specifically including pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazoleyl, pyrazolyl, pyrroleyl, 1,2,3-triazolyl, thiadiazolyl, thiopheneyl, furanyl, pyridazinyl, triazinyl, oxadiazolyl, isoxazolyl, pyranyl, 1,3,4-triazolyl, furanopyrimidinyl, thiophenanopyrimidinyl, pyrrolopyrimidinyl, benzothiazolyl, benzoxazolyl, thiophenanopyrimidinyl, indolyl, quinolinyl, isoquinolinyl, imidazoleanopyridinyl, benzothiadiazolyl, etc. The heteroaryl groups may optionally be substituted by one or more substituents described in this invention.

[0058] The terms "heterocycle" and "heterocyclic group" are used interchangeably to refer to monocyclic, bicyclic, or tricyclic systems comprising 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms, 3-14 ring atoms, 3-8 ring atoms, or 5-8 ring atoms, whether monovalent or polyvalent, wherein one or more atoms on the ring (e.g., 1, 2, 3, or 4 ring atoms) are independently replaced by heteroatoms, which have the meaning as described in this invention, and the ring may be fully saturated or contain one or more degrees of unsaturation. Unless otherwise stated, the -CH2- group on the heterocyclic group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Examples of heterocyclic groups include 5-8 membered heterocyclic groups, 3-8 membered nitrogen-containing heterocyclic groups, 5-8 membered nitrogen-containing heterocyclic groups, and 5-8 membered oxygen-containing heterocyclic groups, specifically including: ethylene oxide, nitrogen-containing heterocyclic butyl, oxo-heterocyclic butyl, thio-heterocyclic butyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiaranyl, dihydrothiaranyl, piperidinyl, morpholinyl, piperazine, dihydropyridinyl, 2-pyridoneyl, 2-oxopyrrolyl, oxo-1,3-thiazolyl, oxazolyl, 2-oxooxazolyl, etc. The heterocyclic group may optionally be replaced by one or more substituents described in this invention. The heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl ring, such as 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.

[0059] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, connected to the rest of the molecule by single bonds. Alkyl groups can have 1-6 carbon atoms, i.e., "C1-C6 alkyl", for example, C... 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C3 alkyl, C4 alkyl. It can also have 1-3 carbon atoms, i.e., "C1-C3 alkyl", for example, C... 1-3 Alkyl, C 1-2Alkyl, C3 alkyl. The term "C1-C5 alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, and C5 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), propyl (including n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2)), butyl (including n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl... 2-pentyl (t-Bu, -C(CH3)3), pentyl (including n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2) ), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), hexyl (including n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)C H(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), etc.

[0060] For example, expressing "C1-C6" or "C 1-6 "Covering a range of 1-6 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C1-C5, C3-C4, C2-C6, C3-C6, C4-C5, C4-C6, C2-C4, etc., and C1, C2, C3, C4, C5, C6, etc. For example, expressing 'C1-C5' or 'C'..." 1-5"Covering a range of 1-5 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, etc., and C1, C2, C3, C4, C5, etc. For example, expressing 'C2-C5' or 'C'..." 2-5 "The term 'covers' a range of 2-5 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-C3, C2-C4, C3-C5, C4-C5, etc., as well as C2, C3, C4, C5, etc. Similarly, the expression '3-8 elements' should be understood to include any subranges within this range and each point value, such as ternary to pentary, ternary to hexanal, ternary to octary, quaternary to pentary, quaternary to hexanal, etc., as well as triadic, quadrilateral, quinary, and quinary elements, etc. Other similar expressions in this text should also be understood in a similar manner."

[0061] The term "one or more" or similar expression "at least one" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. For example, "one or more (substituents)" means 1-6 substituents, 1-5 substituents, 1-4 substituents, 1-3 substituents, 1-2 substituents or 1 substituent, provided that it does not violate the theory of valence bonds.

[0062] The term “selected from…” means one or more elements from the groups listed below, selected independently, and may include combinations of two or more elements.

[0063] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0064] When each carbon atom in the descriptive group can be optionally replaced by a heteroatom, the condition is that the normal atomic valence of all atoms in the group is not exceeded in the present case, and a stable compound is formed.

[0065] The term "heteroatom" refers to oxygen (O), sulfur (S), or nitrogen (N), including nitrogen (N) and sulfur (S) in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form where the hydrogen atom on the nitrogen atom in the heterocycle is substituted, such as N, NH, NR. Further, for example, the term "3-8 membered carbon ring or heterocycle" refers to a ring with 3-8 ring atoms, wherein the ring members may or may not contain heteroatoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and azirropropyl, azirrobutyl, azirropentyl, azirrohexyl, azirroheptyl, azirrooctyl, etc.

[0066] The term "hydrogen (H)" refers to a single hydrogen atom. Such a group of atoms can be attached to other groups, such as oxygen atoms, to form a hydroxyl group.

[0067] The term "halogen" or "halogenated" should be understood to mean fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably fluorine, chlorine or bromine atoms, more preferably fluorine atoms.

[0068] The term "alkoxy group" refers to an alkyl group attached to the remainder of a molecule via an oxygen atom, wherein the alkyl group has the meaning as described in this invention. In one embodiment, the alkoxy group contains 1-6 carbon atoms. In another embodiment, the alkoxy group contains 1-5 carbon atoms; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), etc.

[0069] The term "alkylthio" refers to an alkyl group attached to the remainder of a molecule via a sulfur atom, wherein the alkyl group has the meaning as described in this invention. In one embodiment, the alkylthio group contains 1-6 carbon atoms. In another embodiment, the alkylthio group contains 1-5 carbon atoms; in yet another embodiment, the alkylthio group contains 1-3 carbon atoms. The alkylthio group may optionally be substituted by one or more substituents described in this invention.

[0070] The term "cycloalkyl" refers to a cyclic hydrocarbon group or cyclic alkenyl group composed of carbon and hydrogen atoms, preferably containing one or two rings. Cycloalkyl groups can have 3-8 carbon atoms (C3-C8 cycloalkyl), 3-6 carbon atoms (C3-C6 cycloalkyl), or 4-8 carbon atoms (C4-C8 cycloalkyl), such as C6, C5, C4, and C3 cycloalkyl. Examples of cycloalkyl groups include C3-C8, C4-C8, C4-C6, and C3-C6 cycloalkyl groups, specifically including cyclopropyl, cyclopropenyl, cyclobutenyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, etc. The term also covers cases where the carbon atom can be substituted with an oxygen (=O).

[0071] The term "alkenyl" refers to a general term for hydrocarbons containing carbon-carbon double bonds in their molecules; they are unsaturated aliphatic hydrocarbons. For example, vinyl (-CH2=CH-). The term "alkene" can have 2-6 carbon atoms, i.e., a "C2-C6" alkenyl group, for example, C... 2-6 alkenyl, C 2-4 alkenyl, C 2-5 alkenyl, C3 alkenyl, C4 alkenyl, C6 alkenyl, C 2-6 alkenyl, C 3-6 Alkenyl groups, etc. They can also have 2-5 carbon atoms, i.e., "C2-C5 alkenyl groups", for example, C... 2-5 alkenyl, C 2-3 Alkenyl, C3 alkenyl, C5 alkenyl, etc. Examples of alkenyl groups include, but are not limited to, vinyl (e.g., CH2=CH-), propenyl (e.g., CH2=CH-CH2-), butenyl (e.g., CH2=CH-CH2-CH2-, CH3-CH=CH-CH2-), pentenyl (e.g., CH2=CH-CH2-CH2-CH2-, CH3-CH2-CH=CH-CH2-, -CH(CH3)-CH=CH-CH3), hexenyl, heptenyl, octenyl, etc.

[0072] The term "alkynyl" refers to a general term for hydrocarbons containing a carbon-carbon triple bond in their molecules; they are unsaturated aliphatic hydrocarbons. For example, ethynyl (-C≡CH). These "alkynyl hydrocarbons" can have 2-6 carbon atoms, i.e., "C2-C6" alkynyl groups, such as C... 2-6 alkynyl group, C 2-4 alkynyl group, C 2-5 Alkynyl, C3 alkynyl, C4 alkynyl, C6 alkynyl, C 2-6 alkynyl group, C 3-6 Alkyne groups, etc. They can also have 2-5 carbon atoms, i.e., "C2-C5 alkynyl groups", for example, C... 2-5 alkynyl group, C 2-3Alkynyl, C3 alkynyl, C5 alkynyl, etc. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, penynyl, hexynyl, hepynyl, octyynyl, etc.

[0073] The terms "halogenated alkyl" and "halogen-substituted alkyl" are used interchangeably, referring to an alkyl group that is substituted by one or more halogens. The halogen is selected from fluorine, chlorine, and bromine. Examples include, but are not limited to, halomethyl, haloethyl, halopropyl, halobutyl, and halopentyl groups, wherein the halogenation can be monohalogenated, dihalogenated, or trihalogenated; when the methyl group is trihalogenated, difluoromethyl or trifluoromethyl is further preferred.

[0074] The terms "haloalkoxy" and "halogen-substituted alkoxy" are used interchangeably and refer to an alkoxy group that is substituted with one or more halogens. Examples include, but are not limited to, halomethoxy, haloethoxy, halopropoxy, halobutoxy, and halopentoxy, wherein the halogenation can be monohalogen substitution, dihalogen substitution, or trihalogen substitution.

[0075] The terms "halogenated" and "halogen" refer to fluorine, chlorine, or bromine.

[0076] In the compounds mentioned in this invention, hydrogen atoms may be partially or completely replaced by deuterium. Specifically, the term "deuterated compound" refers to compounds in which hydrogen atoms may be partially or completely replaced by deuterium.

[0077] The term "pharmaceutically acceptable salt" refers to the organic or inorganic salt of the compounds of this invention.

[0078] 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.

[0079] Invention Details

[0080] 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.

[0081] Formula I compound

[0082] This disclosure provides, in one aspect, a compound of formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof.

[0083] R1, R2, and R3 are each independently selected from H, deuterium, halogen, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted hydroxy C1-C6 alkyl, optionally substituted C2-C6 alkenyl, and optionally substituted C2-C6 alkynyl, wherein the optional substituents are independently selected from deuterium and halogen.

[0084] R4 represents a substituent that may be present on the nitrogen-containing heterocycle fused with the pyridine ring;

[0085] Each R4, when present, is independently selected from deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, and hydroxyl, wherein the substituents are independently selected from deuterium and halogens.

[0086] R5 and R6 are each independently selected from hydrogen, deuterium, halogens, and OR. 10 And optionally substituted C1-C6 alkyl groups, provided that at least one of R5 and R6 is deuterium, halogen, or OR. 10 The optional substituents are independently selected from deuterium and halogens;

[0087] R 10 The substituent is H, an optionally substituted C1-C6 alkyl group, or an optionally substituted C3-C8 cycloalkyl group, wherein the substituent is independently selected from deuterium and halogen;

[0088] R 11 For H or deuterium;

[0089] L is selected from any one or more R. 1-1 Replacement C 6-14 aryl, optionally with one or more R 1-1 Substituted 5-14 heteroaryl groups and optionally one or more R 1-1 Substituted 5-14 membered heterocyclic groups;

[0090] Each R 1-1 It is independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, nitro, C1-C6 alkylthio, hydroxyl and cyano;

[0091] A is absent or selected from 5-14 heteroaryl groups, C 6-14 Aryl and 5-14 membered heterocyclic groups;

[0092] When A is absent, the Ra group represents a substituent located on L; when A is present, the Ra group represents a substituent located on A.

[0093] Each Ra, when present, is independently selected from deuterium and arbitrarily selected by one or more R. 1-2 Substituted C1-C6 alkyl groups, optionally with one or more R 1-2 Substituted C1-C6 alkoxy groups, optionally with one or more R 1-2 Substituted C1-C6 alkylthio, halogen, cyano, hydroxyl, nitro, amino, oxo, optionally with one or more R 1-2 Substituted C3-C6 cycloalkyl groups, -N(R8)(R9), -N(R8)(C(=O)R9), -C(=O)-N(R8)(R9), -C(=O)-OR7, -C(=O)-R7, -S(=O)2-R7, -NR 13 -(CH2) r -CR 14 =CRbRc, -CHR 13 -(CH2) r -CR 14 =CRbRc, -O-NR 13 -(CH2) r -CR 14 =CRbRc and -O-CHR 13 -(CH2) r -CR 14 =CRbRc;

[0094] Each R 1-2 Independently selected from deuterium, halogen, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, -N(R8)(R9), -N(R8)(C(=O)R9), -C(=O)-N(R8)(R9), -C(=O)-OR7, -C(=O)-R7 and -S(=O)2-R7;

[0095] R7 is a C1-C6 alkyl group;

[0096] R8 and R9 are each independently selected from H, deuterium, C1-C6 alkyl optionally substituted with one or more Rb, C3-C8 cycloalkyl optionally substituted with one or more Rb, C1-C6 alkoxy optionally substituted with one or more Rb, and C1-C6 alkylthioyl optionally substituted with one or more Rb.

[0097] Each Rb is independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, halogen, -N(CH3)2, -NHCH3 and hydroxyl;

[0098] Rc is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy;

[0099] R13 and R 14 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C2-C6 alkenyl;

[0100] Or R 13 and R 14 The carbon or nitrogen atoms connected to it link to form 3-8 membered carbon rings or heterocycles;

[0101] Alternatively, R8 and R9 can be linked to their connected nitrogen atoms to form optional R... 1-3 Substituted 3- to 8-membered nitrogen-containing heterocyclic groups;

[0102] Each R 1-3 Independently selected from deuterium, hydrogen, halogen, hydroxyl, nitro, amino, C1-C6 alkylthio, C1-C6 deuterated alkylthio, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy;

[0103] m can be 0, 1, 2, 3, or 4;

[0104] p is 0, 1, 2 or 3;

[0105] r is any integer from 0 to 5;

[0106] n is any integer from 0 to 5.

[0107] In one embodiment, the compound of Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

[0108] (1) R1, R2, and R3 are each independently selected from H, deuterium, halogen, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, wherein the substituents are independently selected from deuterium and halogen; and / or

[0109] (2) Each R4, when present, is independently selected from deuterium, optionally substituted C1-C6 alkyl groups, and hydroxyl groups, wherein the substituents are independently selected from deuterium and halogens; and / or

[0110] (3) R5 and R6 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, and OR. 10 and C1-C6 alkyl groups, provided that at least one of R5 and R6 is deuterium, fluorine, or OR. 10 Preferably, R5 and R6 are each independently selected from hydrogen, deuterium, halogens, and OR. 10 The condition is that at least one of R5 and R6 is deuterium, halogen, or OR. 10Preferably, R5 and R6 are each independently selected from hydrogen, deuterium, halogens, and OR. 10 The condition is that one or both of R5 and R6 are deuterium, halogen, or OR. 10 Furthermore, R5 and R6 are not the same; preferably, R5 and R6 are each independently selected from hydrogen, deuterium, and fluorine, provided that one or both of R5 and R6 are deuterium or fluorine, and R5 and R6 are not the same. Preferably, one or both of R5 and R6 are independently deuterium or halogen; preferably, one of R5 and R6 is deuterium or halogen, and the other is hydrogen; preferably, one of R5 and R6 is fluorine, and the other is hydrogen; and / or

[0111] (4) Where R 10 H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, wherein the optional substituents are independently selected from deuterium and halogens; preferably R 10 It is H, methyl, ethyl, cyclopropyl or cyclobutyl; and / or

[0112] (5)R 11 For H or deuterium; and / or

[0113] (6) L is selected from one or more R. 1-1 Replacement C 6-14 aryl, optionally with one or more R 1-1 The substituted 5-10 heteroaryl group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and optionally surrounded by one or more R atoms. 1-1 Substituted with a 5-8 membered heterocyclic group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; and / or

[0114] (7) Each R 1-1 Independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuteralkyl, C1-C6 deuteroxy, C1-C6 alkylthio and hydroxyl; and / or

[0115] (8) A does not exist; or A is selected from 5-8 heteroaryl groups containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, C 6- 14 Aryl groups and 5-8 membered heterocyclic groups containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; and / or

[0116] (9) Each Ra is independently selected from deuterium and arbitrarily selected by one or more R. 1-2 Substituted C1-C6 alkyl groups, optionally with one or more R 1-2 Substituted C1-C6 alkoxy, halogen, cyano, hydroxyl, optionally with one or more R 1-2Substituted C3-C6 cycloalkyl groups, -N(R8)(R9), -N(R8)(C(=O)R9), -C(=O)-N(R8)(R9), -C(=O)-OR7, -C(=O)-R7, -S(=O)2-R7, -NR 13 -(CH2) r -CR 14 =CRbRc, -CHR 13 -(CH2) r -CR 14 =CRbRc, -O-NR 13 -(CH2) r -CR 14 =CRbRc and -O-CHR 13 -(CH2) r -CR 14 =CRbRc; Ra is preferably selected from CF3, OCF2, NH2 and N(CH3)2; and / or

[0117] (10) Each R 1-2 Independently selected from deuterium, C1-C6 alkyl groups, halogens, -N(R8)(R9), and / or

[0118] (11) R7 is C 1-3 Alkyl groups; and / or

[0119] (12) R8 and R9 are each independently selected from H, deuterium, C1-C3 alkyl optionally substituted with one or more Rb, C3-C6 cycloalkyl optionally substituted with one or more Rb, and C1-C3 alkoxy optionally substituted with one or more Rb; or R8 and R9 are linked with the nitrogen atom to which they are attached to form a C1-C3 alkoxy optionally substituted with one or more Rb. 1-3 Substituted 5- to 6-membered nitrogen-containing heterocyclic groups;

[0120] (13) Each Rb is independently selected from deuterium, C1-C3 alkyl, halogen and C1-C3 alkoxy; and / or

[0121] (14) Rc is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy; and / or

[0122] (15)R 13 and R 14 Each is independently selected from H, deuterium, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, and C2-C4 alkenyl; or R 13 and R 14The carbon or nitrogen atoms connected to it link to form 3-6 membered carbon rings or heterocycles, preferably R. 13 and R 14 The carbon or nitrogen atoms connected to it link to form a 4-membered carbon ring or a 4-membered nitrogen-containing heterocycle; and / or

[0123] (16) Each R 1-3 Independently selected from deuterium, hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy; and / or

[0124] (17) m is 0 or 4; and / or

[0125] (18) p is 0, 1, or 2; and / or

[0126] (19) n is 0, 1, 2 or 3; and / or

[0127] (20) r is 0, 1, 2 or 3, preferably 1 or 2.

[0128] Those skilled in the art will understand that in Formula I compounds, the carbon atoms connected to R5 and R6 have chiral centers, and therefore the Formula I compounds described herein include their racemic forms, their enantiomers, and mixtures thereof.

[0129] In one embodiment, the compound represented by Formula I is of Formula VII-A, VII-B, or a mixture thereof:

[0130] Among them, R1, R2, R3, R4, R 10 R 11 As defined above, m, n, p, L, A, and Ra are used to select R5 and R6 independently from hydrogen, deuterium, halogens, and OR. 10 The condition is that one or both of R5 and R6 are deuterium, halogen, or OR. 10 Furthermore, R5 and R6 are not the same; preferably, R5 and R6 are each independently selected from hydrogen, deuterium, and fluorine, provided that one or both of R5 and R6 are deuterium or fluorine, and R5 and R6 are not the same. More preferably, R5 is a halogen, and R6 is hydrogen or deuterium.

[0131] In one embodiment, the compound represented by Formula I is of Formula IA, IB, or a mixture thereof:

[0132] Among them, R5 is deuterium, fluorine or OR. 10 R1, R2, R3, R4, R 10 R 11 m, n, p, L, A, and Ra are as defined above.

[0133] Among the compounds represented by Formula I above, those selected from the following embodiments are preferred:

[0134] In one embodiment, R1, R2, and R3 are each independently selected from H, deuterium, halogen, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, C2-C6 alkenyl, and C2-C6 alkynyl, wherein the substituents are independently selected from deuterium and halogen.

[0135] In one embodiment, R1, R2, and R3 are each independently selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 alkoxy.

[0136] In one embodiment, R1, R2, and R3 are each independently selected from hydrogen, halogens, and C1-C6 alkyl groups.

[0137] In one embodiment, R1 is a halogen or a C1-C6 alkyl group.

[0138] In one embodiment, R1 is chlorine or a C1-C3 alkyl group.

[0139] In one implementation, R2 is hydrogen.

[0140] In one embodiment, R3 is an optionally substituted C1-C6 alkyl group, wherein the substituent is deuterium or a halogen.

[0141] In one embodiment, R3 is an optionally substituted C1-C3 alkyl group, wherein the substituent is deuterium.

[0142] In one embodiment, R1 is a C1-C3 alkyl group, R2 is hydrogen, and R3 is an optionally substituted C1-C3 alkyl group, wherein the substituent is deuterium.

[0143] In one embodiment, each R4 is independently selected from deuterium, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, and hydroxyl, wherein the substituents are independently selected from deuterium and halogens.

[0144] In one embodiment, each R4 is independently selected from deuterium and C1-C6 alkyl groups.

[0145] In one embodiment, R4 is a C1-C3 alkyl group.

[0146] In one implementation, R4 is deuterium.

[0147] In one embodiment, in the compound represented by Formula I, R5 and R6 are each independently selected from hydrogen, deuterium, halogen, and OR. 10 The condition is that at least one of R5 and R6 is deuterium, halogen, or OR. 10 .

[0148] In one embodiment, in the compound represented by Formula I, R5 and R6 are each independently selected from hydrogen, deuterium, halogen, and OR. 10 The condition is that one or both of R5 and R6 are deuterium, halogen, or OR. 10 Furthermore, R5 and R6 are not the same.

[0149] In one embodiment, in the compound represented by Formula I, R5 and R6 are each independently selected from hydrogen, deuterium, and fluorine, provided that one or both of R5 and R6 are deuterium or fluorine, and R5 and R6 are not the same.

[0150] In one embodiment, R6 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, and OR. 10 R5 is deuterium, fluorine, or OR. 10 , where R 10 The substituent is H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, wherein the optional substituent is independently selected from deuterium and halogen.

[0151] In one implementation, R6 is selected from hydrogen, deuterium, fluorine, and OR. 10 R5 is deuterium, fluorine, or OR. 10 , where R 10 It can be H, C1-C6 alkyl, or C3-C8 cycloalkyl.

[0152] In one implementation, R6 is selected from hydrogen, deuterium, fluorine, and OR. 10 R5 is deuterium, fluorine, or OR. 10 , where R 10 It can be H, methyl, ethyl, cyclopropyl, or cyclobutyl.

[0153] In one embodiment, R6 is selected from hydrogen or deuterium, and R5 is fluorine or OR. 10 , where R 10 It can be H, methyl, ethyl, cyclopropyl, or cyclobutyl.

[0154] In one embodiment, R6 is hydrogen, and R5 is deuterium, chlorine, bromine, fluorine, or OR. 10 , where R 10 It can be H, methyl, ethyl, cyclopropyl, or cyclobutyl.

[0155] In one implementation, R6 is deuterium, and R5 is deuterium, chlorine, bromine, fluorine, or OR. 10 , where R 10 It can be H, methyl, ethyl, cyclopropyl, or cyclobutyl.

[0156] In one embodiment, R6 is selected from hydrogen and deuterium, and R5 is fluorine.

[0157] In one implementation, R6 is deuterium and R5 is fluorine.

[0158] In one implementation, R5 is fluorine.

[0159] In one implementation, R5 is chlorine.

[0160] In one implementation, R5 is OR 10 R 10 For H.

[0161] In one implementation, R5 is OR 10 R 10 The substituents are optionally substituted C1-C6 alkyl groups, and the substituents are independently selected from deuterium and halogens.

[0162] In one implementation, R5 is OR 10 R 10 The substituent is an optional C3-C8 cycloalkyl group, and the substituent is independently selected from deuterium and halogens.

[0163] In one implementation, R5 is OR 10 R 10 It is a C3-C8 cycloalkyl group, preferably cyclopropyl or cyclobutyl.

[0164] In one implementation, R6 is hydrogen and R5 is fluorine.

[0165] In one implementation, R 11 For H.

[0166] In one implementation, R 11 It is deuterium.

[0167] In one implementation, L is selected from one or more Rs. 1-1 Replacement C 6-14 aryl, optionally with one or more R 1-1 The substituted 5-10 heteroaryl group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and optionally surrounded by one or more R atoms. 1- 1-substituted 5-8 membered heterocyclic groups containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0168] In one implementation, L is selected from one or more Rs. 1-1 Replacement C 6-14 aryl, optionally with one or more R 1-1 The substituted 5-6-membered heteroaryl group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and optionally surrounded by one or more R atoms. 1- 1-Substituted 5-6 membered heterocyclic groups containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0169] In one implementation, L is selected from one or more Rs. 1-1 Substituted phenyl, optionally with one or more R 1- 1-substituted naphthyl group, optionally with one or more R 1-1 Substituted quinolinyl group, optionally with one or more R 1-1 Substituted pyridinyl group, optionally with one or more R 1-1 Substituted pyrazinyl group, optionally with one or more R 1-1 Substituted pyrimidin group, optionally with one or more R 1-1 Substituted pyridazine group, optionally with one or more R 1-1 Substituted thiazolyl and optionally with one or more R 1-1 Substituted thiophene group.

[0170] In one implementation, L is selected from one or more Rs. 1-1 Substituted phenyl, optionally with one or more R 1- 1-substituted pyridyl group, optionally with one or more R 1-1 Substituted pyridazinyl group, optionally with one or more R 1-1 Substituted pyrazinyl group and optionally with one or more R 1-1 Substituted pyrimidine group.

[0171] In one implementation, L can be any one or more R. 1-1 Substituted phenyl groups.

[0172] In one implementation, L can be any one or more R. 1-1 Substituted pyridinyl group.

[0173] In one implementation, L can be any one or more R. 1-1 Substituted pyrimidine group.

[0174] In one implementation, L can be any one or more R. 1-1 Substituted pyrazinyl group.

[0175] In one implementation, L can be any one or more R. 1-1 Substituted pyridazinyl group.

[0176] In one implementation, L can be any one or more R. 1-1 Substituted thiazole group.

[0177] In one implementation, L can be any one or more R. 1-1 Substituted quinolino group.

[0178] In one implementation, L is selected from... The above substituents may be optionally replaced by one or more R 1-1replace.

[0179] In one implementation, L is selected from... The above substituents may be optionally replaced by one or more R 1-1 replace.

[0180] In one implementation, L is selected from... The above substituents may be optionally replaced by one or more R 1-1 replace.

[0181] In one implementation, L is selected from... The above substituents may be optionally replaced by one or more R 1-1 replace.

[0182] In one implementation, A does not exist.

[0183] In one implementation, L can be any one or more R. 1-1 The substituted phenyl group, and A is not present.

[0184] In one implementation, L can be any one or more R. 1-1 The substituted pyridinyl group is present, and A is absent.

[0185] In one implementation, L can be any one or more R. 1-1 The substituted pyrimidinyl group is present, and A is absent.

[0186] In one implementation, L is selected from... The above substituents may be optionally replaced by one or more R 1-1 Replace, and A does not exist.

[0187] In one implementation, R 1-1 It is selected from deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 alkylthio and hydroxyl.

[0188] In one implementation, R 1-1 It is selected from halogens, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy and hydroxyl.

[0189] In one implementation, R 1-1 It is selected from halogens, C1-C6 alkyl groups and C1-C6 haloalkyl groups.

[0190] In one implementation, R 1-1 It is a C1-C6 haloalkyl group.

[0191] In one implementation, R1-1 It is trifluoromethyl.

[0192] In one embodiment, A is selected from 5-14 membered heteroaryl groups containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, and C... 6- 14 Aryl groups and 5-14 membered heterocyclic groups containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0193] In one embodiment, A is selected from 5-10 heteroaryl groups containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, and C... 6- 10 Aryl groups and 5-10 membered heterocyclic groups containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0194] In one embodiment, A is selected from 5-8 membered heteroaryl groups containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, and C... 6- 14 Aryl groups and 5-8 membered heterocyclic groups containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0195] In one embodiment, A is selected from 5-6 membered heteroaryl groups containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and C... 6- 10 Aryl groups and 5-6 membered heterocyclic groups containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur.

[0196] In one embodiment, A is selected from phenyl, piperazinyl, piperidinyl, pyridinyl, pyrazolyl, quinolinyl, isoquinolinyl, morpholinyl, thiopheneyl, indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, benzodioxacyclopentenyl, imidazopyridinyl, oxazolyl, benzothiadiazolyl, benzothiazolyl, imidazolyl, oxazolylalkyl, and pyrroleyl, preferably selected from phenyl, piperazinyl, piperidinyl, pyridinyl, pyrazolyl, quinolinyl, isoquinolinyl, morpholinyl, thiopheneyl, indololinyl, isoindololinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, benzodioxacyclopentenyl, imidazopyridinyl, benzothiadiazolyl, benzothiazolyl, imidazolyl, oxazolylalkyl, and pyrroleyl.

[0197] In one embodiment, A is selected from phenyl, piperazinyl, piperidinyl, pyridinyl, pyrazolyl, morpholinyl, thiophenyl, indololinyl, isoindololinyl, imidazolyl, and pyrroleyl.

[0198] In one embodiment, when A is a polycyclic heteroaryl group, L can be connected to any ring of the polycyclic heteroaryl group, and Ra can be substituted on any ring of the polycyclic heteroaryl group.

[0199] In one implementation, A is selected from C. 6-10 Aryl group, preferably selected from phenyl group.

[0200] In one embodiment, A is selected from phenyl.

[0201] In one embodiment, A is selected from pyridyl.

[0202] In one implementation, A is selected from 5-6 member nitrogen-containing heterocyclic groups.

[0203] In one embodiment, A is selected from piperazine or piperidinyl.

[0204] In one embodiment, A is selected from 5-6 membered oxygen-containing heterocyclic groups, preferably from morpholine, oxazolyl groups, and more preferably from morpholine.

[0205] In one embodiment, A is selected from benzo5-6-membered oxygen-containing heterocyclic groups, preferably from dihydrobenzofuranyl, dihydroisobenzofuranyl, and benzodioxanepentyl.

[0206] In one embodiment, A is selected from benzo5-6-membered sulfur-containing heterocyclic groups, preferably selected from benzothiadiazole group or benzothiazolium group.

[0207] In one embodiment, A is selected from benzo5-6-membered nitrogen-containing heterocyclic groups, preferably selected from indololinyl, isoindololinyl, oxazolyl, and more preferably selected from indololinyl and isoindololinyl.

[0208] In one implementation scheme for

[0209] In one implementation scheme for

[0210] In one implementation, Ra is selected from deuterium, optionally by one or more R 1-2 Substituted C1-C6 alkyl groups, optionally with one or more R 1-2 Substituted C1-C6 alkoxy, halogen, cyano, hydroxyl, optionally with one or more R 1-2 Substituted C3-C6 cycloalkyl groups, -N(R5)(R6), -N(R5)(C(=O)R6), -C(=O)-N(R5)(R6), -C(=O)-OR7, -C(=O)-R7 and -S(=O)2-R7.

[0211] In one implementation, Ra is selected from deuterium, optionally by one or more R 1-2 Substituted C1-C6 alkyl groups, optionally with one or more R 1-2 Substituted C1-C6 alkoxy groups and halogens.

[0212] In one embodiment, Ra is selected from cyano, hydroxy, or optionally substituted with one or more R groups. 1-2 Substituted C3-C6 cycloalkyl groups, -N(R8)(R9), -N(R8)(C(=O)R9), -C(=O)-N(R8)(R9), -C(=O)-OR7, -C(=O)-R7, -S(=O)2-R7, -NR 13 -(CH2) r -CR 14 =CRbRc, -CHR 13 -(CH2) r -CR 14 =CRbRc, -O-NR 13 -(CH2) r -CR 14 =CRbRc and -O-CHR 13 -(CH2) r -CR 14 =CRbRc.

[0213] In one implementation, Ra is optionally controlled by one or more R 1-2 Substituted C1-C6 alkyl groups.

[0214] In one implementation, Ra is optionally controlled by one or more R 1-2 Substituted C1-C3 alkyl groups.

[0215] In one implementation, Ra is selected from CF3, OCF2, NH2 and N(CH3)2.

[0216] In one implementation, R 1-2 Selected from deuterium, C1-C6 alkyl groups, halogens and -N(R8)(R9).

[0217] In one implementation, R 1-2 Selected from deuterium, C1-C6 alkyl groups and halogens.

[0218] In one implementation, Ra is optionally controlled by one or more R 1-2 Substituted C1-C6 alkyl groups, R 1-2 Selected from deuterium and halogens.

[0219] In one implementation, Ra is optionally controlled by one or more R 1-2 Substituted C1-C6 alkyl groups, R 1-2 It is a halogen.

[0220] In one implementation, Ra is optionally controlled by one or more R 1-2 Substituted C1-C6 alkoxy groups, R 1-2 It is a halogen.

[0221] In one embodiment, Ra is trifluoromethyl.

[0222] In one embodiment, R8 and R9 are each independently selected from H, deuterium, C1-C3 alkyl optionally substituted with one or more Rb, C3-C6 cycloalkyl optionally substituted with one or more Rb, and C1-C3 alkoxy optionally substituted with one or more Rb.

[0223] In one embodiment, R8 and R9 are each independently selected from H, C1-C3 alkyl groups optionally substituted with one or more Rb, cyclopropyl, cyclobutyl, and C1-C3 alkoxy groups optionally substituted with one or more Rb.

[0224] In one embodiment, R8 is selected from H, C1-C3 alkyl groups optionally substituted with one or more Rb, cyclopropyl, cyclobutyl, and C1-C3 alkoxy groups optionally substituted with one or more Rb.

[0225] In one embodiment, R9 is selected from H, C1-C3 alkyl groups optionally substituted with one or more Rb, cyclopropyl, cyclobutyl, and C1-C3 alkoxy groups optionally substituted with one or more Rb.

[0226] In one embodiment, R8 is selected from H and C1-C3 alkyl groups optionally substituted with one or more Rb.

[0227] In one embodiment, R9 is selected from H and C1-C3 alkyl groups optionally substituted with one or more Rb.

[0228] In one embodiment, Rb is selected from deuterium, C1-C3 alkyl, C1-C3 haloalkyl, halogen, and C1-C3 alkoxy.

[0229] In one embodiment, Rb is selected from halogens and C1-C3 alkoxy groups.

[0230] In one embodiment, Rc is selected from hydrogen, deuterium, halogen, hydroxyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy and C1-C3 haloalkoxy.

[0231] In one embodiment, R8 and R9 are linked with their connected nitrogen atoms to form an optional structure with one or more R atoms. 1-3 Substituted 5- to 6-membered nitrogen-containing heterocyclic groups.

[0232] In one implementation, R 1-3 It is selected from deuterium, hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

[0233] In one implementation, R1-3 It is selected from deuterium, hydrogen, halogens and C1-C3 alkyl groups.

[0234] In one implementation, R 1-3 Selected from fluorine, chlorine and C1-C3 alkyl groups.

[0235] In one embodiment, R7 is a C1-C6 alkyl group.

[0236] In one implementation, R7 is C 1-3 alkyl.

[0237] In one implementation, m is 0, 1, 2, 3 or 4, preferably 0 or 4.

[0238] In one embodiment, p is 0, 1, 2, or 3, preferably 0, 1, or 2, and more preferably 1 or 2.

[0239] In one implementation, n is any integer from 0 to 5, preferably, and more preferably 0, 1, 2 or 3.

[0240] In one implementation, m is 0, 1, or 2.

[0241] In one implementation, p is 1 or 2.

[0242] In one implementation, n is any integer from 0 to 4.

[0243] In one implementation, m is 0.

[0244] In one implementation, p is 1.

[0245] In one implementation, m is 1.

[0246] In one implementation, m is 4.

[0247] In one implementation, m is 4, p is 1, and n is 1.

[0248] In one implementation, n is 0, 1, 2, or 3.

[0249] In one implementation, m is 0, p is 1, and n is 0.

[0250] In one implementation, m is 0, p is 1, and n is 1.

[0251] In one implementation, m is 0, p is 1, and n is 2.

[0252] In one implementation, r is 1, 2, or 3.

[0253] In one implementation, r is 2.

[0254] In one embodiment, the compound of formula I is further defined as a compound of formula II:

[0255] Among them, R1, R2, R3, R4, R 11 As defined above, L, m, A, Ra and n are selected independently from hydrogen, deuterium and fluorine, provided that one or both of R5 and R6 are deuterium or fluorine, and R5 and R6 are not the same.

[0256] In one embodiment, the compound represented by Formula II is of Formula II-A, II-B, or a mixture thereof:

[0257] Among them, R5 and R6 are independently selected from hydrogen, deuterium, and fluorine, provided that one or both of R5 and R6 are deuterium or fluorine, and R5 and R6 are different. R1, R2, R3, R4, R 11 L, m, A, Ra, and n are as defined above.

[0258] In one embodiment, the compound of formula I is further defined as a compound of formula II-1:

[0259] R1, R2, R3, R4, R5, L, m, A, Ra and n are as defined above.

[0260] In one embodiment, in the compound of general formula II described above, R5 is deuterium, halogen, or OR. 10 R 10 The substituent is H, an optionally substituted C1-C6 alkyl group, or an optionally substituted C3-C8 cycloalkyl group, wherein the optional substituent is independently selected from deuterium and halogens.

[0261] Furthermore, in one embodiment, R5 is fluorine.

[0262] In one embodiment, the compound of formula I is further a compound of formula III:

[0263] Among them, X1, X2, and X3 are independently selected from CH and N, respectively; R5 and R6 are independently selected from hydrogen, deuterium, and fluorine, provided that one or both of R5 and R6 are deuterium or fluorine, and R5 and R6 are different. 11 m, A, Ra, and n are as previously defined. In one embodiment, the compound of formula I is further a compound of formula III-1:

[0264] Among them, X1, X2, and X3 are independently selected from CH and N, respectively;

[0265] R1, R2, R3, R4, R5, m, A, Ra, and n are as defined above.

[0266] In one embodiment, in the compound of general formula III above, R5 is deuterium, halogen, or OR. 10 R 10 The substituent is H, an optionally substituted C1-C6 alkyl group, or an optionally substituted C3-C8 cycloalkyl group, wherein the optional substituent is independently selected from deuterium and halogens.

[0267] Furthermore, in one embodiment, R5 is fluorine.

[0268] In one implementation, X1, X2, and X3 are independently selected from CH and N, respectively, and at least one of X1, X2, and X3 is N.

[0269] In one embodiment, X3 is N. In one embodiment, the compound of formula I is further a compound of formula IV:

[0270] R1, R2, R3, R5, A, Ra, and n are as defined above.

[0271] In one embodiment, in the compound of formula IV-1 above, R5 is deuterium, halogen, or OR. 10 Preferably, R5 is deuterium or a halogen; more preferably, R5 is deuterium, fluorine, chlorine, or bromine; even more preferably, R5 is deuterium or fluorine. 10 The substituent is H, an optionally substituted C1-C6 alkyl group, or an optionally substituted C3-C8 cycloalkyl group, wherein the optional substituent is independently selected from deuterium and halogens.

[0272] Furthermore, in one embodiment, R5 is fluorine.

[0273] In one embodiment, the compound of formula I is further defined as a compound of formula VI:

[0274] Among them, R5 and R6 are independently selected from hydrogen, deuterium, and fluorine, provided that one or both of R5 and R6 are deuterium or fluorine, and R5 and R6 are different. R1, R2, R3, R4, R 11 m, Ra, and n are as defined above.

[0275] In one embodiment, the compound represented by formula VI is formula VI-A, VI-B, or a mixture thereof:

[0276] Among them, R5 and R6 are independently selected from hydrogen, deuterium, and fluorine, provided that one or both of R5 and R6 are deuterium or fluorine, and R5 and R6 are different. R1, R2, R3, R4, R 11L, m, A, Ra, and n are as defined above.

[0277] In one embodiment, the compound of formula I is further defined as a compound of formula IX:

[0278] R1, R2, R3, R5, A, Ra, and n are as defined above.

[0279] In one embodiment, in the compound of general formula IX above, R5 is deuterium, halogen, or OR. 10 R 10 The substituent is H, an optionally substituted C1-C6 alkyl group, or an optionally substituted C3-C8 cycloalkyl group, wherein the optional substituent is independently selected from deuterium and halogens.

[0280] Furthermore, in one embodiment, R5 is fluorine.

[0281] In one embodiment, the compound of formula I is further defined as a compound of formula XI:

[0282] R1, R2, R3, R5, Ra and n are as defined above.

[0283] In one embodiment, in the compound of general formula XI above, R5 is deuterium, halogen, or OR. 10 R 10 The substituent is H, an optionally substituted C1-C6 alkyl group, or an optionally substituted C3-C8 cycloalkyl group, wherein the optional substituent is independently selected from deuterium and halogens.

[0284] Furthermore, in one embodiment, R5 is fluorine.

[0285] In one embodiment, the compound of formula I is further defined as a compound of formula X:

[0286] R1, R2, R3, R5, Ra and n are as defined above.

[0287] In one embodiment, in the compound of general formula X above, R5 is deuterium, halogen, or OR. 10 R 10 The substituent is H, an optionally substituted C1-C6 alkyl group, or an optionally substituted C3-C8 cycloalkyl group, wherein the optional substituent is independently selected from deuterium and halogens.

[0288] Furthermore, in one embodiment, R5 is fluorine.

[0289] In one embodiment, the compounds of the present invention are selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0290] In one embodiment, the present invention relates to a compound of formula V, a stereoisomer thereof, a deuterated product thereof, or a salt thereof, for the preparation of a compound of formula I:

[0291] Among them, R 12 Selected from C1-C6 alkyl groups; R5, R6, R 11 L, A, Ra, and n are as defined above.

[0292] In one embodiment, the present invention relates to a method for preparing formula V, comprising the following steps:

[0293] The compound shown in VA undergoes a substitution reaction with the compound shown in VB or its salt to produce the compound shown in V.

[0294] Where Y is a halogen; R 12 Selected from C1-C6 alkyl groups; R5, R6, R 11 L, A, Ra, and n are as defined above.

[0295] In one implementation, Y is selected from fluorine, chlorine, and bromine.

[0296] In one implementation, Y is fluorine.

[0297] In one implementation, Y is chlorine.

[0298] In one embodiment, the present invention relates to a method for preparing a compound of formula I, comprising the following steps:

[0299] The compound represented by formula VC or its salt reacts with the compound represented by formula V to produce the compound represented by formula I;

[0300] Among them, R 12 Selected from C1-C6 alkyl groups; R1, R2, R3, R4, m, p, R5, R6, R 11 L, A, Ra, and n are as defined above.

[0301] In one embodiment, the present invention relates to a method for preparing a compound of formula III, comprising the following steps:

[0302] The compound shown in formula VD or its salt reacts with the compound shown in formula V to produce the compound shown in formula III;

[0303] Among them, R 12Selected from C1-C6 alkyl groups; R1, R2, R3, R4, m, p, R5, R6, R 11 L, A, Ra, and n are as defined above.

[0304] Beneficial technical effects

[0305] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0306] In some embodiments, the compounds of the present invention exhibit high allosteric activity against the M4 receptor. In some embodiments, the compounds of the present invention also possess improved physicochemical properties (e.g., solubility, physical and / or chemical stability) and improved pharmacokinetic properties (e.g., activity against cytochrome P450). 450 The compounds of the present invention possess 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 exhibit stronger blood-brain barrier penetration and greater ability to enter the brain. 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 an improved safety window (e.g., a wider safe dosage range, or a lower likelihood of side effects at the same dosage). Example

[0307] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Unless otherwise specified, all proportions, percentages, etc., referred to herein are by weight.

[0308] General formula for synthesis:

[0309] Among them, R1, R2, R3, R5, R 12 Ra, n, A, X1, X2, X3, Y are as described above.

[0310] Step 1: In a two-necked flask equipped with a stir bar, add 1-tert-butoxycarbonyl-3-azacyclobutanone (1.2 eq), substituted triethyl phosphoroacetate (1.0 eq), and DBU (1.5 eq). Add anhydrous dichloromethane at room temperature and allow the reaction to proceed. After the reaction is complete as monitored by TLC, cool to room temperature, quench with saturated ammonium chloride solution, extract with dichloromethane, combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate the organic phase, and perform silica gel column chromatography to obtain intermediate S1.

[0311] Step 2: Add intermediate S1 (1 eq) and Pd / C (catalytic amount) to a single-necked flask equipped with a stirrer. Add methanol at room temperature, purge with hydrogen three times, and react at room temperature. After the reaction is complete as monitored by TLC, filter, concentrate the organic phase, and obtain the crude product. Dissolve the crude product in DCM and react slowly with trifluoroacetic acid (5 eq) at room temperature. After the reaction is complete as monitored by TLC, concentrate the organic phase to obtain intermediate VA-1.

[0312] Step 3: In a single-necked flask equipped with a stirrer, add intermediate VA-1 (1 eq), intermediate VB-1 (1.0 eq), potassium carbonate (2 eq), and cesium fluoride (catalytic amount). Add DMSO at room temperature and react at 120℃. Alternatively, add chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.1 eq), cesium carbonate (3 eq), and anhydrous dioxane under nitrogen protection. After nitrogen evacuation three times, react at 110℃. After the reaction is complete as monitored by TLC, cool to room temperature, quench with water, extract with ethyl acetate, combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate the organic phase, and perform silica gel column chromatography to obtain intermediate V-1.

[0313] Step 4: In a single-necked flask equipped with a stir bar, add intermediate V-1 (1 eq), VC-1 (1 eq), and 1,5,7-triazidobicyclo(4.4.0)dec-5-ene (4 eq). Add anhydrous tetrahydrofuran at room temperature and react at 70°C. After the reaction is complete as monitored by TLC, cool to room temperature, concentrate, and add purified water, saturated sodium chloride solution, and saturated ammonium chloride solution sequentially. Extract with dichloromethane, combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate the organic phase, and perform silica gel column chromatography to obtain the target product I'.

[0314] Preparation Examples

[0315] Example 1: Preparation of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-fluoro-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutan-3-yl)ethane-1-one (I-1)

[0316] Step 1: In a two-necked flask equipped with a stir bar, add 1-tert-butoxycarbonyl-3-azacyclobutanone (848 mg, 4.95 mmol), triethyl 2-fluoro-2-phosphorylacetate (838 μL, 4.13 mmol), and DBU (925 μL, 6.19 mmol). Add anhydrous dichloromethane at room temperature and allow the reaction to proceed. After the reaction is complete as monitored by TLC, cool to room temperature, quench with saturated ammonium chloride solution, extract with dichloromethane, combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate the organic phase, and perform silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 816 mg of an oily substance. 1 H NMR (300MHz, Chloroform-d) 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).

[0317] Step 2: Add 816 mg (3.15 mmol) of 3-(2-ethoxy-1-fluoro-2-oxoethylene)azacyclobutane-1-carboxylic acid tert-butyl ester (Pd / C, catalytic amount) to a single-necked flask equipped with a stirrer. Add methanol at room temperature, purge with hydrogen three times, and react at room temperature. After the reaction is complete as monitored by TLC, filter, concentrate the organic phase, and obtain the crude product. Dissolve the crude product in DCM and react slowly with trifluoroacetic acid (5 eq) at room temperature. After the reaction is complete as monitored by TLC, concentrate the organic phase and separate the oil (quantitative), which requires no further purification.

[0318] Step 3: In a single-necked flask equipped with a stir bar, add 2,2,2-trifluoroacetate of 2-(azacyclobutane-3-yl)-2-fluoroethyl acetate (quantitative), 4-chloro-2-(trifluoromethyl)pyridine (268 μL, 2.09 mmol), and potassium carbonate (527 mg, 3.81 mmol). Add DMSO at room temperature and react at 120 °C. After the reaction is complete as monitored by TLC, cool to room temperature, quench with water, extract with ethyl acetate, combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate the organic phase, and separate by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1), yielding 388 mg of a clear oil. 1H NMR(300MHz,Chloroform-d)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=48.6,5.6H z,1H),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).

[0319] Step 4: In a single-necked flask equipped with a stir bar, add ethyl 2-fluoro-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutane-3-yl)acetate (388 mg, 1.27 mmol), 2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride (280 mg, 1.27 mmol), and 1,5,7-triazidobicyclo(4.4.0)dec-5-ene (705 mg, 5.07 mmol). Add anhydrous tetrahydrofuran at room temperature and react at 70 °C. After the reaction is complete as monitored by TLC, cool to room temperature, concentrate, and add purified water, saturated sodium chloride solution, and saturated ammonium chloride solution sequentially. Extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase, and separate the product (178 mg) by silica gel column chromatography (ethyl acetate), which is the title compound (I-1). 1 H NMR (300MHz, DMSO-d6) δ8.26(d,J=5.6Hz,1H),7.05(s,1H),6.80(d,J=2.3Hz,1H),6.61(dd,J=5.7,2.3Hz,1H),5.68(dt,J=47.5,5.6Hz,1H),4.97 (dd,J=16.8,4.2Hz,2H),4.67(d,J=16.2Hz,2H),4.27–4.02(m,3H),3.94 (t,J=7.2Hz,1H),3.59–3.42(m,1H),2.46(s,3H),2.27(d,J=4.3Hz,3H).

[0320] Chiral splitting of I-1:

[0321] Instruments: SFC-80 preparative version SFC (SFC-1); Column: Chiralpak AY, 250×30mm ID, 10μm; Mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia), gradient: B 40%; Flow rate: 80mL / min; Back pressure: 100bar; Column temperature: 40℃; Detection wavelength: 220nm; Cycle time: 5.5min.

[0322] Among them, the retention time RT = 1.20 min is I-1-A, and the retention time RT = 1.47 min is I-1-B.

[0323] Example 2: Preparation of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-fluoro-2-(1-(2-(difluoromethoxy)pyridin-4-yl)azacyclobutane-3-yl)ethane-1-one (I-2)

[0324] Step 1: In a two-necked flask equipped with a stir bar, add 1-tert-butoxycarbonyl-3-azacyclobutanone (848 mg, 4.95 mmol), triethyl 2-fluoro-2-phosphorylacetate (838 μL, 4.13 mmol), and DBU (925 μL, 6.19 mmol). Add anhydrous dichloromethane at room temperature and allow the reaction to proceed. After the reaction is complete as monitored by TLC, cool to room temperature, quench with saturated ammonium chloride solution, extract with dichloromethane, combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate the organic phase, and perform silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 816 mg of an oily substance. 1 H NMR (300MHz, Chloroform-d) 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: Add 816 mg (3.15 mmol) of 3-(2-ethoxy-1-fluoro-2-oxoethylene)azacyclobutane-1-carboxylic acid tert-butyl ester (Pd / C, catalytic amount) to a single-necked flask equipped with a stirrer. Add methanol at room temperature, purge with hydrogen three times, and react at room temperature. After the reaction is complete as monitored by TLC, filter, concentrate the organic phase, and obtain the crude product. Dissolve the crude product in DCM and react slowly with trifluoroacetic acid (5 eq) at room temperature. After the reaction is complete as monitored by TLC, concentrate the organic phase and separate the oil (quantitative), which requires no further purification.

[0326] Step 3: In a single-necked flask equipped with a stir bar, add 2,2,2-trifluoroacetate of 2-(azacyclobutane-3-yl)-2-fluoroethyl acetate (quantitative), 4-bromo-2-difluoromethoxypyridine (153 μL, 1.14 mmol), chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (89 mg, 0.11 mmol), and cesium carbonate (1.12 g, 3.43 mmol). The reaction was carried out at 120 °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 subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain 500 mg of a clear oil. 1 H NMR(400MHz,Chloroform-d)δ7.84(d,J=5.8Hz,1H),7.43(s,1H),6.12(dd,J=5.8,2.0Hz,1H),5.80(d,J=1.9Hz,1H ),5.07(dd,J=48.6,5.8Hz,1H),4.30(q,J=7.1Hz,2H),4.17–3.92(m,4H),3.47–3.19(m,1H),1.34(t,J=7.1Hz,3H).

[0327] Step 4: In a single-necked flask equipped with a stir bar, add ethyl 2-fluoro-2-(1-(2-(difluoromethoxy)pyridin-4-yl)azacyclobutane-3-yl)acetate (500 mg, 1.64 mmol), 2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride (363 mg, 1.64 mmol), and 1,5,7-triazidobicyclo(4.4.0)dec-5-ene (915 mg, 6.57 mmol). Add anhydrous tetrahydrofuran at room temperature and react at 70 °C. After the reaction is complete as monitored by TLC, cool to room temperature, concentrate, and add purified water, saturated sodium chloride solution, and saturated ammonium chloride solution sequentially. Extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the organic phase, and separate the product (163 mg) by silica gel column chromatography (ethyl acetate), which is the title compound (I-2). 1H NMR(300MHz,Chloroform-d)δ7.81(d,J=5.8Hz,1H),7.54(dd,J=73.7,1.1Hz,1H),6.92(d ,J=2.6Hz,1H),6.11(dd,J=5.8,2.1Hz,1H),5.77(d,J=2.0Hz,1H),5.31(ddd,J=48.2,11.9 ,6.2Hz,1H),5.11–4.69(m,4H),4.24–4.10(m,2H),4.10–3.97(m,1H),3.91(dt,J=8.2,6. 0Hz, 1H), 3.47 (dtt, J = 22.6, 8.4, 6.0Hz, 1H), 2.53 (d, J = 2.7Hz, 3H), 2.27 (d, J = 3.7Hz, 3H).

[0328] Example 3: Preparation of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-fluoro-2-(1-(pyridin-3-yl)azacyclobutane-3-yl)ethane-1-one (I-3)

[0329] The synthesis method of Example 2 was followed, except that 4-bromo-2-difluoromethoxypyridine was replaced with 3-chloropyridine (109 μL, 1.14 mmol), and compound I-3 was prepared by the same method. The product (I-3) was separated by silica gel column chromatography (pure ethyl acetate) to obtain 32 mg. 1 H NMR(300MHz,Chloroform-d)δ8.01(dd,J=4.7,1.3Hz,1H),7.86(d,J=2.8Hz,1H),7.21–7.03( m,1H),6.91(d,J=2.5Hz,1H),6.74(ddd,J=8.3,2.9,1.3Hz,1H),5.34(ddd,J=48.4,14.0,6.7H z,1H),5.09–4.66(m,4H),4.12(ddt,J=8.8,4.7,3.4Hz,2H),3.98(ddd,J=8.2,5.6,3.0Hz,1H) ,3.85(dt,J=7.5,5.3Hz,1H),3.65–3.24(m,1H),2.52(d,J=3.1Hz,3H),2.26(d,J=3.7Hz,3H).

[0330] Example 4: Preparation of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-fluoro-2-(1-(pyrimidin-5-yl)azacyclobutane-3-yl)ethane-1-one (I-4)

[0331] Following the synthetic method of Example 2, except that 4-bromo-2-difluoromethoxypyridine was replaced with 5-chloropyrimidine (131 mg, 1.14 mmol), compound I-4 was prepared by the same method. 97 mg of product (I-4) was separated by silica gel column chromatography (ethyl acetate: methanol: triethylamine = 100:1:0.1). 1 H NMR(300MHz,Chloroform-d)δ8.66(s,1H),7.98(s,2H),6.93(d,J=2.8Hz,1H),5.35(ddd,J=48.3,12.9,6.2Hz,1H),5.14–4.70(m,4H),4.22(q,J=7.3Hz ,2H),4.07(dt,J=7.8,5.3Hz,1H),3.95(dt,J=7.8,5.8Hz,1H),3.54(dtd,J =16.1,13.8,13.1,7.3Hz,1H),2.54(d,J=3.0Hz,3H),2.28(d,J=3.8Hz,3H).

[0332] Example 5: Preparation of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-fluoro-2-(1-(2-(difluoromethyl)pyridin-4-yl)azacyclobutane-3-yl)ethane-1-one (I-5)

[0333] The synthesis method of Example 2 was followed, except that 4-bromo-2-difluoromethoxypyridine was replaced with 4-bromo-2-(difluoromethyl)pyridine (238 mg, 1.14 mmol). The product (I-5) was prepared by the same method and separated into 65 mg by silica gel column chromatography (ethyl acetate: methanol: triethylamine = 100:1:0.1). 1 H NMR(300MHz,Chloroform-d)δ8.25(d,J=5.7Hz,1H),6.94(d,J=2.8Hz,1H),6.79–6.5 1(m,2H),6.40–6.25(m,1H),5.33(ddd,J=48.2,12.5,6.1Hz,1H),5.08(dd,J=14.9,5 .8Hz,1H),5.00–4.72(m,3H),4.32–4.14(m,2H),4.11(dd,J=8.4,5.4Hz,1H),3.99(d t,J=8.3,6.4Hz,1H),3.73–3.15(m,1H),2.55(d,J=3.2Hz,3H),2.29(d,J=4.2Hz,3H).

[0334] Example 6: Preparation of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-(1-(4-(2-(dimethylamino)pyridin-4-yl)phenyl)azacyclobutane-3-yl)-2-fluoroethane-1-one (I-6)

[0335] The synthesis method of Example 2 was followed, except that 4-bromo-2-difluoromethoxypyridine was replaced with 4-(4-chlorophenyl)-N,N-dimethylpyridine-2-amine (400 mg, 1.72 mmol), and compound I-6 was prepared by the same method. 170 mg of the product was separated by silica gel column chromatography (ethyl acetate:methanol:triethylamine = 100:1:0.1). 1 H NMR(300MHz,Chloroform-d)δ8.18(d,J=5.3Hz,1H),7.59–7.46(m,2H),6.93(d,J=3.8Hz,1H),6.77(dd,J =5.4,1.5Hz,1H),6.67(d,J=1.4Hz,1H),6.60–6.44(m,2H),5.36(ddd,J=48.4,18.9,7.0Hz,1H),5.07(dd, J=14.9,7.2Hz,1H),5.02–4.89(m,1H),4.89–4.72(m,2H),4.23–4.07(m,2H),4.02(dt,J=7.7,5.4Hz,1H), 3.88(dt,J=7.7,5.6Hz,1H),3.49–3.27(m,1H),3.16(s,6H),2.55(d,J=4.4Hz,3H),2.29(d,J=6.8Hz,3H).

[0336] Example 7: Preparation of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl-5.5.7.7-d4)-2-fluoro-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutan-3-yl)ethane-1-one (I-7)

[0337] Following the synthetic method of Example 1, except that 2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride was replaced with 2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5,5,7,7-d4 hydrochloride (285.9 mg, 1.27 mmol), compound I-7 was prepared by the same method. 156 mg of the product, namely the title compound (I-7), was separated by silica gel column chromatography (ethyl acetate). 1H NMR (300MHz, DMSO-d6)δ 1 H NMR (400MHz, DMSO-d6) δ8.24(d,J=5.6Hz,1H),7.02(s,1H),6.78(s,1H),6.59(d,J=5.6Hz,1H),4.15(dt,J=16.2,8.2Hz ,2H),4.07(d,J=6.7Hz,1H),3.91(t,J=7.4Hz,1H),3.51–3.43(m,1H),3.41(s,1H),2.43(s,3H),2.24(d,J=5.5Hz,3H).

[0338] Chiral splitting of I-7:

[0339] Instruments: SFC-80 preparative version SFC (SFC-1); Column: Chiralpak AY, 250×30mm ID, 10μm; Mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia), gradient: B 40%; Flow rate: 80mL / min; Back pressure: 100bar; Column temperature: 40℃; Detection wavelength: 220nm; Cycle time: 5min.

[0340] Among them, the retention time RT = 1.18 min is I-7-A, and the retention time RT = 1.68 min is I-7-B.

[0341] Example 8: Preparation of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl-5.5.7.7-d4)-2-fluoro-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutane-3-yl-3-d)ethane-1-one-2-d(I-8)

[0342] The synthesis method of Example 1 was followed, except that the hydrogen gas was replaced by three deuterium gas evacuations. Compound I-8 was prepared by the same method, and 160 mg of the product, namely the title compound (I-8), was separated by silica gel column chromatography (ethyl acetate). 1 H NMR (300MHz, DMSO-d6)δ 1H NMR (400MHz, DMSO-d6) δ8.23(d,J=5.7Hz,1H),7.02(d,J=14.0Hz,1H),6.77(s,1H),6.57(d,J=5.7Hz,1H),4.97(d,J=8.4Hz,1H),4.92(d,J=8. 7Hz,1H),4.66(s,1H),4.62(s,1H),4.14(dd,J=18.0,7.9Hz,2H),4.06(d,J=8.9Hz,1H),3.91(d,J=8.8Hz,1H),2.43(s,3H),2.29–2.20(m,3H).

[0343] Chiral splitting of I-8:

[0344] Instruments: SFC-80 preparative version SFC (SFC-1); Column: Chiralpak AY, 250×30mm ID, 10μm; Mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia), gradient: B 40%; Flow rate: 80mL / min; Back pressure: 100bar; Column temperature: 40℃; Detection wavelength: 220nm; Cycle time: 5min.

[0345] Retention time RT = 1.17 min is I-8-A, and retention time RT = 1.35 min is I-8-B.

[0346] Example 9: Preparation of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-fluoro-2-(1-(2-fluoropyridin-4-yl)azacyclobutane-3-yl)acet-1-one

[0347] Step 1: In a two-necked flask equipped with a stir bar, add 1-tert-butoxycarbonyl-3-azacyclobutanone (848 mg, 4.95 mmol), triethyl 2-fluoro-2-phosphorylacetate (838 μL, 4.13 mmol), and DBU (925 μL, 6.19 mmol). Add anhydrous dichloromethane at room temperature and allow the reaction to proceed. After the reaction is complete as monitored by TLC, cool to room temperature, quench with saturated ammonium chloride solution, extract with dichloromethane, combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate the organic phase, and perform silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain 816 mg of an oily substance. 1H NMR (300MHz, Chloroform-d) 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).

[0348] Step 2: Add 816 mg (3.15 mmol) of 3-(2-ethoxy-1-fluoro-2-oxoethylene)azacyclobutane-1-carboxylic acid tert-butyl ester (Pd / C, catalytic amount) to a single-necked flask equipped with a stirrer. Add methanol at room temperature, purge with hydrogen three times, and react at room temperature. After the reaction is complete as monitored by TLC, filter, concentrate the organic phase, and obtain the crude product. Dissolve the crude product in DCM and react slowly with trifluoroacetic acid (5 eq) at room temperature. After the reaction is complete as monitored by TLC, concentrate the organic phase and separate the oil (quantitative), which requires no further purification.

[0349] Step 3: In a single-necked flask equipped with a stir bar, add 2,2,2-trifluoroacetate of 2-(azacyclobutane-3-yl)-2-fluoroethyl acetate (quantitative), 4-bromo-2-fluoropyridine (234 μL, 2.27 mmol), chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (177 mg, 0.23 mmol), and cesium carbonate (2.22 g, 6.82 mmol). The reaction was carried out at 120 °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 subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain 500 mg of a clear oil. 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, concentrated, and subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to separate 407 mg of a transparent oil. 1 H NMR(300MHz,Chloroform-d)δ7.85(d,J=5.8Hz,1H),6.15(dt,J=5.8,1.9Hz,1H),5.80(d,J=1.9Hz,1H),5.07(dd,J=4 8.6, 5.8Hz, 1H), 4.30 (q, J=7.1Hz, 2H), 4.17–3.89 (m, 4H), 3.33 (dtq, J=22.4, 8.3, 5.7Hz, 1H), 1.33 (t, J=7.1Hz, 3H).

[0350] Step 4: In a single-necked flask equipped with a stir bar, add 200 mg (0.78 mmol) of ethyl 2-fluoro-2-(1-(2-fluoropyridin-4-yl)azacyclobutane-3-yl)acetate, 173 mg (0.78 mmol) of 2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride, and 435 mg (3.12 mmol) of 1,5,7-triazidobicyclo(4.4.0)dec-5-ene. Add anhydrous tetrahydrofuran at room temperature and react at 70 °C. After the reaction is complete as monitored by TLC, cool to room temperature, concentrate, and successively add purified water, saturated sodium chloride solution, and saturated ammonium chloride solution. Extract with dichloromethane, combine the organic phases, dry to anhydrous sodium sulfate, filter, concentrate the organic phase, and separate the product (99 mg, the title compound) by silica gel column chromatography (ethyl acetate). 1 H NMR(300MHz,Chloroform-d)δ7.94–7.67(m,1H),6.95(d,J=5.8Hz,1H),6.17(dt,J=5.8,1 .9Hz,1H),5.81(d,J=1.9Hz,1H),5.33(ddd,J=48.2,11.9,6.2Hz,1H),5.09(t,J=12.7Hz, 1H),4.96(d,J=15.5Hz,1H),4.91–4.71(m,2H),4.29–4.13(m,2H),4.06(dt,J=8.3,5.5Hz ,1H),3.95(dt,J=8.1,6.2Hz,1H),3.62–3.33(m,1H),2.56(s,3H),2.30(d,J=5.8Hz,3H).

[0351] Example 10: Preparation of 1-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-fluoro-2-(1-(2-(((S)-1,1,1,1-trifluoroprop-2-yl)oxy)pyridin-4-yl)azacyclobutane-3-yl)acet-1-one

[0352] The synthesis method of Example 2 was followed, except that 4-bromo-2-difluoromethoxypyridine was replaced with (S)-4-bromo-2-(1,1,1-trifluoroprop-2-yl)oxypyridine (150 mg, 0.56 mmol), and compound I-10 was prepared by the same method. 92 mg of the product was separated by silica gel column chromatography (pure ethyl acetate). 1H NMR (300MHz, DMSO-d6) δ8.41(t,J=6.0Hz,1H),7.77(d,J=5.8Hz,1H),6.23(t,J=2.4Hz,1H),6.16(dd,J=5.8,2.0Hz,1H),5.85(h,J=6.7Hz,1H),5 .77(d,J=1.9Hz,1H),5.13(dd,J=48.9,5.2Hz,1H),4.00(dt,J=20.0,8. 4Hz,2H),3.89–3.75(m,2H),3.28–2.99(m,10H),,1.39(d,J=6.5Hz,3H).

[0353] Example 11: Preparation of 4-(3-(2-(2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-1-fluoro-2-oxoethyl)azacyclobutane-1-yl)pyridinecarboxylonitrile

[0354] The synthesis method of Example 2 was followed, except that 4-bromo-2-difluoromethoxypyridine was replaced with 4-bromopyridine-2-carboxynitrile (300 mg, 1.64 mmol). Compound I-11 was prepared by the same method, and 3 mg of the product was separated by silica gel column chromatography (pure ethyl acetate). 1 H NMR(300MHz,Chloroform-d)δ8.25(d,J=5.8Hz,1H),6.94(d,J=3.4Hz,1H),6.63(d,J=2. 4Hz,1H),6.38(dd,J=5.8,2.4Hz,1H),5.34(ddd,J=48.1,12.8,5.8Hz,1H),5.07(dd,J=1 4.9,6.1Hz,1H),4.98–4.71(m,3H),4.32–4.16(m,2H),4.09(dt,J=9.3,4.9Hz,1H),3.99 (dt,J=8.6,6.4Hz,1H),3.65–3.41(m,1H),2.55(d,J=2.6Hz,3H),2.29(d,J=4.2Hz,3H).

[0355] Example 12: Preparation of 1-(2-methyl-4-(methyl-d3)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-fluoro-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutane-3-yl)ethane-1-one (I-12)

[0356] Following the synthetic method of Example 1, except that 2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride was replaced with 2-methyl-4-(methyl-d3)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride (268.9 mg, 1.2 mmol), compound I-12 was prepared by the same method. The product, namely the title compound (I-12), was separated by silica gel column chromatography (ethyl acetate). 1 H NMR (300MHz, DMSO-d6) δ8.25(d,J=5.5Hz,1H),7.03(s,1H),6.81(d,J=2.4Hz,1H),6.60(d,J=5.7Hz,1H),4.95(d,J=16. 8Hz,2H),4.62(d,J=16.0Hz,2H),4.20–4.07(m,3H),3.92(t,J=7.4Hz,1H),3.57–3.43(m,1H),3.40(s,1H),2.26(s,3H).

[0357] Chiral splitting of I-12:

[0358] Instruments: SFC-80 preparative version SFC (SFC-1); Column: Chiralpak AY, 250×30mm ID, 10μm; Mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia), gradient: B 40%; Flow rate: 80mL / min; Back pressure: 100bar; Column temperature: 40℃; Detection wavelength: 220nm; Cycle time: 5min.

[0359] Among them, the retention time RT = 1.26 min is I-12-A, and the retention time RT = 1.59 min is I-12-B.

[0360] The unresolved compounds in this invention can be resolved to obtain isomers using methods commonly used in the art. The CVL-231 structure mentioned in this disclosure is shown below, and was prepared according to the method in Example 11 of PCT / IB2017 / 053565.

[0361] Test Implementation Examples

[0362] Test Example 1: In vitro positive allosteric regulation assay of M4 receptor

[0363] 1.1 In vitro isotope binding assay

[0364] 1.1.1 Preparation of cell receptor membrane

[0365] 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, buffer was added again, and the mixture was mixed. The cells were then centrifuged at 48000g at 4°C for 25 minutes and stored at -80°C.

[0366] 1.1.2 Preparation of test sample

[0367] 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.

[0368] 1.1.3 Test Procedure

[0369] Step 1: Prepare the membrane into a membrane suspension of a certain concentration using a buffer solution;

[0370] Step 2: Add 50 μL of buffer to the total binding tube (TB) and 50 μL of atropine (final concentration 1.0 × 10⁻⁶) to the nonspecific binding tube (NB). -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;

[0371] Step 3: Add 50 μL of buffer solution to each reaction tube;

[0372] Step 4: Add 50 μL of the corresponding radioactive ligand to each reaction tube;

[0373] Step 5: Add 50 μL of the membrane preparation to each reaction tube;

[0374] 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.

[0375] Step 7: Let stand overnight, then place the filter plate into the liquid scintillation counter for counting.

[0376] 1.2 In vitro inositol 1-phosphate (IP-1) assay method

[0377] (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.

[0378] (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.

[0379] (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.

[0380] (4) Cell addition: Add the cell suspension to the experimental plate at 7 μL / well (i.e., about 15,000 cells / well).

[0381] (5) Addition of 1 x Stimulation buffer and addition of compound:

[0382] Allosteric regulation mode: Add the compound diluted with 1 x Stimulation buffer to the above experimental plate, 3.5 μL / well.

[0383] (6) Reaction incubation: Place the experimental plate in a constant temperature shaking oven at 37℃ and incubate for 20 minutes.

[0384] (7) Adding compounds and agonists at EC20 concentrations:

[0385] Activation mode: Add the compound diluted with 1 x Stimulation buffer to the above experimental plate, 3.5 μL / well.

[0386] Allosteric regulation mode: Add 3.5 μL of EC20 4 x Acetylcholine chloride solution to the above experimental plate.

[0387] (8) Incubate again: Place the experimental plate in a constant temperature shaking box at 37℃ for 60 minutes.

[0388] (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.

[0389] (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.

[0390] 1.3 Test Results

[0391] Table 1-1 Results of in vitro activity tests of the compounds of the present invention

[0392] Table 1-2 Results of in vitro activity tests on some compounds of the present invention " / " indicates that the test was not conducted.

[0393] In vitro isotope binding assays showed that the binding levels of the compounds of the present invention to the M4 receptor were basically equivalent to those of CVL-231, and some compounds were even better; IP-1 assays showed that the functional levels of the compounds of the present invention to the M4 receptor were superior to those of CVL-231, indicating that they are effective positive allosteric regulators of the M4 receptor.

[0394] In summary, the compounds of this invention have the potential to treat schizophrenia.

[0395] Test Example 2: Experiment on the effect of the compound on amphetamine-induced hyperactivity behavior in mice

[0396] 2.1 Test Methods

[0397] Thirty minutes after administering the test substance (or control substance) by gavage, mice were injected intraperitoneally with 2 mg / kg (administration volume 10 mL / kg body weight) of dextromethorphan hydrochloride. The mice were then placed in a self-activity box for video recording for 60 minutes. Video analysis was performed after the recording to evaluate the mice's activity.

[0398] 2.2 Test Results

[0399] Table 2-1 Animal efficacy test results of the compounds of the present invention

[0400] The results show that the compound of the present invention has a good ability to inhibit the hyperactive behavior induced by dextromethorphan hydrochloride in mice, and has the potential to treat schizophrenia.

[0401] Test Example 3: Rat Pharmacokinetic Test

[0402] 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.

[0403] 3.1 Test Methods

[0404] 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.

[0405] Preparation of the oral administration solution: Use 0.5% methylcellulose aqueous solution to aid suspension and dispersion, preparing a 1 mg / mL suspension. The administration volume is 1 mL / 100 g body weight, which, converted to concentration, is 10 mg / kg body weight.

[0406] 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.

[0407] 3.2 Test Results

[0408] Rat pharmacokinetic studies showed that, compared to CVL-231, the compound of this invention exhibited the following effects: 1 / 2 The increased concentration of the compound has the potential to reduce the frequency of medication, improve patient compliance, and reduce the burden on healthcare staff. The significantly increased Cmax indicates a faster onset of action, and the significantly increased AUC suggests a longer duration of action, requiring less dosage and achieving a wider safety window. In particular, the compound improves brain penetration, reducing peripheral drug exposure at the effective dose, which is expected to decrease the occurrence of peripheral adverse reactions such as gastrointestinal and cardiovascular toxicity, thereby increasing patient compliance and safety.

[0409] Table 3. Pharmacokinetic parameters of rats in the examples. " / " indicates that the test was not conducted.

[0410] Test Example 4: Long-term toxicity test in rats and dogs

[0411] In a 4-week continuous oral administration study in rats and dogs, the compound was tested for blood routine, blood biochemistry, histopathology, toxicokinetics and other indicators at different doses. The results showed that the representative compound of this invention exhibited a large safety window.

[0412] Those skilled in the art will understand that numerous modifications and variations can be made to this 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 constitute limitation in any way. The true scope and spirit of the invention are revealed by the appended claims, and the description and embodiments are merely exemplary.

Claims

1. A compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R1, R2and R3are each independently selected from H, deuterium, halogen, hydroxyl, cyano, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted hydroxyl C1-C6alkyl, optionally substituted C2-C6alkenyl, and optionally substituted C2-C6alkynyl, the optional substituents being independently selected from deuterium and halogen; each R4, when present, is independently selected from deuterium, optionally substituted C1-C6alkyl, optionally substituted C1-C6alkoxy, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, and hydroxyl, the optional substituents being independently selected from deuterium and halogen; R5, R6are each independently selected from the group consisting of hydrogen, deuterium, halogen, OR 10 and optionally substituted C1-C6alkyl, provided that at least one of R5and R6is deuterium, halogen or OR 10 , said optional substituents are independently selected from the group consisting of deuterium and halogen; R 10 H, optionally substituted C1-C6alkyl, or optionally substituted C3-C8cycloalkyl, the optional substituent(s) being independently selected from deuterium and halogen; R 11 R is H, deuterium or halogen; L is selected from any one or more R. 1-1 Replacement C 6-14 aryl, optionally with one or more R 1-1 Substituted 5-14 heteroaryl groups and optionally one or more R 1-1 Substituted 5-14 membered heterocyclic groups; Each R 1-1 It is independently selected from deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, nitro, C1-C6 alkylthio, hydroxyl and cyano; A is absent or selected from 5-14 membered heteroaryl, C 6-14 aryl and 5-14 membered heterocyclyl; each Ra, when present, is independently selected from deuterium, optionally substituted Ci-C6alkyl, 1-2 substituted Ci-C6alkyl, optionally substituted by one or more R 1-2 substituted Ci-C6alkoxy, optionally substituted by one or more R 1-2 substituted Ci-C6alkylthio, halogen, cyano, hydroxyl, nitro, amino, oxo, optionally substituted by one or more R 1-2 substituted C3-C6cycloalkyl, -N(R8)(R9), -N(R8)(C(=0)R9), -C(=0)-N(R8)(R9), -C(=0)-OR7, -C(=0)-R7, -S(=0)2-R7, -NR 13 -(CH2) r -CR 14 =CRbRc, -CHR 13 -(CH2) r -CR 14 =CRbRc, -0-NR 13 -(CH2) r -CR 14 =CRbRc, and -0-CHR 13 -(CH2) r -CR 14 =CRbRc; Each R 1-2 Independently selected from deuterium, halogen, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, -N(R8)(R9), -N(R8)(C(=O)R9), -C(=O)-N(R8)(R9), -C(=O)-OR7, -C(=O)-R7 and -S(=O)2-R7; R7is C1-C6alkyl; R8and R9are each independently selected from H, deuterium, C1-C6alkyl optionally substituted with one or more Rb, C3-C8cycloalkyl optionally substituted with one or more Rb, C1-C6alkoxy optionally substituted with one or more Rb, and C1-C6alkylthio optionally substituted with one or more Rb; each Rb is independently selected from hydrogen, deuterium, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, halogen, -N(CH3)2, -NHCH3, and hydroxyl; Rcis selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C1-C6haloalkoxy; R 13 and R 14 each independently is selected from the group consisting of H, deuterium, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, and C2-C6alkenyl; or R 13 and R 14 to the carbon or nitrogen atom to which it is attached to form a 3-8 membered carbocyclic or heterocyclic ring; or R8and R9, together with the nitrogen atom to which they are attached, join to form an optionally substituted 3-8 membered nitrogen-containing heterocyclyl; 1-3 substituted 3-8 membered nitrogen-containing heterocyclyl; Each R 1-3 Independently selected from deuterium, hydrogen, halogen, hydroxyl, nitro, amino, C1-C6 alkylthio, C1-C6 deuterated alkylthio, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; n is any integer from 0-5; r is any integer from 0-5.

2. The compound of claim 1, stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein, one or more of the following conditions are met: (1) R1, R2, R3are each independently selected from H, deuterium, halogen, hydroxyl, cyano, optionally substituted C1-C6alkyl, and optionally substituted C1-C6alkoxy, the optional substituents being independently selected from deuterium and halogen; and / or (2) each R4, when present, is independently selected from deuterium, optionally substituted C1-C6alkyl, and hydroxyl, the optional substituents being independently selected from deuterium and halogen; and / or (3) R5, R6are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, iodine, OR 10 and C1-C6 alkyl, provided that at least one of R5and R6is deuterium, fluorine or OR 10 ; preferably R5and R6are each independently selected from the group consisting of hydrogen, deuterium, halogen and OR 10 , provided that at least one of R5and R6is deuterium, halogen or OR 10 ; preferably R5, R6are each independently selected from the group consisting of hydrogen, deuterium, halogen and OR 10 , provided that one or both of R5and R6is deuterium, halogen or OR 10 , and R5and R6are not identical; preferably R5, R6are each independently selected from the group consisting of hydrogen, deuterium and fluorine, provided that one or both of R5and R6is deuterium or fluorine, and R5and R6are not identical; preferably one or both of R5and R6is independently deuterium or halogen; preferably one of R5and R6is deuterium or halogen, the other is hydrogen; preferably one of R5and R6is fluorine, the other is hydrogen; and / or (4) R 10 is H, optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, the optional substituents being independently selected from deuterium and halogen; preferably R 10 is H, methyl, ethyl, cyclopropyl or cyclobutyl; and / or (5) R 11 H or deuterium; and / or (6) L is selected from optionally substituted C 1-1 substituted C 6-14 aryl, optionally substituted with one or more R 1- 1 substituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur and optionally substituted with one or more R 1-1 substituted 5-8 membered heterocyclyl containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; and / or (7) each R 1-1 independently selected from deuterium, halogen, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6haloalkoxy, Ci-C6deuteroalkyl, Ci-C6deuteroalkoxy, Ci-C6alkylthio, and hydroxyl; and / or (8) A is absent; or A is selected from the group consisting of 5-8 membered heteroaryl containing 1-5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, C 6-14 aryl and 5-8 membered heterocyclyl containing 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and / or (9) Ra is selected from deuterium, and is arbitrarily selected by one or more R. 1-2 Substituted C1-C6 alkyl groups, optionally with one or more R 1-2 Substituted C1-C6 alkoxy, halogen, cyano, hydroxyl, optionally with one or more R 1-2 Substituted C3-C6 cycloalkyl groups, -N(R8)(R9), -N(R8)(C(=O)R9), -C(=O)-N(R8)(R9), -C(=O)-OR7, -C(=O)-R7, -S(=O)2-R7, -NR 13 -(CH2) r -CR 14 =CRbRc, -CHR 13 -(CH2) r -CR 14 =CRbRc, -O-NR 13 -(CH2) r -CR 14 =CRbRc and -O-CHR 13 -(CH2) r -CR 14 =CRbRc; Ra is preferably selected from CF3, OCF2, NH2, N(CH3)2, and / or (10) each R 1-2 independently selected from deuterium, Ci-C6alkyl, halogen, and -N(R8)(R9); and / or (11) R7is C 1-3 alkyl; and / or (12) R8and R9are each independently selected from H, deuterium, C1-C3alkyl optionally substituted with one or more Rb, C3-C6cycloalkyl optionally substituted with one or more Rb, and C1-C3alkoxy optionally substituted with one or more Rb; or R8and R9, together with the nitrogen atom to which they are attached, link to form a 5- to 6-membered nitrogen-containing heterocyclyl optionally substituted with one or more R 1- 3substituted 5- to 6-membered nitrogen-containing heterocyclyl; and / or (13) each Rb is independently selected from deuterium, C1-C3alkyl, halogen, and C1-C3alkoxy; and / or (14) Rcis selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, and C1-C3haloalkoxy; and / or (15) R 13 and R 14 each independently is selected from the group consisting of H, deuterium, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy and C2-C4 alkenyl; or R 13 and R 14 form together with the carbon atom or nitrogen atom to which they are attached a 3- to 6-membered carbocyclic or heterocyclic ring, preferably R 13 and R 14 form together with the carbon atom or nitrogen atom to which they are attached a 4-membered carbocyclic or 4-membered nitrogen-containing heterocyclic ring; and / or (16) each R 1-3 independently selected from deuterium, hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6deuteroalkyl, C1-C6deuteroalkoxy, C1-C6haloalkyl, and C1-C6haloalkoxy; and / or (17) m is 0 or 4; and / or (18) p is 0, 1, or 2; and / or (19) n is 0, 1, 2, or 3; and / or (20) r is 0, 1, 2, or 3, preferably 1 or 2.

3. The compound of formula I as described in claim 1 or 2, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that: The compounds of formula I are compounds of formula VII-A, VII-B or mixtures thereof: Among them, R1, R2, R3, R4, R 10 R 11 , m, n, p, L, A and Ra as defined in any one of claims 1-2, and R5 and R6 are each independently selected from hydrogen, deuterium, halogen and OR. 10 The condition is that one or both of R5 and R6 are deuterium, halogen, or OR. 10 Furthermore, R5 and R6 are not the same; preferably, R5 and R6 are each independently selected from hydrogen, deuterium and fluorine, provided that one or both of R5 and R6 are deuterium or fluorine, and R5 and R6 are not the same.

4. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of any one of claims 1-3, wherein A is absent, or A is phenyl; and / or L is selected from any one or more R. 1-1 Substituted phenyl, optionally with one or more R 1-1 Substituted pyridinyl group, optionally with one or more R 1-1 Substituted pyrazinyl group, optionally with one or more R 1-1 Substituted pyrimidinyl group, optionally with one or more R 1-1 Substituted pyridazine group, optionally with one or more R 1-1 Substituted thiazolyl group, optionally with one or more R 1-1 Substituted thiophene group and optionally one or more R 1-1 Substituted quinolinyl group; preferably selected from those optionally substituted with one or more R groups. 1-1 Substituted phenyl, optionally with one or more R 1-1 Substituted pyridinyl group, optionally with one or more R 1-1 Substituted pyrazinyl group and optionally with one or more R 1-1 Substituted pyrimidine group; further preferably selected from those optionally substituted with one or more R groups. 1-1 Substituted phenyl and optionally with one or more R 1-1 Substituted pyridinyl; and / or R 1-1 selected from halogen, Ci-C6-alkyl, Ci-C6-alkoxy and Ci-C6-haloalkyl.

5. The compound of formula I, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1 to 4, wherein The compound of formula I is a compound of formula II; preferably a compound of formula III: wherein X1, X2, X3are each independently selected from CH and N; R1, R2, R3, R4, R 11 , m, L, A, Raand n are as defined in any one of claims 1-4, R5, R6are each independently selected from the group consisting of hydrogen, deuterium and fluorine, provided that one or both of R5and R6are deuterium or fluorine, and R5and R6are not identical.

6. The compound of formula I, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1 to 5, wherein The compound of Formula I is a compound of Formula VI: wherein R1, R2, R3, R 11 , m, A, Raand n are as defined in any one of claims 1-5; R5, R6are each independently selected from the group consisting of hydrogen, deuterium and fluorine, provided that one or both of R5and R6are deuterium or fluorine, and R5and R6are not the same.

7. The compound of formula I, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1 to 6, wherein selected from the group consisting of the following compounds:

8. A pharmaceutical composition comprising a compound of any one of claims 1-7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. Use of a compound of any one of claims 1-7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 8, for the manufacture of a medicament, preferably for the manufacture of a medicament for the treatment of a M4-mediated or M4-associated disease or disorder.

10. The use of claim 9, wherein the M4-mediated or M4-associated disease or disorder is selected from one or more of Alzheimer’s disease, schizophrenia, pain, addiction, sleep disorder, cognitive disorder, 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, Trisomy 21 syndrome, cerebral amyloid angiopathy, dementia, Dutch-type hereditary amyloid encephalopathy, Creutzfeld-Jakob disease, prion disorder, 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 disorder, preferably schizophrenia.

11. A compound of Formula V: ###0005### V or a stereoisomer thereof, or a salt thereof. wherein R 12 R is C1-C6alkyl; R5, R6, R 11 , L, A, Raand n are as defined in any one of claims 1-7.

12. A process for the preparation of a compound as claimed in any one of claims 1 to 7, characterized in that comprising the steps of: The compound represented by formula V-C or a salt thereof is subjected to a substitution reaction with the compound represented by formula V to produce the compound represented by formula I. wherein R 12 is C1-C6 alkyl; R1, R2, R3, R4, m, p, R5, R6, R 11 , L, A, Raand n are as defined in any one of the preceding claims 1 to 7.

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