Compound, and pharmaceutical composition comprising same, preparation method therefor and use thereof

Abstract

The present application relates to the field of medicinal chemistry, and in particular to a compound, and a pharmaceutical composition comprising same, a preparation method therefor and a use thereof. The compound has a structure represented by formula I, and is used for preventing or treating M4-mediated diseases or conditions.

Description

Compounds, pharmaceutical compositions comprising the same, and methods of making and using the same

[0001] This application claims priority to PCT International Patent Application PCT / CN2025 / 082368 filed March 13, 2025, and to Chinese Patent Application CN202511774322.6 filed November 28, 2025, the entire contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] The present application relates to a compound, a pharmaceutical composition comprising the same, a method of making the same, and use of the same for preventing or treating a muscarinic acetylcholine receptor M4 mediated disease or condition. BACKGROUND

[0003] Muscarinic acetylcholine receptors are G protein-coupled receptors (GPCRs) and are divided into five subtypes, M1, M2, M3, M4, and M5. These subtypes are widely distributed throughout the peripheral and central nervous systems, with M1 and M4 subtypes mainly expressed in the CNS, with M4 receptors mainly expressed in the cerebral cortex, striatum, hypothalamus, and hippocampus (Neuropharmacology 2018, 136, 362-373). M1, M3, and M5 subtypes are mainly coupled to Gq and activate phospholipase C, while M2 and M4 subtypes are mainly coupled to Gi / o and related effector systems.

[0004] A genome-wide association study for schizophrenia identified a single nucleotide polymorphism at locus rs7951870 significantly associated with disease, which includes the M4 gene (Nature genetics 2018, 50, 381-389). In schizophrenia, the high dopaminergic state in the striatum and nucleus accumbens is associated with psychosis, which is the target of current antipsychotic drugs that block dopamine D2 receptors.

[0005] In a recent study, it was demonstrated that M4 PAMs (M4 positive allosteric modulators) reduced amphetamine-induced dopamine release in the striatum of wild-type mice, but not in M4 knockout wild-type mice (Neuropsychopharmacology 2014, 39, 1578). Another study showed that M4 PAMs induced inhibition of glutamate excitatory synaptic transmission at Schaffer collateral-CA1 synapses in the hippocampus (Hippocampus 2017, 27, 794-810). It was shown that M4 PAMs potentiated the effects of the endogenous agonist acetylcholine, revealing the importance of these receptors in controlling dopamine release in the striatum, and their role in key synapses in the hippocampus that are important for cognition. By activating striatal and hippocampal M4 receptors using specific PAMs, it is possible to reduce the hyperdopaminergic state of the striatum and overstimulation of the hippocampus, providing a treatment for the positive and cognitive symptoms of schizophrenia.

[0006] Eli Lilly disclosed a patent for thienopyridine compounds as positive allosteric modulators (M4 PAMs) for muscarinic M4 acetylcholine receptors (WO2006047124A1). Vanderbilt University has disclosed several international patent applications for muscarinic M4 PAMs

[0007] CVL-231 developed by Pfizer for M4 PAMs is currently in clinical phase II, showing good therapeutic effect on schizophrenic patients. However, there is still a defect of fast metabolism, and the pharmacokinetic properties have room for further improvement.

[0008] Recently, clinical studies on patients with Alzheimer's disease have shown that M1 / M4 agonists, such as xanomeline, activate muscarinic receptors to improve cognitive and psychotic symptoms, such as hallucinations, delusions, and vocalizations (Arch Neurol 1997, 54, 465-73). Therefore, M4 PAMs can improve cognitive deficits and reduce psychotic symptoms in patients with Alzheimer's disease. The combination therapy of xanomeline and trospium (KarXT) has achieved positive results in the treatment of schizophrenia, further demonstrating the therapeutic effect of M receptor agonism in this field. However, xanomeline itself is not well selective for M receptors, and it has strong gastrointestinal side effects in clinical use, which must be combined with a peripheral M2, M3 antagonist for use, which brings inconvenience to clinical application.

[0009] Modulating M4 receptor activity is a promising therapeutic strategy for treating or preventing M4-mediated diseases or conditions. It is necessary to provide new compounds, formulations, treatments, and therapies for treating or preventing M4-mediated diseases or conditions. Therefore, there is a need to develop new compounds that modulate M4 receptor activity to meet the clinical needs. SUMMARY

[0010] This invention provides a novel polycyclic compound that can act as a modulator of muscarinic acetylcholine receptor M4 activity, especially a positive allosteric modulator (M4 PAM), and can be used to treat M4 receptor-mediated diseases or disorders. The compound has excellent positive allosteric modulation of M4 and has fewer toxic side effects and good pharmacokinetic properties.

[0011] One aspect of the invention provides compounds of Formula I or thereof, or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites, or prodrugs thereof:

[0012] in:

[0013] Ring A is selected from 5-14 membered heteroaryl rings and C. 6-14 Aromatic rings;

[0014] R 1 R 3 R 4 R 5 Each time it appears, it is independently selected from hydrogen, deuterium, tritium, OR 7 Oxygen, hydroxyl, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -NR 7 R 8 -CONR 7 R 8 -COC 1-6 Alkyl, -NHCOC 1-6 Alkyl, -C(O)OR 7 -OC(O)R 7 -OC(O)NR 7 R 8 -NR 7 C(O)NR 7 R 8 C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally bounded by one or more (e.g., 1, 2, 3, 4, 5, 6) R groups. 9 Replace; or

[0015] Two R atoms bonded to the same carbon atom 4 Or two Rs5 Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group, wherein the cycloalkyl group is optionally bounded by one or more (e.g., 1, 2, 3, 4, 5, or 6) R... 9 replace;

[0016] Furthermore, R 1 It can also be missing;

[0017] R 7 R 8 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein each of the alkyl, cycloalkyl, and heterocyclic groups is optionally surrounded by one or more (e.g., 1, 2, 3, 4, 5, 6) R groups. 9 Replace; or

[0018] R 7 R 8 Together with N atoms, they form 3-8 membered heterocyclic groups, wherein the heterocyclic group is optionally surrounded by one or more (e.g., 1, 2, 3, 4, 5, 6) R atoms. 9 replace;

[0019] R 9 Each time it appears, it is independently selected from H, deuterium, tritium, halogen, -OH, -CN, oxo, and -NR. 7 R 8 -COCH3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl thio, C 1-6 Haloalkylthio, C 2-6 Heteroalkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and 5-10 heteroaryl group, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, or heteroaryl group is optionally each selected independently by one or more (e.g., 1, 2, 3, 4, 5, 6) of a halogen, -OH, -CN, or -NR. 7 R 8 -COC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0020] B ring is selected from 4-8 membered carbocyclic, 4-8 membered heterocyclic, 4-8 membered aromatic, and 4-8 membered heteroaromatic ring;

[0021] C ring is selected from 5-8 membered carbocyclic, 5-8 membered heterocyclic, or 5-8 membered heteroaromatic ring;

[0022] L is selected from C, CR a , and N;

[0023] R a is selected from hydrogen, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl;

[0024] R 2 is -P-R 6 ;

[0025] P is a single bond, a double bond, C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and C 3-8 cycloalkyl, 5-14 membered heteroaryl, and 3-8 membered heterocyclyl, C 6-10 aryl, and 3-8 membered heterocyclyl, 5-14 membered heteroaryl, and C 3-8 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, -R 7 -(C=0)-N(R 8 )-, -N(R 8 )-(C=0)-R 7 -, said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) R 9 ;

[0026] R 6 is selected from absent, H, C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and C 3-8 cycloalkyl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl, C 6-10 aryl, and 3-8 membered heterocyclyl, 5-14 membered heteroaryl, and C 3-8 cycloalkyl, 5-14 membered heteroaryl, and C 6-14 aryl, said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) R 9substituted;

[0027] each m, n, o is independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0028] the compound of Formula I is not compound 1-144, compound 146-533,

[0029] when P is selected from methylene, R 6 when R 9 is not trifluoromethylpyridinyl; or,

[0030] when P is selected from a single bond, R 6 is not cyclopropyl; or,

[0031] when P is selected from cyclopropyl, R 6 is not absent or H.

[0032] Another aspect of the present application provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

[0033] Another aspect of the present application provides the use of a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, or a pharmaceutical composition of the present application, in the manufacture of a medicament for the prevention or treatment of a muscarinic acetylcholine receptor M4-mediated disease or condition.

[0034] Another aspect of the present application provides a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, or a pharmaceutical composition of the present application, for use in the prevention or treatment of a muscarinic acetylcholine receptor M4-mediated disease or condition.

[0035] Another aspect of the present application provides a method of preventing or treating a muscarinic acetylcholine receptor M4-mediated disease or condition, comprising administering to an individual in need thereof an effective amount of a compound of the present application or a pharmaceutically acceptable salt, stereoisomers, tautomer, isotopically-labeled compound, polymorph, solvate, or N-oxide, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention.

[0036] Another aspect of the present application provides a method of making a compound of the present application, comprising the steps of:

[0037] wherein X is a hydroxyl, a halogen (e.g., iodine, bromine, chlorine, fluorine), or a leaving group (e.g., methyl sulfonate, ethyl sulfonate, phenyl sulfonate, p-toluenesulfonate), and the like; and the compound I-A is linked to R 2 X is reacted, preferably, L' is selected from -NH-.

[0038] ring A, ring B, ring C, L, R 1 , R 2 , R 3 , R 4 , R 5 , m, n, o are as defined above.

[0039] or,

[0040] wherein X is a hydroxyl, a halogen (e.g., iodine, bromine, chlorine, fluorine), or a leaving group (e.g., methyl sulfonate, ethyl sulfonate, phenyl sulfonate, p-toluenesulfonate), and the like; and,

[0041] ring A, ring B, ring C, L, R 1 , R 2 , R 3 , R 4 , R 5 , m, n, o, P are as defined above.

[0042] Definitions

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Reference herein to technical terms used herein is intended to refer to the technical terms as commonly understood by those skilled in the art, including variations or substitutions of techniques or replacements of techniques that are apparent to those skilled in the art. Although the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present application.

[0044] The terms "comprising," "including," "having," "containing," or "involving," and any variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps, although other unrecited elements or method steps are not necessarily present (i.e., these terms also cover the terms "consisting essentially of" and "consisting of").

[0045] As used herein, the term "alkyl" defines a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3 carbon atoms. For example, as used herein, the term "C 1-10 alkyl," "C 1-6 alkyl," and "C 1-4 alkyl" refer to linear or branched groups having 1-10 carbon atoms, 1-6 carbon atoms, and 1-4 carbon atoms, respectively (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, or n-hexyl), which are optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen (when the group is referred to as "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C 1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl).

[0046] As used herein, the term "heteroalkyl" refers to a backbone chain of carbon atoms having one or more heteroatoms independently selected from an atom other than carbon, for example oxygen, nitrogen, sulfur, phosphorus, or combinations thereof, in the backbone carbon atoms of an alkyl group. Numerical ranges (e.g., C 2-6 heteroalkyl) refers to the number of carbons in the chain, which in this example includes 2-6 carbon atoms. For example, a -CH2OCH2CH3group is referred to as a C3heteroalkyl, and a -CH2OCH2CH2NHCH3group is referred to as a C4heteroalkyl. Attachment to the rest of the molecule can be through a heteroatom or a carbon atom in the heteroalkyl chain.

[0047] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) same or different halogen atoms, the terms "C 1-8 haloalkyl," "C 1-6 haloalkyl," and "C 1-4 haloalkyl" refer to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1-4 carbon atoms, respectively, for example -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3, etc.

[0048] As used herein, the term "hydroxyalkyl" refers to a group formed by the substitution of one or more hydrogen atoms in an alkyl group with one or more hydroxyl groups, for example C 1-10 hydroxyalkyl, C 1-6 hydroxyalkyl, or C 1-4Hydroxyalkyl groups, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH3, etc.

[0049] As used herein, the term "alkoxy" means -O-alkyl, where the alkyl group is as defined above, for example, C... 1-10 Alkoxy, C 1-8 Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkyl group. C 1-6 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, etc., wherein the alkoxy group is optionally substituted by one or more (such as 1 to 3) identical or different substituents. The term "haloalkoxy" refers to an alkoxy group in which the hydrogen atom is substituted by one or more (such as 1 to 3) identical or different halogen atoms.

[0050] As used herein, the term “fused ring” or “dense ring” refers to a ring system formed by two or more ring structures sharing two adjacent atoms.

[0051] As used herein, the term "spiroring" refers to a ring system consisting of two or more ring structures that share a single ring atom.

[0052] As used in this article, the term "bridged ring" refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.

[0053] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon cycloalkyl group, including but not limited to monocyclic alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicyclic alkyl groups, including spirocyclic, fused-ring (fused-ring) or bridged-ring systems (i.e., spirocyclic alkyl, fused-ring (fused-ring) alkyl, and bridged-ring alkyl groups, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, etc.). In this invention, the cycloalkyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atom on the cycloalkyl group is optionally substituted with an oxo group (i.e., forming C=O). The term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) cyclic carbon atoms, such as C10. 3-6 Cycloalkyl groups can be monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or they can be bicycloalkyl, such as C10, C20, C30, C40, C50, C60, C7 ... 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 fused cycloalkyl, C5-6 Spirocycloalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl groups.

[0054] As used herein, the term "cycloalkoxy" refers to -O-cycloalkyl, where the cycloalkyl group is as defined above. Representative examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0055] As used herein, the term "heterocyclic group" or "heterocycle" refers to an aliphatic monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) group having two or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms, said heteroatoms including, but not limited to, oxygen, nitrogen, sulfur, and silicon atoms, wherein the carbon atoms and heteroatoms on said heterocyclic group are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2), or optionally with one or more (such as 1 to 3) independently selected from halogens and C 1-3 Alkyl substituents. A "heterocyclic group" or "heterocycle" may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms. The term "saturated heterocycle" refers to a fully saturated heterocycle, such as tetrahydrofuran, piperidine, morpholine, tetrahydropyran, piperazine, etc. The term "partially saturated heterocycle" refers to a heterocycle containing both saturated single bonds and unsaturated double bonds, such as 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, dihydropyrrole, dihydrofuran, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, etc. As used herein, the term "3-10 membered heterocyclic group" refers to a heterocyclic group containing 3-10 ring atoms, including but not limited to 4-10 membered heterocyclic groups, 4-9 membered heterocyclic groups, 4-8 membered heterocyclic groups, 4-7 membered heterocyclic groups, 5-6 membered heterocyclic groups, 3-8 membered heterocyclic groups, 3-7 membered heterocyclic groups, 4-7 membered nitrogen-containing heterocyclic groups, 4-7 membered oxygen-containing heterocyclic groups, 4-7 membered sulfur-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 5-6 membered sulfur-containing heterocyclic groups, etc., wherein each of the "nitrogen-containing heterocyclic group," "oxygen-containing heterocyclic group," and "sulfur-containing heterocyclic group" optionally also contains one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of 3-10 membered heterocyclic groups include, but are not limited to, ethylene oxide, aziridinyl, aziridine, oxobutyl, tetrahydrofuranyl, pyrrolylyl, pyrrolidone (e.g., ... ), imidazoalkyl, pyrazolyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazine, trithianyl, dihydrofuranyl, dihydropyrroleyl, dihydrothiophenyl, dihydropyranyl. As used herein, the term "3-8 membered heterocyclic group" refers to a heterocyclic group containing 3-8 ring atoms, including but not limited to 3-8 membered heterocyclic groups, 3-7 membered heterocyclic groups, 3-6 membered heterocyclic groups, 4-8 membered heterocyclic groups, 4-7 membered heterocyclic groups, 4-6 membered heterocyclic groups, 5-6 membered heterocyclic groups, 4-7 membered nitrogen-containing heterocyclic groups, 4-7 membered oxygen-containing heterocyclic groups, 4-7 membered sulfur-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 5-6 membered sulfur-containing heterocyclic groups, etc., wherein each of the "nitrogen-containing heterocyclic group," "oxygen-containing heterocyclic group," and "sulfur-containing heterocyclic group" optionally also contains one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of 3-8 membered heterocyclic groups include, but are not limited to, ethylene oxide, aziridinyl, aziridine, oxobutyl, tetrahydrofuranyl, pyrrolylyl, pyrrolidone (e.g., ... ), imidazoalkyl, pyrazolyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, dihydrofuranyl, dihydropyrroleyl, dihydrothiophenyl, and dihydropyranyl.

[0056] In this invention, the heterocyclic group can form a fused ring structure with a heterocyclic group or a cycloalkyl group. The connection point of the fused ring structure with other groups can be on any heterocyclic group or on a cycloalkyl group. Therefore, the heterocyclic group of this invention also includes (but is not limited to) heterocyclic fused heterocyclic groups, heterocyclic fused cycloalkyl groups, monoheterocyclic fused monoheterocyclic groups, and monoheterocyclic fused monocycloalkyl groups, such as 3-7 membered (mono)heterocyclic fused 3-7 membered (mono)heterocyclic groups, 3-7 membered (mono)heterocyclic fused (mono)cycloalkyl groups, and 3-7 membered (mono)heterocyclic fused C 4-6 (Mono)cycloalkyl groups, examples of which include, but are not limited to, pyrrolidinylcyclopropyl, cyclopentylazirylpropyl, pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, and piperidinylmorpholinyl.

[0057] In this invention, the heterocyclic group also includes bridged heterocyclic groups and spiroheterocyclic groups.

[0058] As used herein, the term "bridged heterocycle" refers to a ring structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, and / or sulfur atoms) formed by two saturated rings sharing two non-directly connected ring atoms. This includes, but is not limited to, 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, and 7-10 membered sulfur-containing bridged heterocycles, etc. The "nitrogen-bridged heterocycle", "oxygen-bridged heterocycle", and "sulfur-bridged heterocycle" may optionally also contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0059] As used herein, the term "spiroheterocycle" refers to a ring structure containing one or more heteroatoms (e.g., oxygen, nitrogen, sulfur) formed by two or more saturated rings sharing a single ring atom. This includes, but is not limited to, 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, and 6-10 membered sulfur-containing spiroheterocycles. The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", and "sulfur-containing spiroheterocycle" may optionally also contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. The term "6-10-membered nitrogen-containing spiroheterocycle group" refers to a spiroheterocycle group containing a total of 6-10 ring atoms, of which at least one ring atom is a nitrogen atom.

[0060] Examples of groups obtained by fusion of heterocyclic and aryl groups include, but are not limited to:

[0061] As used herein, the terms "aryl," "phenyl," or "aromatic ring" refer to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated π-electron system. As used herein, the term "C" refers to a carbon-based monocyclic or fused polycyclic aromatic group. 6-14 Aryl (aromatic ring)", C 6-10 "Aryl (aromatic ring)" refers to an aryl (aromatic ring) containing 6-14 carbon atoms or 6-10 carbon atoms, preferably phenyl (benzene ring) or naphthyl (naphthalene ring). The aryl group may optionally be substituted by one or more (such as 1 to 3) identical or different substituents (e.g., halogen, OH, CN, NO2, C1-C6 alkyl, etc.).

[0062] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryl groups and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, for example 5, 6, 7, 8, 9, or 10 ring atoms, and in each case may additionally be benzofused. The heteroatom may be oxygen, nitrogen, or sulfur. The carbon atom and heteroatom on the heteroaryl group are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2).

[0063] As used herein, the terms “5-14-membered heteroaryl” or “5-14-membered heteroaryl ring” and “5-10-membered heteroaryl” or “5-10-membered heteroaryl ring” refer to heteroaryl (heteroaryl ring) containing 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14) or 5 to 10 (e.g., 5 to 6) ring atoms, including 5-14-membered nitrogen-containing heteroaryl, 5-14-membered oxygen-containing heteroaryl, 5-14-membered sulfur-containing heteroaryl, 5-10-membered nitrogen-containing heteroaryl, 5-10-membered oxygen-containing heteroaryl, 5-10-membered sulfur-containing heteroaryl, 5-6-membered nitrogen-containing heteroaryl, 5-6-membered oxygen-containing heteroaryl, 5-6-membered sulfur-containing heteroaryl, etc. The “nitrogen-containing heteroaryl,” “oxygen-containing heteroaryl,” and “sulfur-containing heteroaryl” each optionally contain one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of these groups include, but are not limited to, thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazole, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, etc., or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., as well as 5-14 membered and 5-10 membered cyclic groups containing these groups.

[0064] In this invention, a heteroaryl group (e.g., a monoheteroaryl group) can share two adjacent atoms with an aryl group (e.g., a monocyclic aryl group, such as a phenyl group), a heterocyclic group (e.g., a monoheterocyclic group), a cycloalkyl group (e.g., a monocycloalkyl group), or another heteroaryl group (e.g., another monoheteroaryl group) to form a fused ring structure. The connection point can be on any heteroaryl ring or other rings, including but not limited to (mono)heteroaryl fused (mono)heteroaryl, (mono)heteroaryl fused (monocyclic) aryl, (mono)heteroaryl fused (mono)heterocyclic, and (mono)heteroaryl fused (mono)cycloalkyl, such as 5-6 membered (mono)heteroaryl fused 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroaryl fused phenyl, 5-6 membered (mono)heteroaryl fused 5-6 membered (mono)heterocyclic, or 5-6 membered (mono)heteroaryl fused C 4-6 (Mono)cycloalkyl groups (e.g., 5-6-membered heteroarylcyclobutyl, 5-6-membered heteroarylcyclopentyl, or 5-6-membered heteroarylcyclohexyl), examples of which include, but are not limited to, benzothiazolyl, indolyl, isoyindolyl, indolyl, benzimidazole, quinolinyl, isoquinolinyl, wait.

[0065] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br, or I.

[0066] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, four, five, or six) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0067] If a substituent is described as “optionally substituted by one or more…”, then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together by independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted by independently selected optional substituents.

[0068] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0069] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, six, seven, eight, nine, or ten.

[0070] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0071] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0072] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., H); 11 C 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.)13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes ... 32 P); and isotopes of sulfur (e.g. 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0073] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, nitroso-oximes can exist in equilibrium in solution in the following tautomer forms:

[0074] It should be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0075] Solid lines may be used in this article. solid wedge Or virtual wedge The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or dashed wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0076] The wavy lines used in this article When used to represent a bond, it implies that the bond configuration is uncertain, such as a wavy line. Placed on the key This indicates that the bond is a connecting bond to other atoms; this bond can be a single bond or a double bond. When When located on a ring, it indicates the connection point on the ring.

[0077] This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0078] Cocrystal refers to the combination of active pharmaceutical molecules and other physiologically acceptable acids, bases, salts, and nonionic compound molecules in the same crystal lattice via hydrogen bonds, π-π stacking interactions, van der Waals forces, and other non-covalent bonds.

[0079] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0080] Pharmaceutically acceptable salts of the compounds of this invention include their acid addition salts and base addition salts. Examples include hexafluorophosphates and meglumine salts. For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002).

[0081] As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0082] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0083] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized to oxides. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including but not limited to the oxidation of heterocycles and tertiary amines using peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp. 748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

[0084] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0085] This invention further includes, within its scope, prodrugs of the compounds of this invention, which are certain derivatives of the compounds of this invention that may themselves have little or no pharmacological activity, and which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of this invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of this invention can be prepared, for example, by replacing suitable functional groups present in the compounds of this invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0086] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in T.W. Greene & P. ​​G. W. M. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0087] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0088] This application is by no means limited to the methods and materials described herein. In the event that one or more of the cited documents, patents and similar materials differ from or contradict this application (including but not limited to defined terms, application of terms, described techniques, etc.), the descriptions and accompanying compound structural formulas of this application shall prevail. In this application, if the chemical name and the chemical structural formula are inconsistent, the chemical structural formula shall prevail.

[0089] compound

[0090] In some embodiments, the present invention provides compounds of Formula I or thereof, or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites, or prodrugs thereof:

[0091] in:

[0092] Ring A is selected from 5-14 membered heteroaryl rings and C. 6-14 Aromatic rings;

[0093] R 1 R 3 R 4 R 5 Each time it appears, it is independently selected from hydrogen, deuterium, tritium, OR 7 hydroxyl, oxo, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -NR 7 R 8 -CONR 7 R 8 -COC 1-6 Alkyl, -NHCOC 1-6 Alkyl, C(O)OR 7 -OC(O)R 7 -OC(O)NR 7 R 8 -NR 7 C(O)NR 7 R 8 C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally bounded by one or more (e.g., 1, 2, 3, 4, 5, 6) R groups. 9 Replace; or

[0094] Two R atoms bonded to the same carbon atom 4 Or two Rs 5 Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group, wherein the cycloalkyl group is optionally bounded by one or more (e.g., 1, 2, 3, 4, 5, or 6) R... 9 replace;

[0095] Furthermore, R 1 It can also be missing;

[0096] R 7 R 8 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein each of the alkyl, cycloalkyl, and heterocyclic groups is optionally surrounded by one or more (e.g., 1, 2, 3, 4, 5, 6) R groups. 9 Replace; or,

[0097] R 7 R 8 The N atom bonded to it forms a 3-8 membered heterocyclic group, which is optionally bonded by one or more (e.g., 1, 2, 3, 4, 5, or 6) R atoms. 9 replace;

[0098] R 9 Each time it appears, it is independently selected from H, deuterium, tritium, halogen, -OH, -CN, oxo, and -NR. 7 R 8 -COCH3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl thio, C 1-6 Haloalkylthio, C 2-6 Heteroalkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and 5-10 heteroaryl group, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, or heteroaryl group is optionally each selected independently by one or more (e.g., 1, 2, 3, 4, 5, 6) of a halogen, -OH, -CN, or -NR. 7 R 8 -COC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0099] Ring B is selected from 4-8 membered carbon rings, 4-8 membered heterocycles, 6-10 membered aromatic rings, and 5-10 membered heteroaromatic rings;

[0100] The C ring is selected from 5-8 membered carbon rings, 5-8 membered heterocycles, or 5-10 membered heteroaromatic rings;

[0101] L is selected from C, CR a and N;

[0102] R a Selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0103] R 2 For -PR 6 ;

[0104] P represents a single bond, a double bond, and C represents a C bond. 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl benzo[C] 3-8 Cycloalkyl, 5-14-membered heteroaryl and 3-8-membered heterocyclic, C 6-10 aryl 3-8 membered heterocyclic, 5-14 membered heteroaryl 3-8 membered heterocyclic 3-8 cycloalkyl, C 6-10 Aryl, 5-14 heteroaryl, -R 7 -(C=O)-N(R 8 )-、-N(R 8 )-(C=O)-R 7 - The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more (e.g., 1, 2, 3, 4, 5, or 6) R 9 replace;

[0105] R 6 Selected from missing, H, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl benzo[C] 3-8 Cycloalkyl, 5-10-membered heteroaryl and 3-8-membered heterocyclic, C 6-10 aryl 3-8 membered heterocyclic, 5-14 membered heteroaryl 3-8 membered heterocyclic 3-8 cycloalkyl, 5-14 membered heteroaryl and C 6-14The aryl group, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more (e.g., 1, 2, 3, 4, 5, or 6) R groups. 9 replace;

[0106] m, n, and o are each independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0107] In some embodiments, the compounds of Formula I do not include compounds that are not compounds 1-144, 146-533, etc.

[0108] When P is selected from methylene, R 6 When selected from nitrogen-containing heterocyclic butanes, R 9 Not trifluoromethylpyridinyl; or,

[0109] When P is selected from a single bond, R 6 Not cyclopropyl; or,

[0110] When P is selected from cyclopropyl, R 6 Not missing or H.

[0111] In some embodiments, the A ring in the Formula I compound provided by the present invention is selected from benzene rings and 5-10 membered heteroaromatic rings.

[0112] In some embodiments, in the Formula I compounds provided by the present invention, ring A is selected from benzene rings, 5-10 member oxygen-containing heteroaromatic rings, 5-10 member sulfur-containing heteroaromatic rings, and 5-10 member nitrogen-containing heteroaromatic rings.

[0113] In some embodiments, in the Formula I compound provided by the present invention, ring A is selected from pyridine, pyrrole, furan, thiophene, benzene, quinoline, indole, pyridopyrrole, pyrimidine, pyrrolopyridine, pyrazolopyridine, imidazopyridine, triazolopyridine, pyrazine, and pyridazine rings.

[0114] In some embodiments, the A ring in the Formula I compound provided by the present invention is selected from benzene rings and 5-9 membered heteroaromatic rings.

[0115] In some embodiments, in the Formula I compounds provided by the present invention, ring A is selected from benzene rings, 5-9 member oxygen-containing heteroaromatic rings, 5-9 member sulfur-containing heteroaromatic rings, and 5-9 member nitrogen-containing heteroaromatic rings.

[0116] In some embodiments, in the Formula I compounds provided by the present invention, ring A is selected from pyridine, pyrrole, furan, thiophene, benzene, indole, pyridopyrrole, pyrimidine, pyrrolopyridine, pyrazolopyridine, imidazoolopyridine, triazolopyridine, pyrazine, and pyridazine rings.

[0117] In some embodiments, in the Formula I compound provided by the present invention, ring A is selected from pyridine, pyrrole, furan, thiophene, benzene, indole, pyridopyrrole, pyrimidine, pyrrolopyridine, pyrazolopyridine, imidazopyridine, and triazolopyridine rings.

[0118] In some embodiments, in the Formula I compound provided by the present invention, ring A is selected from pyridine ring, furan ring, pyrrole, thiophene, and pyridazine.

[0119] In some embodiments, in the compound of formula I provided by the present invention, ring A is selected from the pyridine ring.

[0120] In some embodiments, in the compound of formula I provided by the present invention, ring A is selected from...

[0121] In some embodiments, in the compound of formula I provided by the present invention, ring A is selected from...

[0122] In some embodiments, in the compound of formula I provided by the present invention, ring A is selected from...

[0123] In some embodiments, in the compound of formula I provided by the present invention, R 1 R 3 Independently selected from hydrogen, deuterium, tritium, oxo, OR 7 hydroxyl, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -CONR 7 R 8 -NHCOC 1-6 Alkyl, C 3-8 Cycloalkyl, 5-6 membered heteroaryl, 3-8 membered heterocyclic and -NR 7 R 8 The alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R groups. 9 replace.

[0124] In some embodiments, in the compound of formula I provided by the present invention, R 1 R 3 Independently selected from hydrogen, deuterium, tritium, and OR 7 hydroxyl, halogen, cyano, nitro, C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -CONR 7 R 8 -NHCOC 1-6 Alkyl, C 3-8 Cycloalkyl, 5-6 membered heteroaryl, 3-8 membered heterocyclic, -NR 7 R 8 The alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R groups. 9 replace.

[0125] In some embodiments, in the compound of formula I provided by the present invention, R 1 R 3 Independently selected from hydrogen, deuterium, tritium, oxo, OR 7 hydroxyl, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -CONR 7 R 8 -NHCOC 1-6 Alkyl, C 3-8 Cycloalkyl and 5-6-membered heteroaryl groups, wherein the alkyl, alkenyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R groups. 9 replace.

[0126] In some embodiments, in the compound of formula I provided by the present invention, R 1 R 3 Independently selected from hydrogen, hydroxyl, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Hydroxyalkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, -CONR 7 R 8 -NHCOC 1-4 Alkyl, C 3-5Cycloalkyl, 5-6 membered heteroaryl, 3-6 membered heterocyclic, -NHC 1-4 Alkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R groups. 9 replace;

[0127] R 7 R 8 Each is independently selected from H and C. 1-4 alkyl.

[0128] In some embodiments, in the compound of formula I provided by the present invention, R 1 R 3 Independently selected from oxo (=O), CH3, CH2CH3, F, Cl, Br, cyano, CHF2, CF3, ethynyl, methoxy, -NH-CH3, vinyl, N-heterocyclic butyl CH2OH, In some embodiments, in the compound of formula I provided by the present invention, R 1 R 3 Independently selected from CH3, F, Cl, Br, cyano, CHF2, CF3, ethynyl, vinyl, CH2OH, CH2CH3, -OCH3

[0129] In some embodiments, in the compound of formula I provided by the present invention, R 1 R 3 It is independently selected from CH3, F and Cl.

[0130] In some embodiments, in the compounds of Formula I provided by the present invention, ring B is selected from 4-8 membered carbon rings, 4-8 membered heterocycles, and C... 6-10 Aromatic rings and 5-10 heterocyclic aromatic rings.

[0131] In some embodiments, in the Formula I compounds provided by the present invention, ring B is selected from 4-8 membered carbon rings, 4-8 membered heterocycles, 6-8 membered aromatic rings, and 5-10 membered heteroaromatic rings.

[0132] In the case where ring B of this invention is selected from partially unsaturated 4-8 membered carbon rings or partially unsaturated 4-8 membered heterocycles, since ring A is aromatic, the bond formed between the two atoms in ring B that are shared with ring A must be an unsaturated bond. Therefore, ring B is limited to partially unsaturated 4-8 membered carbon rings or partially unsaturated 4-8 membered heterocycles. In addition to the two atoms in ring B that are shared with ring A forming unsaturated bonds, the bonds in other parts of ring B can be saturated or unsaturated.

[0133] In some embodiments, in the compound of formula I provided by the present invention, ring B is selected from 5-7 member partially unsaturated heterocycles, 5-7 member partially unsaturated carbon rings, 5-6 member heteroaromatic rings, and benzene rings.

[0134] In some embodiments, in the compound of formula I provided by the present invention, ring B is selected from 5-6 member partially unsaturated heterocycles, 5-6 member heteroaromatic rings, and benzene rings.

[0135] In some embodiments, in the compound of formula I provided by the present invention, ring B is selected from benzene ring, dihydropyrrole, tetrahydropyrrole, pyrrole, thiophene, pyrazole, imidazole, etc. Pyridine, cyclohexene, cyclopentene, dihydrofuran ring, and tetrahydropyridine.

[0136] In some embodiments, in the compound of formula I provided by the present invention, ring B is selected from benzene ring, dihydropyrrole, pyrrole, thiophene, pyrazole, imidazole, etc. Pyridine, cyclohexene, cyclopentene, and dihydrofuran ring.

[0137] In some embodiments, in the compound of formula I provided by the present invention, ring B is selected from benzene ring, dihydropyrrole, pyrrole, thiophene, pyrazole, imidazole, etc. Pyridine, cyclohexene, cyclopentene, and dihydrofuran ring.

[0138] In some embodiments, in the compound of formula I provided by the present invention, ring B is selected from...

[0139] In some embodiments, in the compound of formula I provided by the present invention, ring B is selected from...

[0140] In some embodiments, in the compound of formula I provided by the present invention, ring B is selected from...

[0141] In some embodiments, in the compound of formula I provided by the present invention, ring B is selected from...

[0142] In some embodiments, in the compound of formula I provided by the present invention, R 5 Independently selected from hydrogen, deuterium, tritium, oxo, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6hydroxyalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R 9 Replace; or,

[0143] Two R atoms bonded to the same carbon atom 5 Together with the carbon atom it is attached to, they form a 3-5 membered cycloalkyl group, which is optionally bonded by one or more R atoms. 9 replace.

[0144] In some embodiments, in the compound of formula I provided by the present invention, R 5 Independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 hydroxyalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R 9 Replace; or,

[0145] Two R atoms bonded to the same carbon atom 5 Together with the carbon atom it is attached to, they form a 3-5 membered cycloalkyl group, which is optionally bonded by one or more R atoms. 9 replace.

[0146] In some embodiments, in the compound of formula I provided by the present invention, R 5 Independently selected from hydrogen, deuterium, tritium, oxo, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 1-4 hydroxyalkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more R groups. 9 Replace; or,

[0147] Two R atoms bonded to the same carbon atom 5 Together with the carbon atom it is attached to, they form a 3-5 membered cycloalkyl group, which is optionally bonded by one or more R atoms. 9 replace.

[0148] In some embodiments, in the compound of formula I provided by the present invention, R 5 Independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 1-4hydroxyalkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more R groups. 9 Replace; or,

[0149] Two R atoms bonded to the same carbon atom 5 Together with the carbon atom it is attached to, they form a 3-5 membered cycloalkyl group, which is optionally bonded by one or more R atoms. 9 replace.

[0150] In some embodiments, in the compound of formula I provided by the present invention, R 5 Independently selected from H, CH3, oxo (=O), F, Cl, Br, CHF2, and CF3; or, two R atoms bonded to the same carbon atom. 5 Together with the carbon atom it is attached to, it forms a cyclopropyl group.

[0151] In some embodiments, in the compound of formula I provided by the present invention, R 5 Independently selected from H, CH3, F, Cl, Br, CHF2, CF3; or, two R atoms bonded to the same carbon atom. 5 Together with the carbon atom it is attached to, it forms a cyclopropyl group.

[0152] In some embodiments, in the compound of formula I provided by the present invention, R 5 For H.

[0153] In some embodiments, the C ring in the Formula I compound provided by the present invention is selected from 5-7 membered carbon rings, 5-8 membered heterocycles (e.g., nitrogen-containing heterocycles or Si-containing heterocycles), or 5-8 membered heteroaromatic rings (e.g., nitrogen-containing heteroaromatic rings).

[0154] In some embodiments, in the compound of formula I provided by the present invention, the C ring is selected from...

[0155] In some embodiments, in the compound of formula I provided by the present invention, the C ring is selected from...

[0156] In some embodiments, in the compound of formula I provided by the present invention, the C ring is selected from...

[0157] In some embodiments, in the compound of formula I provided by the present invention, the C ring is selected from...

[0158] In some embodiments, in the compound of formula I provided by the present invention, R 4 Independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R 9 Replace; or,

[0159] Two R atoms bonded to the same carbon atom 4 Together with the carbon atom it is attached to, they form a 3-5 membered cycloalkyl group, which is optionally bonded by one or more R atoms. 9 replace.

[0160] In some embodiments, in the compound of formula I provided by the present invention, R 4 Independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 hydroxyalkoxy, wherein the alkyl or alkoxy group is optionally surrounded by one or more R groups. 9 Replace; or,

[0161] Two R atoms bonded to the same carbon atom 4 Together with the carbon atom it is attached to, they form a 3-5 membered cycloalkyl group, which is optionally bonded by one or more R atoms. 9 replace.

[0162] In some embodiments, in the compound of formula I provided by the present invention, R 4 Independently selected from one or more substituents selected from H, deuterium D, CH3, F, Cl, Br, CHF2, and CF3; or, two R groups bonded to the same carbon atom. 4 Together with the carbon atom it is attached to, it forms a cyclopropyl group.

[0163] In some embodiments, in the compound of formula I provided by the present invention, R 4 Independently selected from H, CH3, F, Cl, Br, CHF2, CF3; or, two R atoms bonded to the same carbon atom. 4 Together with the carbon atom it is attached to, it forms a cyclopropyl group.

[0164] In some embodiments, in the compound of formula I provided by the present invention, R 4 H stands for H independently.

[0165] In some embodiments, the compound of formula I provided by the present invention is a compound of formula II:

[0166] Among them, ring A, ring C, and ring R 1 R 2 R 3 R 4 L, m, and n are as defined above for compounds of formula I;

[0167] In B ring, Z represents 1 X 1 X 2 Z 2 X 3 X 4 In Chinese, any two adjacent symbols can be either single or double bonds, provided that the two adjacent bonds are not both double bonds.

[0168] X 1 X 2 Each is independently selected from C and N;

[0169] X 3 X 4 Each is independently selected from C, N, and CR. 5a ;

[0170] Z 1 Z 2 Each is independently selected from single bonds, -(CR 5a R 5b ) q -、CR 5a ,-C(=O)-,-O-,-S-,N,NR 5a -CR 5a R 5b -Z 3 --Z 3 -CR 5a R 5b -、=CR 5a -Z 3 -、-Z 3 -CR 5a =、N=CR 5a and -SiR 5a R 5b -;

[0171] R 5a and R 5b As mentioned above, R in compound I... 5 Defined;

[0172] Z 3 Selected from -O-, -S- and -NR 5a ;

[0173] q is selected from 1 or 2.

[0174] In some embodiments, the compound of formula II provided by the present invention is a compound of formula III:

[0175] Among them, ring A, ring C, and ring R 1 R 2 R 3 R 4 X 1 X 2 X 3 X 4 Z 1 L, m, and n are as defined above for compounds of formula II.

[0176] In some embodiments, the compound of formula III provided by the present invention,

[0177] Z 1 Selected from CR 5a R 5b and CR 5a ;

[0178] X 1 and X 2 Selected from C;

[0179] X 3 Selected from CR 5a Or C;

[0180] X 4 Selected from N.

[0181] In some embodiments, in the compound of formula II provided by the present invention, Z 1 It does not exist; Z 2 Selected from CR 5a ;X 1 X 2 X 3 Selected from C; X 4 Selected from N.

[0182] In some embodiments, in the compound of formula II provided by the present invention, Z 1 Z 2 Selected from -CR 5a R 5b -、-C(=O)-、CR 5a -O-, -S-, N, -NR 7 -;X 1 X 2 Selected from C and N; X 3 X 4 Selected from C, CR 5a and N.

[0183] In some embodiments, the compound of formula II provided by the present invention is a compound of formula V:

[0184] Among them, ring A, ring C, and ring R 1 R 2 R 3 R 4 L, m, and n are as defined above for compounds of formula II;

[0185] Z 1 Z 2 Selected from CR 5a R 5b CR 5a NR 5a N, O and S;

[0186] X 1 X 2 Selected from C;

[0187] X 3 X 4 Selected from C, CR 5a Or N.

[0188] In some embodiments, the compound of formula I provided by the present invention is a compound of formula VI:

[0189] Among them, ring A, ring C, and ring R 1 R 2 R 3 L and m are as defined above for compounds of formula I;

[0190] In B ring, Z represents 1 X 1 X 2 Z 2 X 3 X 4 In Chinese, any two adjacent symbols can be either single or double bonds, provided that the two adjacent bonds are not both double bonds.

[0191] X 1 X 2 Each is independently selected from C and N;

[0192] X 3 X 4 Each is independently selected from C, N, and CR. 5a ;

[0193] Z 1 Z 2 Each is independently selected from single bonds, -(CR 5a R 5b )q -、CR 5a ,-C(=O)-,-O-,-S-,N,NR 5a -CR 5a R 5b -Z 3 -、-Z 3 -CR 5a R 5b -、=CR 5a -Z 3 -、-Z 3 -CR 5a =、N=CR 5a and -SiR 5a R 5b -;

[0194] R 5a and R 5b As mentioned above, R in compound I... 5 Defined;

[0195] Z 3 Selected from -O-, -S- and -NR 7 ;

[0196] Y is selected from single bond, -(CR) 4a R 4b ) p -(CR 4a R 4b )-、CR 4a ,-C(=O)-,C,-O-,-S-,N,NR 4a -CR 4a =CR 4b -、-CR 4a =N-, -SiR 4a R 4b -、-CR 4a R 4b -Z 3 -and-Z 3 -CR 4a R 4b -;

[0197] R 4a and R 4b As mentioned above, R in compound I... 4 Defined;

[0198] p is selected from 0, 1, or 2;

[0199] q is selected from 1 or 2.

[0200] In some embodiments, in the compound of formula VI provided by the present invention, Y is selected from -(CR) 4a R 4b) p -(CR 4a R 4b -, -C(=O)-, -CR 4a =CR 4b -、-CR 4a R 4b =N- and -SiR 4a R 4b -, p is 1, 2, and R 4a and R 4b Each is independently selected from hydrogen and C. 1-6 Alkyl, C 1-6 Haloalkyl, or R 4a and R 4b Together with the carbon atoms they are attached to, they form 3-6 membered cycloalkyl groups.

[0201] In some embodiments, in the compound of formula VI provided by the present invention, Y is selected from -CH2CH2-, -CH(CH3)CH2-, -C(CH3)2CH2-, -CH(CF3)CH2-, CH2, -C(=O)-, (CH2)3, CH(CHF2), -CH(CF3)-, CH=CH, -CH=N-, -C(CH3)=N- and -Si(CH3)2-.

[0202] In some embodiments, the compounds of formula II and formula VI provided by the present invention,

[0203] Z 1 Selected from single bond, -CR 5a R 5b -、CR 5a -O-, -S-, N, -NR 5a -、-SiR 5a R 5b -;

[0204] Z 2 Selected from single bond, -CR 5a R 5b -、CR 5a , N, -NR 7 -、-SiR 5a R 5b -

[0205] In some embodiments, the compounds of formula II and formula VI provided by the present invention,

[0206] Z 1 Selected from -CR 5a R 5b -、CR 5a -O-, -S-, N, -NR 5a-、-SiR 5a R 5b -;

[0207] Z 2 Selected from single bonds;

[0208] X 1 X 2 Selected from C and N;

[0209] X 3 and X 4 Each is independently selected from C, N, and CR. 5a .

[0210] In some embodiments, the compound of formula I provided by the present invention, Selected from the groups shown in Formula 1:

[0211] Among them, in the group shown in Formula 1,

[0212] R 1 R 3 R 5 L, m, o are as defined above for compounds of formula I or formula VI;

[0213] Z 1 X 1 X 2 Z 2 X 3 X 4 As defined above for compounds of formulas II and VI;

[0214] Y is as defined above for compounds of formula VI;

[0215] Y 1 Selected from missing, C, N, and CR 3 ;

[0216] Y 2 Y 3 Y 4 Each is independently selected from C, N, and CR. 3 NR 3 O and S.

[0217] In some embodiments, in the compound of formula I provided by the present invention, the groups represented by formula 1 are selected from:

[0218] Among them, R 1 R 3 R 5 Z 1 X 1 X 2 Z 2X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y, L, m, o are as defined above for the groups in Formula 1.

[0219] In some embodiments, in the compound of formula I provided by the present invention, the groups represented by formula 1 are selected from:

[0220] Among them, R 1 R 3 R 5 Z 1 X 1 X 2 Z 2 X 3 X 4 Y 1 Y 2 Y 3 Y 4 Y, L, m, o are as defined above for the groups in Formula 1, and Y 1 Not missing.

[0221] In some embodiments, in the compound of formula I provided by the present invention, the groups represented by formula 1 are selected from:

[0222] Among them, R 1 R 3 R 5 L, n, o are as defined above for compounds of formula I and groups of formula 1; R 4 n is as defined above for compound I; p is 0, 1 or 2.

[0223] In some embodiments, in the compound of formula I provided by the present invention, the groups represented by formula 1 are selected from:

[0224] Among them, R 1 R 3 R 5 L, n, o are as defined above for compounds of formula I and groups of formula 1; R 4 n is as defined above for compound I; p is 0, 1 or 2.

[0225] In some embodiments, in the compound of formula I provided by the present invention, the groups represented by formula 1 are selected from:

[0226] Among them, R 1 R 3 R 4 R5 , n, o are as defined above for compounds of formula I or groups of formula 1;

[0227] Z 1 As defined above for compounds of formula VI or groups of formula 1; preferably, Z 1 Selected from -CR 5a R 5b -、CR 5a -O-, -S-, N, NR 7 and SiR 5a R 5b .

[0228] In some embodiments, in the compound of formula I provided by the present invention, the groups represented by formula 1 are selected from:

[0229] Among them, R 1 R 3 R 4 R 5 、n、o are as defined above for compounds of formula I or groups of formula 1; Z 1 As defined above for compounds of formula VI or groups of formula 1; preferably, Z 1 Selected from -CR 5a R 5b -、CR 5a -O-, -S-, N, NR 7 and SiR 5a R 5b .

[0230] In some embodiments, the compound of formula I provided by the present invention, Selected from:

[0231] In some embodiments, the compound of formula I provided by the present invention, Selected from:

[0232] In some embodiments, the compound of formula I provided by the present invention, Selected from:

[0233] In some embodiments, the compound of formula I provided by the present invention, Selected from:

[0234] In some embodiments, the compound of formula I provided by the present invention, Selected from:

[0235] In some embodiments, the compound of formula I provided by the present invention, Selected from:

[0236] In some embodiments, in the compound of formula I provided by the present invention, L is selected from CR. 4a and N.

[0237] In some embodiments, in the compound of formula I provided by the present invention, L is selected from CH and N.

[0238] In some embodiments, in the compound of formula I provided by the present invention, P is a single bond, a double bond, or C. 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl benzo[C] 3-8 Cycloalkyl, 5-14-membered heteroaryl and 3-8-membered heterocyclic, C 6-10 aryl 3-8 membered heterocyclic, 5-14 membered heteroaryl 3-8 membered heterocyclic 3-8 cycloalkyl, C 6-10 Aryl, 5-14 heteroaryl, -R 7 -(C=O)-N(R 8 )-、-N(R 8 )-(C=O)-R 7 -, the C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl benzo[C] 3-8 Cycloalkyl, 5-14-membered heteroaryl and 3-8-membered heterocyclic, C 6-10 aryl 3-8 membered heterocyclic, 5-14 membered heteroaryl 3-8 membered heterocyclic 3-8 cycloalkyl, C 6-10 The aryl group and the 5-14 heteroaryl group are each optionally surrounded by one or more (e.g., 1, 2, 3, 4, 5, 6) R groups. 9 replace.

[0239] In some embodiments, in the compound of formula I provided by the present invention, P is selected from single bonds, double bonds, and -C bonds. 1-6 Alkyl-(C=O)-NR 7 -、-NR7 -(C=O)-C 1-6 Alkyl-, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic cycloalkenes 3-6 cycloalkyl and C6 aryl-C 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocyclic or aryl group is optionally each surrounded by one or more R groups. 9 replace.

[0240] In some embodiments, in the compound of formula I provided by the present invention, P is selected from single bonds, double bonds, and C bonds. 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein each cycloalkyl or heterocyclic group is optionally surrounded by one or more R 9 replace.

[0241] In some embodiments, in the compound of formula I provided by the present invention, P is selected from -C 1-4 Alkyl-(C=O)-NR 7 -、-NR 7 -(C=O)-C 1-4 Alkyl-, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic alkyl groups 3-6 cycloalkyl and C6 aryl-C 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocyclic or aryl group is optionally each surrounded by one or more R groups. 9 replace.

[0242] In some embodiments, in the compound of formula I provided by the present invention, P is selected from -C 1-4 Alkyl-(C=O)-NH-, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic alkyl groups 3-6 cycloalkyl and C6 aryl-C 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocyclic or aryl group is optionally each surrounded by one or more R groups. 9 replace.

[0243] In some embodiments, in the compound of formula I provided by the present invention, P is selected from C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein each cycloalkyl or heterocyclic group is optionally surrounded by one or more R groups. 9 replace.

[0244] In some embodiments, in the compound of formula I provided by the present invention, P is selected from -C 1-3 Alkyl-(C=O)-NH-, C1-3 Alkyl, C 1-3 Halogenated alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclobutyl, pyrrolidinyl, piperidinyl, piperazine, wherein each of the alkyl, cycloalkyl, or heterocyclic group is optionally oxidized by one or more R groups. 9 replace.

[0245] In some embodiments, in the compound of formula I provided by the present invention, P is selected from single bonds, double bonds, and -C bonds. 1-3 Alkyl-(C=O)-NH-, methylene, ethylene, propylene, C 1-3 Halogenated alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclobutyl, pyrrolidinyl, piperidinyl, piperazine, and benzocyclopentyl, wherein each of the alkyl, cycloalkyl, benzocyclopentyl, or heterocyclic group is optionally oxidized by one or more R groups. 9 replace.

[0246] In some embodiments, in the compound of formula I provided by the present invention, P is selected from single bonds, double bonds, and -C bonds. 1-3 Alkyl-(C=O)-NH-, methylene, C 1-3 Halogenated alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclobutyl, pyrrolidinyl, piperidinyl, piperazine, and benzocyclopentyl, wherein each of the alkyl, cycloalkyl, benzocyclopentyl, or heterocyclic group is optionally oxidized by one or more R groups. 9 Substitution; preferably, P is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, piperidinyl, piperazine, wherein each of the cycloalkyl or heterocyclic groups is optionally replaced by one or more R 9 replace.

[0247] In some embodiments, in the compound of formula I provided by the present invention, P is selected from single bonds, double bonds, methylene groups, etc. Cyclobutyl,

[0248] Alternatively, P is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2CF3、

[0249] In some embodiments, in the compound of formula I provided by the present invention, P is selected from... Cyclobutyl,

[0250] In some embodiments, in the compound of formula I provided by the present invention, P is

[0251] In some embodiments, in the compound of formula I provided by the present invention, P is a single bond.

[0252] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from missing, H, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl benzo[C] 3-8 Cycloalkyl, 5-10-membered heteroaryl and 3-8-membered heterocyclic, C 6-10 aryl 3-8 membered heterocyclic, 5-14 membered heteroaryl 3-8 membered heterocyclic 3-8 cycloalkyl, 5-14 membered heteroaryl and C 6-14 Aryl, the C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl benzo[C] 3-8 Cycloalkyl, 5-10-membered heteroaryl and 3-8-membered heterocyclic, C 6-10 aryl 3-8 membered heterocyclic, 5-14 membered heteroaryl 3-8 membered heterocyclic 3-8 cycloalkyl, 5-14 membered heteroaryl and C 6-14 Each aryl group is optionally surrounded by one or more (e.g., 1, 2, 3, 4, 5, 6) R 9 replace.

[0253] In some embodiments, in the compound of formula I provided by the present invention, R 6 For missing, P is C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic or C 6- Aryl benzo[C] 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocyclic or aryl group is optionally each surrounded by one or more R groups. 9 replace.

[0254] In some embodiments, in the compound of formula I provided by the present invention, R 6 For missing, P is C 1-4 Halogenated alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, The alkyl, cycloalkyl, or heterocyclic group is optionally each surrounded by one or more R groups. 9 replace.

[0255] In some embodiments, in the compound of formula I provided by the present invention, R 6 The symbol is missing; P represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. -CH2CF3、

[0256] In some embodiments, the compound of formula I provided by the present invention is a compound of formula VII.

[0257] Among them, E 1 E 2 Independently selected from C, CH2, CH, N, NH, O, and S;

[0258] m1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0259] m2 is selected from 0, 1, 2, or 3;

[0260] m3 is selected from 1, 2, or 3;

[0261] Ring A, Ring B, Ring C, R 1 R 3 R 4 R 6 R 9 L, m, n, o are as defined above for compounds of formula I, II, and VI.

[0262] In some embodiments, in the compound of formula VII, rings A, B, C, and R... 1 R 3 R 4 R 6 R 9 L, m, and n are as defined above for compounds of formulas I, II, and VI.

[0263] In some embodiments, the E of compound VII 1 E 2 It is independently selected from C, CH, N, O and S.

[0264] In some embodiments, the compound of formula I provided by the present invention is a compound of formula VII-1.

[0265] Where m2 is selected from 0, 1, 2 or 3;

[0266] m3 is selected from 1, 2, or 3;

[0267] Ring A, Ring B, Ring C, R 1 R 3 R 4 R 6 R 9 L, m, n, o are as defined above for compounds of formulas I, II, and VI, and m1 is as defined in formula VII.

[0268] In some embodiments, in the compound of formula VII-1, rings A, B, C, and R... 1 R 3 R 4 R 6 R 9 L, m, and n are as defined above for compounds of formulas I, II, and VI.

[0269] In some embodiments, in the compound of formula VII-1, m1 is selected from 0 and 1, and m2 and m3 are both 1.

[0270] In some embodiments, the compound of formula I provided by the present invention is a compound of formula VII-2.

[0271] Where m2 is selected from 0, 1, 2 or 3;

[0272] m3 is selected from 1, 2, or 3;

[0273] Ring A, Ring B, Ring C, R 1 R 3 R 4 R 6 R 9 L, m, n, o are as defined above for compounds of formulas I, II, and VI, and m1 is as defined in formula VII.

[0274] In some embodiments, in the compound of formula VII-2, rings A, B, C, and R... 1 R 3 R 4 R 6 R 9 L, m, and n are as defined above for compounds of formulas I, II, and VI.

[0275] In some embodiments, the compound of formula I provided by the present invention is a compound of formula VIII.

[0276] Among them, E 1 E 2 Independently selected from C, CH2, CH, N, NH, O, S;

[0277] m1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0278] m2 is selected from 0, 1, 2, or 3;

[0279] m3 is selected from 1, 2, or 3;

[0280] Ring A, Ring B, Ring C, R 1 R 3 R 4 R9 L, m, n, o are as defined above for compounds of formula I, II, and VI.

[0281] In some embodiments, in the compound of formula VIII, rings A, B, C, and R... 1 R 3 R 4 R 9 L, m, and n are as defined above for compounds of formulas I, II, and VI.

[0282] In some embodiments, the E of compound VIII 1 E 2 It is independently selected from C, CH, N, O and S.

[0283] In some embodiments, the compound of formula I provided by the present invention is a compound of formula VIII-1.

[0284] in,

[0285] m1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0286] m2 is selected from 0, 1, 2, or 3;

[0287] m3 is selected from 1, 2, or 3;

[0288] Ring A, Ring B, Ring C, R 1 R 3 R 4 R 9 L, m, n, o are as defined above for compounds of formula I, II, and VI.

[0289] In some embodiments, in the compound of formula VIII-1, rings A, B, C, and R... 1 R 3 R 4 R 9 L, m, and n are as defined above for compounds of formulas I, II, and VI.

[0290] In some embodiments, the compound of formula I provided by the present invention is a compound of formula VIII-2.

[0291] Where m1 is selected from 0, 1, 2, 3, 4, 5 or 6; m2 is selected from 0, 1, 2 or 3; m3 is selected from 1, 2 or 3;

[0292] Ring A, Ring B, Ring C, R 1 R 3 R 4 R 9L, m, n, o are as defined above for compounds of formula I, II, and VI.

[0293] In some embodiments, in compound VIII-2, rings A, B, C, and R... 1 R 3 R 4 R 9 L, m, and n are as defined above for compounds of formulas I, II, and VI.

[0294] In some embodiments, in the compound of formula I provided by the present invention, R 6 It is absent or selected from 3-10 membered heterocyclic groups, 5-14 membered heteroaryl groups and C 6-14 Aryl, wherein each of the aryl or heteroaryl groups is optionally surrounded by one or more R 9 replace.

[0295] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from Among them, G 1 G 2 G 3 G 4 G 5 Each is independently selected from CH and N. Indicates a single bond or a double bond.

[0296] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from deletions, 3-8 membered heterocyclic groups, 5-14 membered heteroaryl groups, C 6-14 Aryl, C 1-6 Alkyl, C 1-6 Haloalkyl, wherein the alkyl, heterocyclic, aryl, or heteroaryl group is optionally oxidized by one or more R groups. 9 replace.

[0297] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from 5-10 heteroaryl and C 6-10 Aryl, wherein each of the aryl or heteroaryl groups is optionally surrounded by one or more R 9 replace.

[0298] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from 5-6 nitrogen-containing heteroaryl and phenyl groups, wherein each of the aryl or heteroaryl groups is optionally surrounded by one or more R groups. 9 replace.

[0299] In some embodiments, in the compound of formula I provided by the present invention, R 6Selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazoleyl, thiadiazolyl, piperidinyl, thiazolyl, thiopheneyl, And benzimidazole group, wherein phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazoleyl, thiadiazolyl, piperidinyl, thiazolyl, thiopheneyl, Each of the benzimidazole groups is optionally surrounded by one or more R groups. 9 replace.

[0300] In some embodiments, in the compound of formula I provided by the present invention, R 6 The group is selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazoleyl, thiadiazolyl, piperidinyl, thiazolyl, and benzimidazoleyl, wherein each of the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazoleyl, thiadiazolyl, piperidinyl, thiazolyl, and benzimidazoleyl groups is optionally separated by one or more R groups. 9 replace.

[0301] In some embodiments, in the compound of formula I provided by the present invention, R 6 The aryl or heteroaryl group is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazoleyl, thiadiazolyl, piperidinyl, thiazolyl, and benzimidazolyl, wherein each aryl or heteroaryl group is optionally surrounded by one or more R groups. 9 replace.

[0302] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from Among them, G 1 G 2 G 3 G 4 G 5 Each is independently selected from CH and N.

[0303] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from

[0304] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from

[0305] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from

[0306] In some embodiments, in the compound of formula I provided by the present invention, R 9 Each is independently selected from hydrogen, deuterium, halogens, and carbon.1-4 Alkyl, -CN, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 3-6 Halogenated cycloalkoxy groups, -NH2, -NH(CH2CH3), -N(CH3)2, C 1-4 Haloalkylthio, C 3-6 cycloalkyl and 5-6 heteroaryl, wherein the 5-6 heteroaryl is optionally C 1-4 Alkyl, C 1-4 Alkyl halogenates are substituted.

[0307] In some embodiments, in the compound of formula I provided by the present invention, R 9 Each is independently selected from hydrogen, deuterium, F, Cl, Br, CH3, -CN, -CHF2, -CF3, -CHF2, -OCH3, -OCHF2, trifluoromethoxy, -OCH2CF3, -OCH(CH3)CF3, -NH2, -NH(CH2CH3), -N(CH3)2, -SCF3, cyclopropyl,

[0308] In some embodiments, in the compound of formula I provided by the present invention, R 9 Each is independently selected from -CF3,

[0309] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from missing, -CH3, -CH2CF3 and -CH2CH3.

[0310] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from

[0311] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from missing, -CH3, -CH2CF3 and -CH2CH3.

[0312] In some embodiments, in the compound of formula I provided by the present invention, R6 Selected from

[0313] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from

[0314] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from CH3, CH2CF3 and CH2CH3.

[0315] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from

[0316] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from missing,

[0317] In some embodiments, in the compound of formula I provided by the present invention, R 9 Each is independently selected from hydrogen, deuterium, halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -NR 7 R 8 CN, C 3-8 cycloalkyl, C 1-6 Haloalkylthio, C 1-6 Halogenated alkyloxy group and 5-10 heteroaryl group, wherein the 5-10 heteroaryl group is optionally surrounded by one or more groups selected from C 1-6 Alkyl groups are substituted.

[0318] In some embodiments, in the compound of formula I provided by the present invention, R 9 Each is independently selected from H, deuterium, F, Cl, Br, cyclopropyl, -CH2CH3, -CHF2, -CF3, -CH3, -OCH3, -OCH(CH3)CF3, -CH2CF3, -OCHF2, -OCH2CF3, -SCF3, -CN, -NH(CH2CH3), -N(CH3)2, -NH2,

[0319] In some embodiments, in the compound of formula I provided by the present invention, R 9 Selected from hydrogen, halogens, C 1-6 Haloalkyl, C 1-6 Alkoxy, -NR 7 R 8 CN, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl thiols and C 1-6 Halogenated alkyloxy groups.

[0320] In some embodiments, in the compound of formula I provided by the present invention, R 9 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkylthio, C 1-6 Alkoxy and -NR 7 R 8 .

[0321] In some embodiments, in the compound of formula I provided by the present invention, R 9 Selected from H, F, Cl, cyclopropyl, -CH2CH3, -CHF2, -CF3, -CH3, -OCH3, -OCH(CH3)CF3, -CH2CF3, -OCHF2, -OCH2CF3, -SCF3, -CN, -NH(CH2CH3), -N(CH3)2 and -NH2.

[0322] In some embodiments, in the compound of formula I provided by the present invention, R 9 Selected from H, F, CHF2, CF3, CH3, -OCH3 and NH2.

[0323] The compound of this invention modulates the allosteric activity of the muscarinic receptor M4 (EC) 50 The range is 1 to 10000 nM, preferably ≤1000 nM, further preferably ≤200 nM, and more preferably ≤100 nM.

[0324] In some embodiments, the compounds of the present invention include, but are not limited to:

[0325] In the compounds of Formula I of the present invention, the functional groups in all embodiments can be suitably selected and combined in any way to obtain different general formula ranges or specific embodiments. These ranges and embodiments are all within the scope of this invention. This invention covers compounds obtained by arbitrarily combining the various embodiments.

[0326] Preparation method

[0327] The compounds of the present invention can be prepared by any method known in the art. Reagents and starting materials are readily available to those skilled in the art. Individual isomers, enantiomers and diastereomers can be separated or resolved at any convenient point in the synthesis by methods such as selective crystallization techniques or chiral chromatography (see, for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Leel and S.H. Wilen).

[0328] In some embodiments, the present invention provides a first method for preparing a compound of formula I, comprising the following steps:

[0329] Make compound IA and compound R 2 The -X reaction yields the compound of formula I;

[0330] Wherein, X is a hydroxyl group, a halogen (e.g., iodine, bromine, chlorine, fluorine), or a leaving group (e.g., methanesulfonate, ethylsulfonate, phenylsulfonate, p-toluenesulfonate), etc.; and, the compound IA is connected to R through the L' position. 2 -X reaction, preferably, L' is selected from -NH-;

[0331] Ring A, Ring B, Ring C, L, R 1 R 2 R 3 R 4 R 5 m, n, and o are defined as above.

[0332] In some embodiments of the present invention, a method for preparing a compound of formula I of the present invention is provided, wherein L is C, or CR. a Compound IA and compound R 2 -X preferably forms chemical bonds through addition reactions or metal coupling reactions.

[0333] The addition reaction is carried out in the presence of a suitable base. The base may be selected from NaH, NaOH, LDA, LiHDMS, n-BuLi, K₂CO₃, Cs₂CO₃, C S F, DIPEA, TEA, etc. The addition reaction is preferably carried out in a suitable solvent. The solvent may be selected from THF, 1,4-dioxane, DMF, DMSO, NMP, acetonitrile, etc. The reaction is carried out at a suitable temperature, for example, between -78°C and 150°C.

[0334] The metal coupling reaction is preferably a metal-catalyzed CH-activated coupling. The metal coupling reaction is preferably carried out in the presence of a catalyst. The catalyst can be a palladium catalyst (e.g., palladium acetate, palladium chloride, etc.), a rhodium catalyst, a ruthenium catalyst, a nickel catalyst, etc. The metal coupling reaction can be carried out under literature conditions or similar conditions.

[0335] In some embodiments of the present invention, a method for preparing a compound of formula I, wherein L is N, and the compound of formula IA and compound R... 2 -X preferably forms chemical bonds through addition reactions or metal coupling reactions.

[0336] The addition reaction is carried out in the presence of a suitable base. The base may be selected from NaH, NaOH, LDA, LiHDMS, n-BuLi, K₂CO₃, Cs₂CO₃, C S F, DIPEA, TEA, etc. The addition reaction is preferably carried out in a suitable solvent. The solvent may be selected from THF, 1,4-dioxane, DMF, DMSO, NMP, acetonitrile, etc. The reaction is carried out at a suitable temperature, for example, between -78°C and 150°C.

[0337] The preferred metal coupling reactions are the Ullman coupling reaction, the Buchwald–Hartwig coupling reaction, and the Chan-Lam coupling reaction.

[0338] The Ullmann coupling reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably a copper catalyst. The Ullmann coupling reaction is preferably carried out in the presence of a ligand. The ligand is preferably a nitrogen-containing ligand. The Ullmann coupling reaction is carried out in the presence of a suitable base. The Ullmann coupling reaction is carried out in a suitable solvent. The Ullmann coupling reaction is carried out at a suitable temperature, for example, under heating conditions.

[0339] The Buchwald–Hartwig coupling reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably a palladium catalyst. The Buchwald–Hartwig coupling reaction is preferably carried out in the presence of a ligand. The Buchwald–Hartwig coupling reaction is carried out in the presence of a suitable base. The Buchwald–Hartwig coupling reaction is carried out in a suitable solvent. The Buchwald–Hartwig coupling reaction is carried out at a suitable temperature, for example, under heating conditions.

[0340] The Chan-Lam coupling reaction, compound R 2 In -X, X represents boric acid or a borate ester. The Chan-Lam coupling reaction is carried out under oxygen or air conditions. The Chan-Lam coupling reaction is carried out under alkaline conditions. The Chan-Lam coupling reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably a copper catalyst.

[0341] In some embodiments, the present invention provides a second method for preparing a compound of formula I, comprising the following steps:

[0342] Make compound IB and compound R 2 The -X reaction yields the compound of formula I;

[0343] Wherein, X is a hydroxyl group, a halogen (e.g., iodine, bromine, chlorine, fluorine), or a leaving group (e.g., methanesulfonate, ethylsulfonate, phenylsulfonate, p-toluenesulfonate), etc.

[0344] Ring A, Ring B, Ring C, L, R 1 R 2 R 3 R 4 R 5 P, m, n, o are defined as above.

[0345] In some embodiments of the present invention, the method for preparing the compound of formula I of the present invention, the compound of formula IB and compound R 6 -X preferably forms chemical bonds through addition reactions or metal coupling reactions.

[0346] The addition reaction is carried out in the presence of a suitable base. The base may be selected from NaH, NaOH, LDA, LiHDMS, n-BuLi, K₂CO₃, Cs₂CO₃, CSF, DIPEA, TEA, etc. The addition reaction is preferably carried out in a suitable solvent. The solvent may be selected from THF, 1,4-dioxane, DMF, DMSO, NMP, acetonitrile, etc. The reaction is carried out at a suitable temperature, for example, between -78°C and 150°C.

[0347] The preferred metal coupling reactions are the Ullman coupling reaction, the Buchwald–Hartwig coupling reaction, and the Chan-Lam coupling reaction.

[0348] The Ullmann coupling reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably a copper catalyst. The Ullmann coupling reaction is preferably carried out in the presence of a ligand. The ligand is preferably a nitrogen-containing ligand. The Ullmann coupling reaction is carried out in the presence of a suitable base. The Ullmann coupling reaction is carried out in a suitable solvent. The Ullmann coupling reaction is carried out at a suitable temperature, for example, under heating conditions.

[0349] The Buchwald–Hartwig coupling reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably a palladium catalyst. The Buchwald–Hartwig coupling reaction is preferably carried out in the presence of a ligand. The Buchwald–Hartwig coupling reaction is carried out in the presence of a suitable base. The Buchwald–Hartwig coupling reaction is carried out in a suitable solvent. The Buchwald–Hartwig coupling reaction is carried out at a suitable temperature, for example, under heating conditions.

[0350] The Chan-Lam coupling reaction, compound R 2 In the equation -X, X is preferably boric acid or a borate ester. The Chan-Lam coupling reaction is preferably carried out under oxygen or air conditions. The Chan-Lam coupling reaction is preferably carried out under alkaline conditions. The Chan-Lam coupling reaction is preferably carried out in the presence of a catalyst, preferably a copper catalyst.

[0351] Those skilled in the art should understand that, depending on the desired product structure, one or more steps in the above preparation method may be omitted, and the order of reaction steps may be appropriately adjusted, and protection / deprotection reaction steps may be added or omitted as needed.

[0352] Pharmaceutical compositions, formulations and treatments

[0353] In some embodiments, the present invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically labeled compound thereof, and one or more pharmaceutically acceptable carriers.

[0354] In some embodiments, the present invention provides a pharmaceutical formulation comprising a preventatively or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically labeled compound thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical formulation is preferably a solid, semi-solid, liquid, or gaseous formulation.

[0355] In some embodiments, the pharmaceutical composition or pharmaceutical formulation may also contain one or more other therapeutic agents.

[0356] In some embodiments, the pharmaceutical composition or pharmaceutical preparation is preferably administered via oral, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal routes.

[0357] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites or prodrugs of the present invention, or pharmaceutical compositions or pharmaceutical preparations of the present invention, in the preparation of a medicament for the prevention or treatment of M4-mediated diseases or conditions.

[0358] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites or prodrugs of the present invention, or pharmaceutical compositions or pharmaceutical preparations of the present invention, in the preparation of a medicament for modulating (preferably orthoallosteric modulating) M4 activity.

[0359] In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites or prodrugs thereof, or pharmaceutical compositions of the present invention, or pharmaceutical formulations of the present invention, for the prevention or treatment of M4-mediated diseases or conditions.

[0360] In some embodiments, the present invention provides a method for preventing or treating M4-mediated diseases or conditions, the method comprising administering to an individual in need an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug of the present invention, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention.

[0361] In some implementations, the M4-mediated diseases or conditions include Alzheimer's disease, schizophrenia, psychosis, Parkinson's disease, pain, addiction, Huntington's disease, sleep disorders, cognitive impairments (e.g., mild cognitive impairment, age-related mild cognitive impairment, and amnesic mild cognitive impairment), movement disorders, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, trisomy 21 (Down syndrome), cerebral amyloid angiopathy, dementia, Hereditary Dutch amyloid hemorrhage (HCHWA-D), Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis.

[0362] In some implementations, the M4-mediated disease or condition is preferably Alzheimer's disease, schizophrenia, psychosis, Parkinson's disease, pain, addiction, and Huntington's disease.

[0363] The positive allosteric regulatory activity of the compounds of this invention on the muscarinic acetylcholine receptor M4 EC 50 The range is 1 to 10000 nM, preferably ≤1000 nM, further preferably ≤200 nM, and more preferably ≤100 nM.

[0364] In this invention, "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0365] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0366] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered via suitable routes.

[0367] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms.

[0368] As used in this article, the term "effective amount" refers to the amount of a compound that, when administered, will alleviate one or more symptoms of the treated condition to some extent.

[0369] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0370] The amount of the compound of the present invention administered will depend on the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compound, and the judgment of the prescribing physician. Generally, the effective dose is from about 0.0001 to about 50 mg per kg of body weight per day. In some cases, dose levels not exceeding the lower limit of the foregoing range may be sufficient, while in other cases, larger doses may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

[0371] The content or amount of the compound of the present invention in a pharmaceutical composition or pharmaceutical preparation may be from about 0.01 mg to about 1000 mg.

[0372] Unless otherwise stated, as used herein, the term “treating” means to reverse, alleviate, or inhibit the progression of a disease or condition or one or more symptoms of such a disease or condition to which such term is applied, or to prevent such a disease or condition or one or more symptoms of such a disease or condition.

[0373] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0374] In some embodiments, the pharmaceutical compositions or formulations of the present invention may further comprise one or more additional therapeutic or preventative agents (e.g., other drugs for treating M4-mediated diseases or conditions). In some embodiments, the treatment methods of the present invention may further include administration of one or more additional therapeutic or preventative agents (e.g., other drugs for treating M4-mediated diseases or conditions). Detailed Implementation

[0375] Example

[0376] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

[0377] The compounds of this invention are separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or fast column chromatography (Flash column chromatography), and their structures are determined by... 1 Confirmation was performed using 1H NMR and / or MS. Reaction monitoring was performed using TLC or LC-MS.

[0378] 1 The H NMR spectroscopy method was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400MHz).

[0379] LC / MS uses Aglient 1260Infinity / Aglient 6120Quadrupole.

[0380] TLC uses silica gel GF 254 as the stationary phase.

[0381] Column chromatography typically uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase.

[0382] The rapid column chromatography method uses the Biotage rapid column chromatograph.

[0383] Prep-HPLC was performed using an Agilent 1260 and a Waters 2489.

[0384] The microwave reaction was carried out using the BiotageInitiator microwave reactor.

[0385] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).

[0386] The reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, or TEB Chemicals, etc.

[0387] Example 1: Synthesis of 8-(1-(2-fluoro-6-methylpyridin-4-yl)azacyclobutane-3-yl)-2,4-dimethyl-8,9,10,10-tetrahydropyrido[2,3-a]indoleazine-7(5H)-one (compound 507A)

[0388] Step 1: Compound 95-3 was separated using a Unichiral CNZ-5H column and a mobile phase of n-hexane-anhydrous ethanol (50:50 and 80:20) to obtain compound 95-3A (520 mg, RT = 9.37 min), compound 95-3B (500 mg, RT = 11.91 min), compound 95-3C (550 mg, RT = 15.18 min), and compound 95-3D (550 mg, RT = 16.26 min).

[0389] Step 2: Synthesis of 8-(azacyclobutan-3-yl)-2,4-dimethyl-8,9,10,10-tetrahydropyrido[2,3-a]indoleazine-7(5H)-one (compound 507A-1)

[0390] Add 95-3D (550 mg, 1.48 mmol) and dichloromethane (5 mL) to a single-necked flask, and slowly add trifluoroacetic acid (2 mL) while stirring. Stir the reaction mixture at 25 °C for 5 hours. The reaction was confirmed to be complete by LCMS, and the solution was concentrated under reduced pressure to give compound 507A-1 (720 mg, crude product).

[0391] Step 3: Synthesis of 8-(1-(2-fluoro-6-methylpyridin-4-yl)azacyclobutane-3-yl)-2,4-dimethyl-8,9,10,10-tetrahydropyrido[2,3-a]indoleazine-7(5H)-one (compound 507A)

[0392] Add 507A-1 (100 mg, 368.52 μmol), dioxane (5 mL), cesium carbonate (360.21 mg, 1.11 mmol), 2-dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′-biphenyl (35 mg, 73.70 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II) (31 mg, 36.85 μmol), and 2-fluoro-4-iodo-6-methylpyridine (131 mg, 552.78 μmol) to a single-necked flask, purge with nitrogen, heat to 90 °C and stir for 12 hours. The reaction was confirmed to be complete by LCMS. Saturated sodium chloride solution was added, and the mixture was extracted with ethyl acetate, concentrated under reduced pressure, and purified by Prep-HPLC to obtain the title compound 507A (9.7 mg, 25.50 μmol).

[0393] MS[ESI]: m / z = 381.2[M+H] + . 1H NMR (400MHz, CD3OD) δ7.08 (s, 1H), 6.13 (s, 1H), 5.74 (d, J = 1.6Hz, 1H), 4.87-4 .83(m,2H),4.53(d,J=15.2Hz,1H),4.24(t,J=8.4Hz,1H),4.12(t,J=8.4Hz,1 H),3.88(dd,J=8.8,6.0Hz,1H),3.80(dd,J=8.0,6.0Hz,1H),3.08-3.01(m,1H ),2.90-2.83(m,1H),2.62-2.55(m,1H),2.51(s,3H),2.32-2.24(m,7H),1.62 -1.50(m,2H).

[0394] Referring to the synthesis method of Example 1, the following compounds can be synthesized:

[0395] Example 4: Synthesis of 8-(1-(2-fluoro-6-methylpyridin-4-yl)azacyclobutane-3-yl)-2,4-dimethyl-8,9,10,10-tetrahydropyrido[2,3-a]indoleazine-7(5H)-one (compound 507B)

[0396] Referring to the synthesis method in Example 4, the following compounds can be synthesized.

[0397] Example 7: Synthesis of 3-fluoro-2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutane-3-yl)-8,9,10,10a-tetrahydropyrido[2,3-a]indoleazine-7(5H)-one (compound 534)

[0398] Step 1: Synthesis of Compound 534-2

[0399] Compound 534-1 (130 g, 877 mmol) was dissolved in acetonitrile (1300 mL), and 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2]octane di(tetrafluoroborate) (434 g, 1228 mmol) was added at room temperature. The reaction was carried out at 50 °C for 3 hours under a nitrogen atmosphere. The reaction was monitored by LCMS until complete. The mixture was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 534-2 (16.5 g, 99.3 mmol), MS m / z (ESI): 167.0 [M+H]. + .

[0400] 1H NMR (400MHz, CDCl3) δ2.45 (d, J = 2.0Hz, 3H), 2.44 (d, J = 2.8Hz, 3H).

[0401] Step 2: Synthesis of Compound 534-3

[0402] Compound 534-2 (16.5 g, 99.3 mmol) was dissolved in 1,4-dioxane (200 mL), and phosphorus tribromooxy (85.4 g, 297.9 mmol) was added at room temperature. The reaction was carried out at 100 °C for 3 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was allowed to return to room temperature. The mixture was quenched with ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 534-3 (9.8 g, 42.8 mmol).

[0403] 1 H NMR (400MHz, DMSO-d6) δ2.49 (d, J = 1.6 Hz, 3H), 2.45 (d, J = 2.0 Hz, 3H).

[0404] Step 3: Synthesis of Compound 534-4

[0405] Compound 534-3 (8 g, 34.8 mmol) was dissolved in tetrahydrofuran (100 mL). A 1 M, 87 mL solution of borane in tetrahydrofuran was added dropwise to the reaction mixture under a nitrogen atmosphere, and the mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the reaction mixture was poured into methanol under an ice bath and stirred for half an hour. The solution was then concentrated under reduced pressure to obtain compound 534-4 (8 g, 34.2 mmol), which was used directly in the next reaction. MS m / z (ESI): 232.9 [M+H] + .

[0406] Step 4: Synthesis of Compound 534-5

[0407] Compound 534-4 (6 g, 25.7 mmol) was dissolved in dichloromethane (60 mL), and di-tert-butyl dicarbonate (8.41 g, 38.55 mmol) and triethylamine (7.79 g, 77.1 mmol) were added at room temperature. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, the solution was diluted with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 534-5 (6 g, 18 mmol), MS m / z (ESI): 334.9 [M+H]. + .

[0408] Step 5: Synthesis of Compound 534-6

[0409] Compound 534-5 (6 g, 18 mmol) was dissolved in N,N-dimethylformamide / water = 10 / 1 (60 mL). Compound 2A (6.1 g, 27 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (1.47 g, 1.8 mmol), and cesium carbonate (17.59 g, 54 mmol) were added at room temperature. The reaction was carried out at 130 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was allowed to return to room temperature, diluted with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 534-6 (6 g, 17.0 mmol), MS m / z (ESI): 353.1 [M+H]. + .

[0410] Step Six: Synthesis of Compound 534-7

[0411] Compound 534-6 (1.6 g, 4.5 mmol) was dissolved in ultradry tetrahydrofuran (20 mL), and a 2.5 M lithium aluminum hydride tetrahydrofuran solution (3.7 mL) was slowly added dropwise under a nitrogen atmosphere at -60 °C. The temperature was slowly raised to 0 °C, and the reaction was allowed to proceed for 2 hours. After the reaction was complete, the mixture was quenched with water in an ice bath, filtered through diatomaceous earth, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain compound 534-7 (1.3 g), MS m / z (ESI): 311.0 [M+H]. + .

[0412] 1 H NMR (400MHz, DMSO-d6) δ4.81 (s, 1H), 4.66-4.55 (m, 1H), 4.52-4.41 (m, 1H), 4.35 (t, J = 5.2Hz, 1H), 3.4 8-3.40(m,1H),3.31-3.24(m,1H),2.41(d,J=2.8Hz,3H),2.18(s,3H),2.13-1.98(m,2H),1.46(s,9H).

[0413] Step 7: Synthesis of Compound 534-8

[0414] Compound 534-7 (1.3 g, 4.2 mmol) was dissolved in 1,4-dioxane hydrochloride (20 mL). The reaction was carried out at 25 °C for 16 hours. After the reaction was completed, the solution was concentrated under reduced pressure to give compound 534-8 (850 mg, 4.04 mmol), which was used directly in the next reaction. MS m / z (ESI): 211.1 [M+H] + .

[0415] Step 8: Synthesis of Compound 534-9

[0416] Compound 534-8 (850 mg, 4.04 mmol) was dissolved in dichloromethane (10 mL), and compound 225-12 (1209 mg, 4.84 mmol), HATU (1845 mg, 4.84 mmol), and N,N-diisopropylethylamine (2088 mg, 16.16 mmol) were added at room temperature. The reaction was carried out at 25 °C for 2 hours. After the reaction was completed, the mixture was diluted with water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 534-9 (1.1 g, 2.26 mmol), MS m / z (ESI): 442.1 [M+H]. + .

[0417] Step Nine: Synthesis of Compound 534-10

[0418] Compound 534-9 (500 mg, 1.13 mmol) and triethylamine (458 mg, 4.53 mmol) were dissolved in ultradry dichloromethane (10 mL), and methanesulfonyl chloride (468 mg, 1.44 mmol) was slowly added dropwise under an ice bath nitrogen atmosphere. The mixture was stirred at 0 °C for 0.5 h under nitrogen atmosphere. After the reaction was complete, the mixture was brought to room temperature, and the reaction solution was purified by silica gel column chromatography to give compound 534-10 (390 mg, 0.75 mmol), MS m / z (ESI): 520.2 [M+H]. + .

[0419] Step 10: Synthesis of Compound 534-11

[0420] Compound 534-10 (390 mg, 0.75 mmol) was dissolved in ultradry tetrahydrofuran (10 mL), and a 2 M solution of lithium diisopropylamino in tetrahydrofuran (0.6 mL) was slowly added dropwise under a nitrogen atmosphere at -60 °C. The mixture was slowly brought to room temperature and stirred overnight. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give compound 534-11 (90 mg, 0.22 mmol), MS m / z (ESI): 424.1 [M+H]. + .

[0421] Step 11: Synthesis of Compound 534-12

[0422] Compound 534-11 (75 mg, 0.18 mmol) and 10% wet palladium on carbon (19 mg, 0.02 mmol) were dissolved in ultradry methanol (10 mL). The reaction mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure. Compound 534-12 (45 mg, 0.16 mmol), MS m / z (ESI): 289.7 [M+H] + .

[0423] Step 12: Synthesis of Compound 534

[0424] Compound 534-12 (45 mg, 0.16 mmol), compound 534-13 (34 mg, 0.19 mmol), cesium fluoride (24 mg, 0.16 mmol), and N,N-diisopropylethylamine (60 mg, 0.47 mmol) were dissolved in ultradry dimethyl sulfoxide (1.5 mL). The mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was purified by prep-HPLC to obtain compound 534 (10.14 mg, 23.3 μmol), MS m / z (ESI): 434.7 [M+H]. + .

[0425] 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.21 (d, J = 5.6Hz, 1H), 6.71 (d, J = 2.0Hz, 1H), 6.53 (dd, J = 5.6, 2.0Hz, 1H), 4.97–4.72 (m, 2H), 4.53–4.30 (m, 1H), 4.25–4.07 (m, 2H), 3.92–3.73 (m, 2H), 3.03–2.92 (m, 1H), 2.87–2.75 (m, 1H), 2.42 (d, J = 3.2Hz, 3H), 2.39–2.33 (m, 1H), 2.22 (s, 3H), 2.19–2.09 (m, 1H), 1.59–1.32 (m, 2H). Step Thirteen: Splitting

[0426] Compound 534 (1.17 g) was resolved by SFC to obtain compounds 534A (192.7 mg), 534B (192.1 mg), 534C (204.3 mg) and 534D (257.3 mg). The resolution method was as follows: mobile phase: isopropanol (0.2% 7M NH3), flow rate: 2.0 mL / min, column temperature: 35℃, detection wavelength: 200-400 nm, column: CHIRALPAK AS-3 (4.6*100 mm).

[0427] Analytical method: Mobile phase: n-hexane-anhydrous ethanol 89:11, flow rate: 1.0 mL / min, column temperature: 30℃, detection wavelength: 250 nm, injection volume: 10 μL, sample: 1 mg / mL, chromatographic column: AS-H 4.6*250 mm 5 μm.

[0428] Compound characterization:

[0429] 534A: Retention time: 6.950 minutes. MS[ESI]: m / z = 435.2, [M+H] + , 1 H NMR(400MHz,Chloroform-d)δ8.28(d,J=5.7Hz,1H),6.59(d,J=2.2Hz,1H),6.34(dd,J=5.7,2.3Hz,1H),4.9 1(dd,J=15.8,2.0Hz,1H),4.76(dd,J=10.7,4.4Hz,1H),4.50(d,J=15.8Hz,1H),4.34(t,J=8.4Hz,1H),4.18 (t,J=8.1Hz,1H),3.98(dd,J=8.7,5.8Hz,1H),3.78(dd,J=8.1,6.0Hz,1H),3.18–3.07(m,1H),2.78–2.69(m ,1H),2.62–2.54(m,1H),2.51(d,J=3.3Hz,3H),2.25(d,J=1.6Hz,3H),2.24–2.15(m,1H),1.66–1.53(m,2H).

[0430] 534B: Retention time: 7.867 minutes. MS[ESI]: m / z = 435.2, [M+H] + , 1 H NMR(400MHz,Chloroform-d)δ8.29(d,J=5.6Hz,1H),6.60(d,J=2.3Hz,1H),6.35(dd,J=5.7 ,2.3Hz,1H),5.06(d,J=15.9Hz,1H),4.73–4.65(m,1H),4.39(d,J=15.9Hz,1H),4.28(t,J= 8.4Hz,1H),4.23–4.11(m,2H),3.85(dd,J=8.0,6.3Hz,1H),3.24–3.12(m,1H),2.76–2.64( m,2H),2.50(d,J=3.3Hz,3H),2.33–2.26(m,1H),2.24(d,J=1.6Hz,3H),1.71–1.51(m,2H).

[0431] 534C: Retention time: 8.873 minutes. MS[ESI]: m / z = 435.1, [M+H] + , 1 H NMR(400MHz,Chloroform-d)δ8.29(d,J=5.7Hz,1H),6.60(d,J=2.3Hz,1H),6.35(dd,J=5.7 ,2.3Hz,1H),5.06(d,J=15.9Hz,1H),4.73–4.65(m,1H),4.39(d,J=15.9Hz,1H),4.28(t,J= 8.4Hz,1H),4.23–4.13(m,2H),3.85(dd,J=8.0,6.3Hz,1H),3.24–3.12(m,1H),2.76–2.63( m,2H),2.50(d,J=3.3Hz,3H),2.33–2.26(m,1H),2.24(d,J=1.6Hz,3H),1.71–1.52(m,2H).

[0432] 534D: Retention time: 10.125 minutes. MS[ESI]: m / z = 435.1, [M+H] + , 1 H NMR(400MHz,Chloroform-d)δ8.28(d,J=5.7Hz,1H),6.59(d,J=2.3Hz,1H),6.33(dd,J=5.7,2.3Hz,1H),4 .91(dd,J=15.7,1.9Hz,1H),4.80–4.72(m,1H),4.50(d,J=15.8Hz,1H),4.34(t,J=8.4Hz,1H),4.18(t,J= 8.1Hz,1H),3.97(dd,J=8.6,5.8Hz,1H),3.78(dd,J=8.1,6.0Hz,1H),3.18–3.06(m,1H),2.78–2.68(m,1H ),2.63–2.54(m,1H),2.51(d,J=3.3Hz,3H),2.25(d,J=1.6Hz,3H),2.24–2.16(m,1H),1.66–1.51(m,2H).

[0433] Except for the compounds in the above examples, the other compounds can be prepared according to the methods of the examples in WO2025201078A1 (e.g., Examples 93-94), the entire contents of which are incorporated herein by reference.

[0434] Biological evaluation

[0435] Experimental Example 1: Assay of the activity of muscarinic acetylcholine receptor M4 orthoallosteric modulator (M4 PAM)

[0436] This study used a stable cell line expressing the human M4 receptor (hM4) (hereinafter referred to as the M4 cell line) to incubate with different concentrations of test compounds. The effect of the test compounds on hM4 was studied by measuring the changes in the fluorescence intensity of the fluorescent dye using the FLIPR CALCIUM 6ASSAY KIT kit, and the corresponding concentration-effect curves were calculated.

[0437] M4 cell line (M4-Gqi5-CHO, derived from ICE) was cultured in F12 medium (derived from Hyclone) containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B at 37°C and 5% carbon dioxide.

[0438] Testing process:

[0439] (1) Cell plating: Cells in the logarithmic growth phase were digested and collected. After resuspending the cells in fresh F12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B, the cells were counted using a cell counter and plated at 1.2 × 10⁻⁶ cells / mL. 4 Seed cells at 25 μL / well into 384-well cell culture plates, and then incubate the cell culture plates at 37°C in a 5% CO2 incubator for about 16-20 h.

[0440] (2) Remove the culture medium from the cell plate and quickly add an appropriate amount of 1× (loading buffer) prepared in advance to each well (see FLIPR CALCIUM 6ASSAY KIT instructions for preparation method). After centrifugation, place the cell plate at 37°C and incubate in the dark for 120 min.

[0441] (3) Prepare gradient dilution working solutions of the test compounds and prepare EC with a working concentration of 30 nM using DMSO solvent. 20 Acetylcholine agonist working solution. The positive compound acetylcholine / test compound working solution and the agonist working solution were mixed at a volume ratio of 1:1, and 20 μL / well was transferred to a 384-well plate containing the positive compound / test compound. A separate group was set up without the agonist working solution, with the test compound concentration at 10 μM, to detect its background agonist effect.

[0442] (4) Using FLIPR Tetra, add 10 μL of the diluted compound from step 3 into each well and collect data at wavelengths of 515 nm to 575 nm.

[0443] (5) By plotting the signal values ​​against the compound concentrations, curve fitting and EC were performed using the nonlinear regression method in GraphPad Prism software. 50 The calculations and results are shown in Table 1.

[0444] EC of compounds calculated using GraphPad nonlinear fitting formula 50 :Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)*HillSlope)); where Y is the percentage of M4 receptor activation relative to the maximum acetylcholine response at the corresponding compound concentration, Top and Bottom are the maximum and minimum values ​​of the fitted curve, respectively, X is the logarithmic concentration of the compound, and Hillslope is the slope of the curve.

[0445] The formula for calculating the percentage excitation rate is: in The average value is the positive control (final concentration 10 μM acetylcholine). The mean value is the negative control (0.1% DMSO).

[0446] Table 1. Activity of the compounds of the present invention against hM4

[0447] EC values ​​of compounds in Table 1 50 The value has the following meanings: A: ≤200nM; B: >200nM and ≤1000nM.

[0448] The compounds in this application all exhibit good agonistic activity towards hM4, such as EC. 50 (nM) ranges from 1nM to 10000nM.

[0449] Experimental Example 2: Assay of the activity of muscarinic acetylcholine receptor M4 orthoallosteric modulator (M4 PAM) (cAMP)

[0450] This study used a stable cell line expressing the human M4 receptor (hM4) to incubate with different concentrations of test compounds. The effect of the test compounds on hM4 was investigated by measuring the changes in fluorescence intensity of fluorescent dyes using a cAMP kit (Perkin Elmer), and the corresponding concentration-effect curves were calculated.

[0451] The cell culture method and the stable cell line expressing the human M4 receptor (hM4) used were the same as in Experimental Example 1.

[0452] Testing process:

[0453] (1) Dissolve the test compound in 10 mM stock solution using DMSO as solvent and perform a 3-fold serial dilution. Transfer the test compound diluted with DMSO to a 384-well plate. The final test starting concentration of the test compound is 10 μM.

[0454] (2) Transfer acetylcholine (EC20, final concentration 4 nM) and isoproterenol (EC80, final concentration 30 nM) to 384-well plates;

[0455] (3) Collect cells in the logarithmic growth phase by digestion, resuspend the cells in fresh DMEM medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B, and adjust the cell suspension to 2.5 × 10⁻⁶. 5 Add 20 μL of the solution per well to a 384-well plate, with 5000 cells per well. Incubate the 384-well plate at 37°C in a 5% CO2 incubator for 30 minutes.

[0456] (4) Dilute Eu-cAMP tracer (1 / 50) with the lysis buffer in the kit and add 5 μl / well to the detection plate (384-well plate);

[0457] (5) Dilute Ulight-anti-cAMP (1 / 150) with the lysis buffer in the kit and add 5 μl / well to the detection plate;

[0458] (6) After incubating at room temperature for 1 hour, the fluorescence signal values ​​were read on an Envision 2105 plate reader at wavelengths of 665 nm and 615 nm.

[0459] (7) Calculate EC by plotting the signal value against the compound concentration. 50 The values ​​are shown in Table 2.

[0460] EC of compounds 50 :Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)*HillSlope)); where Y is the percentage of M4 receptor activation relative to the maximum acetylcholine response at the corresponding compound concentration, Top and Bottom are the maximum and minimum values ​​of the fitted curve, respectively, X is the logarithmic concentration of the compound, and Hillslope is the slope of the curve.

[0461] The formula for calculating the percentage excitation rate is: in The average value is the positive control (final concentration 10 μM acetylcholine). The mean value is the negative control (0.1% DMSO).

[0462] Table 2: Activity of the compounds of this invention against hM4 (cAMP)

[0463] EC values ​​of compounds in Table 2 50 The values ​​have the following meanings: A: ≤200 nM; B: >200 nM and ≤1000 nM. The compounds of this invention all exhibit good agonistic activity against hM4, EC... 50 (nM) ranges from 1nM to 10000nM.

[0464] Experiment Example 3: Cell Permeability Test

[0465] This experiment used MDCK-MDR1 cells to evaluate the cell permeability and efflux of the tested compounds.

[0466] Experimental methods:

[0467] 1. Cell Culture and Monolayer Preparation

[0468] MDCK-MDR1 cells (purchased from National Institutes of Health) were cultured in DMEM Medium (Gibco) supplemented with a mixture of 10% fetal bovine serum (Gibco) and 1% penicillin-streptomycin (Solarbio). Cell passaging was performed in DMEM Medium (Gibco) supplemented with a mixture of 10% fetal bovine serum (Gibco), 1% penicillin-streptomycin (Solarbio), and 80 ng / ml colchicine disulfate (National Institutes for Food and Drug Control). Culture conditions were 37°C, 5% CO2, and 95% relative humidity. Cells were seeded into plates after reaching 70-90% confluence, with a final cell concentration of 8 × 10⁶ cells / mL. 5 Inoculate cells / mL into Transwell (Corning 3391) and culture for 4-8 days, changing the medium every other day.

[0469] 2. Experimental Procedure

[0470] 1) Remove the MDCK-MDR1 plate from the incubator, remove the culture medium, wash the cell monolayer with preheated HBSS (10mM HEPES, pH 7.4), add 100μL of HBSS to each well, and then incubate at 37°C for 30 minutes.

[0471] 2) Dilute the propranolol stock solution to obtain a 5 μM working solution. Dilute the stock solutions of the test compound and digoxin to obtain a 1 μM working solution. The final concentration of DMSO in the culture system is 0.5%.

[0472] 3) Add 125 μL of working solution to the Transwell insert (top chamber) and immediately transfer 50 μL of working solution from the top chamber to 200 μL of acetonitrile containing internal standards (100 nM ketoprofen, 200 nM labetalol and 100 nM tolbutamide) as the initial sample (AB).

[0473] 4) Add 285 μL of working solution to the well of the receiving plate (outer chamber of the substrate), and immediately transfer 50 μL of working solution from the outer chamber of the substrate to 200 μL of acetonitrile containing internal standards (100 nM ketoprofen, 200 nM labetalol and 100 nM tolbutamide) as the initial sample (BA).

[0474] 5) After incubating the plate at 37°C for 2 hours, take 50 μL samples from the donor side (the top chamber of the A→B flux and the basal outer chamber of the B→A flux) and the recipient side (the basal outer chamber of the A→B flux and the top chamber of the B→A flux) and transfer them to the wells of a new 96-well plate. Then add 4 volumes of acetonitrile containing the internal standard and centrifuge.

[0475] 6) Add 100 μM Luciferox yellow solution (TargetMol) to each Transwell insert (top chamber), incubate at 37 °C for 30 minutes, and then measure the fluorescence signal at 485 nM excitation and 538 nM emission wavelengths.

[0476] 3. Data Analysis

[0477] The apparent permeability (Papp) of drug transport can be calculated using the following formula:

[0478] Where: P app It is the apparent permeability (cm / s×10). -6 );V A The volume of the receiving pore (ml); Area is the surface area of ​​the membrane (0.143 cm² for the Transwell 96-well permeability support plate); time is the total transport time (seconds).

[0479] The efflux ratio can be calculated using the following formula:

[0480] Among them, P app(B-A) The apparent permeability, P, is shown in the direction from the outer edge of the substrate to the top. app(A-B) The apparent permeability coefficient is represented in the direction from the tip to the outer side of the substrate. The permeability evaluation results of the test material of this invention are shown in Table 3.

[0481] Table 3. Permeability evaluation results of the compounds of this invention.

[0482] In conclusion, the compounds of this invention exhibit good cell permeability.

[0483] Experiment Example 4: Efficacy evaluation of the compound in a mouse model of high spontaneous activity induced by D-amphetamine (AMP).

[0484] Experimental materials:

[0485] C57BL / 6J male mice, 7-8 weeks old, 20-25 grams; test chamber equipped with Any Maze video analysis system.

[0486] Experimental methods:

[0487] After C57BL / 6J mice were placed in the test chamber to acclimatize to the experimental environment for 1 hour, they were divided into a control group, a model group, and a test group, with 8-12 mice in each group. First, mice in the control and model groups were administered solvent 1 (DMSO / Solutol HS-15 / Saline (5 / 10 / 85, v / v / v)), while mice in the test group were administered the test compound (dissolved in solvent 1) by gavage. The administration volume for both groups was 10 mL / kg, and the dose of the test compound was 20 mg / kg. Then, the mice were placed in the test chamber and allowed to move freely. The distance (in meters) of free movement within 40 minutes was recorded. Afterward, the mice were removed. Mice in the control group were injected intraperitoneally with saline, while mice in the model and test groups were injected abdominally with 2 mg / kg D-amphetamine (dissolved in saline). The test continued for another 90 minutes. A video tracking system collected data every 5 minutes, recording the total distance the mice moved within 90 minutes. The experimental results are shown in Table 4.

[0488] Table 4. Effects of compounds on D-amphetamine-induced hyperactivity behavior in C57BL / 6J mice.

[0489] Conclusion: The compounds of the present invention, such as compounds 63b, 84b and 84d, have a significant regulatory effect on D-amphetamine-induced hyperactivity behavior in mice.

[0490] Experimental Example 5: Study on Hepatocyte Stability

[0491] Prepare working solutions for the test and control compounds, and prepare hepatocytes. Transfer the prepared hepatocytes into uncoated 96-well plates. Place the plate in an incubator on a fixed-track shaker to preheat the hepatocytes for 10 minutes. Transfer the test compound or positive control solution into the corresponding wells and start the reaction. The final concentration of the test compound or positive control compound is 1 μM. Return the plate to the incubator and place it on a fixed-track shaker. Add the test compounds to the wells of a new reaction plate containing cold acetonitrile containing internal standards (200 nM labetalol, 100 nM tolbutamide, and 100 nM ketoprofen). Incubate for 15, 30, 60, 90, and 120 minutes. After thorough shaking, centrifuge, collect the supernatant, dilute with ultrapure water, and use for LC-MS / MS analysis. Determine the in vitro half-life (T0) by regression analysis of the percentage decrease of the compound versus time curves. 1 / 2 ), where T 1 / 2 =0.693 / k, k = rate constant. The metabolic stability of the compound in mouse and human hepatocytes is evaluated as shown in Table 5.

[0492] Table 5. Metabolic stability of the compounds of this invention in mouse hepatocytes (T1). 1 / 2 (min)

[0493] The compounds of this invention exhibit good metabolic stability.

[0494] The above embodiments do not limit the scope of the invention in any way. In addition to those described herein, various modifications of the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug: in: Ring A is selected from 5-14 membered heteroaryl rings and C. 6-14 Aromatic rings; R 1 R 3 R 4 R 5 Each time it appears, it is independently selected from hydrogen, deuterium, tritium, OR 7 hydroxyl, oxo, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -NR 7 R 8 -CONR 7 R 8 -COC 1-6 Alkyl, -NHCOC 1-6 Alkyl, C(O)OR 7 -OC(O)R 7 -OC(O)NR 7 R 8 -NR 7 C(O)NR 7 R 8 C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 3-8 Cycloalkoxy, C 6-10 aryl and 5-10 heteroaryl groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl or heteroaryl group is optionally each surrounded by one or more R groups. 9 Replace; or Two R atoms bonded to the same carbon atom 4 Or two Rs 5 Together with the carbon atom it is attached to, they form a 3-6 membered cycloalkyl group, which is optionally bonded by one or more R atoms. 9 replace; Furthermore, R 1 It can also be missing; R 7 R 8 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, cycloalkyl, and heterocyclic groups are each optionally surrounded by one or more R groups. 9 Replace; or, R 7 R 8 The N atom attached to it forms a 3-8 membered heterocyclic group, which is optionally surrounded by one or more R atoms. 9 replace; R 9 Each time it appears, it is independently selected from H, deuterium, tritium, halogen, -OH, -CN, oxo, and -NR. 7 R 8 -COCH3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl thio, C 1-6 Haloalkylthio, C 2-6 Heteroalkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, or heteroaryl group is optionally selected by one or more elements independently selected from halogen, -OH, -CN, -NR. 7 R 8 -COC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups; Ring B is selected from 4-8 membered carbon rings, 4-8 membered heterocycles, 6-10 membered aromatic rings, and 5-10 membered heteroaromatic rings; The C ring is selected from 5-8 membered carbon rings, 5-8 membered heterocycles, or 5-10 membered heteroaromatic rings; L is selected from C, CR a and N; R a Selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups; R 2 For -PR 6 ; P represents a single bond, a double bond, and C represents a C bond. 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl benzo[C] 3-8 Cycloalkyl, 5-14-membered heteroaryl and 3-8-membered heterocyclic, C 6-10 aryl 3-8 membered heterocyclic, 5-14 membered heteroaryl 3-8 membered heterocyclic 3-8 cycloalkyl, C 6-10 Aryl, 5-14 heteroaryl, -R 7 -(C=O)-N(R 8 )-、-N(R 8 )-(C=O)-R 7 - The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more (e.g., 1, 2, 3, 4, 5, or 6) R 9 replace; R 6 Selected from missing, H, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl benzo[C] 3-8 Cycloalkyl, 5-10-membered heteroaryl and 3-8-membered heterocyclic, C 6-10 aryl 3-8 membered heterocyclic, 5-14 membered heteroaryl 3-8 membered heterocyclic 3-8 cycloalkyl, 5-14 membered heteroaryl and C 6-14 aryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally each bound by one or more R 9 replace; m, n, and o are each independently selected from 0, 1, 2, 3, 4, 5, or 6; The compounds of Formula I do not include compounds 1-144, 146-533, etc. When P is selected from methylene, R 6 When selected from nitrogen-containing heterocyclic butanes, R 9 Not trifluoromethylpyridinyl; or, When P is selected from a single bond, R 6 Not cyclopropyl; or, When P is selected from cyclopropyl, R 6 Not missing or H.

2. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, Ring A is selected from C 6-10 Aromatic rings and 5-10 membered heteroaromatic rings; preferably, ring A is selected from pyridine rings; Preferably, ring A is selected from 3. The compound of any one of claims 1-2 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, R 1 R 3 Independently selected from hydrogen, deuterium, tritium, oxo, OR 7 hydroxyl, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -CONR 7 R 8 -NHCOC 1-6 Alkyl, C 3-8 Cycloalkyl, 5-6 membered heteroaryl, 3-8 membered heterocyclic and -NR 7 R 8 The alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R groups. 9 replace; Preferably, R 1 R 3 Independently selected from oxo (=O), CH3, CH2CH3, F, Cl, Br, cyano, CHF2, CF3, ethynyl, methoxy, -NH-CH3, vinyl, N-heterocyclic butyl, CH2OH, Preferably, R 1 R 3 It is independently selected from CH3, F and Cl.

4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, Ring B is selected from partially unsaturated 4-8 membered carbon rings, partially unsaturated 4-8 membered heterocycles, 6-10 membered aromatic rings, and 5-10 membered heteroaromatic rings; Preferably, ring B is selected from benzene ring, dihydropyrrole, tetrahydropyrrole, pyrrole, thiophene, pyrazole, imidazole, etc. Pyridine, cyclohexene, cyclopentene, dihydrofuran ring, and tetrahydropyridine; More preferably, ring B is selected from More preferably, ring B is selected from 5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, R 5 Independently selected from hydrogen, deuterium, tritium, hydroxyl, oxo, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 hydroxyalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R 9 Substitution; or, two R atoms bonded to the same carbon atom 5 Together with the carbon atom it is attached to, they form a 3-5 membered cycloalkyl group, which is optionally bonded by one or more R atoms. 9 Replace; or, R 4 Independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R 9 Substitution; or, two R atoms bonded to the same carbon atom 4 Together with the carbon atom it is attached to, they form a 3-5 membered cycloalkyl group, which is optionally bonded by one or more R atoms. 9 replace; Preferably, R 5 For H.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, The C ring is selected from 5-7 membered carbon rings, 5-8 membered heterocycles, or 5-8 membered heteroaromatic rings; Preferably, ring C is selected from Preferably, ring C is selected from 7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, The compound has the structure shown in Formula II: in, In B ring, Z represents 1 X 1 X 2 Z 2 X 3 X 4 In Chinese, any two adjacent symbols can be either single or double bonds, provided that the two adjacent bonds are not both double bonds. X 1 X 2 Each is independently selected from C and N; X 3 X 4 Each is independently selected from C, N, and CR. 5a ; Z 1 Z 2 Each is independently selected from single bonds, -(CR 5a R 5b ) q -、CR 5a ,-C(=O)-,-O-,-S-,N,NR 5a -CR 5a R 5b -Z 3 --Z 3 -CR 5a R 5b -、=CR 5a -Z 3 -、-Z 3 -CR 5a =、N=CR 5a and -SiR 5a R 5b -; R 5a and R 5b R in claim 1 5 Defined; Z 3 Selected from -O-, -S- and -NR 5a ; q is selected from 1 or 2; L is selected from C, CR a and N, the remaining groups as defined in any one of claims 1-6; or, The compound has the structure shown in Formula III: in, Z 1 Selected from CR 5a R 5b and CR 5a ; X 1 and X 2 Selected from C; X 3 Selected from CR 5a and C; X 4 Selected from N; R 5a R 5b R in claim 1 5 As defined, L is selected from C and CR. a and N, the remaining groups as defined in any one of claims 1-6; or, The compound has the structure shown in Formula IV: in, Z 1 Selected from CR 5a ; X 1 X 2 X 4 Selected from C; X 3 Selected from N; L is selected from C, CR a and N, the remaining groups as defined in any one of claims 1-6; or, The compound has the structure shown in Formula V: in, Z 1 and Z 2 Selected from CR 5a R 5b CR 5a NR 5a N, O and S; X 1 and X 2 Selected from C; X 3 and X 4 Selected from C, CR 5a Or N; L is selected from C, CR a and N, the remaining groups as defined in any one of claims 1-6; or, The compound has the structure shown in Formula VI. Wherein, Y is selected from single bonds, -(CR) 4a R 4b ) p -(CR 4a R 4b )-、CR 4a ,-C(=O)-,C,-O-,-S-,N,NR 4a -CR 4a =R 4b -、-CR 4a =N-, -SiR 4a R 4b -、-CR 4a R 4b -Z 3 -and-Z 3 -CR 4a R 4b -; R 4a and R 4b R in claim 1 4 Defined; p is selected from 0, 1, or 2; L is selected from C, CR a And N, the remaining groups are as defined in any one of claims 1-6.

8. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, Y is selected from -(CR) 4a R 4b ) p -(CR 4a R 4b -, -C(=O)-, -CR 4a =R 4b -、-CR 4a R 4b =N- and -SiR 4a R 4b -, p is 1, 2, and R 4a and R 4b Each is independently selected from hydrogen and C. 1-6 Alkyl and C 1-6 Haloalkyl, or R a and R b Together with the carbon atoms they are attached to, they form 3-6 membered cycloalkyl groups.

9. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, Selected from the groups shown in Formula 1, Among them, Y 1 Selected from missing, C, N, and CR 3 ; Y 2 Y 3 Y 4 Each is independently selected from C, N, and CR. 3 NR 3 O and S; In Equation 1, L is independently selected from C and CR. a And N, the remaining groups as defined in any one of claims 1-8.

10. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, Selected from: Preferably, Selected from:

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, L is selected from CR 9a And N; preferably, L is selected from CH and N.

12. The compound of any one of claims 1-11 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, P is selected from single bond, double bond, -C 1-6 Alkyl-(C=O)-NR 7 -、-NR 7 -(C=O)-C 1-6 Alkyl-, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic cycloalkenes 3-6 cycloalkyl and C6 aryl-C 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocyclic or aryl group is optionally each surrounded by one or more R groups. 9 replace; Preferably, P is selected from bond, double bond, -C 1-3 Alkyl-(C=O)-NH-, methylene, ethylene, propylene, C 1-3 Halogenated alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclobutyl, pyrrolidinyl, piperidinyl, piperazine, and benzocyclopentyl, wherein each of the alkyl, cycloalkyl, benzocyclopentyl, or heterocyclic group is optionally oxidized by one or more R groups. 9 replace; Preferably, P is selected from bonds, double bonds, methylene groups, etc. Cyclobutyl, Preferably, P is 13. The compound of any one of claims 1-12 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, The compound has the structure shown in Formula VII: Among them, E 1 E 2 Independently selected from C, CH2, CH, N, NH, O, S; m1 is selected from 0, 1, 2, 3, 4, 5 or 6; m2 is selected from 0, 1, 2, or 3; m3 is selected from 1, 2, or 3; Ring A, Ring B, Ring C, R 1 R 3 R 4 R 5 R 6 R 9 、n、o are as defined in any one of claims 1-12.

14. The compound of any one of claims 1-13 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, R 6 Selected from deletions, 3-10 membered heterocyclic groups, 5-14 membered heteroaryl groups, C 6-14 Aryl, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups, wherein the alkyl, aryl, or heteroaryl groups are each optionally oxidized by one or more R groups. 9 replace.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, R 6 Selected from R 9 Each time it appears, it is independently selected from H, deuterium, tritium, halogen, -OH, -CN, oxo, and -NR. 7 R 8 -COCH3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl thio, C 1-6 Haloalkylthio, C 2-6 Heteroalkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 Aryl and 5-10 heteroaryl groups, wherein each of the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, or heteroaryl groups is independently and optionally composed of one or more elements selected from halogen, -OH, -CN, -NR. 7 R 8 -COC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups; Preferably, R 9 Selected from hydrogen, deuterium (D), halogens, and carbon. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -NR 7 R 8 CN, C 3-8 cycloalkyl, C 1-6 Haloalkylthio, C 1-6 Halogenated alkyloxy group and 5-10 heteroaryl group, wherein the 5-10 heteroaryl group is optionally surrounded by one or more groups selected from C 1-6 Alkyl-substituted; more preferably, R 9 Each time it appears, it is independently selected from H, deuterium D, F, Cl, Br, cyclopropyl, -CH2CH3, -CHF2, -CF3, -CH3, -OCH3, -OCH(CH3)CF3, -CH2CF3, -OCHF2, -OCH2CF3, -SCF3, -CN, -NH(CH2CH3), -N(CH3)2, -NH2, m1 is selected from 0, 1, 2, 3, 4, 5, and 6; Preferably, R 6 Selected from R 9 Each is independently selected from -CF3, m1 is 1; Preferably, R 6 Selected from 16. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, The compound is selected from:

17. A pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of any one of claims 1-16 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug, and one or more pharmaceutically acceptable carriers.

18. Use of any compound of claims 1-16 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug of the present invention, or the pharmaceutical composition of claim 17, in the preparation of a medicament for the prevention or treatment of diseases or conditions mediated by muscarinic acetylcholine receptor M4. Preferably, the M4-mediated diseases or conditions include Alzheimer's disease, schizophrenia, psychosis, Parkinson's disease, pain, addiction, Huntington's disease, sleep disorders, cognitive impairment, movement disorders, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, Down syndrome, cerebral amyloid angiopathy, dementia, Dutch amyloid hemorrhage, Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, and pancreatic diseases.

19. The compound of any one of claims 1-16 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug of the same or the pharmaceutical composition of claim 17 for the prevention or treatment of diseases or conditions mediated by muscarinic acetylcholine receptor M4. Preferably, the M4-mediated diseases or conditions include Alzheimer's disease, schizophrenia, psychosis, Parkinson's disease, pain, addiction, Huntington's disease, sleep disorders, cognitive impairment, movement disorders, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, Down syndrome, cerebral amyloid angiopathy, dementia, Dutch amyloid hemorrhage, Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, and pancreatic diseases.

20. A method for preventing or treating diseases or conditions mediated by muscarinic acetylcholine receptor M4, the method comprising administering to an individual in need an effective amount of the compound of any one of claims 1-16 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug, or the pharmaceutical composition of claim 17; Preferably, the M4-mediated diseases or conditions include Alzheimer's disease, schizophrenia, psychosis, Parkinson's disease, pain, addiction, Huntington's disease, sleep disorders, cognitive impairment, movement disorders, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, Down syndrome, cerebral amyloid angiopathy, dementia, Dutch amyloid hemorrhage, Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, and pancreatic diseases.

Images