Condensed ring compound, pharmaceutical composition containing fused ring compound, and preparation method and application of fused ring compound

Abstract

The present application relates to fused ring compounds, pharmaceutical compositions comprising the same, methods for their preparation and their use in the prevention or treatment of diseases or conditions associated with muscarinic receptors (M-type receptors for short). The structure of the compound is shown in the following formula,

Description

Invention Field

[0001] This invention relates to fused-ring compounds, pharmaceutical compositions comprising the same, methods for their preparation, and their use in the prevention or treatment of diseases or conditions associated with muscarinic receptors (M-type receptors). Background of the Invention

[0002] Muscarinic receptors are a class of G protein-coupled receptors (GPCRs) comprising five distinct subtypes: M1, M2, M3, M4, and M5. These receptor subtypes are distributed throughout the peripheral and central nervous systems, with M1 and M4 subtypes showing particularly prominent expression in the central nervous system (CNS). M4 receptors are primarily expressed in the cerebral cortex, striatum, hypothalamus, and hippocampus (Neuropharmacology 2018, 136, 362-373). M1, M3, and M5 subtypes mainly bind to Gq proteins and activate phospholipase C, while M2 and M4 subtypes tend to bind to Gi / o proteins and their associated effector systems.

[0003] A genome-wide association study involving 11,260 patients with schizophrenia and 24,542 controls found that a single nucleotide polymorphism (SNP) at locus rs7951870 was significantly associated with disease risk, and this polymorphism included the M4 gene (Nature Genetics 2018, 50, 381-389). In schizophrenia patients, a high dopaminergic state in the striatum and nucleus accumbens is associated with psychotic symptoms, which explains why current antipsychotic drugs act on dopamine D2 receptors to alleviate symptoms.

[0004] Recent studies have shown that orthoallosteric modulators of the M4 receptor (M4 PAM) can reduce dopamine release in the striatum of wild-type mice after amphetamine treatment, but this effect is not observed in M4 receptor knockout wild-type mice (Neuropsychopharmacology 2014, 39, 1578). Another study indicated that M4 PAM can inhibit glutamate excitatory synaptic transmission at the CA1 synapse of the Schaeffer collateral in the hippocampus (Hippocampus 2017, 27, 794-810). These findings suggest that M4 PAM plays an important role in controlling striatal dopamine release and cognitive function of key synapses in the hippocampus by enhancing the effects of the endogenous agonist acetylcholine. By specifically activating M4 receptors in the striatum and hippocampus, the hyperdopaminergic state of the striatum can be reduced, thus decreasing overstimulation of the hippocampus and providing a potential therapeutic strategy for psychiatric symptoms and cognitive impairment in patients with schizophrenia.

[0005] The above findings demonstrate that modulating M4 receptor activity is a promising therapeutic strategy for treating or preventing M4-mediated diseases or conditions. Therefore, it is essential to develop novel compounds, formulations, treatments, and therapies for the treatment or prevention of M4-related diseases or conditions. Invention Overview

[0006] This invention provides fused-ring compounds that can act as modulators of the activity of M-type receptors, particularly as orthoallosteric modulators of the M4 receptor, and possess good efficacy, pharmacokinetic properties, and safety.

[0007] One aspect of the present invention provides a compound of formula I, a stereoisomer, tautomer, or mixture thereof, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound:

[0008]

[0009] in:

[0010] Ring A is selected from C 6-10 Aromatic rings, 5-6 quinary heteroaryl aromatic rings, C 3-8 Carbon rings and 4-11 membered heterocycles;

[0011] Ring B is selected from C 6-10 Aromatic rings, 5-6 quinary heteroaryl aromatic rings, C 3-8 Carbon rings and 4-11 membered heterocycles;

[0012] The ring C is a 4-11 member heterocyclic group;

[0013] E, F, G, and H are each independently selected from: C, CH, and N;

[0014] X is selected from single bonds, -C(R1R2)-, -O-, and -S-.

[0015] R1 and R2 are each independently selected from H, OH, CN, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 aryl, 5-6 membered heteroaryl; or R1 and R2 together with the carbon atom they are attached to form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0016] L is a 3-8 membered heterocycle, which is optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, NO2, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, oxo group (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-6 membered heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0017] Ar is selected from C 6-10 Aromatic rings and 5-10 membered heteroaromatic rings; said aromatic rings and heteroaromatic rings are optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogens, C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -NR 10a R 10b -OR 11 -SR 11 -S(=O)R 12 -S(=O)2R 12 -S(=O)NR 10a R 10b -S(=O)2NR 10a R 10b -NR 10a S(=O)R 10b -NR 10aS(=O)2R 10b -C(=O)R 11 -C(=O)NR 13a R 13b -NR 13a C(=O)R 13b -OC(=O)NR 13a R 13b and -NR 14a C(=O)NR 15a R 15b The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0018] R a R b and R c Each time it appears, it is independently selected from hydroxyl, halogen, CN, NO2, oxo group (=O), C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 20a R 20b -OR 21 -SR 21 -S(=O)R 22 -S(=O)2R 22 -S(=O)NR 20a R 20b -S(=O)2NR 20a R 20b -NR 20a S(=O)R 20b -NR 20a S(=O)2R 20b -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a C(=O)R 23b -OC(=O)NR 23a R 23b and -NR24a C(=O)NR 25a R 25b The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy groups and 4-10 membered heterocyclic groups;

[0019] R 10a R 10b R13a R 13b R 13c R 14a R 15a R 15b R 20a R 20b R 23a R 23b R 23c R 24a R 25a and R 25b Each is independently selected from H, OH, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl; or R 20a With R 20b R 23a With R 23b Or R 25a With R 25b Together with the atoms to which it is attached, it forms a 3-8 membered cycloalkyl or heterocyclic group, wherein each of the alkyl, alkoxy, cycloalkyl, and heterocyclic groups is optionally substituted by one or more substituents selected from: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0020] R 30a R 30b R 33a R 33b R 34a R 35a and R 35b Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups;

[0021] R 11 R 12 R 21 R 22 R 31 and R 32 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12The aryl group and 5-10 heteroaryl group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, halogen, CN, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl and 4-10 membered heterocyclic groups;

[0022] m can be 0, 1, 2, 3, 4, 5, or 6;

[0023] n is 0, 1, 2, 3, 4, 5, or 6; and

[0024] p can be 0, 1, 2, 3, 4, 5, or 6.

[0025] Another aspect of the invention provides a pharmaceutical composition comprising a preventatively or therapeutically effective amount of the compound of the invention, a stereoisomer, tautomer, or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable salt, eutectic, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound. Optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

[0026] Another aspect of the invention provides the use of the compounds of the invention, stereoisomers, tautomers or mixtures thereof, N-oxides of the compounds, pharmaceutically acceptable salts, cocrystals, polymorphs or solvates of the compounds, or stable isotope derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, in the preparation of medicaments for the prevention or treatment of diseases or conditions associated with M-type receptors (e.g., M4 receptors).

[0027] Another aspect of the invention provides compounds of the invention, stereoisomers, tautomers or mixtures thereof, N-oxides of the compounds, pharmaceutically acceptable salts, eutectics, polymorphs or solvates of the compounds, or stable isotope derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, for the prevention or treatment of diseases or conditions associated with M-type receptors (e.g., M4 receptors).

[0028] Another aspect of the invention provides a method for preventing or treating diseases or conditions associated with M-type receptors (e.g., M4 receptors), the method comprising administering to an individual in need an effective amount of a compound of the invention, a stereoisomer, tautomer, or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above.

[0029] Another aspect of the present invention provides a method for preparing the compounds of the present invention. Invention Details

[0030] definition

[0031] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0032] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps, although such other unlisted elements or method steps may not necessarily exist (i.e., these terms also cover the terms “consistently made up of” and “composed of”).

[0033] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example, 1 to 6 carbon atoms. For example, as used herein, the term "C" is used to refer to... 1-6 "alkyl" and "C" 1-4 "Alkyl" refers to a linear or branched group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl) having 1-6 carbon atoms and 1-4 carbon atoms, respectively, optionally substituted by one or more (e.g., 1 to 3) suitable substituents such as halogens (in which case the group is called "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). The term "C" refers to a linear or branched group having 1-6 carbon atoms and 1-4 carbon atoms respectively. 1-4"Alkyl" refers to a linear or branched aliphatic hydrocarbon chain with 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl). The term "alkylene" indicates the corresponding divalent group, including, for example, "C..." 1-8 Alkylene, C 1-6 Alkylene, C 1-4 "alkylene", etc., specific examples include but are not limited to: methylene (-CH2-), ethylene (-CH2CH2- or -CH(CH3)-), propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH2-), butylene, pentylene, hexylene, etc. The alkylene may optionally be substituted by one or more (such as 1 to 3) identical or different substituents.

[0034] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms, and the term "C" refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms. 1-8 "Halogenated alkyl", "C" 1-6 "Halogenated alkyl" and "C" 1-4 "Halogenated alkyl" refers to alkyl haloatoms having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0035] As used herein, the term "hydroxyalkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with hydroxyl groups, such as C10. 1-4 Hydroxyalkyl or C 1-3 Hydroxyalkyl groups, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH3, -C(CH3)2OH, etc.

[0036] As used herein, the term "alkoxy" means a group in which an oxygen atom is inserted at any reasonable position in an alkyl group (as defined above), preferably 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, -CH2-OCH3, etc., wherein the alkoxy group is optionally substituted by one or more (such as 1 to 3) identical or different substituents.

[0037] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2–6 carbon atoms ("C").2-6 The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may exist in pure E (iso-side), pure Z (iso-side), or any mixture thereof. The term "alkenyl" refers to the corresponding divalent group, including, for example, "C..." 2-6 "Ideinyl", "C" 2-4 "Alkenyl", etc., specific examples of which include, but are not limited to: -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, butenyl, pentenyl, hexenyl, cyclopentenyl, cyclohexenyl, etc.

[0038] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group comprising one or more triple bonds, preferably having 2, 3, 4, 5, or 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group is optionally substituted by one or more (such as 1 to 3) identical or different substituents. The term "ynynyl" refers to the corresponding divalent group, including, for example, "C..." 2-8 "Isynyne", "C" 2-6 "Isynyne", "C" 2-4 Examples include, but are not limited to, "ethynyl groups". The alkyne group is optionally substituted by one or more (such as 1 to 3) identical or different substituents.

[0039] 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.

[0040] As used herein, the term "spiroring" refers to a ring system consisting of two or more ring structures that share a single ring atom.

[0041] 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.

[0042] As used herein, the term "cycloalkyl" or "carbocyclic" 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" is used in this invention. 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 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 Polycyclic alkyl, C 5-6 Spirocycloalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl groups.

[0043] As used herein, the term "heterocyclic group" or "heterocycle" refers to a saturated or unsaturated non-aromatic cyclic 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. The "heterocyclic group" or "heterocycle" includes monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) groups, wherein the heteroatoms include, but are not limited to, oxygen, nitrogen, and sulfur atoms, and the carbon atoms and heteroatoms on the heterocyclic group are optionally substituted with oxo groups (e.g., forming C=O, S(=O), or S(=O)2).

[0044] As used herein, the term "4-11 membered heterocyclic group" refers to a heterocyclic group containing 4-11 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 selected from oxygen, nitrogen, and sulfur. Examples of 4-11 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.

[0045] As used herein, the term "heterocyclic base" or "heterocyclic" encompasses fused rings, bridged rings, and helical ring structures.

[0046] As used herein, the term "aryl" or "aromatic ring" refers to a fully carbon monocyclic or fused polycyclic aromatic group having a conjugated π-electron system. As used herein, the term "C" refers to a carbon monocyclic or fused polycyclic aromatic group. 6-12 "Aryl (aromatic ring)" refers to an aryl (aromatic ring) containing 6 to 12 carbon atoms, preferably C64-12 ... 6-10 Aryl (aromatic ring), preferably phenyl or naphthyl. The aryl group is optionally substituted by one or more (such as 1 to 3) identical or different substituents (e.g., halogen, OH, CN, NO2, C1-C6 alkyl, etc.).

[0047] 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. 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).

[0048] As used herein, the term "heteroaryl" encompasses a fused ring structure, wherein the connection point between the fused ring structure and other groups can be on any ring of the fused ring structure. Therefore, the heteroaryls of the present invention also include, but are not limited to, (mono)heteroaryl benzo(mono)heteroaryl, (mono)heteroaryl benzo(monocyclic)aryl, (mono)heteroaryl benzo(mono)heterocyclic, and (mono)heteroaryl benzo(mono)cycloalkyl, such as 5-6 membered (mono)heteroaryl benzo5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroaryl benzophenyl, 5-6 membered (mono)heteroaryl benzo5-6 membered (mono)heterocyclic, or 5-6 membered (mono)heteroaryl benzoC 4-6 (Mono)cycloalkyl (e.g., 5-6-membered heteroarylcyclobutyl, 5-6-membered heteroarylcyclopentyl or 5-6-membered heteroarylcyclohexyl), examples of which include, but are not limited to, indole, isoindole, indazole, benzimidazole, quinolinyl, isoquinolinyl, etc.

[0049] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br, or I.

[0050] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) 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.

[0051] If a substituent is described as "optionally...substituted", 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.

[0052] 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.

[0053] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, or ten.

[0054] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0055] 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.

[0056] 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., ... 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 15N); 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.

[0057] 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, this can result in exo / meta-racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. 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 tautomeric forms:

[0058]

[0059] 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%).

[0060] Solid lines (-) and solid wedges can be used in this article. 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).

[0061] 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.

[0062] 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.

[0063] 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.

[0064] Pharmaceutically acceptable salts of the compounds of this invention include their acid addition salts and base addition salts. Examples include hexafluorophosphate 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).

[0065] 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 invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the invention may themselves be esters.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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)).

[0070] 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.

[0071] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0072] compound

[0073] One aspect of the present invention provides a compound of formula I, a stereoisomer, tautomer, or mixture thereof, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound:

[0074]

[0075] in:

[0076] Ring A is selected from C 6-10 Aromatic rings, 5-6 quinary heteroaryl aromatic rings, C 3-8Carbon rings and 4-11 membered heterocycles;

[0077] Ring B is selected from C 6-10 Aromatic rings, 5-6 quinary heteroaryl aromatic rings, C 3-8 Carbon rings and 4-11 membered heterocycles;

[0078] The ring C is a 4-11 member heterocyclic group;

[0079] E, F, G, and H are each independently selected from C and N;

[0080] X is selected from single bond, -C(R1R2)-, -O-, -S-, -NR'-;

[0081] R1 and R2 are each independently selected from H, OH, CN, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 aryl, 5-6 membered heteroaryl; or R1 and R2 together with the carbon atom they are attached to form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0082] R' is selected from H and C. 1-6 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0083] L is C 3-8A carbocyclic or 3-8 membered heterocyclic ring, wherein the carbocyclic or heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, oxo group (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-6 membered heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0084] Ar is selected from C 6-10 Aromatic rings and 5-10 membered heteroaromatic rings; said aromatic rings and heteroaromatic rings are optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogens, C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -NR 10a R 10b -OR 11 -SR 11 -S(=O)R 12 -S(=O)2R 12 -S(=O)NR 10a R 10b -S(=O)2NR 10a R 10b -NR 10a S(=O)R 10b -NR 10a S(=O)2R 10b -C(=O)R 11 -C(=O)NR 13a R 13b -NR 13a C(=O)R 13b -OC(=O)NR 13a R 13b and -NR14a C(=O)NR 15a R 15b The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0085] R a R b and R c Each time it appears, it is independently selected from hydroxyl, halogen, CN, NO2, oxo group (=O), C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 20a R 20b -OR 21 -SR 21 -S(=O)R 22 -S(=O)2R 22 -S(=O)NR 20a R 20b -S(=O)2NR 20a R 20b -NR 20a S(=O)R 20b -NR 20a S(=O)2R 20b -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a C(=O)R 23b -OC(=O)NR 23a R 23b and -NR 24a C(=O)NR 25a R 25b The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy groups and 4-10 membered heterocyclic groups;

[0086] R 10a R 10b R 13a R 13b R 13c R 14a R 15a R 15b R 20a R 20b R 23a R 23b R 23c R24a R 25a and R 25b Each is independently selected from H, OH, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl; or R 20a With R 20b R 23a With R 23b Or R 25a With R 25b Together with the atoms to which it is attached, it forms a 3-8 membered cycloalkyl or heterocyclic group, wherein each of the alkyl, alkoxy, cycloalkyl, and heterocyclic groups is optionally substituted by one or more substituents selected from: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0087] R 30a R 30b R 33a R 33b R 34a R 35a and R 35b Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups;

[0088] R 11 R 12 R 21 R 22 R 31 and R 32 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 The aryl group and 5-10 heteroaryl group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, halogen, CN, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl and 4-10 membered heterocyclic groups;

[0089] m can be 0, 1, 2, 3, 4, 5, or 6;

[0090] n is 0, 1, 2, 3, 4, 5, or 6; and

[0091] p can be 0, 1, 2, 3, 4, 5, or 6.

[0092] In some embodiments, ring A is selected from benzene rings, 5-6 membered heteroaromatic rings, C 3-8 Carbon rings and 4-6 membered heterocycles.

[0093] In some embodiments, ring A is selected from benzene rings, 5-6 membered nitrogen-containing heteroaromatic rings, 4-6 membered nitrogen-containing heterocycles and 4-6 membered oxygen-containing heterocycles, wherein the ring atom of the nitrogen-containing heterocycle optionally further includes 1 to 2 oxygen atoms or sulfur atoms.

[0094] In some embodiments, ring A is selected from benzene rings, 5-6 membered nitrogen-containing heteroaromatic rings, 5-6 membered nitrogen-containing heterocycles and 5-6 membered oxygen-containing heterocycles, wherein the ring atom of the nitrogen-containing heterocycle optionally further includes one oxygen atom or a sulfur atom.

[0095] In some implementations, ring B is a benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered heterocycle.

[0096] In some embodiments, ring B is selected from benzene rings, 5-6 member nitrogen-containing heteroaromatic rings, 5-6 member sulfur-containing heteroaromatic rings, 5-6 member oxygen-containing heteroaromatic rings, 5-6 member nitrogen-containing heterocyclic rings, 5-6 member sulfur-containing heterocyclic rings, and 5-6 member oxygen-containing heterocyclic rings.

[0097] In some embodiments, ring B is selected from benzene rings, 5-6 member nitrogen-containing heteroaromatic rings, 5-6 member sulfur-containing heteroaromatic rings, 5-6 member nitrogen-containing heterocycles, and 5-6 member sulfur-containing heterocycles.

[0098] In some embodiments, ring B is selected from benzene rings, 5-6 member nitrogen-containing heteroaromatic rings, 5 member sulfur-containing heteroaromatic rings, 5-6 member nitrogen-containing heterocycles, and 5 member sulfur-containing heterocycles.

[0099] In some implementations, the ring C is a 4-11 member nitrogen-containing heterocyclic group.

[0100] In some implementations, the ring C is a 5-7 member nitrogen-containing heterocyclic group.

[0101] In some implementations, The structure is selected from the following structures, which are optionally further selected from R. a R b and R c Substituents:

[0102]

[0103] In some implementations, X is selected from -C(R1R2)-, -O-, and -NR'-.

[0104] In some implementations, X is selected from -CH2-, -O-, and -NH-.

[0105] In some implementations, R1 and R2 are each independently selected from H, OH, CN, halogens, and C. 1-4 Alkyl, C 1-4 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocyclic, phenyl, 5-6 membered heteroaryl; or R1 and R2 together with the carbon atom they are attached to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0106] In some implementations, R1 and R2 are each independently selected from H, OH, CN, halogens, and C. 1-4 Alkyl, C 1-4 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2; or R1 and R2 together with the carbon atoms they are attached to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl and heterocyclic group are each optionally substituted by one or more substituents selected from: OH, CN, halogen, NO2, -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0107] In some implementations, R1 and R2 are each independently selected from H, OH, CN, halogens, and C. 1-4 Alkyl, C 1-4 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4Alkyl group 2; or R1 and R2 together with the carbon atoms they are attached to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl and heterocyclic group are each optionally substituted by one or more substituents selected from: OH, CN, halogen, NO2, -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0108] In some implementations, R1 and R2 are each independently selected from H, halogens, and C. 1-4 alkyl.

[0109] In some implementations, R' is selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0110] In some implementations, R' is selected from H and C. 1-4 alkyl.

[0111] In some implementations, R' is H.

[0112] In some implementations, L is C 3-6 A carbocyclic or 3-6 membered heterocycle, wherein the heterocycle is optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, oxo group (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10Aryl, 5-6 membered heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0113] In some implementations, L is C 3-6 A carbon ring or a 3-6 membered nitrogen-containing heterocycle, wherein the carbon ring or nitrogen-containing heterocycle is optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, oxo group (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-6 membered heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0114] In some implementations, L is C 3-6 A carbon ring or a 3-6 membered nitrogen-containing heterocycle, wherein the carbon ring or nitrogen-containing heterocycle is optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, oxo group (=O), C 1-6 Alkyl, C 1-6 Alkoxy group; the alkyl group and alkoxy group are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0115] In some embodiments, L is cyclopropane, cyclobutane, cyclopentane, azircyclopropane, azircyclobutane, or azircyclopentane, wherein the cyclopropane, cyclobutane, cyclopentane, azircyclopropane, azircyclobutane, or azircyclopentane is optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, oxo group (=O), C 1-6 Alkyl, C 1-6 Alkoxy group; the alkyl group and alkoxy group are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0116] In some embodiments, L is cyclopropane, cyclobutane, aziridine, or aziridine, said cyclopropane, cyclobutane, aziridine, or aziridine optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, oxo group (=O), C 1-6 Alkyl, C 1-6 Alkoxy group; the alkyl group and alkoxy group are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0117] In some implementations, L is C 3-6 A carbon ring or a 3-6 membered nitrogen-containing heterocycle, wherein the carbon ring or nitrogen-containing heterocycle is optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, C. 1-6 Alkyl, C 1-6 Alkyl group.

[0118] In some embodiments, L is cyclopropane, cyclobutane, aziridine, or aziridine, which is optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, C. 1-6 Alkyl, C 1-6 Alkyl group.

[0119] In some embodiments, Ar is selected from benzene rings and 5-6 membered heteroaromatic rings; said aromatic rings and heteroaromatic rings are optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogens, C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -NR 10a R 10b -OR 11 -SR 11 -S(=O)R 12 -S(=O)2R 12 -S(=O)NR 10a R 10b -S(=O)2NR 10a R 10b -NR 10a S(=O)R 10b -NR 10a S(=O)2R 10b -C(=O)R 11 -C(=O)NR 13a R 13b -NR 13a C(=O)R 13b -OC(=O)NR 13a R 13b and -NR 14a C(=O)NR 15a R 15b The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0120] In some embodiments, Ar is selected from benzene rings and 5-6 membered nitrogen-containing heteroaromatic rings; said aromatic rings and heteroaromatic rings are optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogens, C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -NR 10a R 10b -OR 11 -SR 11 -S(=O)R 12 -S(=O)2R 12 -S(=O)NR 10a R 10b -S(=O)2NR 10a R 10b -NR 10a S(=O)R 10b -NR 10a S(=O)2R 10b -C(=O)R 11 -C(=O)NR 13a R 13b -NR 13a C(=O)R 13b -OC(=O)NR 13a R 13b and -NR 14a C(=O)NR 15a R 15b The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0121] In some embodiments, Ar is selected from benzene rings and 5-6 membered nitrogen-containing heteroaromatic rings; said aromatic rings and heteroaromatic rings are optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogens, C. 1-6 Alkyl, C 1-6 Alkoxy group; the alkyl group and alkoxy group are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0122] In some embodiments, Ar is selected from benzene rings and 5-6 membered nitrogen-containing heteroaromatic rings; said aromatic rings and heteroaromatic rings are optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogens, C. 1-6 Alkyl, C 1-6 Alkoxy group; the alkyl group and alkoxy group are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0123] In some embodiments, Ar is selected from benzene rings, pyridine, pyrimidine, pyrazine, and pyridazine; said benzene rings, pyridine, pyrimidine, pyrazine, and pyridazine are optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy group; the alkyl group and alkoxy group are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0124] In some implementations, R a R b and R c Each time it appears, it is independently selected from hydroxyl, halogen, CN, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 20a R 20b -OR 21 -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a C(=O)R 23b -OC(=O)NR 23a R 23b and -NR 24a C(=O)NR 25a R25b The alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy groups and 4-10 membered heterocyclic groups.

[0125] In some implementations, R a R b and R c Each time it appears, it is independently selected from hydroxyl, halogen, CN, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-6 membered heterocyclic groups and -NR 20a R 20b The alkyl, alkoxycycloalkyl, cycloalkoxy, and heterocyclic groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkyl group.

[0126] In some implementations, R a R b and R c Each time it appears, it is independently selected from halogen, CN, C. 1-6 Alkyl, C 3-8 Cycloalkyl, 4-6 membered heterocyclic groups and -NR 20a R 20b The alkyl, alkoxycycloalkyl, cycloalkoxy, and heterocyclic groups are each optionally substituted by one or more substituents selected from the following: hydroxyl and halogen.

[0127] In some implementations, R 10a R 10b R 13a R 13b R 13c R 14a R 15a R 15b R 20a R 20b R 23a R 23b R 23c R 24a R 25a and R 25b Each is independently selected from H and C. 1-6 alkyl.

[0128] In some implementations, R 30a R 30b R 33a R 33b R 34a R 35a and R 35b Each is independently selected from H and C. 1-6 alkyl.

[0129] In some implementations, R 11 R 12 R 21 R 22 R 31 and R 32 Each is independently selected from H and C. 1-6 alkyl.

[0130] In some implementations, m is 0, 1, 2, or 3.

[0131] In some implementations, n is 0, 1, or 2.

[0132] In some implementations, p is 0, 1, or 2.

[0133] In some embodiments, ring A is selected from benzene rings, 5-6 membered nitrogen-containing heteroaromatic rings, 5-6 membered nitrogen-containing heterocycles and 5-6 membered oxygen-containing heterocycles, wherein the ring atom of the nitrogen-containing heterocycle optionally further includes one oxygen atom or a sulfur atom;

[0134] Ring B is selected from benzene rings, 5-6 member nitrogen-containing heteroaromatic rings, 5-6 member sulfur-containing heteroaromatic rings, 5-6 member oxygen-containing heteroaromatic rings, 5-6 member nitrogen-containing heterocycles, 5-6 member sulfur-containing heterocycles, and 5-6 member oxygen-containing heterocycles;

[0135] The ring C is a 5-7 member nitrogen-containing heterocyclic group;

[0136] X is selected from -C(R1R2)-, -O-, and -NR'-;

[0137] R1 and R2 are each independently selected from H, OH, CN, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2; or R1 and R2 together with the carbon atoms they are attached to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl and heterocyclic group are each optionally substituted by one or more substituents selected from: OH, CN, halogen, NO2, -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0138] R' is selected from H and C. 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0139] L is C 3-6A carbon ring or a 3-6 membered nitrogen-containing heterocycle, wherein the carbon ring or nitrogen-containing heterocycle is optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, oxo group (=O), C 1-6 Alkyl, C 1-6 Alkoxy group; the alkyl group and alkoxy group are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0140] Ar is selected from benzene rings and 5-6 membered nitrogen-containing heteroaromatic rings; said aromatic rings and heteroaromatic rings are optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy group; the alkyl group and alkoxy group are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0141] R a R b and R c Each time it appears, it is independently selected from hydroxyl, halogen, CN, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-6 membered heterocyclic groups and -NR 20a R 20b The alkyl, alkoxycycloalkyl, cycloalkoxy, and heterocyclic groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy;

[0142] R 20a R 20b Each is independently selected from H and C. 1-6 alkyl;

[0143] m can be 0, 1, 2, or 3;

[0144] n is 0, 1, or 2; and

[0145] p can be 0, 1, or 2.

[0146] This invention covers any combination of the above embodiments.

[0147] In some embodiments, the compounds of the present invention include, but are not limited to:

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160] intermediate

[0161] In some embodiments, the present invention provides intermediate compounds having the following structures:

[0162]

[0163] Gp is ​​selected from: H, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -NR 10a R 10b -OR11 -SR 11 -S(=O)R 12 -S(=O)2R 12 -S(=O)NR 10a R 10b -S(=O)2NR 10a R 10b -NR 10a S(=O)R 10b -NR 10a S(=O)2R 10b -C(=O)R 11 -C(=O)NR 13a R 13b -NR 13a C(=O)R 13b -OC(=O)NR 13a R 13b and -NR 14a C(=O)NR 15a R 15b The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0164] R 10a R 10b R 13a R 13b R 13c R 14a R 15a and R 15b Each is independently selected from H, OH, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl; or R 20a With R 20b R 23a With R 23b Or R 25a With R 25b Together with the atoms to which it is attached, it forms a 3-8 membered cycloalkyl or heterocyclic group, wherein each of the alkyl, alkoxy, cycloalkyl, and heterocyclic groups is optionally substituted by one or more substituents selected from: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups;

[0165] R 11 and R 12 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 The aryl group and 5-10 heteroaryl group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, halogen, CN, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl groups and 4-10 membered heterocyclic groups; and

[0166] q can be 1, 2, 3, or 4.

[0167] In some implementations, Gp is ​​selected from: H, OH, CN, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-6 membered heteroaryl; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0168] In some implementations, Gp is ​​C 1-6 The alkyl haloide is q = 1.

[0169] Preparation method

[0170] In some embodiments, the compound of formula I can be synthesized by the method shown in the following route:

[0171]

[0172] in:

[0173] Ring A, Ring B, Ring C, R a R b R cE, F, G, H, X, L, Ar, m, n, and p are as described in any of the above.

[0174] In some embodiments, the above reaction is carried out in the presence of one or more of the following reagents: HATU, DIPEA, TCFH, NMI, triethylamine, DIEA.

[0175] In some implementations, the above reaction is carried out at room temperature.

[0176] Pharmaceutical compositions, formulations and treatments

[0177] In some embodiments, the present invention provides pharmaceutical compositions comprising a preventatively or therapeutically effective amount of the compound of the present invention, a stereoisomer, tautomer, or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable salt, eutectic, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound. Optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

[0178] In some embodiments, the present invention provides a pharmaceutical formulation, preferably a solid, semi-solid, liquid, or gaseous formulation. In some embodiments, the pharmaceutical composition may also contain one or more other therapeutic agents.

[0179] In some embodiments, the pharmaceutical composition or pharmaceutical preparation is preferably administered orally, intravenously, intra-arterially, subcutaneously, intraperitoneally, intramuscularly, or transdermally.

[0180] In some embodiments, the present invention provides the use of the compounds of the present invention, stereoisomers, tautomers or mixtures thereof of the compounds, N-oxides of the compounds, pharmaceutically acceptable salts, cocrystals, polymorphs or solvates of the compounds, or stable isotopic derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, or pharmaceutical preparations of the present invention in the preparation of medicaments for the prevention or treatment of diseases or conditions associated with M-type receptors.

[0181] In some implementations, the M-type receptor is the M4 receptor.

[0182] In some embodiments, the present invention provides the use of the compounds of the present invention, stereoisomers, tautomers or mixtures thereof of the compounds, N-oxides of the compounds, pharmaceutically acceptable salts, cocrystals, polymorphs or solvates of the compounds, or stable isotope derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, or pharmaceutical formulations of the present invention in the preparation of a medicament for modulating (e.g. activating) the activity of M-type receptors.

[0183] In some embodiments, the present invention provides the use of the compounds of the present invention, stereoisomers, tautomers or mixtures thereof of the compounds, N-oxides of the compounds, pharmaceutically acceptable salts, cocrystals, polymorphs or solvates of the compounds, or stable isotope derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, or pharmaceutical formulations of the present invention in the preparation of a medicament for selectively activating the activity of the M4 receptor.

[0184] In some embodiments, the present invention provides the use of the compounds of the present invention, stereoisomers, tautomers or mixtures thereof of the compounds, N-oxides of the compounds, pharmaceutically acceptable salts, cocrystals, polymorphs or solvates of the compounds, or stable isotopic derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, or pharmaceutical formulations of the present invention in the preparation of a medicament as an M4 receptor allosteric modulator.

[0185] In some embodiments, the present invention provides compounds of the present invention, stereoisomers, tautomers or mixtures thereof of the compounds, N-oxides of the compounds, pharmaceutically acceptable salts, cocrystals, polymorphs or solvates of the compounds, or stable isotope derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, or pharmaceutical preparations of the present invention, for the prevention or treatment of diseases or conditions associated with M-type receptors.

[0186] In some embodiments, the present invention provides compounds of the present invention, stereoisomers, tautomers or mixtures thereof of the compounds, N-oxides of the compounds, pharmaceutically acceptable salts, cocrystals, polymorphs or solvates of the compounds, or stable isotope derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, or pharmaceutical preparations of the present invention, for the prevention or treatment of diseases or conditions associated with the M4 receptor.

[0187] In some embodiments, the present invention provides a method for preventing or treating diseases or conditions associated with M-type receptors, the method comprising administering to an individual in need an effective amount of a compound of the present invention, a stereoisomer, tautomer, or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, or a pharmaceutical formulation of the present invention.

[0188] In some embodiments, the present invention provides a method for preventing or treating diseases or conditions associated with the M4 receptor, the method comprising administering to an individual in need an effective amount of a compound of the present invention, a stereoisomer, tautomer, or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, or a pharmaceutical formulation of the present invention.

[0189] In some implementations, the diseases or conditions associated with the M4 receptor include: Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive impairment (e.g., mild cognitive impairment), Parkinson's disease, Parkinson's disease-levodopa-induced motor disorders, Huntington's disease, motor disorders, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, Down syndrome (trisomy 21), cerebral amyloid angiopathy, dementia, hereditary cerebral hemorrhage with Holland amyloidosis (HCHWA-D), Creutzfeldt-Jakob disease, prion diseases, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis.

[0190] 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.

[0191] 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).

[0192] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered via suitable routes.

[0193] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] The content or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg.

[0198] 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.

[0199] 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.).

[0200] In some embodiments, the pharmaceutical composition of the present invention may further comprise one or more additional therapeutic or preventative agents (e.g., other drugs for treating cancer or tumor diseases). In some embodiments, the method of the present invention may further comprise administering one or more additional therapeutic or preventative agents (e.g., other drugs for treating cancer or tumor diseases). Example

[0201] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

[0202] The abbreviations used in this article have the following meanings:

[0203]

[0204]

[0205] 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 obtained by... 1 Confirmation was performed using 1H NMR and / or MS. Reaction monitoring was performed using TLC or LC-MS.

[0206] 1 The H NMR spectroscopy was performed using a Bruker AVANCE Ⅲ HD 400MHz nuclear magnetic resonance spectrometer.

[0207] LC / MS was performed using an Aglient 1260 Infinity / Aglient 6120 Quadrupole mass spectrometer (ESI).

[0208] TLC uses silica gel GF254 as the stationary phase.

[0209] Column chromatography typically uses 200-300 mesh silica gel (Qingdao Marine) as the stationary phase.

[0210] Rapid column chromatography was performed using the Biotage rapid column chromatograph.

[0211] Pre-HPLC was performed using an Agilent 1260 and a Waters 2489 chromatograph.

[0212] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).

[0213] The reagents used in this application were purchased from Aldrich Chemical Company, Aladdin Reagents, and Bidex Pharmaceuticals, among others.

[0214] Example 1: Synthesis of Int-01 (Intermediate Preparation)

[0215]

[0216] Step 1: Synthesis of compound Int-01-2

[0217] Compound Int-01-1 (5g, 21.81mmol) was dissolved in DCM (8mL), and TFA (8mL) was added to the reaction solution. The mixture was stirred at room temperature for 3 hours. The reaction was confirmed to be complete by LC-MS. The solvent was removed by concentration to obtain crude product Int-01-2 (5g).

[0218] Step 2: Synthesis of compound Int-01-3

[0219] Crude Int-01-2 (5 g, 20.65 mmol, TFA), 4-chloro-2-trifluoromethylpyridine (4.12 g, 22.71 mmol), DIPEA (2.67 g, 20.65 mmol, 3.60 mL), and cesium fluoride (9.41 g, 61.94 mmol, 2.29 mL) were added to NMP (50 mL). The mixture was heated to 80 °C for 15 hours under nitrogen protection. LC-MS showed that the reaction was complete. The mixture was diluted with water (300 mL), extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give crude compound Int-01-3 (5 g).

[0220] Step 3: Synthesis of compound Int-01

[0221] The crude compound Int-01-3 (2.0 g, 7.29 mmol) was dissolved in a mixed solvent of methanol (10 mL) and water (2 mL), and lithium hydroxide monohydrate (918.11 mg, 21.88 mmol) was added. The mixture was stirred at room temperature for 2 hours. LC-MS showed that the reaction was complete. After concentrating to remove the solvent, the product was dissolved in water (50 mL), the pH was adjusted to 5-6 with 1 N HCl, and the product was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude product. The crude product was purified by reverse-phase C18 column chromatography to obtain compound Int-01 (1.5 g, yield 79.04%). MS [ESI]: m / z = 261.1 [M+H] + .

[0222] Example 1: Synthesis of 1-(5,6-dimethyl-7,9-dihydro-8H-imidazo[1,2-a]pyrrolo[3,4-c]pyridin-8-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azadin-3-yl)acet-1-one (compound 01)

[0223]

[0224] Step 1: Synthesis of Compound 1-03

[0225] PPA (100 g) was heated to flowability at 100 °C. Then, PPA (100 g) was added to a mixture of tert-butyl 3-cyano-4-oxopyrrolidine-1-carboxylate (5.00 g, 23.8 mmol) and butanone (20 ml). The mixture was refluxed at 120 °C for 4 hours. LC-MS was used to monitor the reaction until complete, yielding compound 1-02. The reaction solution was diluted in ice water, and the pH was adjusted to 10 with sodium hydroxide aqueous solution. BOC anhydride (7.79 g, 35.7 mmol) was added, and the mixture was stirred at room temperature for half an hour. The mixture was extracted three times with ethyl acetate. The crude product was subjected to C18 reversed-phase chromatography (eluting with a water / methanol gradient) to give compound 1-03 (500 mg, yield 7.95%). MS (ESI): m / z = 265.1 [M+H] + .

[0226] Step 2: Synthesis of Compound 1-04

[0227] Compound 1-03 (500 mg, 1.59 mmol) was dissolved in 10 mL of DCM, and TEA (957 mg, 9.46 mmol) was added. After stirring for half an hour, Tf₂O (640 mg, 2.27 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for 2 hours. LC-MS monitoring showed that the reaction of the starting material was complete. The crude product was purified by medium-pressure rapid column chromatography (eluting with a gradient of n-heptane / ethyl acetate) to give compound 1-04 (400 mg, yield 53.35%), MS (ESI): m / z = 399.1 [M+H]. + .

[0228] Step 3: Synthesis of Compound 1-06

[0229] Compound 1-04 (200 mg, 504.56 μmol), BINAP (62.84 mg, 100.91 μmol), Pd(OAc)2 (11.33 mg, 50.46 μmol), Cs2CO3 (493.46 mg, 1.51 mmol), and 7 mL of toluene were added to the reaction flask. Separately, compound 1-05 (79.57 mg, 756.85 μmol, 82.46 μL) was dissolved in 3 mL of toluene and added to the reaction flask. The reaction was carried out at 100 °C for 5 hours under N2 protection. LC-MS was used to monitor the reaction until complete. The reaction solution was concentrated to obtain a crude product, which was purified by medium-pressure rapid column chromatography (eluting with a gradient of n-heptane / ethyl acetate) to obtain compound 1-06 (91 mg, yield 51.32%), MS (ESI): m / z = 352.2 [M+H]. + .

[0230] Step 4: Synthesis of Compound 1-07

[0231] Compound 1-06 (65 mg, 184.95 μmol) was added to concentrated sulfuric acid (0.5 mL), and heated at 60 °C for 1 hour. LC-MS showed the reaction was complete. The reaction solution was poured into ice water, and the pH was adjusted to 10-11 with 1N NaOH solution. Boc₂O (60.55 mg, 277.43 μmol) was dissolved in THF (3 mL) and added to the above reaction solution. The mixture was stirred at room temperature for 3 hours. LC-MS showed the reaction was complete. The reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by medium-pressure rapid column chromatography (eluting agent: n-heptane / ethyl acetate gradient elution) to obtain compound 1-07 (50 mg, yield 94.08%), MS (ESI): m / z = 288.1 [M+H⁺]. + .

[0232] Step 5: Synthesis of Compound 1-08

[0233] Compound 1-07 (50 mg, 174.00 μmol) was added to a 15% TFA DCM solution and stirred at room temperature for 1 hour. LC-MS showed that the reaction was complete. The crude product 1-08 (33 mg, trifluoroacetate) was concentrated and directly carried out in the next step of the reaction.

[0234] Step Six: Synthesis of Compound 01

[0235] Compound Int-01 (55.03 mg, 211.49 μmol), HATU (80.42 mg, 211.49 μmol), and DIPEA (54.67 mg, 422.99 μmol, 73.68 μL) were mixed with 1 mL of DMF and stirred at 0 °C for 60 min. Compound 1-08 (33 mg, 176.24 μmol) was mixed with 1 mL of DCM, and then DIPEA (27 mg) was added to the reaction flask in one batch. The mixture was stirred at RT for 2 h, and the reaction was confirmed to be complete by LC-MS. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was then subjected to Pre-HPLC to prepare compound 01 (15.7 mg, yield 20.74%). MS (ESI): m / z = 430.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.28(d,J=5.6Hz,1H),7.65(d,J=1.2Hz,1H),7.52(d,J=1.2Hz,1H),6.59(d,J=2.2Hz,1H),6.34(dd,J=5.6,2.0Hz,1H),5.1 7-5.09(m,2H),4.88-4.79(m,2H),4.28(t,J=8.0Hz,2H),3.83-3.72(m, 2H), 3.40-3.26 (m, 1H), 2.86 (d, J = 7.8Hz, 2H), 2.59 (s, 3H), 2.30 (s, 3H).

[0236] Example 2: Synthesis of 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutane-3-yl)-1-(3,5,6-trimethyl-7,9-dihydro-8H-imidazo[1,5-a]pyrrolo[3,4-c]pyridin-8-yl)acet-1-one (compound 03)

[0237]

[0238] Step 1: Synthesis of Compound 2-01

[0239] Compound 1-04 (400 mg, 1.01 mmol) was dissolved in 10 mL of 1,4-dioxane and 1 mL of water. Potassium N-aminomethyltrifluoroborate (478 mg, 2.02 mmol), Ruphos (141 mg, 302 μmol), Ruphos G3 Pd (84 mg, 101 μmol), and cesium carbonate (986 mg, 3.03 mmol) were added sequentially. The mixture was purged with nitrogen three times and heated to 110 °C for 10 hours. Thin-layer chromatography (TLC) (PE:EA = 5:1) showed complete reaction of the starting material. The crude product was purified by medium-pressure rapid column chromatography (eluting with a gradient of n-heptane / ethyl acetate) to give compound 2-01 (200 mg, yield 52.5%), MS (ESI): m / z = 380.2 [M+H). + .

[0240] Step 2: Synthesis of Compound 2-02

[0241] Compound 2-01 (200 mg, 529 μmol) was dissolved in 5 mL of DCM, and 2 mL of TFA was added. The mixture was stirred at room temperature for 1 hour. Thin-layer chromatography (TLC) (PE:EA = 5:1) showed that the reaction proceeded completely. The crude compound 2-02 (147 mg) was obtained by concentration. MS (ESI): m / z = 280.6 [M+H] + .

[0242] Step 3: Synthesis of Compound 2-03

[0243] Compound 2-02 (147 mg, 527 μmol) was dissolved in 5 mL of DCM. Acetic anhydride (211 mg, 830 μmol) and DIPEA (643 mg, 4.9 mmol) were added under ice bath conditions, and the mixture was stirred at room temperature for 4 hours. Thin-layer chromatography (TLC) (PE:EA = 5:1) showed complete reaction of the starting material. The crude product was purified by medium-pressure rapid column chromatography (eluting with a gradient of n-heptane / ethyl acetate) to give compound 2-03 (100 mg, yield 72.73%), MS (ESI): m / z 262.1 [M+H]. + .

[0244] Step 4: Synthesis of Compound 2-04

[0245] Compound 2-03 (100 mg, 382 μmol) was dissolved in 10 mL of DCE, and phosphorus oxychloride (117 mg, 765 μmol) was added. The mixture was heated to 70 °C and reacted for 8 hours. Thin-layer chromatography (TLC) (PE:EA = 5:1) showed that the reaction proceeded completely. The crude product was purified by medium-pressure rapid column chromatography (eluting with a gradient of n-heptane / ethyl acetate). The target compound 2-04 (80 mg, 85.9% yield) was obtained by adjusting the ethyl acetate volume ratio from 0 to 20%. MS (ESI): m / z = 244.1 [M+H] + .

[0246] Step 5: Synthesis of Compound 2-05

[0247] Compound 2-04 (80 mg, 328 μmol) was dissolved in 2 mL of ethanol, and concentrated hydrochloric acid (0.5 mL) was added. The mixture was heated to 80 °C and reacted for 4 hours. The reaction was monitored by LC-MS to ensure complete reaction of the starting material. The crude compound 2-05 (66 mg) was obtained by concentration. MS (ESI): m / z = 202.1 [M+H] + .

[0248] Step Six: Synthesis of Compound 03

[0249] Compound 2-05 (66 mg, 328 μmol) was dissolved in 2 mL of dichloromethane. TCFH (184 mg, 655 μmol) and NMI (161 mg, 1.97 mmol) were added at 0 °C. After stirring at room temperature for half an hour, compound Int-01 (90 mg, 328 μmol) was added, and stirring continued at room temperature for 8 hours. The reaction was monitored by LC-MS to ensure complete reaction. The crude product was purified by C18 reversed-column chromatography (eluting with a gradient of water / acetonitrile) to give the target compound 03 (10 mg, yield 6.9%). MS (ESI): m / z = 444.1 [M+H]+ , 1 H NMR (400MHz, MeOD) δ8.14(d,J=5.6Hz,1H),7.11(d,J=6.8Hz,1H),6.69(s,1H),6.50(d,J=4.8Hz,1H),4.91-4.60(m,4H),4.27( t,J=8.2Hz,2H),3.88-3.75(m,2H),3.29-3.20(m,1H),2.99(s,3H),2.94(d,J=7.0Hz,2H),2.80(s,3H),2.18(d,J=2.8Hz,3H).

[0250] Example 3: Synthesis of 1-(4-methyl-1,3-dihydro-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyridin-2-yl)-2-(3-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutan-1-yl)acet-1-one (compound 28)

[0251]

[0252] Step 1: Synthesis of Compound 3-02

[0253] Compound 3-01 (10 g, 53.5 mmol), anhydrous ethanol (100 mL), and p-methoxybenzylamine (8.8 g, 64.2 mmol) were added sequentially to a dry round-bottom flask. The mixture was heated to 90 °C and reacted for 12 hours. The reaction was confirmed to be complete by LC-MS. The reaction solution was concentrated, and the crude product was purified by medium-pressure rapid column chromatography to obtain compound 3-02 (8.2 g, yield 53.30%). MS [ESI]: m / z = 288.2 [M+H] + .

[0254] Step 2: Synthesis of Compound 3-03

[0255] Compound 3-02 (5 g, 17.4 mmol), Pd(dppf)₂Cl₂ (0.63 g, 0.86 mmol), methanol (50 mL), and triethylamine (5.28 g, 52.1 mmol) were added sequentially to a pressurized reactor. The reactor was pressurized to 1 MPa with carbon monoxide, and then heated to 90 °C for 12 hours. The reaction was confirmed to be complete by LC-MS. The reaction solution was concentrated, and the crude product was purified by medium-pressure rapid column chromatography to obtain compound 3-03 (2.9 g, yield 53.60%). MS [ESI]: m / z = 312.1 [M+H] + .

[0256] Step 3: Synthesis of Compound 3-04

[0257] Compound 3-03 (2.9 g, 9.31 mmol), methanol (20 mL), and Raney nickel (0.5 g) were added sequentially to a pressurized reactor. The reactor was pressurized to 1 MPa with hydrogen and heated to 60 °C for 12 hours. The reaction was confirmed to be complete by LC-MS. After returning to room temperature, the reaction solution was filtered through diatomaceous earth. The filter cake was washed three times with methanol. The filtrate was concentrated under reduced pressure. The crude product was purified by medium-pressure rapid column chromatography to obtain compound 3-04 (1.2 g, yield 45.47%). MS [ESI]: m / z = 284.1 [M+H] + .

[0258] Step 4: Synthesis of Compound 3-05

[0259] Compound 3-04 (1.2 g, 4.24 mmol), dichloromethane (10 mL), and trifluoroacetic acid (4.58 g, 42.4 mmol) were added to a dry round-bottom flask. The mixture was heated to 40 °C and reacted for 10 hours. The reaction was monitored by LC-MS until complete. After cooling to room temperature, the pH was adjusted to 7-8 with 6N NaOH solution. The mixture was extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by medium-pressure rapid column chromatography to obtain compound 3-05 (0.31 g, yield 44.85%). MS [ESI]: m / z = 164.1 [M+H] + .

[0260] Step 5: Synthesis of Compound 3-06

[0261] Compound 3-05 (0.31 g, 1.9 mmol), ethanol (1 mL), 2-chloro-1,1-dimethoxyethane (0.7 g, 5.7 mmol), and 40% hydrobromic acid solution (0.76 g, 9.5 mmol) were added to a dry round-bottom flask. The mixture was heated to 80 °C and reacted for 12 hours. The reaction was monitored by LC-MS until complete. After cooling to room temperature, the pH was adjusted to 7-8 with 6N NaOH aqueous solution. The mixture was extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by medium-pressure rapid column chromatography to obtain compound 3-06 (0.15 g, yield 42.18%). MS [ESI]: m / z = 188.1 [M+H] + .

[0262] Step Six: Synthesis of Compound 3-07

[0263] Compound 3-06 (0.15 g, 0.8 mmol) and anhydrous tetrahydrofuran (2 mL) were added to a dry round-bottom flask. After purging with nitrogen three times, the borane tetrahydrofuran complex (2 mmol) was slowly added under ice bath conditions. After the addition was complete, the temperature was raised to 70 °C and the reaction was continued for 4 hours. The reaction was confirmed to be complete by LC-MS. The mixture was then cooled to room temperature, and the reaction was quenched by adding methanol (5 mL) under ice bath conditions. After no more gas was released, the mixture was evaporated to dryness, dissolved in 3 mL of methanol, and then 4 M hydrochloric acid (1 mL) was added. The mixture was heated to 60 °C and reacted for 2 hours. After cooling to room temperature, the pH was adjusted to 7-8 by adding NaOH aqueous solution under ice bath conditions. The mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase C18 column chromatography to obtain compound 3-07 (86 mg, yield 61.96%). MS [ESI]: m / z = 174.1 [M+H] + .

[0264] Step 7: Synthesis of Compound 28

[0265] Compound Int-01 (54.0 mg, 0.20 mmol), DMF (1 mL), HATU (98.7 mg, 0.26 mmol), and triethylamine (52.5 mg, 0.52 mmol) were added sequentially to a dry round-bottom flask. After reacting at room temperature for 30 minutes, compound 3-07 (30 mg, 0.17 mmol) was slowly added. The reaction was continued for 4 hours after the addition was complete. LC-MS analysis confirmed the reaction was complete. Compound 28 (25.2 mg, yield 34.75%) was obtained by pre-HPLC purification. MS [ESI]: m / z = 416.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.22(d,J=5.6Hz,1H),7.62(s,1H),7.40(s,1H),7.30 / 7.24(s,1 H),6.52(d,J=2.2Hz,1H),6.52(d,J=2.2Hz,1H),6.27(dd,J=5.6,2.2Hz,1H),4.91(d, J=11.4Hz,2H),4.77(dd,J=7.8,5.0Hz,2H),4.23(t,J=8.0Hz,2H),3.69(dd,J=8.0,5. 4Hz, 2H), 3.29 (ddt, J=10.6, 8.0, 4.0Hz, 1H), 2.82 (d, J=7.8Hz, 2H), 2.31 / 2.30 (s, 3H).

[0266] Example 4: Synthesis of 1-(10-methyl-3,4-dihydropyrazinyl[1,2-a]indol-2(1H)-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azatidine-3-yl)acetic acid-1-one (compound 65)

[0267]

[0268] Step 1: Synthesis of Compound 4-02

[0269] 3-Methyl-1H-indole-2-carboxylic acid (4.0 g, 22.83 mmol) was added to dry methanol (40 mL) and thionyl chloride (5.98 g, 50.23 mmol). The reaction mixture was heated to 60 °C and reacted for 3 hours. The reaction solution was cooled to room temperature, and the pH was adjusted to weakly alkaline with saturated ammonium chloride aqueous solution. The mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 1-02 (4.75 g). MS [ESI]: m / z = 190.2, [M+H] + .

[0270] Step 2: Synthesis of Compound 4-04

[0271] Compound 4-02 (4.75 g, 25.10 mmol) was added to DMF (15 mL), followed by N-Boc-bromoethylamine (8.44 g, 37.66 mmol), potassium iodide (4.17 g, 25.10 mmol, 1.34 mL), and cesium carbonate (16.36 g, 50.21 mmol). The mixture was heated to 80 °C and stirred for 3 hours. Thin-layer chromatography (TLC) (n-heptane:ethyl acetate = 2:1) showed complete reaction of the starting material. The crude product was purified by medium-pressure rapid column chromatography (eluting with a gradient of n-heptane / ethyl acetate) to give compound 4-04 (4.8 g, 57.52%). MS [ESI]: m / z = 333.4, [M+H] + .

[0272] Step 3: Synthesis of Compound 4-05

[0273] Compound 4-04 (4.8 g, 14.44 mmol) was added to a hydrochloric acid-dioxane solution (15 mL). The reaction was stirred at room temperature for 3 hours. Thin-layer chromatography (TLC) (n-heptane:ethyl acetate = 3:1) showed that the reaction proceeded completely. The crude product was purified by medium-pressure rapid column chromatography (eluting with a gradient of n-heptane / ethyl acetate) to give compound 4-05 (3.1 g, yield 98.36%). MS [ESI]: m / z = 233.2, [M+H] + .

[0274] Step 4: Synthesis of Compound 4-06

[0275] Compound 4-05 (2.0 g, 8.61 mmol) was added to methanol (8 mL) and potassium carbonate (2.38 g, 17.22 mmol, 1.04 mL). The mixture was heated to 60 °C and stirred for 2 hours. The reaction solution was then cooled to room temperature, and thin-layer chromatography (TLC) (n-heptane:ethyl acetate = 2:1) showed that the starting material had reacted completely. The crude product was purified by medium-pressure rapid column chromatography (eluting with a gradient of n-heptane / ethyl acetate) to give compound 4-06 (800 mg, yield 46.40%). MS [ESI]: m / z = 201.2, [M+H] + .

[0276] Step 5: Synthesis of Compound 4-07

[0277] Compound 4-06 (800 mg, 4.00 mmol) was added to a borane-tetrahydrofuran solution (1.72 g, 19.98 mmol). The mixture was heated to 60 °C and stirred for 4 hours. Thin-layer chromatography (TLC) (n-heptane:ethyl acetate = 0:1) showed that the reaction proceeded completely. The reaction was quenched with methanol, concentrated, and then extracted with water and ethyl acetate. The combined organic phases were concentrated to obtain the crude product. The crude product was purified by medium-pressure rapid column chromatography (eluting with a gradient of n-heptane / ethyl acetate) to give compound 4-07 (35 mg, yield 4.70%). MS [ESI]: m / z = 187.1, [M+H] + .

[0278] Step Six: Synthesis of Compound 65

[0279] Compound Int-01 (48.90 mg, 187.92 μmol) was added to solvents DMF (0.5 mL) and HATU (107.75 mg, 281.88 μmol). After stirring at room temperature for ten minutes, compound 4-07 (35 mg, 187.92 μmol) was added, along with solvents DMF (0.5 mL) and DIEA (72.86 mg, 563.75 μmol, 98.20 μL). The reaction was continued to be stirred at room temperature for 3 hours. The reaction solution was then cooled to room temperature, and LCMS was used to confirm the completeness of the reaction. The mixture was filtered, and the reaction solution was concentrated under reduced pressure. The crude product was then subjected to Pre-HPLC to prepare compound 65 (30 mg, yield 37.26%). MS [ESI]: m / z = 429.4, [M+H] +. 1H NMR (400MHz, DMSO) δ8.19(d,J=5.6Hz,1H),7.47(d,J=7.7Hz,1H),7.35(d,J=8.0Hz,1H),7 .14-7.06(m,1H),7.05-7.00(m,1H),6.69(d,J=2.2Hz,1H),6.51(dd,J=5.6,2.2Hz,1H),4. 86(s,0.8H),4.79(s,1.2H),4.19-4.11(m,3H),4.03(d,J=5.4Hz,1H),3.96(t,J=5.2Hz,2 H),3.70-3.65(m,2H),3.13-3.03(m,1H),2.99-4.11(m,2H),2.20(s,1.2H),2.17(s,1.8H)

[0280] Example 5: Synthesis of 1-(7-fluoro-6-methoxy-4-methyl-3,4-dihydropyrrolo[3,4-b]indol-2(1H)-yl)-2-(1-(2-(trifluoromethyll)pyridin-4-yl)aza-3-yl)cyclobutane-1-one (compound 104)

[0281]

[0282] Step 1: Synthesis of Compound 5-02

[0283] (4-fluoro-3-methoxyphenyl)hydrazine hydrochloride (3.0 g, 19.2 mmol) and tert-butyl-3-pyrrolidone-1-carboxylic acid ester (10.65 g, 57.6 mmol) were added sequentially to a 100 mL single-necked flask. After dissolution in 30 mL of methanol, the mixture was reacted at room temperature for 48 hours. After the reaction was complete as detected by LCMS, the methanol was removed by low-temperature concentration. The residue was extracted with 40 mL of water and ethyl acetate. The organic phase was washed with saturated sodium chloride, dried, and concentrated to obtain the crude product. The crude product was purified by medium-pressure rapid column chromatography (eluting with PE / EA gradient) to give a mixture of compounds 5-02-A and 5-02-B (300 mg, yield: 5.1%). MS [ESI]: m / z = 307.1 [M+H] + .

[0284] Step 2: Synthesis of Compound 5-03

[0285] A mixture of compounds 5-02-A and 5-02-B (300 mg, 0.98 mmol), DCM (6 mL), and TFA (1 mL) were added sequentially to a reaction flask. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was completed by LCMS monitoring, the solvent was directly concentrated to obtain 160 mg of crude product, and the next step was performed directly. MS [ESI]: m / z = 206.09, [M+H]+: 207.1.

[0286] Step 3: Synthesis of Compound 5-04

[0287] In a reaction flask, Int-01 (200 mg, 0.77 mmol), a crude mixture of 5-03-A and 5-03-B (160 mg, 0.77 mmol), and 3 mL of DMF were added sequentially. HATU (585.2 mg, 1.54 mmol) was then added, and the mixture was reacted at room temperature for 3 hours. After completion, the reaction was monitored by thin-layer chromatography (TLC) (DCM:MeOH = 10:1). The mixture was then extracted with water and ethyl acetate. The organic phase was washed with saturated ammonium chloride, dried, filtered, and concentrated to obtain the crude product. This crude product was purified by medium-pressure rapid column chromatography (eluting with a gradient of n-heptane / ethyl acetate) to give a mixture of 5-03-A and 5-03-B (110 mg, yield 31.8%). MS [ESI]: m / z = 449.1 [M+H] + .

[0288] Step 4: Synthesis of Compound 104

[0289] A mixture of 5-03-A and 5-03-B (110 mg, 0.245 mmol), DMF (5 mL), 60% sodium hydride (29.4 mg, 0.736 mmol), and methyl iodide (41.7 mg, 0.294 mmol) were added sequentially to a reaction tube. The mixture was stirred under closed pressure at 20 °C for 12 h. After the final reaction, the reaction solution was purified by Pre-HPLC. The sample was concentrated and lyophilized to obtain a mixture of compounds 104 and 104-iso (21 mg, yield 15.5%, HPLC 32.9% / 64.2%). MS [ESI]: m / z = 463.1, [M+H] + , 1HNMR (400MHz, CD3OD) δ8.04(d,J=5.8Hz,1H),7.03(dd,J=11.6,6.8Hz,1H),6.96(d,J=7.2Hz,1H),6.61(d,J=1.8Hz,1H),6.44-6.38(m,1H),4. 76-4.48(m,4H),4.18(t,J=8.4Hz,2H),3.82(s,3H),3.72(dd,J=8.2,6.0Hz,2H),3.61(s,3H),3.22-3.17(m,1H),2.83(dd,J=7.8,3.6Hz,2H).

[0290] Example 6: Synthesis of 1-(6-fluoro-1,3-dihydro-2H-benzo[4,5]thieno[2,3-c]pyrrolo-2-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azadin-3-yl)acetate-1-one (compound 108):

[0291]

[0292] Step 1: Synthesis of Compound 6-02

[0293] Compound 2,4-difluoroacetophenone (5 g, 32.2 mmol) and ethyl mercaptoacetate (7.79 g, 65.2 mmol) were added sequentially to a dry round-bottom flask. DBU (9.54 g, 64.05 mmol) was slowly added dropwise under ice bath conditions. The mixture was then allowed to react at room temperature for 24 hours. LC-MS analysis confirmed the reaction was complete. The compound 6-02 (3.2 g, 41.94% yield) was purified by medium-pressure rapid column chromatography. MS [ESI]: m / z = 239.2, [M+H] + .

[0294] Step 2: Synthesis of Compound 6-03

[0295] At room temperature, compound 6-02 (3.2 g, 13.43 mmol), dichloroethane (20 mL), NBS (3.59 g, 20.14 mmol), and benzoyl peroxide (3.9 g, 16.12 mmol) were added sequentially to a dry round-bottom flask. The mixture was then heated to 60 °C and reacted for 12 hours. The reaction was confirmed to be complete by LC-MS. Compound 6-03 (2.2 g, yield 51.65%) was purified by medium-pressure rapid column chromatography. MS [ESI]: m / z = 318.2, [M+H] + .

[0296] Step 3: Synthesis of Compound 6-04

[0297] Compound 6-03 (2.2 g, 6.94 mmol), 15 mL of 7 N ammonia-methanol solution, and potassium carbonate (1.15 g, 8.32 mmol) were added to a reaction flask at room temperature. The mixture was then heated to 80 °C and reacted for 24 hours. The reaction was confirmed to be complete by LC-MS. Compound 6-04 (0.5 g, yield 34.79%) was purified by medium-pressure rapid column chromatography. MS [ESI]: m / z = 208.2, [M+H] + .

[0298] Step 4: Synthesis of Compound 6-05

[0299] Compound 6-04 (0.5 g, 2.41 mmol) and anhydrous tetrahydrofuran (3 mL) were added to a dry round-bottom flask. After purging with nitrogen three times, the borane tetrahydrofuran complex (6.03 mmol) was slowly added under ice bath conditions. After the addition was complete, the mixture was heated to 60 °C and reacted for 12 hours. The reaction was confirmed to be complete by LC-MS. The mixture was then cooled to room temperature, and the reaction was quenched by adding methanol (5 mL) under ice bath conditions. After no more gas was released, the mixture was evaporated to dryness, dissolved in 3 mL of methanol, and then 4 M hydrochloric acid (1 mL) was added. The mixture was heated to 60 °C and reacted for 2 hours. After cooling to room temperature, the pH was adjusted to 7-8 by adding NaOH aqueous solution under ice bath conditions. The mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse-phase chromatography using a C18 column to obtain compound 6-05 (0.27 g, yield 57.91%). MS [ESI]: m / z = 194.1, [M+H] + .

[0300] Step 5: Synthesis of Compound 108

[0301] Compound Int-01 (161.5 mg, 0.62 mmol), DMF (1 mL), HATU (295.1 mg, 0.77 mmol), and triethylamine (157.1 mg, 1.5 mmol) were added sequentially to a dry round-bottom flask. After reacting at room temperature for 30 minutes, compound 6-05 (0.1 g, 1.4 mmol) was slowly added. The reaction was continued for 4 hours after the addition was complete. LC-MS analysis confirmed the reaction was complete. Compound 108 (120 mg, 53.25% yield) was purified by reversed-phase pre-HPLC. MS [ESI]: m / z = 436.3, [M+H] + . 1 H NMR (400MHz, CDCl3) 1H NMR (400MHz, CDCl3) δ8.21(d,J=5.6Hz,1H),7.54-7.40(m,2H),7.11-7.09(m,1H),6.52(d,J=2.0Hz,1H),6.27(dd,J=5.6, 2.0Hz,1H),4.86-4.69(m,4H),4.24(t,J=8.0Hz,2H),3.77-3.64(m,2H),3.32-3.25(m,1H),2.78(dd,J=12.4,7.6Hz,2H).

[0302] Biological evaluation

[0303] Experimental Example 1. The ability of compounds to positive allosteric regulation (PAM) of M4

[0304] This study utilized a stable CHO cell line expressing the human M4 receptor, incubated with different concentrations of the test compound, and employed the FLIPR CALCIUM 6ASSAY KIT kit to investigate the activity of the compound against the M4 receptor based on changes in the fluorescence intensity of the fluorescent dye, calculating the corresponding concentration-effect curves. The main experimental steps are as follows:

[0305] (1) Cells were cultured in F12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B at a temperature of 37°C and a carbon dioxide concentration of 5%.

[0306] (2) Seed the cells obtained in step (1) into a 384-well cell plate, and then place the cell plate in a 37°C, 5% CO2 incubator for about 16-20 hours.

[0307] (3) Remove the culture medium from the cell plate, quickly add an appropriate amount of the prepared 1× loading buffer to each well, centrifuge, and then incubate the cell plate at 37°C in the dark for 120 minutes.

[0308] (4) Prepare gradient dilution working solutions and agonist working solutions for the test compounds. The agonist working solution is prepared using EC. 20 Acetylcholine (acetylcholine at the concentration that produces 20% of the maximum effect). A positive control or working solution of the compound of this invention and the agonist were mixed 1:1, and 20 μL / well was transferred to a 384-well plate containing the compound; the positive control used acetylcholine (ACh) at a final concentration of 10 μM. A separate working solution without the agonist was used, with the test compound at a concentration of 10 μM, to detect its background agonistic effect.

[0309] (5) Use FLIPR Tetra to add 10 μL of the diluted compound from step (4) into each well and collect data at wavelengths of 515 nm to 575 nm.

[0310] (6) 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.

[0311] 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.

[0312] The formula for calculating the percentage excitation rate is: in The average value is the positive control (10 μM Ach). The mean value is the negative control (0.1% DMSO).

[0313] Table 1. Activity of the compounds of the present invention against M4

[0314] Compound numbering EC 50 (nM) <![CDATA[PAM Max / But Max ,%]]> 01 68.17 75.78 03 135.30 75.30 28 212.80 77.11

[0315] Experimental results demonstrate that the compounds of the present invention (e.g., compounds 01, 03, 28) exhibit excellent M4 receptor agonist activity.

[0316] The above embodiments do not limit the scope of this application in any way. In addition to those described herein, various modifications to 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, a stereoisomer, tautomer, or mixture thereof, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, wherein the compound has the structure of Formula I: in: Ring A is selected from C 6-10 Aromatic rings, 5-6 quinary heteroaryl aromatic rings, C 3-8 Carbon rings and 4-11 membered heterocycles; Ring B is selected from C 6-10 Aromatic rings, 5-6 quinary heteroaryl aromatic rings, C 3-8 Carbon rings and 4-11 membered heterocycles; The ring C is a 4-11 member heterocyclic group; E, F, G, and H are each independently selected from: C, CH, and N; X is selected from single bonds, -C(R1R2)-, -O-, and -S-. R1 and R2 are each independently selected from H, OH, CN, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 aryl, 5-6 membered heteroaryl; or R1 and R2 together with the carbon atom they are attached to form C 3-8 Cycloalkyl or 3-8 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy groups; L is a 3-8 membered heterocycle, which is optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, NO2, -NH2, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl group 2, oxo group (=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-6 membered heteroaryl; the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy groups; Ar is selected from C 6-10 Aromatic rings and 5-10 membered heteroaromatic rings; said aromatic rings and heteroaromatic rings are optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, oxo group (=O), C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -NR 10a R 10b -OR 11 -SR 11 -S(=O)R 12 -S(=O)2R 12 -S(=O)NR 10a R 10b -S(=O)2NR 10a R 10b -NR 10a S(=O)R 10b -NR 10a S(=O)2R 10b -C(=O)R 11 -C(=O)NR 13a R 13b -NR 13a C(=O)R 13b -OC(=O)NR 13a R 13b and -NR 14a C(=O)NR 15a R 15b The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy groups; R a R b and R c Each time it appears, it is independently selected from hydroxyl, halogen, CN, NO2, oxo group (=O), C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 20a R 20b -OR 21 -SR 21 -S(=O)R 22 -S(=O)2R 22 -S(=O)NR 20a R 20b -S(=O)2NR 20a R 20b -NR 20a S(=O)R 20b -NR 20a S(=O)2R 20b -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a C(=O)R 23b -OC(=O)NR 23a R 23b and -NR 24a C(=O)NR 25a R 25b The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -SR 31 -S(=O)R 32 -S(=O)2R 32 -S(=O)NR 30a R 30b -S(=O)2NR 30a R 30b -NR 30a S(=O)R 30b -NR 30a S(=O)2R 30b -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy groups and 4-10 membered heterocyclic groups; R 10a R 10b R 13a R 13b R 13c R 14a R 15a R 15b R 20a R 20b R 23a R 23b R 23c R 24a R 25a and R 25b Each is independently selected from H, OH, and C. 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 cycloalkyl; or R 20a With R 20b R 23a With R 23b or R 25a With R 25b Together with the atoms to which it is attached, it forms a 3-8 membered cycloalkyl or heterocyclic group, wherein each of the alkyl, alkoxy, cycloalkyl, and heterocyclic groups is optionally substituted by one or more substituents selected from: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy groups; R 30a R 30b R 33a R 33b R 34a R 35a and R 35b Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy groups; R 11 R 12 R 21 R 22 R 31 and R 32 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 The aryl group and 5-10 heteroaryl group, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, halogen, CN, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl and 4-10 membered heterocyclic groups; m can be 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6; and p can be 0, 1, 2, 3, 4, 5, or 6.

2. The compound of claim 1, a stereoisomer, tautomer, or mixture thereof, the N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, wherein: Ring A is selected from benzene ring, 5-6 membered nitrogen-containing heteroaromatic ring, 4-6 membered nitrogen-containing heterocycle and 4-6 membered oxygen-containing heterocycle, wherein the ring atom of the nitrogen-containing heterocycle may optionally include 1-2 oxygen atoms or sulfur atoms; Preferably, ring A is selected from benzene ring, 5-6 member nitrogen-containing heteroaromatic ring, 5-6 member nitrogen-containing heterocycle and 5-6 member oxygen-containing heterocycle, and the ring atom of the nitrogen-containing heterocycle optionally further includes one oxygen atom or sulfur atom.

3. The compound of claim 1 or 2, a stereoisomer, tautomer, or mixture thereof, the N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, wherein: Ring B is selected from benzene rings, 5-6 member nitrogen-containing heteroaromatic rings, 5-6 member sulfur-containing heteroaromatic rings, 5-6 member oxygen-containing heteroaromatic rings, 5-6 member nitrogen-containing heterocycles, 5-6 member sulfur-containing heterocycles, and 5-6 member oxygen-containing heterocycles; Preferably, ring B is selected from benzene rings, 5-6 member nitrogen-containing heteroaromatic rings, 5-6 member sulfur-containing heteroaromatic rings, 5-6 member nitrogen-containing heterocycles, and 5-6 member sulfur-containing heterocycles.

4. The compound according to any one of claims 1 to 3, a stereoisomer, tautomer, or mixture thereof of the compound, the N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, wherein: The ring C is a 4-11 member nitrogen-containing heterocyclic group; Preferably, the ring C is a 5-7 member nitrogen-containing heterocyclic group.

5. The compound according to any one of claims 1 to 4, a stereoisomer, tautomer, or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, wherein: The structure is selected from the following structures, which are optionally further selected from R. a R b and R c Substituents:

6. The compound according to any one of claims 1 to 5, a stereoisomer, tautomer, or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, wherein: R1 and R2 are each independently selected from H, OH, CN, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2; or R1 and R2 together with the carbon atoms they are attached to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl and heterocyclic group are each optionally substituted by one or more substituents selected from: OH, CN, halogen, NO2, -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy groups; Preferably, R1 and R2 are each independently selected from H, OH, CN, halogens, and C. 1-4 Alkyl, C 1-4 Alkoxy, -NH2, -NH(C) 1-4 alkyl), -N(C) 1-4 Alkyl group 2; or R1 and R2 together with the carbon atoms they are attached to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl and heterocyclic group are each optionally substituted by one or more substituents selected from: OH, CN, halogen, NO2, -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy groups; and / or R' is selected from H and C. 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocyclic, phenyl, 5-6-membered heteroaryl, wherein each of the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-4 alkyl), -N(C) 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy group; preferably, R' is selected from H and C. 1-4 alkyl.

7. The compound according to any one of claims 1 to 6, a stereoisomer, tautomer, or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, wherein: L is C 3-6 A carbon ring or a 3-6 membered nitrogen-containing heterocycle, wherein the carbon ring or nitrogen-containing heterocycle is optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, oxo group (=O), C 1-6 Alkyl, C 1-6 Alkoxy group; the alkyl group and alkoxy group are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy groups; Preferably, L is cyclopropane, cyclobutane, cyclopentane, azircyclopropane, azircyclobutane, or azircyclopentane, wherein the cyclopropane, cyclobutane, cyclopentane, azircyclopropane, azircyclobutane, or azircyclopentane is optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl group 2, oxo group (=O), C 1-6 Alkyl, C 1-6 Alkoxy group; the alkyl group and alkoxy group are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy groups; and / or Ar is selected from benzene rings and 5-6 membered nitrogen-containing heteroaromatic rings; said aromatic rings and heteroaromatic rings are optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogen, C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl, 5-6 quinone heteroaryl, -NR 10a R 10b -OR 11 -SR 11 -S(=O)R 12 -S(=O)2R 12 -S(=O)NR 10a R 10b -S(=O)2NR 10a R 10b -NR 10a S(=O)R 10b -NR 10a S(=O)2R 10b -C(=O)R 11 -C(=O)NR 13a R 13b -NR 13a C(=O)R 13b -OC(=O)NR 13a R 13b and -NR 14a C(=O)NR 15a R 15b The alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy groups; Preferably, Ar is selected from benzene rings and 5-6 membered nitrogen-containing heteroaromatic rings; said aromatic rings and heteroaromatic rings are optionally substituted by one or more substituents selected from the group consisting of: H, OH, CN, halogens, C. 1-6 Alkyl, C 1-6 Alkoxy group; the alkyl group and alkoxy group are each optionally substituted by one or more substituents selected from the following: OH, CN, halogen, NO2, C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy groups.

8. The compound of claim 1, a stereoisomer, tautomer, or mixture thereof, an N-oxide of the compound, a pharmaceutically acceptable salt, eutectic, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound. R a R b and R c Each time it appears, it is independently selected from hydroxyl, halogen, CN, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 20a R 20b -OR 21 -C(=O)R 21 -C(=O)NR 23a R 23b -NR 23a C(=O)R 23b -OC(=O)NR 23a R 23b and -NR 24a C(=O)NR 25a R 25b The alkyl, alkoxy, cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, 4-10 membered heterocyclic groups, C 6-12 Aryl, 5-10 quinone heteroaryl, -NR 30a R 30b -OR 31 -C(=O)R 31 -C(=O)NR 33a R 33b -NR 33a C(=O)R 33b -OC(=O)NR 33a R 33b and -NR 34a C(=O)NR 35a R 35b The cycloalkyl, cycloalkoxy, heterocyclic, aryl, and heteroaryl groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, NO2, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy groups and 4-10 membered heterocyclic groups; Preferably, R a R b and R c Each time it appears, it is independently selected from hydroxyl, halogen, CN, C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-6 membered heterocyclic groups and -NR 20a R 20b The alkyl, alkoxycycloalkyl, cycloalkoxy, and heterocyclic groups are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, CN, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 alkoxy; and / or R 10a R 10b R 13a R 13b R 13c R 14a R 15a R 15b R 20a R 20b R 23a R 23b R 23c R 24a R 25a and R 25b Each is independently selected from H and C. 1-6 Alkyl groups; and / or R 30a R 30b R 33a R 33b R 34a R 35a and R 35b Each is independently selected from H and C. 1-6 Alkyl groups; and / or R 11 R 12 R 21 R 22 R 31 and R 32 Each is independently selected from H and C. 1-6 alkyl.

9. The compound according to any one of claims 1-8, a stereoisomer, tautomer, or mixture thereof, the N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, wherein: m is 0, 1, 2, or 3; and / or n is 0, 1, or 2; and / or p can be 0, 1, or 2.

10. The compound of claim 1, a stereoisomer, tautomer, or mixture thereof, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound. The compounds mentioned therein are selected from:

11. A method for preparing the compound of any one of claims 1-10, the method comprising the following steps: in: Ring A, Ring B, Ring C, R a R b R c E, F, G, H, X, L, Ar, m, n, and p as described in any one of claims 1-10.

12. A pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of any one of claims 1-10, a stereoisomer, tautomer, or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound; Optionally, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers.

13. The use of a compound according to any one of claims 1-10, a stereoisomer, tautomer or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound, or the use of the pharmaceutical composition of claim 12 in the preparation of a medicament for the prevention or treatment of diseases or conditions associated with M-type receptors; Preferably, the M-type receptor is an M4 receptor; Preferably, the disease or condition is Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorder, cognitive impairment (e.g., mild cognitive impairment), Parkinson's disease, Parkinson's disease-levodopa-induced motor disorder, Huntington's disease, motor disorder, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, Down syndrome (trisomy 21), cerebral amyloid angiopathy, dementia, hereditary cerebral hemorrhage with Holland amyloidosis (HCHWA-D), Creutzfeldt-Jakob disease, prion diseases, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis.

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