Dihydropyrrolopyridine derivatives and uses thereof

Abstract

This disclosure relates to compounds exhibiting activity in activating the M4 receptor, pharmaceutical compositions comprising such compounds, and methods for treating diseases or medical conditions by modulating M4 and / or M4-related cellular processes through administration of such compounds or pharmaceutical compositions.

Description

Technical Field

[0001] This disclosure generally relates to dihydropyrrolopyridine compounds that exhibit activity in modulating muscarinic M4 receptors; pharmaceutical compositions comprising these compounds; and the use of these compounds or pharmaceutical compositions in treating diseases or medical conditions by modulating muscarinic M4 receptors. Background Technology

[0002] In vertebrate organ systems, muscarinic cholinergic receptors respond to acetylcholine and initiate intracellular signaling cascades to regulate various physiological functions. In the central nervous system, muscarinic receptors are known to regulate pain perception, movement, motivational behavior, attention, learning, and memory (Thiele et al., Muscarinic Signaling in the Brain). Annual Review of Neuroscience , 36(1), 271-294 (2013) ; Martino et al., “The M1 / M4preferring agonist xanomeline is analgesic in rodent models of chronic inflammatory and neuropathic pain via central site of action.” Pain vol. 152, 12 (2011): 2852-2860 ; Nathanson et al., *Muscarinic Acetylcholine Receptors*, *Reference Module in Biomedical Sciences*, Elsevier (2018) ISBN 9780128012383). In the peripheral organ system, muscarinic receptors are typically activated by parasympathetic input, causing physiological changes such as pupillary constriction, decreased heart rate and blood pressure, and increased digestion (ibid.).

[0003] There are five subtypes of muscarinic receptors: M1, M2, M3, M4, and M5, each with different expression profiles across tissues and cell types. The M4 receptor is prominently expressed in the central nervous system, primarily distributed in neurons of the striatum, hippocampus, and cerebral cortex (Lebois et al., *Muscarinic receptor subtype distribution in the central nervous system and relevance to aging and Alzheimer's disease*). Neuropharmacology. July 1, 2018; 136(Pt C):362-373.(and information about M4 in the human protein atlas). In the striatum, M4 plays an important role in regulating striatal dopamine signaling. M4 knockout mice express enhanced motor stimulation mediated by D1 dopamine receptor (Gomeza et al., Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M(4) muscarinic acetylcholine receptor knockoutmice). Proc Nat Acad Sci USA. 1999;96(18):10483-10488 Increased cocaine self-administration in M4 muscarinicacetylcholine receptor knockout mice (Schmidt et al.). Psychopharm. 2011;216(3):367-378. However, in rodent models of psychosis, the response to the muscarinic agonist xanomeline is diminished (Woolley et al.). , Attenuation of amphetamine-induced activity by the non-selective muscarinicreceptor agonist, xanomeline, is absent in muscarinic M4 receptor knockoutmice and attenuated in muscarinic M1 receptor knockout mice. Eur J Pharmacol. January 28, 2009; 603(1-3):147-9. ; Dencker et al. Involvement of a subpopulation of neuronal M4 muscarinic acetylcholine receptors in the antipsychotic-likeeffects of the M1 / M4 preferring muscarinic receptor agonist xanomeline. J Neurosci. April 20, 2011;31(16):5905-8.Furthermore, M4 receptors in striatal D1 spinous neurons have been shown to mediate analgesia in mouse models of rodent pain (Grauer et al., Antinociceptive effects of potent, selective and brain penetrant muscarinic M4 positive allosteric modulators in rodent pain models). Brain Res. June 15, 2020; 1737:146814 In the hippocampus, M4 regulates glutamatergic synaptic transmission from the Schaffer collateral pathway to CA1 pyramidal neurons (Shirey et al.). (2008). An allosteric potentiator of M4 mAChRmodulates hippocampal synaptic transmission. Nat. Chem. Biol., 4: 42-50 Dasari and Gulledge (2011) . M1 and M4 receptors modulate hippocampal pyramidalneurons. J. Neurophysiol., 105(2): 779-792. Thorn et al. (2017) . Effects of M1and M4 activation on excitatory synaptic transmission in CA1. Hippocampus. 27: 794-810 The specific regulatory role of M4 in the striatum and hippocampus suggests that targeting M4 could treat mental and neurological disorders associated with dysfunction in these brain regions and their interconnections, including, but not limited to, schizophrenia, bipolar disorder, obsessive-compulsive disorder, pain, addiction, Alzheimer's disease, Huntington's disease, drug-induced motor difficulties, and dystonia.

[0004] Compared to other muscarinic receptor subtypes, the M4 receptor possesses unique expression and functional characteristics outside the central nervous system. For example, M4 is present in intestinal goblet cells and may help regulate mucus production, intestinal immunity, and inflammation (Knoop et al.). , Microbial sensing by goblet cells controls immune surveillance ofluminal antigens in the colon. Mucosal Immunol. January 2015;8(1):198-210. ; Uwada et al. ,Role of Muscarinic Acetylcholine Receptors in Intestinal EpithelialHomeostasis: Insights for the Treatment of Inflammatory Bowel Disease. Int J Mol Sci. March 30, 2023; 24(7):6508 M4 has also been found in epidermal keratinocytes and can promote keratinocyte migration and wound healing (Chernyavsky et al.). , The M4 muscarinic receptor-selective effects on keratinocyte crawling locomotion. Life Sci. March 28, 2003; 72(18- 19):2069-73. Chernyavsky et al. , Novel signaling pathways mediating reciprocalcontrol of keratinocyte migration and wound epithelialization through M3 andM4 muscarinic receptors. J Cell Biol. July 19, 2004; 166(2):261-72 。).

[0005] Positive ectopic modulators (PAMs) selectively targeting the M4 receptor (M4 PAMs) have been used to explore the benefits of targeting M4. For example, in animal models, M4 PAMs have been shown to rescue behavioral phenotypes associated with psychosis (Gould et al.). , Cognitive enhancement and antipsychotic-like activity following repeated dosing with the selective M4 PAM VU0467154. Neuropharmacology. 2018 January; 128:492-502. Bubser et al. , Selective activation of M4 muscarinicacetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents. ACS Chem Neurosci. October 15, 2014; 5 (10):920-42.Byun et al. , Antipsychotic drug-like effects of the selective M4muscarinic acetylcholine receptor positive allosteric modulator VU0152100. Neuropsychopharmacology. 2014 Jun;39(7):1578-93. Chan et al. , Allostericmodulation of the muscarinic M4 receptor as an approach to treating schizophrenia. Proc Natl Acad Sci US A. 2008 Aug 5;105(31):10978-83. Brady et al. , Centrally active allosteric potentiators of the M4 muscarinicacetylcholine receptor reverse amphetamine-induced hyperlocomotor activity inrats. J Pharmacol Exp Ther. Dec 2008;327(3):941-53 ), enhancing learning and memory (Gould et al.) , Cognitive enhancement and antipsychotic-like activity following repeated dosing with the selective M4 PAM VU0467154. Neuropharmacology. 2018 Jan;128: 492-502. Bubser et al. , Selective activation of M4 muscarinic acetylcholinereceptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents. ACS Chem Neurosci. 2014 Oct 15;5(10):920- 42 ), increasing the cumulative duration of total sleep and non-rapid eye movement (NREM) sleep (Gould et al.). ,State-dependent alterations in sleep / wake architecture elicited by the M4 PAMVU0467154 - Relation to antipsychotic-like drug effects. Neuropharmacology. March 2016; 102:244-53 ( ), suppressing cravings for cocaine and reducing cocaine intake (Thomsen et al.) , Effects of acute and repeated administration of the selective M4 PAM VU0152099 oncocaine versus food choice in male rats. Addict Biol. March 2022; 27(2): e13145 It also improves L-DOPA-induced motor difficulties (Shen et al.) , M4 Muscarinic ReceptorSignaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia. Neuron. 18 November 2015;88(4):762-73 ) and motor deficits associated with Huntington's disease (Pancani et al.) , Allosteric activation of M4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128mice. Proc Natl Acad Sci US A. 2015 Nov 10;112(45):14078-83. ).

[0006] Therefore, there is a need in this field to develop more compounds that can modulate muscarinic receptors, especially the M4 receptor. Summary of the Invention

[0007] This disclosure provides compounds capable of modulating M4 receptors; pharmaceutical compositions comprising these compounds; and the use of said compounds or pharmaceutical compositions for treating diseases or medical conditions by modulating M4 receptors and / or M4 receptor-related cellular processes.

[0008] In one aspect, this disclosure provides a compound having formula (I): (I) Or its pharmaceutically acceptable salt. in Each R 1 Independently selected from deuterium, halogen, cyano, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, -N(R) a (R) b ), -N(R a )C(=O)(R a -C(=O)N(R) a (R) b -OC(=O)-N(R) a (R) b -C(=O)R a and -C(=O)OR a The group consisting of wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, alkathioyl, haloalkyl, hydroxyalkyl, and cycloalkyl groups are independently and optionally influenced by one or more R groups. c replace; n1 is 0, 1, 2 or 3; Each R 2 Independently selected from deuterium, cyano, or optionally by one or more R c Substituted alkyl groups; n2 is 0, 1, 2, 3 or 4; Ring A is selected from , or The end of ring A is connected to Y; X is selected from CH or N; m is 0, 1, or 2; q can be 0, 1, 2, 3, or 4; Each R 5 Independently selected from deuterium, halogens, and optionally by one or more R c Substituted alkyl or alkoxy; or R 5 One of them and R 3 Together with intermediate atoms therein, they form cycloalkyl or heterocyclic groups, which are optionally surrounded by one or more R groups. c replace; Each time it appears independently ; Each time it appears, it is selected independently. or ; Each R 3 Independently selected from hydrogen or alkyl; n3 can be 0, 1, or 2; n4 is either 0 or 1; L is selected from the following: -O-, -S-, -N(R) a )-、 , or ; i is 0, 1, or 2; j is 1, 2, or 3; k is 0, 1, or 2; Ring B is selected from the group consisting of cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Each R 4 Independently selected from deuterium, halogen, amino, cyano, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic, -N(R) a (R) b ), -N(R a )C(=O)(R a -C(=O)N(R) a (R) b -OC(=O)-N(R) a (R) b -C(=O)R a -OR a and -C(=O)OR a The group consisting of wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, and heterocyclic groups are independently and optionally constituted by one or more R groups. c replace; n5 can be 0, 1, 2, 3, 4 or 5; R a and R b Each of the following groups is independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, or cycloalkyl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, and cycloalkyl groups are independently and optionally influenced by one or more R groups. c Replace; or R a and R b Together with the nitrogen to which it is attached, a cycloalkyl or heterocyclic group is formed, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more groups independently selected from deuterium, halogen, amino, cyano, hydroxyl, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, alkoxy, alkathiol, haloalkyl, and hydroxyalkyl; and Each R cIt is independently selected from the group consisting of deuterium, halogen, amino, cyano, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, aryl, heteroaryl, -NH (alkyl) and -N (alkyl)2.

[0009] In another aspect, a compound having the following formula is provided: (Ia) (Ib) (Ic) (Id) (Ie) Or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

[0010] In another aspect, a compound having the following formula is provided: (Ia-1) (Ia-2) (Ia-3) (Ia-4) (Id-1) (Ie-1) Or its pharmaceutically acceptable salt.

[0011] In another aspect, a compound having the following formula is provided: (Ib-1) (Ib-2) (Ic-1) (Ic-2) Or its pharmaceutically acceptable salt.

[0012] In another aspect, this disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0013] In another aspect, this disclosure provides a method for treating a disease or medical condition by modulating M4 and / or M4-related cellular processes, comprising administering to a subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[0014] In another aspect, this disclosure provides a method for modulating (e.g., activating) the M4 receptor in a subject in need, comprising administering to the subject in need an effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

[0015] In another aspect, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in the manufacture of a medicament for treating a disease or medical condition by modulating M4 and / or M4-related cellular processes.

[0016] In another aspect, this disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof for the treatment of diseases or medical conditions by modulating M4 and / or M4-related cellular processes. Detailed Implementation

[0017] Reference will now be made in detail to certain embodiments of this disclosure, examples of which are shown in the accompanying structures and formulas. While this disclosure will be described in conjunction with the enumerated embodiments, it should be understood that they are not intended to limit this disclosure to those embodiments. Rather, this disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of this disclosure as defined in the claims. Those skilled in the art will recognize that many methods and materials similar to or equivalent to those described herein can be used in the practice of this disclosure. This disclosure is by no means limited to the methods and materials described. If one or more of the incorporated references and similar materials differ from or contradict this application, including but not limited to defined terminology, use of terminology, described techniques, etc., this disclosure shall prevail. All references, patents, and patent applications cited in this disclosure are incorporated herein by reference in their entirety.

[0018] It should be recognized that, for clarity, certain features of this disclosure described in the context of individual embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of this disclosure described in the context of individual embodiments may also be provided individually or in any suitable sub-combination. It must be noted that, as used in the specification and appended claims, the singular forms “a / an” and “the” include their plural forms unless the context explicitly specifies otherwise. Thus, for example, a reference to “a compound” includes a plural of compounds.

[0019] definition The definitions of specific functional groups and chemical terms are described in more detail below. For clarity, chemical elements are identified according to the periodic table (CAS version), Handbook of Chemistry and Physics, 75th edition, inner pages, and specific functional groups are generally defined as described therein. Furthermore, the general principles of organic chemistry, as well as specific functional groups and reactivity, are described in the following references: Organic Chemistry, Thomas Sorrell, 2nd edition, University Science Books, Sausalito, 2006; Smith and March March's Advanced Organic Chemistry, 6th edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th edition, Cambridge University Press, Cambridge, 2004; the entire contents of each reference are incorporated herein by reference.

[0020] Linking substituents are described in various places within this disclosure. Specifically, each linking substituent includes both the forward and reverse forms of the linking substituent. For example, -NR(CR'R'')- includes -NR(CR'R'')- and -(CR'R'')NR-. When the structure explicitly requires a linking group, the Markush variable listed for said group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition of said variable lists "alkyl", then "alkyl" should be understood to represent a linked alkylene group.

[0021] When a substituent's bond shows a bond that passes through two atoms in the linking ring, then the substituent can bond to any atom in the ring. When a substituent is listed without specifying which atom it bonds to the remainder of the compound in a given formula, then the substituent can bond to any atom in the formula. Combinations of substituents and / or variables are permitted, provided that such combinations produce a stable compound.

[0022] When any variable (e.g., R) iWhen a compound appears more than once in any component or formula, its definition for each occurrence is independent of its definitions for all other occurrences. Therefore, for example, if a group is shown to be surrounded by 0-2 R... i If partially substituted, then the group may optionally be replaced by up to two R groups. i Partial replacement, and each occurrence of R i All independent of R i The definition is selected. Furthermore, combinations of substituents and / or variables are permitted, provided that such combinations produce stable compounds.

[0023] As used in this article, the term "C" i-j "" represents the range of carbon atoms, where i and j are integers. The range includes the endpoints (i.e., i and j) and all integer points in between, and j is greater than i. For example, C 1-6 The range represents 1 to 6 carbon atoms, including 1, 2, 3, 4, 5, and 6 carbon atoms. In some implementations, the term "C" is used... 1-12 "" indicates 1 to 12 carbon atoms, particularly 1 to 10 carbon atoms, particularly 1 to 8 carbon atoms, particularly 1 to 6 carbon atoms, particularly 1 to 5 carbon atoms, particularly 1 to 4 carbon atoms, particularly 1 to 3 carbon atoms, or particularly 1 to 2 carbon atoms.

[0024] As used herein, the term "alkyl" whether used as part of another term or independently refers to a saturated straight-chain or branched hydrocarbon group, which may optionally be independently substituted by one or more substituents as described herein. The term "C i-j "Alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 9 carbon atoms. In some embodiments, the alkyl group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. "C 1-10 Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. "C" 1-6Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, etc. In some embodiments, the alkyl group contains 9 to 30 carbon atoms. In some embodiments, the alkyl group contains... It has 9 to 28 carbon atoms, 9 to 26 carbon atoms, 9 to 24 carbon atoms, 10 to 28 carbon atoms, 10 to 26 carbon atoms, 10 to 24 carbon atoms, 12 to 28 carbon atoms, 12 to 26 carbon atoms, 12 to 24 carbon atoms, 14 to 28 carbon atoms, 14 to 26 carbon atoms, 14 to 24 carbon atoms, 14 to 22 carbon atoms, 14 to 20 carbon atoms, 14 to 18 carbon atoms, 14 to 16 carbon atoms, 16 to 22 carbon atoms, 16 to 20 carbon atoms, 16 to 18 carbon atoms, 18 to 22 carbon atoms, 18 to 20 carbon atoms, or 20 to 22 carbon atoms.

[0025] As used herein, the term "alkathio" refers to an alkyl (-S-alkyl) molecule partially linked to a parent molecule via a sulfur atom. In some embodiments, the alkathio group contains 1 to 10 carbon atoms. In some embodiments, the alkathio group contains 1 to 9 carbon atoms. In some embodiments, the alkathio group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkathio groups include, but are not limited to, methylthio, ethylthio, propylthio, etc.

[0026] As used herein, the term "alkenyl," whether used as part of another term or independently, refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon double bond, which may optionally be independently substituted by one or more substituents described herein. Alkenyl groups include those having "cis" and "trans" orientations, or "E" and "Z" orientations. In some embodiments, the alkenyl group contains 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms. In some embodiments, the alkenyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms. In some embodiments, the alkenyl group contains 9 to 30 carbon atoms. In some embodiments, the alkenyl group contains 9 to 28 carbon atoms, 9 to 26 carbon atoms, 9 to 24 carbon atoms, 10 to 28 carbon atoms, 10 to 26 carbon atoms, 10 to 24 carbon atoms, 12 to 28 carbon atoms, 12 to 26 carbon atoms, 12 to 24 carbon atoms, 14 to 28 carbon atoms, 14 to 26 carbon atoms, 14 to 24 carbon atoms, 14 to 22 carbon atoms, 14 to 20 carbon atoms, 14 to 18 carbon atoms, 14 to 16 carbon atoms, 16 to 22 carbon atoms, 16 to 20 carbon atoms, 16 to 18 carbon atoms, 18 to 22 carbon atoms, 18 to 20 carbon atoms, or 20 to 22 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (ethylenyl / vinyl), propenyl (allyl), butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, etc.

[0027] As used herein, the term "alkoxy" whether used as part of another term or independently refers to an alkyl (-O-alkyl) molecule partially linked to a parent molecule via an oxygen atom. In some embodiments, the alkoxy group contains 1 to 10 carbon atoms. In some embodiments, the alkoxy group contains 1 to 9 carbon atoms. In some embodiments, the alkoxy group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, etc.

[0028] As used herein, the term "alkynyl" (whether used as part of another term or independently) refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon triple bond, which may optionally be independently substituted by one or more substituents as described herein. In some embodiments, the alkynyl group contains 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms. In some embodiments, the alkynyl group contains 9 to 30 carbon atoms. In some embodiments, the alkynyl group contains 9 to 28 carbon atoms, 9 to 26 carbon atoms, 9 to 24 carbon atoms, 10 to 28 carbon atoms, 10 to 26 carbon atoms, 10 to 24 carbon atoms, 12 to 28 carbon atoms, 12 to 26 carbon atoms, 12 to 24 carbon atoms, 14 to 28 carbon atoms, 14 to 26 carbon atoms, 14 to 24 carbon atoms, 14 to 22 carbon atoms, 14 to 20 carbon atoms, 14 to 18 carbon atoms, 14 to 16 carbon atoms, 16 to 22 carbon atoms, 16 to 20 carbon atoms, 16 to 18 carbon atoms, 18 to 22 carbon atoms, 18 to 20 carbon atoms, or 20 to 22 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, etc.

[0029] As used herein, the term "amino" refers to the -NH2 group. Amino groups can also be substituted by one or more groups, such as alkyl, aryl, carbonyl, or other amino groups.

[0030] As used herein, the term "aryl," whether used as part of another term or independently, refers to a group derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. Aryl groups can be monocyclic or polycyclic (including, but not limited to, bicyclic, tricyclic, or tetracyclic) ring systems. In the case of polycyclic systems, they can include fused-ring or spirocyclic systems. For example, a polycyclic aryl group may comprise an aromatic ring fused with one or more additional rings, such as cycloalkyl (which may be spirocycloalkyl) or aryl rings. In some embodiments, the aryl group is C6-C. 12 Aryl group. In some embodiments, the aryl group is C6-C. 11 Aryl group. In some embodiments, the aryl group is C6-C. 10Aryl group. In some embodiments, the aryl group is a C6-C9 aryl group. In some embodiments, the aryl group is a C6-C8 aryl group. Aryl groups include, but are not limited to, aryl groups derived from hydrocarbon ring systems of anthracene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise expressly stated in this specification, the aryl group may optionally be substituted at one or more ring positions with the substituents described herein.

[0031] As used herein, the term "cycloalkyl," whether used as part of another term or independently, refers to a partially or fully saturated, monocyclic or polycyclic carbocyclic ring. In the case of a polycyclic carbocyclic system, it may include a fused ring (e.g., fused with another cycloalkyl ring), a spirocyclic, or a bridged ring system. In some embodiments, the cycloalkyl group is fully saturated. In some embodiments, the cycloalkyl group is partially saturated. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having 3 to 15 carbon atoms (C3-C4). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), cycloalkyl groups with 3 to 10 carbon atoms (C3-C4) 10 Fully saturated cycloalkyl or C3-C 10Cycloalkyl groups are 3 to 8 carbon atoms (C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkyl), 3 to 6 carbon atoms (C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkyl), 3 to 5 carbon atoms (C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkyl), or 3 to 4 carbon atoms (C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkyl). In some embodiments, the cycloalkyl group is a 3 to 12-membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 3 to 10-membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 3 to 6-membered cycloalkyl group. In some embodiments, the cycloalkyl group is a 5 to 6-membered cycloalkyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise expressly stated in this specification, cycloalkyl groups may optionally be substituted at one or more ring positions with the substituents described herein.

[0032] As used in this article, the term "cyano" refers to -CN.

[0033] As used herein, the term "halogen" refers to an atom selected from fluorine, chlorine, bromine, and iodine.

[0034] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogens. In some embodiments, the haloalkyl group may contain 1 to 6 carbon atoms. In some embodiments, the haloalkyl group may contain 1 to 4 carbon atoms. In some embodiments, the haloalkyl group may contain 1 to 3 carbon atoms. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromomethyl, tribromomethyl, and tetrafluoroethyl.

[0035] As used herein, the term “heteroatom” refers to nitrogen, oxygen, sulfur, phosphorus, or silicon, including any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen (including N-oxides).

[0036] As used herein, the term "heteroalkyl" refers to an alkyl group in which at least one carbon atom is substituted with a heteroatom selected from N, O, or S. Heteroalkyl groups can be carbonyl or heteroatomyl (i.e., heteroatoms can appear in the middle or at the end of the group) and can optionally be substituted independently by one or more substituents described herein. The term "heteroalkyl" includes alkoxy and heteroalkoxy groups.

[0037] As used herein, the term "heteroalkenyl" refers to an alkenyl group in which at least one carbon atom is replaced by a heteroatom selected from N, O, or S. Heteroalkenyl groups can be carbonyl or heteroatomyl (i.e., heteroatoms can appear in the middle or at the end of the group) and can optionally be independently substituted by one or more substituents described herein.

[0038] As used herein, the term "heterynyl" refers to an ynyl group in which at least one carbon atom is replaced by a heteroatom selected from N, O, or S. The heterynyl group may be a carbonyl group or a heteroatom group (i.e., the heteroatom may appear in the middle or at the end of the group) and may optionally be independently substituted by one or more substituents described herein.

[0039] As used herein, the term "heteroaryl," whether used as part of another term or independently, refers to an aromatic ring having one or more heteroatoms in addition to a carbon atom, which may optionally be oxidized or quaternized. Heteroaryl groups can be monocyclic or polycyclic (including, but not limited to, bicyclic, tricyclic, or tetracyclic) ring systems. In the case of polycyclic ring systems, they may include fused-ring or spirocyclic systems. For example, a polycyclic heteroaryl group may include a heteroaryl ring fused with one or more additional rings (e.g., cycloalkyl, heterocyclic, aryl, or heteroaryl rings), or an aryl ring fused with one or more additional rings (e.g., heterocyclic or heteroaryl rings). In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, and 1,4-benzodioxolyl. anyl), benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl / benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl (benzo[4,6]imidazo[1,2-a]pyridyl)2-a]pyridinyl), carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, furyl, isothiazolyl, imidazolyl, indazole, indole, isoindole, indolinyl, isoindolinyl, isoquinolinyl, indoleazinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, ethylene oxide, 1-oxopyridyl, 1-oxopyrimidinyl, 1-oxopyrazinyl 1-O-pyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridyl 1-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and phenylthioyl (i.e., thiophene). Unless otherwise expressly stated in this specification, heteroaryl groups may optionally be substituted at one or more ring positions with the substituents described herein.

[0040] As used herein, the term "heterocyclic group," whether used as part of another term or independently, refers to a 3- to 24-membered partially or fully saturated cyclic group comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur, which may optionally be oxidized or quaternized. In some embodiments, the heterocyclic group is fully saturated. In some embodiments, the heterocyclic group is partially unsaturated. The heterocyclic group may be a monocyclic or polycyclic (including, but not limited to, bicyclic, tricyclic, or tetracyclic) ring system. In the case of a polycyclic ring system, it may include a fused ring, a spirocyclic, or a bridged ring system. For example, a polycyclic heterocyclic group may include a heterocyclic ring fused with one or more additional rings (e.g., a cycloalkyl or heterocyclic ring), or a cycloalkyl ring fused with one or more heterocyclic rings. Examples of heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, dihydrofuryl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopipirylalkyl, oxazolidinyl, piperidinyl, and piperazine. 4-piperidinone, pyrrolyl, pyrazolyl, quininecycloyl, thiazolyl, tetrahydrofuryl, trithiayl, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl The heterocyclic groups include sobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. Unless otherwise expressly stated in this specification, the heterocyclic group may optionally be substituted at one or more ring positions with the substituents described herein.

[0041] As used in this article, the term "hydroxyl group" refers to -OH.

[0042] As used herein, the term "hydroxyalkyl" refers to -alkyl-OH.

[0043] As used herein, the terms “partially saturated” or “partially unsaturated” refer to a group containing at least one double or triple bond. The terms “partially saturated” or “partially unsaturated” are intended to cover rings having multiple unsaturated sites, but are not intended to include aromatic (i.e., completely unsaturated) moieties.

[0044] As used herein, the term “substitution,” whether or not it begins with the term “optionally,” indicates that one or more hydrogen atoms of a specified moiety are substituted with suitable substituents. Typical substituents include, but are not limited to, the functional groups described herein, such as halogens, hydroxyl groups, amino groups, cyano groups, alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, etc., and each substituent may be similarly substituted. It should be understood that “substitution” or “substituted as” includes the implicit condition that the substitution conforms to the permissible valence of the substituted atom and that the substitution produces a stable or chemically viable compound, for example, one that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. Unless otherwise stated, when the term “substitution” is used with groups such as alkylaryl groups having two or more substituted moiety, the substituent may be attached to the aryl moiety, the alkyl moiety, or both. Unless otherwise stated, a “optionally substituted” group may have suitable substituents at each substituted position of the group, and when multiple positions in any given structure are substituted by multiple substituents selected from the specified group, the substituents may be the same or different at each position. Those skilled in the art will understand that the substituted element itself can be substituted if appropriate. Unless specifically stated as “unsubstituted,” references to the chemical part herein should be understood to include substituted variants. For example, references to the “aryl” group or part implicitly include both substituted and unsubstituted variants.

[0045] compound This disclosure provides novel compounds of formula (I) and their pharmaceutically acceptable salts, synthetic methods for preparing said compounds, pharmaceutical compositions containing said compounds, and various uses of the disclosed compounds.

[0046] In one aspect, this disclosure provides compounds having formula (I): (I) Or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently selected from deuterium, halogen, cyano, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, -N(R) a (R)b ), -N(R a )C(=O)(R a -C(=O)N(R) a (R) b -OC(=O)-N(R) a (R) b -C(=O)R a and -C(=O)OR a The group consisting of wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, alkathioyl, haloalkyl, hydroxyalkyl, and cycloalkyl groups are independently and optionally influenced by one or more R groups. c replace; n1 is 0, 1, 2 or 3; Each R 2 Independently selected from deuterium, cyano, or optionally by one or more R c Substituted alkyl groups; n2 is 0, 1, 2, 3 or 4; Ring A is selected from , or The end of ring A is connected to Y; X is selected from CH or N; m is 0, 1, or 2; q can be 0, 1, 2, 3, or 4; Each R 5 Independently selected from deuterium, halogens, and optionally by one or more R c Substituted alkyl or alkoxy; or R 5 One of them and R 3 Together with intermediate atoms therein, they form cycloalkyl or heterocyclic groups, which are optionally surrounded by one or more R groups. c replace; Each time it appears independently ; Each time it appears, it is selected independently. or ; Each R 3 Independently selected from hydrogen or alkyl; n3 can be 0, 1, or 2; n4 is either 0 or 1; L is selected from the following: -O-, -S-, -N(R) a )-、 , or ; i is 0, 1, or 2; j is 1, 2, or 3; k is 0, 1, or 2; Ring B is selected from the group consisting of cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Each R 4 Independently selected from deuterium, halogen, amino, cyano, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic, -N(R) a (R) b ), -N(R a )C(=O)(R a -C(=O)N(R) a (R) b -OC(=O)-N(R) a (R) b -C(=O)R a -OR a and -C(=O)OR a The group consisting of wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, and heterocyclic groups are independently and optionally constituted by one or more R groups. c replace; n5 can be 0, 1, 2, 3, 4 or 5; R a and R b Each of the following groups is independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, or cycloalkyl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, and cycloalkyl groups are independently and optionally influenced by one or more R groups. c Replace; or R a and R b Together with the nitrogen atoms to which they are attached, they form cycloalkyl or heterocyclic groups, which are optionally substituted by one or more groups independently selected from deuterium, halogen, amino, cyano, hydroxyl, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, alkoxy, alkylthio, haloalkyl, and hydroxyalkyl; and Each R c It is independently selected from the group consisting of deuterium, halogen, amino, cyano, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, aryl, heteroaryl, -NH (alkyl) and -N (alkyl)2.

[0047] In some implementations, each R 1 Independently selected from deuterium, halogen, cyano, and alkyl (e.g., C10) 1-6 Alkyl, C 1-5 Alkyl, C1-4 Alkyl, C 1-3 Alkyl or C 1-2 The group consisting of alkyl groups, wherein the alkyl group is optionally composed of one or more R groups. c replace.

[0048] In some implementations, each R 1 The group consisting of halogen, cyano, -CH3 and -CD3 is selected independently.

[0049] In some implementations, n1 is 1, 2, or 3.

[0050] In some implementations, n1 is 1. In some implementations, n1 is 1 and R 1 Alkyl (e.g., C10) 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group). In some embodiments, n1 is 1 and R 1 It is -CH3.

[0051] In some implementations, n1 is 2. In some implementations, n1 is 2, and each R 1 It is independently a halogen, cyano or alkyl (e.g., C10) 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group). In some embodiments, n1 is 2, and one R 1 One is a halogen or cyano group, and the other is an alkyl group (e.g., C10). 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group). In some embodiments, n1 is 2, and one R 1 One is a halogen or cyano group, and the other is -CH3.

[0052] In some implementations, n1 is 3. In some implementations, n1 is 3, and each R 1 It is independently a halogen, cyano or alkyl (e.g., C10) 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group). In some embodiments, n1 is 3, and one R 1 One is a halogen or cyano group, and the other two are alkyl groups (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-6 Alkyl, C1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group). In some embodiments, n1 is 3, and one R 1 One is a halogen or cyano group, and the other two are -CH3.

[0053] In some implementations, n2 is 0.

[0054] In some implementations, n2 is 1. In some implementations, n2 is 1 and R 2 Alkyl (e.g., C10) 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl group). In some embodiments, n2 is 1 and R 2 It is -CH3.

[0055] In some implementations, ring A is .

[0056] In some implementations, ring A is And X is N. In some implementations, X is N and m is 1. In some implementations, q is 0.

[0057] In some implementations, ring A is And X is CH. In some embodiments, X is CH and m is 0. In some embodiments, q is 0. In some embodiments, n3 and n4 are 0.

[0058] In some implementations, ring A is X is CH, and m is 2. In some implementations, q is 0. In some implementations, n3 and n4 are 0.

[0059] In some implementations, ring A is X is CH, and m is 1.

[0060] In some implementations, ring A is X is CH, m is 1, and each R5 is independently selected from deuterium, halogen, alkyl (e.g., C) 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl) and alkoxy (e.g., C) 1-6 Alkoxy, C 1-5 Alkoxy, C 1-4 Alkoxy, C 1-3Alkoxy or C 1-2 The group consisting of alkoxy groups.

[0061] In some implementations, ring A is selected from the group consisting of: , , and .

[0062] In some implementations, n3 and n4 are 0.

[0063] In some implementations, n3 is 1 or 2, n4 is 0 or 1, and R 5 One of them with R 3 Together with the intermediate atoms therein, they form an optional structure consisting of one or more R atoms. c Substituted cycloalkyl or heterocyclic groups.

[0064] In some implementations, ring A is X is N or CH, n3 is 1 or 2, n4 is 0 or 1, and R 5 One of them and R 3 Together with the intermediate atoms therein, they form an optional structure consisting of one or more R atoms. c Substituted cycloalkyl or heterocyclic groups.

[0065] In some implementations... -CH2CH(R) 3 )-、-CH2N(R 3 )-、-CH2CH2CH(R 3 - or -CH2CH2N(R) 3 )-.

[0066] In some implementation methods Selected from , , , , , or , where the ** end is connected to L.

[0067] In some implementations, ring A is .

[0068] In some implementations, ring A is .

[0069] In some implementations, ring A is n3 is 0, and n4 is 0.

[0070] In some implementations, ring A is n3 is 0, and n4 is 0.

[0071] In some implementations, ring A is .

[0072] In some implementations, ring A is In some implementations, n3 is 0, and n4 is 0.

[0073] In some implementations, L is -O-.

[0074] In some implementations, L stands for key.

[0075] In some implementations, L is In some implementations, L is -CH2-, -CH2CH2-, or -CH2CH2CH2-.

[0076] In some implementations, L is In some implementations, L is -OCH2-, -CH2O-, -OCH2CH2-, -CH2OCH2-, or -CH2CH2O-.

[0077] In some implementations, L is -N(R) a )-or In some embodiments, L is -NH-, -N(CH3)-, -NHCH2-, -CH2NH-, -NHCH2CH2-, -CH2NHCH2-, or -CH2CH2NH-.

[0078] In some embodiments, ring B is a heteroaryl group, such as 5 to 12-membered heteroaryl, 5 to 11-membered heteroaryl, 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, 5 to 8-membered heteroaryl, 5 to 7-membered heteroaryl, or 5 to 6-membered heteroaryl.

[0079] In some embodiments, ring B is selected from pyrazolyl, isothiazolyl, thiazolyl, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, triazolyl, oxazolyl, isoxazolyl, dihydropyrrolopyrazolyl, pyrazinyl, indazoleyl, pyrazolo[3,4-] b ]Pyridyl, 2,3-dihydro-1 H -pyrrolo[2,3- b ]pyridyl, 2,3-dihydro-1 H -pyrrolo[2,3- c ]pyridyl, 2,3-dihydro-1 H -pyrrolo[3,2- c ]Pyridyl, 2,3-dihydro-1 H -pyrrolo[3,2- b ]pyridyl, 1 H -benzo[d Imidazolyl or imidazo[1,2-] a ]Pyridyl.

[0080] In some implementations, each R 4 Independently selected from the group consisting of: cyano, halogen, alkyl (e.g., C10, C20, C30, C40, C50, C60, C7 ... 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 Alkyl), haloalkyl (e.g., C10) 1-6 Haloalkyl, C 1-5 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Halogenated alkyl or C 1-2 Halogenated alkyl groups), alkoxy groups (e.g., C464), and alkyl groups (e.g., C464) 1-6 Alkoxy, C 1-5 Alkoxy, C 1-4 Alkoxy, C 1-3 Alkoxy or C 1-2 alkoxy), cycloalkyl (e.g., C10), 3-12 cycloalkyl, C 3-11 cycloalkyl, C 3-10 cycloalkyl, C 3-9 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl or C 3-4 cycloalkyl groups), heterocyclic groups (e.g., 5- to 12-membered heterocyclic groups, 5- to 11-membered heterocyclic groups, 5- to 10-membered heterocyclic groups, 5- to 9-membered heterocyclic groups, 5- to 8-membered heterocyclic groups, 5- to 7-membered heterocyclic groups, or 5- to 6-membered heterocyclic groups), and -OR a The alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclic groups are independently and optionally influenced by one or more R groups. c replace.

[0081] In some implementations, R a Selected from hydrogen, alkyl, or cycloalkyl, wherein the alkyl and cycloalkyl groups are optionally independently derived from one or more R groups. c replace.

[0082] In some implementations, each R c It is independently selected from deuterium, halogen, alkoxy, cycloalkyl, aryl, heteroaryl, -NH (alkyl) or -N (alkyl)2.

[0083] In some implementations, each R 4It is independently selected from -CN, -F, -Cl, -CH3, -CD3, -CF3, -CF2H, -CH2CH3, -CD2CD3, -OCH3, -OCF2H, -CH2OCH3, -CH2-cyclopropyl, -O-cyclopropyl, -CH2-phenyl, -CH2CH2N(CH3)2, cyclopropyl, oxetane, tetrahydropyranyl, azirane, pyrrolidinyl or piperidinyl.

[0084] In some implementations, n4 is 0, 1, or 2.

[0085] In some implementations... Choose from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0086] In another aspect, compounds selected from the following formulas are provided: (Ia) (Ib) (Ic) (Id) (Ie) Or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

[0087] In some embodiments, the compound has a formula selected from the following: (Ia-1) (Ia-2) (Ia-3) (Ia-4) (Id-1) (Ie-1) Or its pharmaceutically acceptable salt.

[0088] In some embodiments, the compound has a formula selected from the following: (Ib-1) (Ib-2) (Ic-1) (Ic-2) Or its pharmaceutically acceptable salt.

[0089] In some implementations, each R 1 Independently selectable from halogen, cyano, alkyl (e.g., C) 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl or C 1-2 The group consisting of alkyl groups and deuterated alkyl groups.

[0090] In some implementations, L is a bond, O, or -CH2-.

[0091] In some embodiments, ring B is a heteroaryl group, such as 5 to 12-membered heteroaryl, 5 to 11-membered heteroaryl, 5 to 10-membered heteroaryl, 5 to 9-membered heteroaryl, 5 to 8-membered heteroaryl, 5 to 7-membered heteroaryl, or 5 to 6-membered heteroaryl.

[0092] In some implementations, each R 4 Independently selected from the group consisting of: halogens, alkyl groups (e.g., C14, C24, C34, C4 ... 1-6 Alkyl, C 1-5 Alkyl, C1-4 alkyl, C 1-3 Alkyl or C 1-2 Alkyl), haloalkyl (e.g., C10) 1-6 Haloalkyl, C 1-5 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Halogenated alkyl or C 1-2 Halogenated alkyl groups), alkoxy groups (e.g., C464), and alkyl groups (e.g., C464) 1-6 Alkoxy, C 1-5 Alkoxy, C 1-4 Alkoxy, C 1-3 Alkoxy or C 1-2 alkoxy), cycloalkyl (e.g., C10), 3-12 cycloalkyl, C 3-11 cycloalkyl, C 3-10 cycloalkyl, C 3-9 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl or C 3-4 Cycloalkyl groups and heterocyclic groups (e.g., 5- to 12-membered heterocyclic groups, 5- to 11-membered heterocyclic groups, 5- to 10-membered heterocyclic groups, 5- to 9-membered heterocyclic groups, 5- to 8-membered heterocyclic groups, 5- to 7-membered heterocyclic groups, or 5- to 6-membered heterocyclic groups), wherein the alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclic groups are independently and optionally influenced by one or more R groups. c Replace, and each R c It is independently selected from deuterium, halogen, alkoxy, cycloalkyl, aryl, heteroaryl, -NH (alkyl) or -N (alkyl)2.

[0093] In some embodiments, the compound has the formula (Id-1): (Id-1) Or its pharmaceutically acceptable salt, wherein L represents the bond; Each R 1 Independently selected from the group consisting of: halogen, cyano, and optionally deuterated C.1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 hydroxyalkyl or -(C 1-4 Alkyl)(C 1-4 Alkyl group substitution; Each R 4 Choose independently from the following groups: halogens, C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkoxy groups, each optionally substituted with deuterium; Cycle B is a 5- to 10-membered heteroaryl group; n1 is 0, 1, 2, or 3; and n5 can be 0, 1, 2, or 3.

[0094] In another aspect, this disclosure provides compounds selected from Table 1 or Table 2.

[0095] Table 1 Exemplary Compounds Table 2 Exemplary Compounds The compounds provided in this disclosure are described with reference to general formulas and specific compounds. Furthermore, the compounds of this disclosure may exist in a variety of different forms or derivatives, all within the scope of this disclosure. These forms or derivatives include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, solvated forms, amorphous forms, different crystalline forms, or polymorphs.

[0096] The compounds disclosed herein may contain one or more asymmetric centers, which, depending on the choice of substituents, can therefore exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. As used herein, the term "enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other. The term "diastereomer" refers to a pair of optical isomers that are not mirror images of each other. Carbon-carbon bonds in the compounds provided herein can be represented by solid lines (…). wedge bond ), dashed wedge key ( ), bold key ( ) or dashed key ( The solid lines used to represent bonds with asymmetric carbon atoms are intended to indicate all possible stereoisomers of said carbon atom (e.g., specific enantiomers, racemic mixtures, etc.). Wedge-shaped bonds have the same meaning as bold bonds, and dashed wedge-shaped bonds have the same meaning as dashed bonds. The compounds disclosed herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers.

[0097] The compounds disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via a low-energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol, amide-imine, lactam-lactamimide, imine-enamine isomerization, and cyclic forms where a proton can occupy two or more positions in a heterocyclic system (e.g., 1H- and 3H-imidazolium, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole). Valence tautomers include interconversions that occur through the recombination of some bonding electrons. Tautomers may be in equilibrium or spatially locked into one form by appropriate substitution. Unless otherwise stated, the compounds of this disclosure identified as a particular tautomer form by name or structure are intended to include other tautomer forms.

[0098] This disclosure is also intended to include all isotopic notations of the compounds. Isotopes of atoms include atoms having the same atomic number but different mass numbers. For example, unless otherwise stated, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of this disclosure are also intended to include their isotopes, such as, but not limited to, those of other atoms. 1 H, 2 H, 3 H, 11 C 12 C 13 C 14 C 14 N、 15 N、 16 O、 17 O、 18 O、 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl、 37 Cl、 79 Br、 81 Br、 124 I, 127 I and 131 I. Isotope-enriched compounds of formula (I) or (II) can be prepared using appropriate isotope enrichment reagents and / or intermediates by conventional techniques well known to those skilled in the art or by methods similar to those described in the schemes and examples herein, without requiring extensive experimentation.

[0099] In some embodiments, this disclosure includes compounds in which one or more hydrogen atoms linked to carbon atoms are replaced by deuterium. Such compounds exhibit resistance to increased metabolism and can therefore be used to increase the half-life of the compound when administered to a subject (e.g., a mammal, particularly a human). See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984). In view of this disclosure, such compounds are synthesized by methods known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0100] In vivo metabolites of the compounds described in this disclosure are also within the scope of this document, provided that such products are novel and non-obvious relative to the prior art. These products may be generated, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the applied compound, primarily due to enzymatic processes. Therefore, this includes novel and non-obvious compounds produced by methods comprising a period sufficient to expose the compound to a mammal to produce its metabolites.

[0101] The compounds disclosed herein can be formulated into pharmaceutically acceptable salts. Unless otherwise stated, the compounds provided herein include pharmaceutically acceptable salts of such compounds.

[0102] As used in this disclosure, the term "pharmaceutically acceptable" means that the substance or composition is chemically and / or toxicologically compatible with other components in the formulation and / or with the subject being treated therein.

[0103] As used herein, unless otherwise stated, the term "pharmaceutically acceptable salt" includes salts that retain the bioavailability of the free acid and base of a particular compound and are not biologically or otherwise undesirable. Intended pharmaceutically acceptable salt forms include, but are not limited to, single, double, triple, and tetrasalts. Pharmaceutically acceptable salts are non-toxic at the amount and concentration at which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical properties of the compound without preventing it from exerting its physiological effects. Useful alterations to physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher drug concentrations.

[0104] Pharmaceutically acceptable salts include acid addition salts, such as those containing sulfates, chlorides, hydrochlorides, fumarates, maleates, phosphates, aminosulfonates, acetates, citrates, lactates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylaminosulfonates, and quinates. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, aminosulfonic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminosulfonic acid, fumaric acid, and quinates.

[0105] Pharmaceutically acceptable salts also include base addition salts, such as those containing benzathine penicillin, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when an acidic functional group (e.g., carboxylic acid or phenol) is present. See, for example, Remington's Pharmaceutical Sciences, 19th edition, Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using appropriate corresponding bases.

[0106] Pharmaceutically acceptable salts can be prepared using standard techniques. For example, the free base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous alcoholic solution containing a suitable acid, and then separated by evaporation of the solution. Thus, if a particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, by treating the free base with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or with organic acids (e.g., acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranoside (e.g., glucuronic acid or galacturonic acid), α-hydroxy acids (e.g., citric acid or tartaric acid), amino acids (e.g., aspartic acid or glutamic acid), aromatic acids (e.g., benzoic acid or cinnamic acid), sulfonic acids (e.g., p-toluenesulfonic acid or ethanesulfonic acid), etc.

[0107] Similarly, if a particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, such as treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide. Exemplary examples of suitable salts include organic salts derived from amino acids (e.g., L-glycine, L-lysine, and L-arginine), ammonia, primary, secondary, and tertiary amines, and cyclic amines (e.g., hydroxyethylpyrrolidine, piperidine, morpholine, or piperazine), as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0108] It should also be understood that the compounds disclosed herein may exist in non-solventized, solvated (e.g., hydrated) and solid (e.g., crystalline or polymorphic) forms, and this disclosure is intended to cover all such forms.

[0109] As used herein, the terms "solvent" or "solventized form" refer to a solvation form containing a stoichiometric or non-stoichiometric solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in their crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcohol. A hydrate is formed by the combination of one or more water molecules with a molecule of a substance, wherein the water retains its molecular state as H₂O. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0110] The terms “crystal form,” “crystalline shape,” “polymorph,” and “polymorphic compound” used herein are used interchangeably to refer to the crystalline structures in which a compound (or its salts or solvates) can crystallize in different crystalline arrangements, all of which have the same elemental composition. Different crystal forms typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can cause one crystal form to dominate. Crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

[0111] Compound Synthesis Methods for preparing the compounds described herein or their pharmaceutically acceptable salts are also an object of this disclosure.

[0112] The synthesis of the compounds described herein and their pharmaceutically acceptable salts is illustrated in the synthetic protocols of the examples. The compounds provided herein can be prepared using any known organic synthetic technique and can be synthesized according to any of many possible synthetic routes; therefore, these protocols are illustrative only and do not imply limitation on other possible methods that can be used to prepare the compounds provided herein. Furthermore, the steps in the protocols are for better illustration and may be modified as needed. The compounds in the examples were synthesized for research purposes and possibly for submission to regulatory agencies.

[0113] The reactions to prepare the compounds disclosed herein can be carried out in suitable solvents, which can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are substantially unreactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction proceeds (e.g., a temperature range from the solvent's solidification temperature to its boiling temperature). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, those skilled in the art can select a suitable solvent for that particular reaction step.

[0114] The preparation of the compounds disclosed herein may involve the protection and deprotection of various chemical groups. Those skilled in the art can readily determine the need for protection and deprotection, as well as the selection of appropriate protecting groups. The chemical properties of protecting groups can be found, for example, in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd ed., Wiley & Sons, Inc., New York (1999); P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003; and Peter GM Wuts, Greene's Protective Groups in Organic Synthesis, 5th ed., Wiley, 2014, all of which are incorporated herein by reference in their entirety.

[0115] The reaction can be monitored using any suitable method known in the art. For example, product formation can be monitored by spectroscopic methods, such as nuclear magnetic resonance spectroscopy (e.g., nuclear magnetic resonance spectroscopy). 1 H or 13C) Infrared spectroscopy, spectrophotometry (e.g., UV-Vis), mass spectrometry, or chromatography, such as high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin-layer chromatography (TLC). Those skilled in the art can purify compounds using a variety of methods, including high-performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, which are incorporated herein by reference in their entirety) and normal-phase silica gel chromatography.

[0116] If the starting material or intermediate contains a stereoisomeric center, the compounds provided herein can be obtained as diastereomers or mixtures of enantiomers, which can be separated by methods well known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. For example, racemic compounds can be separated into their enantiomers by diastereomer salts, crystallization with optically pure acid, or by specific chromatographic methods using chiral adsorbents or chiral eluents.

[0117] The starting materials known in this disclosure can be used or synthesized according to methods known in the art, or can be purchased from commercial suppliers. Unless otherwise stated, analytical grade solvents and commercially available reagents are used, and no further purification is required.

[0118] For ease of illustration, the Examples section below illustrates synthetic routes for preparing the compounds of this disclosure and key intermediates. Those skilled in the art will understand that other synthetic routes can be used to synthesize the compounds of this invention. Although specific starting materials and reagents are described, they can be readily substituted with other starting materials and reagents to provide various derivatives and / or reaction conditions. Furthermore, many compounds prepared by the methods described below can be further modified according to this disclosure using conventional chemical methods well known to those skilled in the art.

[0119] Use of compounds In one aspect, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is capable of modulating (e.g., activating) the M4 receptor. Therefore, the compounds of this disclosure or pharmaceutically acceptable salts thereof can be used as medicines, and particularly as therapeutic or preventative agents, effective against diseases or medical conditions treated by modulating M4 and / or M4-related cellular processes.

[0120] As used herein, the term “treatment” is intended to have its normal meaning, namely, addressing a disease to completely or partially alleviate one, some, or all of its symptoms, or to correct or compensate for the underlying pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of this disclosure, beneficial or desired clinical outcomes include, but are not limited to, symptom relief, reduction in disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or mitigation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. “Treatment” may also mean extended survival compared to expected survival without treatment. People requiring treatment include those who already have the condition or disease, those who are susceptible to the condition or disease, or those who need prevention of the condition or disease. Unless there is a specific indication to the contrary, the term “treatment” also includes prevention. The terms “therapeutic” and “therapeutic” should be interpreted accordingly.

[0121] The term “treatment” is used synonymously with “therapeutic therapy.” Similarly, the term “treatment” can be considered as “the application of a therapeutic therapy,” where “therapeutic therapy” is as defined herein.

[0122] As used in this article, the term “prevention” is intended to have its normal meaning and includes primary prevention against the development of disease and secondary prevention after the disease has developed, in which patients are temporarily or permanently protected from disease progression or the appearance of new disease-related symptoms.

[0123] In another aspect, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof in the treatment of diseases or medical conditions treated by modulating M4 and / or M4-related cellular processes.

[0124] In another aspect, this disclosure provides the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in the manufacture of a medicament for treating a disease or medical condition by modulating M4 and / or M4-related cellular processes.

[0125] Pharmaceutical Composition For drug administration purposes, in some embodiments, the compounds provided herein are administered as raw material chemicals or formulated into pharmaceutical compositions.

[0126] Therefore, in another aspect, a pharmaceutical composition comprising one or more of the compounds disclosed herein or pharmaceutically acceptable salts thereof is provided.

[0127] In some embodiments, the pharmaceutical compositions of this disclosure comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of this disclosure comprise a first compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more additional compounds of the same formula, but the first compound and the additional compounds are not the same molecule.

[0128] As used herein, the term "pharmaceutical composition" refers to a formulation containing molecules or compounds of the present disclosure in a form suitable for administration to a subject.

[0129] In some embodiments, the pharmaceutical compositions of this disclosure comprise a therapeutically effective amount of one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof.

[0130] As used herein, the term "therapeutic effective amount" refers to the amount of a molecule, compound, or composition comprising said molecule or compound for the treatment, improvement, or prevention of an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. This effect can be detected by any assay known in the art. The precise effective amount for a subject will depend on the subject's weight, body type, and health status; the nature and severity of the condition; the rate of administration; the choice of treatment or combination of treatments for administration; and the prescribing physician's judgment. The therapeutic effective amount for a given situation can be determined through routine laboratory testing within the skill and judgment of a clinician.

[0131] In another aspect, a pharmaceutical composition comprising one or more compounds disclosed herein or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient is provided.

[0132] As used herein, the term "pharmaceuticalally acceptable excipient" refers to an excipient that can be used to prepare a pharmaceutical composition, said excipient being generally safe, non-toxic, and free from biological and other adverse effects, and includes excipients suitable for both veterinary and human pharmaceutical use. As used herein, "pharmaceuticalally acceptable excipient" includes one or more such excipients. The term "pharmaceuticalally acceptable excipient" also includes "pharmaceuticalally acceptable carriers" and "pharmaceuticalally acceptable diluents."

[0133] In some embodiments, the compounds of this disclosure may be administered orally, such as orally (e.g., in the form of tablets, coated tablets, sugar-coated pills, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions); nasally (e.g., in the form of nasal sprays); rectically (e.g., in the form of suppositories); parenterally, such as intramuscularly or intravenously (e.g., in the form of injectable solutions); or topically (e.g., transdermal, or in the form of eye drops or ear drops).

[0134] The specific excipients used will depend on the manner of administration and purpose of the compounds disclosed herein. Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols. Suitable excipients for preparing solutions and syrups include, for example, water, alcohols, polyols, sucrose, glucose, invert sugar, and vegetable oils. Suitable excipients for topical ophthalmic preparations include, for example, cyclodextrin, mannitol, or many other carriers and excipients known in the art.

[0135] In some embodiments, the pharmaceutical compositions of this disclosure may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, flavorings, and other known additives to provide an appealing presentation of the pharmaceutical (i.e., the compounds of this disclosure or pharmaceutical compositions thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a drug).

[0136] In some embodiments, the pharmaceutical compositions of this disclosure may be formulated into unit dosage forms. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of an active substance calculated to produce the desired therapeutic effect and combined with a suitable pharmaceutical excipient. The amount of the compound provided herein in a unit dosage form will vary depending on the condition to be treated, the subject to be treated (e.g., the age, weight, and response of an individual subject), the specific route of administration, the compound actually administered and its relative activity, and the severity of the subject's symptoms.

[0137] In some embodiments, the dosage level of the pharmaceutical composition of this disclosure can be between 0.001 and 1000 mg / kg body weight / day, for example, 0.001-1000 mg / kg body weight / day, 0.001-900 mg / kg body weight / day, 0.001-800 mg / kg body weight / day, 0.001-700 mg / kg body weight / day, 0.001-600 mg / kg body weight / day, 0.001-500 mg / kg body weight / day, 0.001-400 mg / kg body weight / day, 0.001-300 mg / kg body weight / day, 0.001-200 mg / kg body weight / day, 0.001-100 mg / kg body weight / day, 0.001-50 mg / kg body weight / day, 0.001-40 mg / kg body weight / day, 0.001-300 mg / kg body weight / day. mg / kg body weight / day, 0.001-20 mg / kg body weight / day, 0.001-10 mg / kg body weight / day, 0.001-5 mg / kg body weight / day, 0.001-1 mg / kg body weight / day, 0.001-0.5 mg / kg body weight / day, 0.001-0.4 mg / kg body weight / day, 0.001-0.3 mg / kg body weight / day, 0.001-0.2 mg / kg body weight / day, 0.001-0.1 mg / kg body weight / day, 0.005-0.1 mg / kg body weight / day, 0.01-0.1 mg / kg body weight / day, 0.02-0.1 mg / kg body weight / day, 0.03-0.1 mg / kg body weight / day, 0.04-0.1 mg / kg body weight / day, 0.05-0.1 mg / kg body weight / day, 0.06-0.1 mg / kg body weight / day. mg / kg body weight / day, 0.07-0.1 mg / kg body weight / day, 0.08-0.1 mg / kg body weight / day, or 0.09-0.1 mg / kg body weight / day.

[0138] The compounds or pharmaceutical compositions disclosed herein may be administered to subjects, including mammals. Mammals may include, but are not limited to, canines, felines, bovines, caprines, equines, sheep, suidae, rodents, rabbits, primates, and other mammals, including those in the womb. In some embodiments, humans are suitable subjects. Human subjects may be of any sex and at any developmental stage.

[0139] Treatment In another aspect, this disclosure provides for treating diseases or medical conditions by modulating M4 and / or M4-related cellular processes, which includes administering a therapeutically effective amount of any of the compounds described herein to a subject.

[0140] In some implementations, the diseases or medical conditions treated by modulating M4 and / or M4-related cellular processes are selected from the group consisting of: schizophrenia, bipolar disorder, post-traumatic stress disorder (PTSD), autism, chronic or acute pain, addiction, sleep disorders, Alzheimer's disease, Lewy body dementia, Parkinson's dementia, frontotemporal dementia, age-related TDP-43 encephalopathy with limbic system predominance, mild cognitive impairment, drug-induced motor difficulties, drug-induced psychotic symptoms, progressive supranuclear palsy, Huntington's disease, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, intestinal obstruction, inflammatory bowel disease, urinary incontinence, urinary retention, glaucoma, ocular hypertension, skin lesions, Down syndrome, cerebral amyloid angiopathy, Dutch hereditary cerebral hemorrhage with amyloidosis (HCHWA-D), Creutzfeld-Jakob disease, and prion disease. Disorders), amyotrophic lateral sclerosis, inclusion body myositis, other peripheral amyloidosis, diabetes, atherosclerosis, head trauma, stroke, alcoholic liver disease, pancreatitis.

[0141] In some implementations, the diseases or medical conditions treated by modulating M4 and / or M4-related cellular processes are selected from the group consisting of: schizophrenia, bipolar disorder, chronic or acute pain, addiction, Alzheimer's disease, Huntington's disease, drug-induced motor difficulties, drug-induced psychotic symptoms, inflammatory bowel disease, and skin lesions.

[0142] In another aspect, this disclosure provides a method for activating the M4 receptor in a subject in need, comprising administering to the subject an effective amount of the compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition provided herein.

[0143] Example For illustrative purposes, the following examples are included. However, it should be understood that these examples are not intended to limit the present disclosure, but are merely intended to provide methods for practicing the present disclosure. Those skilled in the art will recognize that the described chemical reactions are readily adaptable to the preparation of many other compounds of the present disclosure, and alternative methods for preparing the compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of non-exemplary compounds according to the present disclosure can be successfully carried out with modifications readily apparent to those skilled in the art, such as by appropriately protecting interfering groups, by using other suitable reagents and structural units known in the art besides the stated reagents and structural units, and / or by conventional modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for the preparation of other compounds of the present disclosure.

[0144] The abbreviations used in the synthesis of the compounds presented in this article are listed below: Preparation 1 3-Chloro-2,4-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridine hydrochloride (P4) Step 1. Synthesis of methyl 5-chloro-3-cyano-4,6-dimethylpyridinecarboxylate (P1).

[0145] TEA (20.4 mL, 146 mmol), palladium(II) acetate (837 mg, 3.73 mmol), and 1,1-bis(diphenylphosphine)ferrocene (4.14 g, 7.47 mmol) were added to a solution of 2,5-dichloro-4,6-dimethylpyridin-3-onitrile (15.0 g, 74.6 mmol) in MeOH (600 mL). Carbon monoxide was bubbled through the mixture, and the reaction mixture was heated at 70 °C for 24 hours at 2 MPa under carbon monoxide conditions. After the reaction was complete, the mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure. Silica gel chromatography (PE:EtOAc, 3:1) was performed to give the title compound (14.5 g, 88% yield). 1 H NMR (400 MHz, DMSO- d 6) δ 3.94 (s, 3H), 2.67 (d, J = 1.1 Hz, 3H), 2.61 (d, J = 1.1 Hz, 3H). LCMS ( m / z ): 224.9 [M+H] + Step 2. 3-Chloro-2,4-dimethyl-5,6-dihydro-7 H -pyrrolo[3,4- b Synthesis of pyridin-7-one (P2).

[0146] Raney nickel (30.0 g) was added to a solution of P1 (14.5 g, 64.73 mmol) in MeOH (250 mL), and the reaction mixture was stirred at room temperature under 4 MPa hydrogen atmosphere for 18 hours. The catalyst was removed by filtration, the filter cake was washed with DCM (5 × 200 mL), the filtrates were combined, concentrated under vacuum, and the residue was wet-milled with MTBE (600 mL) to give the title compound (12.5 g, 90% yield). 1 H NMR (400 MHz, DMSO- d6) δ 8.94 (s, 1H), 4.36 (s, 2H), 2.63 (s, 3H), 2.37 (s, 3H). LCMS ( m / z ): 197.0 [M+H] + Step 3. 3-Chloro-2,4-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (P3).

[0147] A borane-dimethyl sulfide complex (10M dimethyl sulfide solution; 50.9 mL, 509 mmol) was added dropwise to a solution of P2 (12.5 g, 63.6 mmol) in THF (500 mL) at 0 °C. The reaction mixture was heated under reflux for 16 h and then cooled to 0 °C. The reaction was quenched by the slow addition of MeOH (200 mL) and aqueous HCl solution (6 M; 400 mL), and the resulting mixture was then heated to 80 °C for 3 h. The mixture was cooled to room temperature and treated with 2N NaOH aqueous solution until the pH of the solution was approximately 9–10. Di-tert-butyl dicarbonate (20.8 g, 95.3 mmol) was added and the mixture was stirred again at room temperature for 16 h. After removing the organic solvent under vacuum, the residue was diluted with saturated NH4Cl aqueous solution (1 L) and extracted with EtOAc (3 × 1 L). The combined organic layers were washed with brine (2 × 1 L). The sample was dried over Na2SO4, filtered, and concentrated under vacuum. Silica gel chromatography (PE:EtOAc, 20:1) yielded the title compound (8.1 g, 47% yield). 1 H NMR (400MHz, DMSO- d 6) δ 4.58 (d, J = 9.8 Hz, 2H), 4.50 (d, J = 9.0 Hz, 2H), 2.53 (s,3H), 2.27 (d, J = 3.9 Hz, 3H), 1.46 (d, J = 3.0 Hz, 6H). LCMS ( m / z ): 282.9 [M+H] + Step 4. 3-Chloro-2,4-dimethyl-6,7-dihydro-5- H -pyrrolo[3,4- b Synthesis of pyridine hydrochloride (P4).

[0148] A solution of HCl in dioxane (4 M; 20 mL, 80 mmol) was added dropwise to a solution of P3 (4.0 g, 14.1 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under vacuum to give the crude title compound (2.8 g, 100%), which could be used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 2H), 4.57 (t, J = 5.6 Hz, 2H), 4.43 (t, J = 5.8 Hz, 2H), 2.56 (s, 3H), 2.32 (s, 3H). LCMS ( m / z ): 183.0 [M+H] + The following compounds were prepared basically according to the method described in Preparation 1. Preparation 2 2-Chloro-4-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridine hydrochloride (P10), 4-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridine trifluoroacetate (P12), and 4-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridine hydrochloride (P13) Step 1. 2-Chloro-4-methyl-6,7-dihydro-5- H -pyrrolo[3,4- b Synthesis of pyridin-5-one (P6) At room temperature, ethyl 6-chloro-2-(chloromethyl)-4-methylpyridine-3-carboxylate (20.0 g, 80.613 mmol) and ammonia (25%, 200 mL) were added to a 500 mL flask. The resulting mixture was stirred at 70 °C for 3 hours. The precipitate was collected by filtration and washed with MeOH (3 × 50 mL) to give the title compound (10.0 g, 54.762 mmol, 68%). LCMS ( m / z ): 183.0 [M+H] + Step 2. 2-Chloro-4-methyl-5-oxo-5,7-dihydro-6 H-pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (P7) Boc₂O (7.77 g, 35.595 mmol), DMAP (0.33 g, 2.738 mmol), and Et₃N (11.418 mL, 82.142 mmol) were added to a stirred solution of P₆ (5.0 g, 27.381 mmol) in DCM (50 mL) at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc:DCM, 1:10) to give the title compound (7.0 g, 24.759 mmol, 90%). 1 H NMR (400 MHz, DMSO- d 6) δ 7.55 (s, 1H), 5.76 (s, 1H), 4.73 (s, 2H), 2.60 (s, 3H), 1.52 (s, 9H). LCMS ( m / z ): 283.3 [M+H] + Step 3. 2-Chloro-4-methyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (P8) DIBAL-H (1M DCM solution, 569.67 mg, 2.122 mmol) was added to a THF (1 mL) solution of P7 (100 mg, 0.354 mmol), and the reaction was stirred at 0 °C for 1 hour. Na₂SO₄ was added at 0 °C. The reaction was quenched with 10H₂O. The resulting mixture was concentrated under reduced pressure. Then, NaBN₃CN (66.74 mg, 1.062 mmol) and AcOH (1 mL) were added, and the mixture was stirred at room temperature for 1 hour. After the imine intermediate was completely consumed, the reaction was quenched with ice / water. The residue was purified by silica gel column chromatography (PE:EtOAc, 1:10) to give the title compound (54 mg, 57%). LCMS ( m / z ):269.4 [M+H] + Step 4. 2-Cyano-4-methyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (P9) Zn(CN)₂ (90.88 mg, 0.774 mmol) and Pd(PPh₃)₄ (44.72 mg, 0.039 mmol) were added to a DMF (2 mL) solution of P₈ (103.9 mg, 0.387 mmol) at room temperature and under N₂. The resulting mixture was stirred at 120 °C for 1 hour. The mixture was quenched with deionized water (5 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, concentrated, and purified by silica gel column chromatography (PE:EtOAc = 5:1) to give the title compound (100 mg, 0.386 mmol, 99%). 1 H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 4.75 - 4.65 (m, 4H), 2.34 (s, 3H), 1.52 (s, 9H). LCMS ( m / z ): 259.9 [M+H] + Step 5. 2-Chloro-4-methyl-6,7-dihydro-5- H -pyrrolo[3,4- b Synthesis of pyridine hydrochloride (P10) At room temperature, a solution of P8 (200 mg, 0.744 mmol) in dioxane (2 mL) was treated with HCl (4.0 M 1,4-dioxane solution, 2 mL, 3.720 mmol). After 1 hour, the mixture was concentrated under reduced pressure to give the crude title compound (120 mg, 0.712 mmol, 96%), which could be used directly in the next step without further purification. LCMS ( m / z ):168.9 [M+H] + Step 6. 4-Methyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (P11) To a solution of P8 (300 mg, 1.116 mmol) in propan-2-ol (5 mL), KOAc (109.56 mg, 1.116 mmol) and Pd / C (10%, 35.64 mg, 0.335 mmol) were added, and the reaction mixture was stirred at room temperature for 4 hours under a hydrogen balloon. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 3 mL). The combined filtrates were concentrated under reduced pressure to give the crude title compound (210 mg, 0.896 mmol, 80%), which could be used directly in the next step without further purification. LCMS ( m / z ): 234.9[M+H] + Step 7. 4-Methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Synthesis of pyridine trifluoroacetate (P12) TFA (0.2 mL) was added to a 1 mL DCM solution of P11, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum to obtain the crude title compound (100 mg, 0.745 mmol, 83%), which could be used directly in the next step without further purification. LCMS ( m / z ):135.0 [M+H] + Step 8. 4-Methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Synthesis of pyridine-2-nitrile hydrochloride (P13) A solution of P9 (90 mg, 0.347 mmol) in 1,4-dioxane (2 mL) was treated with HCl (4.0 M 1,4-dioxane solution, 1 mL) at room temperature. After 1 hour, the mixture was concentrated under reduced pressure to give the crude title compound (90 mg, 0.57 mmol), which could be used directly in the next step without further purification. LCMS ( m / z ):159.9 [M+H] + Preparation 3 2,4-Dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-onitrile (P15) Step 1. Synthesis of tert-butyl 3-cyano-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (P14) A solution of P3 (500 mg, 1.768 mmol) and K4[Fe(CN)6] (651.24 mg, 1.768 mmol), Pd(OAc)2 (39.69 mg, 0.177 mmol), butyldi-1-adamantylphosphine (63.39 mg, 0.177 mmol), and Na2CO3 (56.22 mg, 0.530 mmol) in NMP (5 mL) was heated in a microwave at 160 °C for 4 hours under a N2 atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (PE:EtOAc, 3:1) to give the title compound (180 mg, 0.461 mmol, 26%). LCMS ( m / z ):273.9 [M+H] + Step 2. Synthesis of 2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-nitrile hydrochloride (P15) HCl (4.0 M MeOH solution, 0.5 mL) was added to a 2 mL solution of P14 (160 mg, 0.585 mmol) in MeOH at room temperature. After 1 hour, the solvent was removed under vacuum to give the crude title compound (140 mg, 0.485 mmol, 83%). LCMS ( m / z ):173.9 [M+H] + The following compounds were prepared basically according to the method described in preparation 3. Preparation 4 3-(2-(trifluoromethyl)pyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P19) Step 1. Synthesis of 1-(1,3-dioxoisoindoline-2-yl)-3-methylbicyclo[1.1.1]pentane-1,3-dicarboxylate (P17).

[0149] To a DCM (30 mL) solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (2.0 g, 11.754 mmol), 2-hydroxyisoindole-1,3-dione (2.11 g, 12.929 mmol), DCC (2.91 g, 14.104 mmol), and DMAP (0.29 g, 2.351 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration and washed with DCM (3 × 50 mL). The filtrate was concentrated under reduced pressure to give the crude title compound (3.4 g, 10.784 mmol, 92%), which could be used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO- d 6) δ 8.01-7.93 (m, 4H), 3.66 (s, 3H), 2.52 (s, 6H). LCMS ( m / z ): 348.2 [M+Na] + Step 12. Synthesis of methyl 3-(2-(trifluoromethyl)pyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxylate (P18) 4-Iodo-2-(trifluoromethyl)pyridine (3.0 g, 10.989 mmol), P17 (5.20 g, 16.484 mmol), unactivated Zn powder (5.71 g, 87.912 mmol) and [(bipy)2Ni2(µ-Cl)2Cl2(H2O)2] (1.33 g, 2.198 mmol) (reference) Org. Lett. The mixture of 2022, 24, 25, 8441-8446 was added in one go to a three-necked flask. The flask was evacuated and then purged with argon (× 3), and subsequently cooled to 0 °C. A solution of TMSCl (36 μL, 0.30 mmol) in DMA (0.5 mL, 0.2 M) was cooled to 0 °C and then added in one go to the reaction mixture. The reaction was stirred at 0 °C for 2 hours. After the starting material was exhausted (LCMS), the reaction was carefully quenched with a saturated aqueous solution of NH4Cl and then diluted with EtOAc (30 mL). The solution was extracted with EtOAc (× 3). The combined organic layers were washed with brine (3 × 60 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (PE:EtOAc, 85:15) to give the title compound (1.2 g, 4.424 mmol, 40%). 1 H NMR (400 MHz, CDCl3) δ 8.66 (d, J= 4.9 Hz, 1H), 7.49 (dd, J =1.6, 0.8 Hz, 1H), 7.32 (dd, J = 5.0, 1.6 Hz, 1H), 3.74 (s, 3H), 2.40 (s, 6H). LCMS ( m / z ): 271.9 [M+H] + Step 3. Synthesis of 3-(2-(trifluoromethyl)pyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P19) A mixture of P18 (180 mg, 0.664 mmol) and LiOH (139.23 mg, 3.318 mmol) was stirred in THF (1 mL) and H2O (1 mL) at room temperature for 1 hour. The mixture was acidified to pH 7 with 2M HCl. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude title compound (150 mg, 0.583 mmol, 88%), which could be used directly in the next step without further purification. LCMS ( m / z ): 257.9 [M+H] + The following compounds were prepared basically according to the method described in preparation 4. Preparation 5 3-(1-Methyl-1H-pyrazole-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P41) Step 1. Synthesis of methyl 3-(chlorocarbonyl)bicyclo[1.1.1]pentane-1-carboxylate (P37) At room temperature, a solution of 1-(methoxycarbonyl)bicyclo[1.1.1]pentane-3-carboxylic acid (3.0 g, 17.6 mmol) in DCM (2 mL) was treated with DMF (0.01 mL, 0.18 mmol). Oxaloyl chloride (4.5 g, 35.3 mmol) was added dropwise to the mixture at 0 °C. After 1 hour, the mixture was concentrated under reduced pressure to give the crude title compound (3.3 g, 17.5 mmol, 99%), which could be used directly in the next step without further purification.

[0150] Step 2. Synthesis of methyl 3-acetylbicyclo[1.1.1]pentane-1-carboxylate (P38) A solution of CuI (4.0 g, 21.0 mmol) in THF (15 mL) was treated with MeLi (1.6 M Et₂O solution, 27.34 mL, 43.741 mmol) at 0 °C and N₂. A solution of P₃₇ (3.2 g, 17.5 mmol) in THF (5 mL) was added to the mixture at -78 °C. The resulting mixture was stirred at -78 °C for another 2 hours. After the reaction was complete, a saturated aqueous solution of NH₄Cl (10 mL) was added at room temperature to quench the reaction. The resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with water (2 × 10 mL) and dried over Na₂SO₄. After drying over Na₂SO₄, the mixture was filtered, concentrated, and the crude title compound was obtained, which could be used directly in the next step without further purification.

[0151] Step 3. E Synthesis of methyl 1-pentane-1-carboxylate (P39) of 3-(3-(dimethylamino)acryloyl)bicyclo[1.1.1]pentane-1-carboxylate A solution of P38 (2.6 g, 15.459 mmol) in NMP (5 mL) was treated with dimethylformamide dimethyl acetal (5.5 g, 46.4 mmol) under N2 conditions. The mixture was heated to 90 °C for 1 hour. The resulting mixture was concentrated and purified by silica gel column chromatography (PE:EtOAc, 2:1) to give the title compound (2.1 g, 9.406 mmol, 61%). LCMS ( m / z ): 224.0 [M+H] + Step 4. 3-(1-methyl-1-yl) H Synthesis of methyl 1-pentane-1-carboxylate (P40) of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate To a solution of P39 (2.0 g, 8.958 mmol) in MeOH (15 mL), methylhydrazine dihydrochloride (1.1 g, 8.958 mmol) was added. The reaction mixture was stirred at 80 °C for 1 h. The mixture was concentrated and purified by reversed-phase rapid chromatography [column, C18 silica gel; mobile phase A: water (0.5% NH4HCO3), B: MeCN, 10% to 70%] to give the title compound (600 mg, 2.909 mmol, 32%). LCMS ( m / z ): 207.0 [M+H] + Step 5. 3-(1-methyl-1-yl) H Synthesis of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P41) The title compound was synthesized using P40 as the starting material, basically following the method described in step 3 of the 4-step preparation procedure. LCMS ( m / z ):193.0 [M+H] + .

[0152] The following compounds were prepared basically according to the method described in preparation 5. Preparation of 6 3-(1-trifluoromethyl-1 H -pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P50) and 3-(1-trifluoromethyl-1 H (-pyrazol-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P51) Step 1. 3-(1 H Synthesis of methyl 1-pentane-1-carboxylate (P45) of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate The title compound was prepared essentially following step 4 of a 5-step preparation method, using P39 and hydrazine hydrochloride as starting materials. LCMS ( m / z ): 193.0 [M+H] + Step 2. 3-(1-(bromodifluoromethyl)-1 H 3-pyrazole-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (P46) and 3-(1-(bromodifluoromethyl)-1 H Synthesis of a mixture of pyrazol-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (P47) NaH (60% mineral oil, 120 mg, 3.121 mmol) was added to a stirred solution of P45 (500 mg, 2.601 mmol) in DMF (5 mL) at 0 °C. After 1 hour, dibromodifluoromethane (1255.30 mg, 5.983 mmol) was added at 0 °C and the mixture was stirred at room temperature for 15 hours. Water (20 mL) was added at room temperature to quench the reaction. The resulting mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na2SO4, filtered, concentrated, and purified by reversed-phase rapid chromatography [column, C18 silica gel; mobile phase A: water (0.1% FA), B: MeCN, 10% to 60%] to give the title compound (200 mg, 0.623 mmol, 24%) of the mixture as regioisomers. LCMS ( m / z 320.9 [M+H] + Step 3. 3-(1-(trifluoromethyl)-1 H 3-pyrazole-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (P48) and 3-(1-(trifluoromethyl)-1 H Synthesis of a mixture of pyrazol-3-yl)bicyclo[1.1.1]pentane-1-carboxylate (P49) AgBF4 (121.28 mg, 0.623 mmol) was added to a stirred solution of a mixture of P46 and P47 (200 mg, 0.623 mmol) in DCM (1.5 mL) at -78 °C, and the mixture was stirred at room temperature for 15 hours under a N2 atmosphere. The reaction was quenched by adding water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na₂SO₄, filtered, concentrated, and purified by reversed-phase rapid chromatography [Xselect CSHMPrep C18 5 μm 30*150 mm OBD; mobile phase A: water (0.1% FA), B: MeCN; flow rate: 60 mL / min; gradient: 33% B to 50% B over 10 min] to obtain P49 (20 mg, 0.077 mmol, 25%) as the first eluent, LCMS (m / z) 261.0 [M+H] + ; and P48 (30 mg, 0.115 mmol, 37%) as the second eluent; LCMS (m / z) 261.0 [M+H] + .pass 19 F- 1The H NOESY study confirmed the regional chemistry of the two isomers.

[0153] Step 4. 3-(1-(trifluoromethyl)-1 H Synthesis of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P50) The title compound was synthesized using P48 as the starting material, basically following the method described in step 3 of section 4. LCMS ( m / z ): 247.0 [M+H] + Step 5. 3-(1-(trifluoromethyl)-1 H Synthesis of pyrazol-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P51) The title compound was synthesized using P49 as the starting material, basically following the method described in step 3 of preparation 4. LCMS ( m / z ): 247.0 [M+H] + Preparation 7 3-(4-methoxy-1-methyl-1- H -pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P54) and 3-(4-fluoro-1-methyl-1 H (-pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P56) Step 1. 3-(4-chloro-1-methyl-1-) H Synthesis of methyl 1-pentane-1-carboxylate (P52) of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate A mixture of P40 (150 mg, 0.727 mmol) and NCS (194.91 mg, 1.455 mmol) in THF (3 mL) and DMF (0.5 mL) was heated to 100 °C and maintained for 5 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with a saturated aqueous solution of NaHCO3 and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by reversed-phase rapid chromatography [column, C18 silica gel; mobile phase A: water (0.5% NH4HCO3), B: MeCN, 0% to 60%] to give the title compound (100 mg, 0.414 mmol, 57%). 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 3.85 (s, 3H), 3.72 (s, 3H), 2.59 (s, 6H). LCMS ( m / z ): 241.0 [M+H] + Step 2. 3-(4-methoxy-1-methyl-1- H Synthesis of methyl 1-pentane-1-carboxylate (P53) of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate CuI (60.11 mg, 0.316 mmol) and NaOMe (85.24 mg, 1.578 mmol) were added to a stirred solution of P52 (300 mg, 1.052 mmol) in MeOH (3 mL). The mixture was stirred overnight at 110 °C. Water (20 mL) was added at room temperature to quench the reaction. The resulting mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na2SO4, filtered, concentrated, and purified by reversed-phase rapid chromatography [column, C18 silica gel; mobile phase A: water (0.1% TFA), B: MeCN, 15% to 48%] to give the title compound (50 mg, 0.212 mmol, 20%). LCMS ( m / z 237.1[M+H] + Step 3. 3-(4-methoxy-1-methyl-1- H Synthesis of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P54) The title compound was synthesized using P53 as the starting material, basically following the method described in step 3 of preparation 4. LCMS ( m / z ): 223.0 [M+H] + Step 4. Synthesis of methyl 3-(4-fluoro-1-methyl-1H-pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate (P55) To a solution of P40 (350 mg, 1.697 mmol) in MeCN (8 mL), NaHCO3 (114 mg, 1.358 mmol) and Selectfluor (601 mg, 1.697 mmol) were added, and the reaction mixture was stirred at 65 °C for 16 hours. The mixture was cooled to room temperature, diluted with saturated NH4Cl aqueous solution, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give the title compound (150 mg, 39% yield). LCMS ( m / z ): 224.9 [M+H] + Step 5.3 Synthesis of (4-fluoro-1-methyl-1H-pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P56) The title compound was synthesized using P55 as the starting material, following the method described in step 3 of section 4. LCMS (m / z): 210.9 [M+H] + The following compounds were prepared in accordance with the method described in preparation 7. Preparation of 8 3-(1 H (-Imidazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P62) Step 1. Synthesis of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (P60) HCl (4 M dioxane solution, 1.2 mL) was added to methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (1.5 g, 6.217 mmol) in a stirred solution of DCM (15 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the crude title compound (800 mg, 5.667 mmol, 91%), which could be used directly for the next step without further purification. 1 H NMR (400 MHz, DMSO- d 6) δ 9.10-9.04 (m, 2H), 3.63 (s, 3H), 2.24 (s, 6H). LCMS ( m / z ): 142.2[M+H] + Step 2. 3-(1)H Synthesis of methyl 1-pentane-1-carboxylate (P61) of (-imidazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylate P60 (800 mg, 5.667 mmol), glyoxal (361.8 mg, 6.234 mmol), formaldehyde (0.230 mL, 6.234 mmol), and ammonium acetate (480.49 mg, 6.234 mmol) were stirred overnight at room temperature in a solution of MeOH (2 mL). An aqueous solution of NaHCO3 was added to quench the reaction. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 15 mL), dried over Na2SO4, filtered, concentrated, and purified by reversed-phase rapid chromatography [column, C18 silica gel; mobile phase A: water (0.5% NH4HCO3), B: MeCN, 5% to 20%] to give the title compound (600 mg, 3.121 mmol, 55%). 1 H NMR (400 MHz, DMSO- d 6) δ 7.70 (d, J = 1.2 Hz, 1H), 7.24 (t, J = 1.3Hz, 1H), 6.93 (t, J = 1.1 Hz, 1H), 3.66 (s, 4H), 2.48 (s, 7H). LCMS ( m / z ):193.1 [M+1] + Step 3. 3-(1) H Synthesis of 1-imidazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P62) The compound was synthesized using P61 as the starting material, basically following the method described in step 3 of preparation 4. LCMS ( m / z ): 179.3 [M+H] + Preparation 9 (1 r ,3 r )-3-(pyridin-4-yl)cyclobutane-1-carboxylic acid (P67) and (1 s ,3 s 3-(pyridin-4-yl)cyclobutane-1-carboxylic acid (P68) Step 1. Synthesis of methyl 3-hydroxy-3-(pyridin-4-yl)cyclobutane-1-carboxylate (P63) At -78 °C and under N2, 4-iodopyridine (2000 mg, 9.756 mmol) was added dropwise to a 50 mL solution of THF. n -BuLi (2.5 M hexane solution, 5.85 mL). After reacting at -78 °C for 30 min, methyl 3-oxocyclobutane-1-carboxylate (2125 mg, 16.585 mmol) was added dropwise at -78 °C. The mixture was stirred at room temperature for 1 h. After quenching with saturated NH4Cl aqueous solution (50 mL) at 0 °C, the mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (PE:EtOAc, 1:10) to give the title compound (850 mg, 4.102 mmol, 42%). LCMS ( m / z ): 208.4 [M+H] + Step 2. Synthesis of methyl 3-(((methylthio)carbonthio)oxy)-3-(pyridin-4-yl)cyclobutane-1-carboxylate (P64) NaH (60% mineral oil, 382.18 mg, 15.924 mmol) was added dropwise to a THF (30 mL) solution of P63 (1100 mg, 5.308 mmol) at 0 °C. After stirring at 0 °C for 30 min, CS2 (0.971 mL, 15.924 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h. Then MeI (1.292 mL, 15.924 mmol) was added, and the mixture was stirred at room temperature for 1 h. The reaction was quenched by adding saturated NH4Cl aqueous solution (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over Na2SO4, filtered, and concentrated to give the crude title compound, which could be used directly for the next step without further purification. LCMS ( m / z ): 298.4 [M+H] + Step 3. Synthesis of methyl 3-(pyridin-4-yl)cyclobutane-1-carboxylate (P65) Under N2 conditions, AIBN (174.06 mg, 1.060 mmol) and Bu3SnH (2.3 g, 7.950 mmol) were added to a 10 mL solution of crude P64 (1.6 g, 5.3 mmol) in toluene. After reacting at 70 °C for 2 hours, the mixture was concentrated and purified by silica gel column chromatography (PE: EtOAc, 4:1) to give the title compound (220 mg, 1.150 mmol, 22%). 1 H NMR (400 MHz, CDCl3) δ 8.53 (td, J = 4.5, 1.5 Hz, 2H), 7.15 (d, J = 5.2 Hz, 2H), 4.24 - 4.09 (m, 0.5H), 3.73 (d, J = 21. 0 Hz, 3H), 3.55 - 3.39 (m, 0.6H), 3.22 - 3.12 (m, 1H), 2.79 - 2.62 (m, 2H), 2.44 (dddd, J = 10.4,7.4, 4.2, 2.0 Hz, 2H). LCMS( m / z ):192.4[M+H] + Step 4. (1) r ,3 r )-3-(pyridin-4-yl)cyclobutane-1-carboxylic acid (P67) and (1 s ,3 s Synthesis of 3-(pyridin-4-yl)cyclobutane-1-carboxylic acid (P68) LiOH (17.6 mg, 0.733 mmol) was added to a solution of P65 (80 mg, 0.418 mmol) in THF (1 mL), MeOH (1 mL), and water (1 mL). The reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under vacuum. Crude P66 was purified by reversed-phase rapid chromatography [column: YMC Triart C18 ExRs 5 μm, 30 mm * 150 mm; mobile phase A: water (10 mM NH4HCO3), B: MeCN; 3% B to 25% B] to give P67 (30 mg, 0.169 mmol, 40%) as the first eluent. 1H NMR (400 MHz, CD3OD) δ 8.50 - 8.37 (m, 2H), 7.42 -7.30 (m, 2H), 3.71 (p, J = 8.3 Hz, 1H), 3.10 - 2.98 (m, 1H), 2.77 - 2.63 (m,2H), 2.38 (tdd, J = 9.6, 7.4, 2.3 Hz, 2H); LCMS ( m / z ):178.4 [M+H] + , and P68 (40 mg, 0.226 mmol, 54%) as the second eluent; 1 H NMR (400 MHz, CD3OD) δ 8.39 - 8.19 (m,2H), 7.31 - 7.17 (m, 2H), 3.31 (p, J = 9.1 Hz, 1H), 2.99 - 2.86 (m, 1H), 2.49(qd, J = 8.3, 2.7 Hz, 2H), 2.22 (qd, J = 10.0, 2.7 Hz, 2H). LCMS ( m / z ):178.4[M+H] + The cis / trans stereochemistry was confirmed through NOE studies.

[0154] The following compounds were prepared basically according to the method described in Preparation 9. Preparation 10 (1 s ,3 s 3-(5-fluoro-1-methyl-1H-pyrazol-4-yl)cyclobutane-1-carboxylic acid (P75) Step 1. 3-(5-fluoro-1-methyl-1- H Synthesis of methyl pyrazol-4-yl)-3-hydroxycyclobutane-1-carboxylate (P73) At -78 °C under N2, n-BuLi (2.5 M hexane solution, 1.770 mL) was added dropwise to a THF (20 mL) solution of 4-bromo-5-fluoro-1-methylpyrazole (660 mg, 3.687 mmol). The reaction mixture was stirred at -78 °C for 30 min. Then, methyl 3-oxocyclobutane-1-carboxylate (708.69 mg, 5.531 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 h. The reaction was quenched by adding a saturated aqueous solution of NH4Cl (20 mL) at room temperature. The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (DCM:MeOH, 20:1) to give the title compound (680 mg, 2.980 mmol, 81%). LCMS ( m / z ): 229.1 [M+H] + Step 2. (1) s ,3 s )-3-(5-fluoro-1-methyl-1 H Synthesis of methyl cyclobutane-1-carboxylate (P74) A solution of P73 (300 mg, 1.315 mmol) in TFA (5 mL) was stirred at room temperature for 4 hours. Then, Pd / C (10 wt.%, 139.89 mg, 0.131 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 10 mL). The filtrate was concentrated and purified by reversed-phase rapid chromatography [column: XselectCSHTM Prep C18 5 μm 30*150 mm OBD; mobile phase A: water (0.05% TFA), B: MeCN; 21% to 34%] to give the title compound (150 mg, 0.707 mmol, 54%). 1 H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 3.8 Hz, 1H), 3.80 (dd, J = 4.7, 1.2 Hz, 3H), 3.73 (d, J = 13.1 Hz, 3H), 3.27 (qd, J = 9.6, 7.7 Hz, 1H), 3.11 (ddt, J= 18.1, 10.0, 6.7 Hz, 1H), 2.69- 2.53 (m, 2H), 2.47 - 2.31 (m, 2H). LCMS( m / z ):213.4[M+H] + Step 3. (1) s ,3 s )-3-(5-fluoro-1-methyl-1 H Synthesis of pyrazol-4-yl)cyclobutane-1-carboxylic acid (P75) The title compound was synthesized using P74 as the starting material, basically following the method described in step 3 of preparation 4. LCMS ( m / z ):199.1 [M+H] + The following compounds were prepared basically according to the method for preparing 10. Preparation 11 (1 s ,3 s )-3-(1-methyl-1 H 5-pyrazol-5-yl)cyclobutane-1-carboxylic acid (P85) Step 1. 3-(1-methyl-1-yl) H Synthesis of methyl pyrazol-5-yl)cyclobut-2-ene-1-carboxylate (P83) At room temperature, methyl 3-(2-toluenesulfonylhydrazinyl)cyclobutane-1-carboxylate [J. Med. Chem. 2021, 64 (9), 6358 - 6380] (2.0 g, 6.749 mmol) and 5-iodo-1-methyl-1H-pyrazole (1.54 g, 7.424 mmol) in a stirred solution of 1,4-dioxane (30 mL) were added with Ph3P (0.49 g, 0.675 mmol), Pd2(dba)3 (0.62 g, 0.675 mmol), and Cs2CO3 (2.20 g, 6.749 mmol). The reaction was placed under positive nitrogen pressure and subjected to three evacuation / refill cycles under high vacuum. The resulting mixture was stirred overnight at 85 °C. After cooling to room temperature, water (20 mL) was added to quench the reaction. The mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na₂SO₄, filtered, concentrated, and purified by silica gel column chromatography (PE:EtOAc, 5:1) to give the title compound (400 mg, 2.081 mmol, 31%). LCMS ( m / z ): 193.1 [M+H] + Step 2. (1) s ,3 s )-3-(1-methyl-1 H Synthesis of methyl cyclobutane-1-carboxylate (P84) To a flask containing P83 (400 mg, 2.081 mmol), add 10 mL of MeOH, followed by Pd / C (10 wt.% loading, 220.58 mg, 2.081 mmol). Place the mixture under an H2 balloon and stir at room temperature for 1 hour. Filter the reaction mixture to remove insoluble solids. Wash the filter cake with MeOH (2 × 10 mL). Concentrate the filtrate to give the crude title compound, which can be used directly for the next step without further purification. LCMS (ESI, m / z ):195.0 [M+H] + Step 3. (1) s ,3 s Synthesis of 3-(1-methyl-1H-pyrazol-5-yl)cyclobutane-1-carboxylic acid (P85) The title compound was synthesized using P84 as the starting material, following the procedure in step 3 of section 4. LCMS (ESI, m / z): 181.0 [M+H] + The following compounds were prepared basically according to the method described in Preparation 11. Preparation 12 3-(2-(2-(dimethylamino)ethyl)pyridin-4-yl)cyclobutane-1-carboxylic acid (P91) Step 1. Synthesis of methyl 3-(2-(2-(dimethylamino)ethyl)pyridin-4-yl)cyclobutane-1-carboxylate (P90) To 2-(4-bromopyridin-2-yl)- N,N A solution of dimethyl ethyl-1-amine (1.0 g, 4.365 mmol) in DMA (10 mL) was supplemented with methyl 3-bromocyclobutane-1-carboxylate (0.84 g, 4.365 mmol), N-(phenyl(pyridin-2-yl)methyl)pyridineamide (0.190 g, 6.55 mmol), zinc (1.43 g, 21.823 mmol), NiCl₂(PCy₃)₂ (0.301 g, 0.437 mmol), and MgCl₂ (0.44 g, 0.44 mmol). The reaction mixture was stirred at 100 °C for 18 hours. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 5 mL). The filtrate was concentrated and purified by reversed-phase rapid chromatography [column, C18 silica gel; mobile phase A: water (0.5% NH4HCO3), B: MeCN, 16% to 670%] to give the title compound (320 mg, 1.220 mmol, 28%). LCMS ( m / z ): 285.1 [M+Na] + Step 2. Synthesis of 3-(2-(2-(dimethylamino)ethyl)pyridin-4-yl)cyclobutane-1-carboxylic acid (P91) The title compound was synthesized using P90 as the starting material, basically following the method described in step 3 of section 4. LCMS ( m / z ): 249.0 [M+H] + The following compounds were prepared in accordance with the method used in preparation 12. Preparation 13 (1 s ,3 s )-3-(thiazolyl-5-yl)cyclobutane-1-carboxylic acid (P112) and (1r ,3 r 3-(thiazolyl-5-yl)cyclobutane-1-carboxylic acid (P113) Step 1. Synthesis of methyl 3-hydroxy-3-(thiazolyl-5-yl)cyclobutane-1-carboxylate (P108) At -78 °C, n-BuLi (2.5 M hexane solution, 13.985 mL, 34.963 mmol) was added to a solution of 2-(trimethylsilyl)-1,3-thiazole (5 g, 31.784 mmol) in Et₂O (50 mL). The mixture was stirred at -78 °C for 0.5 h. Then, a solution of methyl 3-oxocyclobutane-1-carboxylate (4.07 g, 31.784 mmol) in Et₂O (10 mL) was added dropwise. The mixture was stirred at 20 °C for 1 h. The mixture was poured into ice-cold NH₄Cl solution (100 mL) and extracted with EtOAc (50 mL × 3). The organic layer was dried over Na₂SO₄, filtered, concentrated, and purified by silica gel column chromatography (PE:EtOAc, 2:1) to give the title compound (4.0 g, 16.882 mmol, 53%). 1 H NMR (400 MHz, DMSO- d 6)δ 8.99 (d, J = 0.7 Hz, 1H), 7.93 (d, J = 0.8 Hz, 1H), 6.33 (s, 1H), 3.63 (s,3H), 2.91 (tt, J = 10.2, 8.3 Hz, 1H), 2.66 - 2.62 (m, 2H), 2.60 - 2.55 (m, 2H). LCMS ( m / z ): 213.9 [M+H] + Step 2. Synthesis of methyl 3-fluoro-3-(thiazolyl-5-yl)cyclobutane-1-carboxylate (P109) At 0 °C, DAST (6.05 g, 37.515 mmol) was added to a DCM (40 mL) solution of P108 (4.0 g, 18.757 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was poured into an aqueous solution of NaHCO3 and extracted with DCM (30 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude title compound (3.0 g, 12.544 mmol, 67%), which could be used directly in the next step without further purification. LCMS ( m / z ): 216.0 [M+H] + Step 3. (1) s ,3 s )-3-(thiazolyl-5-yl)cyclobutane-1-carboxylic acid methyl ester (P110) and (1 r ,3 r Synthesis of methyl 3-(thiazolyl-5-yl)cyclobutane-1-carboxylate (P111) At room temperature, Pd / C (10 wt.%, 20 g, 187.935 mmol) and formic acid (5 mL, 0.139 mmol) were added to a MeOH (30 mL) solution of crude P109 (3 g, 13.938 mmol). The mixture was stirred under an H2 balloon for 3 hours. The mixture was filtered, concentrated, and purified by reversed-phase rapid chromatography [column: Xselect CSH™ Prep C18 5 μm 30*150 mm OBD; mobile phase A: water (0.1% FA), B: MeCN; 16% B to 40% B] to give P110 (180 mg, 0.821 mmol, 6%) as the first eluent. 1 H NMR (400 MHz, CD3OD) δ 8.86 (d, J = 0.8 Hz, 1H), 7.65 (t, J = 0.8 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.68 (s, 3H), 3.20 (tt, J = 9.8, 8.2 Hz, 1H), 2.76 - 2.66 (m, 2H), 2.41 - 2.32 (m, 2H); LCMS ( m / z ):198.1 [M+H] + , and P111 (185 mg, 0.844 mmol, 6.06%) as the second eluent; 1 H NMR (400 MHz, methanol-)d 4) δ 8.87 (d, J = 0.8 Hz, 1H), 7.69 (t, J = 0.9 Hz, 1H), 3.98 (ttt, J =8.7, 7.5, 1.2 Hz, 1H), 3.72 (s, 3H), 3.25 (tdd, J = 9.4, 4.7, 1.3 Hz, 1H), 2.80 - 2.72 (m, 2H), 2.49 - 2.41 (m, 2H). LCMS ( m / z ): 198.1 [M+H] + Step 4. (1) s ,3 s Synthesis of methyl 3-(thiazolyl-5-yl)cyclobutane-1-carboxylate (P112) The compound was synthesized using P110 as the starting material, basically following the method described in step 3 of preparation 4. LCMS ( m / z ): 184.3 [M+1] + Step 5. (1) r ,3 r Synthesis of methyl 3-(thiazolyl-5-yl)cyclobutane-1-carboxylate (P113) The compound was synthesized using P111 as the starting material, basically following the method described in step 3 of preparation 4. LCMS ( m / z ): 184.3 [M+1] + Preparation 14 3-(1 H 1-Pyrazol-1-yl)cyclobutane-1-carboxylic acid (P116) Step 1. Synthesis of methyl 3-(toluenesulfonyloxy)cyclobutane-1-carboxylate (P114) At room temperature, methyl 3-hydroxycyclobutane-1-carboxylate (3.0 g, 23.052 mmol) was mixed with TsCl (4.39 g, 23.052 mmol), DMAP (0.28 g, 2.305 mmol), and pyridine (5.593 mL, 69.156 mmol) in a stirred solution of DCM (30 mL). After 1 hour, water (20 mL) was added to quench the reaction. The resulting mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na₂SO₄, filtered, and concentrated to give the crude title compound, which could be used directly for the next step without further purification. LCMS ( m / z ): 302.0 [M+H2O] + Step 2. 3-(1) H Synthesis of methyl 1-pyrazole-1-yl)cyclobutane-1-carboxylate (P115) At room temperature, P114 (5.0 g, 17.585 mmol) and 1 H -Pyrazole (1.0 g, 14.689 mmol) was added to a stirred solution of DMF (30 mL) with K2CO3 (6.1 g, 44.139 mmol). After 1 hour, the reaction was quenched by adding water (20 mL). The resulting mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (PE:EtOAc, 5:1) to give the title compound (300 mg, 1.665 mmol, 9%). LCMS ( m / z ): 181.1[M+H] + Step 3. Synthesis of 3-(1H-pyrazol-1-yl)cyclobutane-1-carboxylic acid (P116) The title compound was synthesized using P115 as the starting material, basically following the method described in step 3 of preparation 4. LCMS ( m / z ): 167.1 [M+H] + The following compounds were prepared basically according to the method used in preparation 14. Preparation 15 3-(pyridin-4-ylmethyl)cyclobutane-1-carboxylic acid (P130) Step 1. Synthesis of methyl 3-(pyridin-4-ylmethylene)cyclobutane-1-carboxylate (P124) Potassium tert-butoxide (1M THF solution, 15.06 mL, 15.06 mmol) was added dropwise to a solution of triphenyl(pyridin-4-ylmethyl)phosphonium chloride (7.30 g, 18.731 mmol) in toluene (10 mL). After stirring at room temperature for 0.5 hours, the solution was cooled to 0 °C, and then a solution of methyl 3-oxocyclobutane-1-carboxylate (2 g, 15.609 mmol) in toluene (2 mL) was rapidly added. The mixture was heated at 110 °C for 3 hours, then cooled to room temperature and partitioned between water (25 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with water (2 × 20 mL) and brine (20 mL), dried over anhydrous MgSO4, concentrated, and purified by reversed-phase rapid chromatography [column, C18 silica gel; mobile phase A: water (0.5% NH4HCO3), B: MeCN, 10%] to give the title compound (115 mg, 0.566 mmol, 4%). LCMS: ( m / z ): 204.0 [M+H] + Step 2. Synthesis of methyl 3-(pyridin-4-ylmethyl)cyclobutane-1-carboxylate (P125) A solution of P124 (105 mg, 0.517 mmol) and Pd / C (10 wt%, 54.98 mg, 0.0517 mmol) in MeOH (5 mL) was stirred at room temperature for 3 hours under a 3 MPa H2 atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeOH (2 × 5 mL). The filtrate was concentrated under reduced pressure to give the crude title compound (95 mg), which could be used directly in the next step without further purification. LCMS: ( m / z ): 206.1 [M+H] + Step 3. Synthesis of 3-(pyridin-4-ylmethyl)cyclobutane-1-carboxylic acid (P126) The title compound was synthesized using P125 as the starting material, following the method described in step 3 of section 4. LCMS: (m / z): 192.0 [M+H] + Preparation of 16 2-(1-methyl-1 H -pyrazol-4-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid (P128) Step 1. Synthesis of methyl 2-azaspiro[3.3]heptane-6-carboxylate trifluoroacetate (P127) TFA (1 mL, 13.059 mmol) was added to a DCM (5 mL) solution of methyl 2-{[(2-methylprop-2-yl)oxy]carbonyl}-2-azaspiro[3.3]heptane-6-carboxylate (500 mg, 1.958 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to give the crude title compound (400 mg, 2.577 mmol). LCMS ( m / z ): 156.0 [M+H] + Step 2. 2-(1-methyl-1-yl) H Synthesis of pyrazol-4-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid (P128) Under N2, P127 (360 mg, 2.320 mmol), GPhos Pd G6 (219.07 mg, 0.232 mmol), and sodium trimethylsilanolate (1040.85 mg, 9.278 mmol) were added to a THF (5 mL) solution of 4-bromo-1-methylpyrazole (373.45 mg, 2.320 mmol), and the reaction mixture was stirred at 80 °C for 18 hours. The resulting mixture was filtered. The filter cake was washed with MeOH (3 × 3 mL). The filtrate was concentrated and purified by reversed-phase column chromatography [column: YMC Triart C18 Ex 5 μm, 30 mm * 150 m; mobile phase A: water (10 mM NH4HCO3), B: MeCN; 2% to 15%] to give the title compound (70 mg, 0.316 mmol, 14%). 1 H NMR (400 MHz, DMSO- d 6) δ 7.03 (d, J = 0.9 Hz, 1H), 6.85 (d, J = 1.0 Hz, 1H), 3.68 (s, 3H), 2.82 (p, J = 8.2 Hz, 1H), 2.26 (dd, J = 9.2, 2.7 Hz, 4H). LCMS ( m / z ): 222.0 [M+H] + Preparation of 17 2-(pyridin-4-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid (P130) Step 1. Synthesis of methyl 2-(pyridin-4-yl)-2-azaspiro[3.3]heptane-6-carboxylate (P129) Pd-PEPPSI™-IPent catalyst (25 mg, 0.026 mmol), 4-iodopyridine (528.35 mg, 2.577 mmol), and Cs₂CO₃ (2519.2 mg, 7.732 mmol) were added to a dioxane (5 mL) solution of P127 (400 mg, 2.577 mmol), and the reaction mixture was stirred at 100 °C for 2 h under an argon atmosphere. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc, 6:1) to give the title compound (331 mg, 1.283 mmol, 50%). LCMS ( m / z ): 233.0 [M+H] + Step 2. Synthesis of 2-(pyridin-4-yl)-2-azaspiro[3.3]heptane-6-carboxylic acid (P130) The title compound was synthesized using P129 as the starting material, basically following the method described in step 3 of preparation 4. LCMS ( m / z ): 219.0 [M+H] + The following compounds were prepared basically according to the method used for preparation 17. Preparation of 18 1-(1-methyl-1 H -pyrazol-4-yl)azacyclobutane-3-carboxylic acid (P133) Step 1. 1-(1-methyl-1 H Synthesis of 4-pyrazole-3-yl)azonylbutane-3-carboxylic acid ethyl ester (P132) Add (1-methyl-1-ethylhexane-3-carboxylate hydrochloride) to a solution of ethyl hexacyclobutane-3-carboxylate hydrochloride (1.0 g, 7.742 mmol) in MeCN (10 mL). Hpyrazol-4-yl)boronic acid (974.91 mg, 7.742 mmol), TEA (5.381 mL, 38.712 mmol), and Cu(OAc)₂ (703.12 mg, 3.871 mmol) were added, and the reaction was stirred at room temperature for 1 hour. The residue was purified by silica gel column chromatography (PE:EtOAc, 1:1) to give the title compound (300 mg, 1.434 mmol, 19%). LCMS ( m / z ): 210.0 [M+H] + Step 2. 1-(1-methyl-1-yl) H Synthesis of pyrazol-4-yl)azacyclobutane-3-carboxylic acid (P133) The title compound was synthesized using P132 as the starting material, basically following the method described in step 3 of the 4-step preparation procedure. LCMS ( m / z ): 182.0 [M+H] + .

[0155] The following compounds were prepared basically according to the method used for preparing 18. Preparation of 19 3-(pyridazin-4-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P137) Step 1. Synthesis of methyl 3-(3,6-dichloro-1,2-diazin-4-yl)bicyclo[1.1.1]pentane-1-carboxylate (P135) AgNO3 (1.91 g, 0.588 mmol), ammonium persulfate (3.00 g, 0.588 mmol), and H2SO4 (98%, 1.8 mL, 33.649 mmol, dissolved in 5 mL water) were added to a mixture of 1-(methoxycarbonyl)bicyclo[1.1.1]pentane-3-carboxylic acid (2.0 g, 11.754 mmol) in water (20 mL), and the reaction was stirred at 70 °C for 1 h. The pH of the mixture was adjusted to 7–8 by adding solid NaHCO3. The reaction mixture was diluted with EtOAc. The organic layer was separated, washed with brine, concentrated, and purified by silica gel column chromatography to give the title compound (860 mg, 3.149 mmol, 27%). LCMS ( m / z ):273.1[M+H] + Step 2. Synthesis of methyl 3-(1,2-diazin-4-yl)bicyclo[1.1.1]pentane-1-carboxylate (P136) Pd / C (10 wt%, 300 mg, 1.098 mmol) was added to a solution of P135 (300 mg, 1.098 mmol) in MeOH (5 mL) and NH3·H2O (0.1 mL). The reaction mixture was stirred at room temperature for 2 hours under an H2 balloon. The mixture was filtered, concentrated, and purified by silica gel column chromatography to give the title compound (200 mg, 0.979 mmol, 89%). LCMS ( m / z ): 205.1 [M+H] + Step 3. Synthesis of 3-(1,2-diazin-4-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (P137) The title compound was synthesized using P136 as the starting material, basically following the method described in step 3 of preparation 4. LCMS ( m / z ): 179.10 [M+H] + The following compounds were prepared basically according to the method used for preparation 19. Preparation 20 (1 s ,3 s )-3-(5-methoxy-1-methyl-1 H -pyrazol-4-yl)cyclobutane-1-carboxylic acid (P139) Step 1. (1) s ,3 s )-3-(5-methoxy-1-methyl-1 H Synthesis of pyrazol-4-yl)cyclobutane-1-carboxylic acid (P139) CH3ONa (55 mg, 1.009 mmol) was added to a DMSO (1 mL) solution of P75 (40 mg, 0.202 mmol). The mixture was stirred at 115 °C for 2 hours. The reaction mixture was purified directly by reversed-phase chromatography [column, C18 silica gel; mobile phase A: water (0.1% TFA), B: MeCN] to give the title compound (42 mg, 0.199 mmol, 99%). LCMS ( m / z ): 210.9 [M+H] + Preparation 21 (1 s ,3 s )-3-(5-(azacyclobutane-1-yl)-1-methyl-1 H-pyrazol-4-yl)cyclobutane-1-carboxylic acid (P143) Step 1. Synthesis of methyl 3-(5-bromo-1-methylpyrazol-4-yl)cyclobutane-1-carboxylate (P141) NBS (705 mg, 3.964 mmol) was added to a solution of P140 (700 mg, 3.604 mmol) in MeCN (2 mL), and the reaction was stirred at room temperature for 3 hours. The reaction mixture was diluted with saturated NH4Cl aqueous solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give the title compound (500 mg, 0.915 mmol, 25%). LCMS ( m / z ): 273.0 [M+H] + Step 2. Synthesis of methyl 3-[5-(azacyclobutan-1-yl)-1-methylpyrazol-4-yl]cyclobutane-1-carboxylate (P142) To a solution of P141 (200 mg, 0.732 mmol) in dioxane (2 mL), aziridine (63 mg, 1.098 mmol), Cs₂CO₃ (716 mg, 2.197 mmol), Pd₂(dba)₃ (134 mg, 0.146 mmol), and Xantphos (85 mg, 0.146 mmol) were added, and the reaction mixture was stirred at 120 °C and N₂ for 3 hours. The mixture was concentrated and purified by silica gel column chromatography to give the title compound (150 mg, 0.301 mmol, 41%). LCMS ( m / z ): 250.1 [M+H] + Step 3. (1) s ,3 s )-3-[5-(azacyclobutane-1-yl)-1-methyl-1 H Synthesis of pyrazol-4-yl]cyclobutane-1-carboxylic acid (P143) The title compound was synthesized using P142 as the starting material, basically following the method described in step 3 of preparation 4. LCMS ( m / z ): 236.1 [M+H] + Preparation 22 3-Chloro-2,4,5-trimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridine trifluoroacetate (P150) Step 1. Synthesis of 5-chloro-2-(hydroxymethyl)-4,6-dimethylpyridin-3-onitrile (P144).

[0156] At 0 °C, NaBH4 (0.89 g, 23.64 mmol) was added to a solution of P1 (1.77 g, 7.88 mmol) in THF (20 mL) and MeOH (50 mL). The mixture was stirred at room temperature for 18 hours. Water was added to the mixture at 0 °C. The mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with a saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound (1.50 g, 7.63 mmol, 97%), which could be used directly for the next step without further purification. LCMS ( m / z ): 197.1 [M+H] + Step 2. Synthesis of 3-chloro-2,4-dimethyl-5,7-dihydrofurano[4,3-b]pyridin-5-one (P145).

[0157] H₂SO₄ (98%, 12 mL, 224.04 mmol) was added to a solution of P144 (1.5 g, 7.63 mmol) in EtOH (30 mL) at room temperature. The mixture was stirred at 90 °C for 18 hours. The mixture was cooled to 0 °C and diluted with water. The pH of the mixture was adjusted to 7–8 by adding solid NaHCO₃. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, concentrated, and purified by silica gel column chromatography to give the title compound (1.21 g, 6.12 mmol, 80%). LCMS ( m / z ): 198.1 [M+H] + Step 3. Synthesis of 3-chloro-2,4,5-trimethyl-5,7-dihydrofurano[4,3-b]pyridine-5-ol (P146).

[0158] CH3MgBr (1 M HF solution) (30.61 mL, 30.61 mmol) was added dropwise to a solution of P145 (1.21 g, 6.12 mmol) in THF (60 mL) at 0 °C. The mixture was stirred at room temperature for 3 hours. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product (1.23 g, 5.76 mmol, 94%), which could be used directly in the next step without further purification. LCMS ( m / z ): 214.1 [M+H] + Step 4. Synthesis of 1-[5-chloro-2-(hydroxymethyl)-4,6-dimethylpyridin-3-yl]ethanol-1-ol (P147).

[0159] NaBH4 (0.89 g, 23.40 mmol) was added to a solution of crude P146 (1.0 g, 4.68 mmol) in MeOH (20 mL) at 0 °C. The mixture was stirred at 25 °C for 18 hours. Water was added to the mixture at 0 °C. The mixture was concentrated under reduced pressure to obtain a residue. The residue was diluted with a saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give the product (470 mg, 2.18 mmol, 46%). LCMS ( m / z ): 216.1 [M+H] + .

[0160] Step 5. Synthesis of 5-chloro-3-(1-chloroethyl)-2-(chloromethyl)-4,6-dimethylpyridine (P148).

[0161] A solution of P147 (470 mg, 2.18 mmol) in SOCl2 (10 mL) was stirred at 50 °C for 3 hours. The mixture was concentrated under reduced pressure to give the crude title compound (750 mg, 2.23 mmol), which could be used directly in the next step without further purification. LCMS ( m / z ): 253.9 [M+H] + Step 6. 3-Chloro-6-[(2,4-dimethoxyphenyl)methyl]-2,4,5-trimethyl-6,7-dihydro-5 H -pyrrolo[4,3- b Synthesis of pyridine (P149).

[0162] DIPEA (345 mg, 2.67 mmol) and (2,4-dimethoxyphenyl)methylamine (179 mg, 1.07 mmol) were added to a solution of crude P148 (300 mg, 0.89 mmol) in MeCN (15 mL) and DCM (3 mL) at room temperature. The mixture was stirred at 75 °C for 3 hours. The mixture was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give the title compound (225 mg, 0.65 mmol, 73%). LCMS ( m / z ): 347.2 [M+H] + Step 8.3-Chloro-2,4,5-trimethyl-6,7-dihydro-5 H -pyrrolo[4,3- b Synthesis of pyridine trifluoroacetate (P150).

[0163] A mixture of P149 (225 mg, 0.65 mmol) in TFA (5 mL) and triethylsilane (5 mL) was stirred at 70 °C for 2 hours. The mixture was concentrated under reduced pressure to give the crude title compound (140 mg, 0.71 mmol, 109.74%), which could be used directly in the next step without further purification. LCMS ( m / z ): 197.2 [M+H] + .

[0164] Preparation 23 3-Chloro-2,4,7-trimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridine trifluoroacetate (P159) Step 1. Synthesis of 2,5-dichloro-4,6-dimethylpyridine-3-carboxylic acid (P151) H₂SO₄ (98%, 15.0 mL, 280.055 mmol) was added to 2,5-dichloro-4,6-dimethylpyridin-3-onitrile (5.00 g, 24.869 mmol). The mixture was stirred at 80 °C for 2 hours, and then a solution of NaNO₂ (3.94 g, 57.062 mmol) in water (25 mL) was slowly added to the mixture at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, and then quenched with ice. The solid was filtered and washed with water to give the crude title compound (4.11 g, 18.632 mmol, 75%), which could be used directly for the next step without further purification. LCMS ( m / z) 220.0 [M+H] + Step 2. Synthesis of methyl 2,5-dichloro-4,6-dimethylpyridine-3-carboxylate (P152) Cs₂CO₃ (11.85 g, 36.36 mmol) and CH₃I (3.87 g, 27.27 mmol) were added to a solution of P151 (4.00 g, 18.18 mmol) in DMF (100 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was separated, washed with brine, and concentrated to give the crude title compound (3.62 g, 15.38 mmol, 85%), which could be used directly for the next step without further purification. LCMS ( m / z ): 234.0 [M+H] + Step 3. Synthesis of methyl 5-chloro-2-cyano-4,6-dimethylpyridine-3-carboxylate (P153) To a solution of P152 (3.50 g, 14.95 mmol) in DMF (30 mL), dppf (0.83 g, 1.5 mmol), Zn(CN)2 (0.88 g, 7.48 mmol), and Pd2(dba)3 (1.37 g, 1.5 mmol) were added. The reaction mixture was stirred at 110 °C for 2 hours under N2. The reaction mixture was diluted with saturated NH4Cl aqueous solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give the title compound (3.22 g, 14.24 mmol, 95%). LCMS ( m / z ): 225.0 [M+H] + Step 4. 3-Chloro-2,4-dimethyl-5,7-dihydrofurano[4,3- b Synthesis of pyridin-7-one (P154) At 0 °C, NaBH4 (1.62 g, 42.735 mmol) was added fractionally to a solution of P153 (3.22 g, 14.245 mmol) in a mixture of THF (40 mL) and MeOH (90 mL). The reaction mixture was stirred at room temperature for 8 hours, then water was added, and the organic solvent was removed under vacuum. The aqueous residue was diluted with a saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude product. The crude product was dissolved in EtOH (50 mL), cooled to 0 °C, and treated dropwise with concentrated H2SO4 (98%, 40 mL, 746.814 mmol). The reaction mixture was then heated at 90 °C for 18 hours. The mixture was cooled to 0 °C and diluted with water. The pH of the mixture was adjusted to 7–8 by adding solid NaHCO3. Volatile substances were removed under vacuum, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, concentrated, and purified by silica gel column chromatography to give the title compound (1.72 g, 8.602 mmol, 60%). LCMS ( m / z ): 198.0 [M+H] + Step 5. Synthesis of 3-chloro-2,4,7-trimethyl-5,7-dihydrofurano[4,3-b]pyridine-7-ol (P155) CH3MgBr (3.5 mL, 10.626 mmol) was added to a 20 mL THF solution of P154 (700 mg, 3.542 mmol), and the mixture was stirred at -40 °C for 2 hours. The reaction mixture was diluted with EtOAc and saturated NH4Cl solution. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give the title compound (200 mg, 0.936 mmol, 26%). LCMS ( m / z ): 214.1 [M+H] + Step 6. Synthesis of 1-[5-chloro-3-(hydroxymethyl)-4,6-dimethylpyridin-2-yl]ethanol-1-ol (P156) NaBH4 (42 mg, 1.123 mmol) was added to a stirred solution of P155 (200 mg, 0.936 mmol) in MeOH (2 mL) at 0 °C. The mixture was stirred at room temperature for 1 hour and concentrated. The residue was purified by silica gel column chromatography to give the title compound (160 mg, 0.742 mmol, 79%). LCMS ( m / z ): 181 [M-2OH] + Step 7. Synthesis of 5-chloro-2-(1-chloroethyl)-3-(chloromethyl)-4,6-dimethylpyridine (P157) A mixture of P156 (160 mg, 0.742 mmol) and thionyl chloride (2.5 mL) was stirred at 45 °C for 2 hours. The reaction mixture was concentrated under vacuum to give the crude title compound (160 mg, 0.634 mmol, 85%), which could be used directly in the next step without further purification. LCMS ( m / z ): 252.0 [M+H] + Step 8. 3-Chloro-6-[(2,4-dimethoxyphenyl)methyl]-2,4,7-trimethyl-6,7-dihydro-5 H Synthesis of pyrrolo[4,3-b]pyridine (P158) TEA (0.264 mL, 1.902 mmol) was added to a solution of P157 (160 mg, 0.634 mmol) in a mixture of CH2Cl2 (1 mL) and MeCN (5 mL). The resulting mixture was stirred at room temperature for 10 minutes, followed by dropwise addition of (2,4-dimethoxyphenyl)methylamine (116.61 mg, 0.697 mmol), and the reaction mixture was stirred at 75 °C for 3 hours. The reaction mixture was concentrated and purified by silica gel column chromatography to give the title compound (100 mg, 0.288 mmol, 46%). LCMS ( m / z ): 347.2 [M+H] + Step 9. 3-Chloro-2,4,7-trimethyl-6,7-dihydro-5 H -pyrrolo[4,3- b Synthesis of pyridine trifluoroacetate (P159) P158 (15 mg, 0.043 mmol) was dissolved in a solution of triethylsilane (2.5 mL) and TFA (0.5 mL) and stirred at 70 °C for 2 hours. The reaction mixture was concentrated to give the crude title compound (15 mg, 0.076 mmol) as a TFA salt, which could be used directly in the next step without further purification. LCMS ( m / z ): 197.1 [M+H] + Preparation 24 3-((3-fluoropyridin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (T31) Step 1. Synthesis of methyl 3-((3-fluoropyridin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate (T30) A solution of 4-chloro-3-fluoropyridine (500 mg, 3.801 mmol) in dioxane (15 mL) was added with methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate (536.65 mg, 3.801 mmol), XPhos-Pd-G2 (298.72 mg, 0.380 mmol), and Cs2CO3 (3096.44 mg, 9.504 mmol), and the reaction mixture was stirred at 120 °C for 18 h. The reaction mixture was diluted with EA and water. The organic layer was separated, washed with saturated brine, and concentrated under vacuum. The residue was purified by preparative HPLC to give the title compound (300 mg, 1.270 mmol, 33%). LCMS ( m / z ): 237.1 [M+H] + Step 2. Synthesis of 3-((3-fluoropyridin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (T31) The title compound was prepared primarily via a 4-step, 3-step method. LCMS ( m / z ): 223.1 [M+H] + The following compounds were prepared basically according to the method used for preparation 24. Preparation 25 3-(methyl(pyridin-2-yl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (T42) Step 1. Synthesis of methyl 3-(methyl(pyridin-2-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate (T41) A solution of methyl 3-iodobicyclo[1.1.1]pentane-1-carboxylate (300 mg, 1.19 mmol) in dioxane (4 mL) was supplemented with 2-(methylamino)pyridine (128 mg, 1.19 mmol), K3PO4 (757 mg, 3.57 mmol), and copper bis(2,2,6,6-tetramethyl-3,5-heptadecyl acetate) (255 mg, 0.59 mmol). The mixture was stirred at 120 °C for 16 hours. The mixture was filtered, concentrated, and purified by silica gel column chromatography to give the title product (85 mg, 0.36 mmol, 30%) as a yellow oil. LCMS ( m / z ): 233.1 [M+H] + Step 2. Synthesis of 3-(methyl(pyridin-2-yl)amino)bicyclo[1.1.1]pentane-1-carboxylic acid (T42) The title compound was prepared primarily via a 4-step, 3-step method. LCMS ( m / z ): 219.1 [M+H] + The following compounds were prepared basically according to the method used for preparing 25. Preparation 26 3-(3-chloro-1) H (-pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T56) Step 1. O' 1 O 1 -(trimethyl-λ) 3 Synthesis of 3,3'-dimethylbis(bicyclo[1.1.1]pentane-1,3-dicarboxylate) (T54) Add diacetic acid trimethyl-λ to a solution of 1-(methoxycarbonyl)bicyclo[1.1.1]pentane-3-carboxylic acid (4.0 g, 23.50 mmol) in toluene (25 mL). 3 - Iodoalkyl diester (4.3 g, 11.75 mmol). The mixture was stirred at 55 °C for 10 min. The mixture was filtered, concentrated, and purified by silica gel column chromatography to give the title product (6.8 g, 11.59 mmol, 49%) as a white solid. LCMS ( m / z ): 585.1 [M+H]+ Step 2. 3-(3-chloro-1) H Synthesis of methyl 1-pyrazole-1-yl)bicyclo[1.1.1]pentane-1-carboxylate (T55) Add 5-chloro-1 to a solution of T54 (2.28 g, 3.90 mmol) in dioxane (20 mL). H -Pyrazole (500 mg, 4.87 mmol), copper thiophenecarboxylate (CuTC, 277 mg, 1.46 mmol), and phenanthroline (Bphen, 162 mg, 0.48 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was filtered, concentrated, and purified by silica gel column chromatography to give the title product (100 mg, 0.44 mmol, 9.05%) as a blue oil. LCMS ( m / z) 227.1 [M+H] + Step 3. 3-(3-chloro-1) H Synthesis of pyrazol-1-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T56) The title compound was prepared primarily via a 4-step, 3-step method. LCMS ( m / z ): 213.1[M+H] + The following compounds were prepared basically according to the method used for preparation 26. Preparation 27 2,3,4-Trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (T60) Step 1. 2,3,4-Trimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Synthesis of pyridine (T60) Pd2(dba)3 (89.6 mg, 0.098 mmol), X-Phos (93.3 mg, 0.196 mmol), and K2CO3 (1081 mg, 7.824 mmol) were added to a solution of P4 (500 mg, 1.956 mmol) in toluene (5 mL) and H2O (0.5 mL), and the reaction mixture was stirred overnight at 110 °C under N2. The reaction mixture was filtered through a diatomaceous earth mat and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude substance was purified by silica gel column chromatography to give the title compound (113 mg, 0.696 mmol, 36%) as a brown solid. LCMS ( m / z ): 162.9 [M+H] + Preparation 28 3-Fluoro-2,4-Dimethyl-6,7-Dihydro-5 H -pyrrolo[3,4- b Pyridine hydrochloride (T65) Step 1. Synthesis of 3-cyano-5-fluoro-4,6-dimethylpyridin-2-yl trifluoromethanesulfonic acid ester (T61) At 0°C, 5-fluoro-4,6-dimethyl-2-oxo-1 H A solution of pyridine-3-carboxynitrile (45 g, 270.823 mmol) and 4-(dimethylamino)pyridine (99.26 g, 812.470 mmol) in pyridine (450 mL) was added to trifluoromethanesulfonic anhydride (229.22 g, 812.470 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was poured into ice water (500 mL) and extracted with EA (200 mL × 3). The organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 5:1) to give the title compound (20 g, 60.36 mmol, 22%) as a yellow oil. LCMS ( m / z ): 299.0 [M+H] + Step 2. Synthesis of 3-cyano-5-fluoro-4,6-dimethylpyridinecarboxylic acid (T62) A solution of T61 (5 g, 16.767 mmol) in DMSO (50 mL) was added with 1,3-bis(diphenylphosphino)propane (0.83 g, 2.012 mmol), Pd(OAc)₂ (0.38 g, 1.677 mmol), TEA (7.0 mL, 50.300 mmol), and H₂O (18.2 mL, 1006.002 mmol). The mixture was then stirred at 65 °C under 1 MPa CO₂ atmosphere for 12 h. The mixture was purified by reversed-phase rapid chromatography under the following conditions ([column, C18; mobile phase A: water (0.05% TFA), B: MeCN]) to give the title compound (900 mg, 4.172 mmol, 25%) as a yellow oil. LCMS ( m / z ): 195.0 [M+H] + Step 3. Synthesis of methyl 3-cyano-5-fluoro-4,6-dimethylpyridinecarboxylate (T63) At room temperature, a solution of T62 (300 mg, 1.545 mmol) in Et2O (3 mL) and MeOH (1.5 mL) was added to (diazomethyl)trimethylsilane (1.55 mL, 3.090 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum to give a crude title compound (400 mg, 1.729 mmol, 112%) as a green solid, which was used in the next step without further purification. LCMS ( m / z) 209.1 [M+H] + Step 4. 3-Fluoro-2,4-dimethyl-5,6-dihydro-7 H -pyrrolo[3,4- b Synthesis of pyridin-7-one (T64) Reichelk nickel (800 mg, 13.631 mmol) was added to a solution of T63 (400 mg, 1.921 mmol) in MeOH (3 mL) at 25 °C under a 50 PSI H₂ atmosphere. The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated to give a crude title compound (300 mg, 1.499 mmol, 78%) as a brown solid. LCMS ( m / z ): 181.1 [M+H] + Step 5. 3-Fluoro-2,4-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Synthesis of pyridine hydrochloride (T65) At 0°C, borane dimethyl sulfide (2 mL) was added to a solution of T64 (300 mg, 1.665 mmol) in THF (30 mL). The mixture was then stirred at 70°C for 12 hours. The mixture was cooled to 0°C and MeOH (10 mL) was added. 6M HCl (2 mL) was then added to the mixture. The mixture was heated to 70°C for 1 hour. The mixture was concentrated to give a crude title compound (210 mg, 0.933 mmol, 56%) as a grayish-white solid, which was used in the next step without further purification. LCMS ( m / z ): 167.1 [M+H] + Preparation 29 3-Chloro-2-methoxy-4-methyl-6,7-dihydro-5 H -pyrrolo[4,3- b Pyridine TFA salt (T68) Step 1. 3-Chloro-2-methoxy-4-methyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (T67) 2-methoxy-4-methyl-5,7-dihydro-6 H -pyrrolo[3,4- b 1 g of tert-butyl pyridine-6-carboxylate (3.783 mmol) was prepared substantially according to the method described in Preparation 1, starting with 2-chloro-6-methoxy-4-methylpyridine-3-carboxynitrile; and NCS (0.51 g, 3.783 mmol) in AcOH (5 mL) was stirred overnight at room temperature. The reaction mixture was quenched with NaHCO3 (aqueous solution) at room temperature. The resulting mixture was extracted with EA (3 × 10 mL) and dried over anhydrous Na2SO4. The mixture was filtered, concentrated, and purified by silica gel column chromatography (PE:EA, 4:1) to give the title compound (300 mg, 1.004 mmol, 26%) as a grayish-white solid. LCMS ( m / z ): 299.1 [M+H] + Step 2. 3-Chloro-2-methoxy-4-methyl-6,7-dihydro-5- H -pyrrolo[3,4- b Synthesis of pyridine (T68) The mixture of T67 (200 mg, 0.669 mmol) and TFA (1 mL, 13.059 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give the crude title compound (100 mg, 0.503 mmol, 75%), which was used directly in the next step without further purification. LCMS ( m / z ): 199.1 [M+H] + Preparation 30 3-Chloro-4-methyl-2-(trifluoromethyl)-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridine (T71) Step 1. 3-Chloro-2-hydroxy-4-methyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (S4) A mixture of T67 (400 mg, 1.339 mmol) and L-trisec-butylborohydride (1519 mg, 8.033 mmol) in THF (5 mL) was stirred overnight at 80 °C. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 5:1) to give the title compound (200 mg, 0.702 mmol, 52.46%) as a brown solid. LCMS ( m / z ): 285 [M+H] + Step 2. 3-Chloro-2-iodo-4-methyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (T69) At 25°C, pyridine (0.23 mL, 2.81 mmol) and trifluoromethanesulfonic anhydride (1.585 g, 5.62 mmol) were added to a solution of S4 (375 mg, 1.41 mmol) in DCM (5 mL). The mixture was stirred for 1 hour. The solvent was removed, and the residue was dissolved in MeCN (5 mL). NaI (947 mg, 6.32 mmol) was added at 25°C. The mixture was stirred at 80°C for 2 days. Additional DCM (5 mL), TEA (0.52 mL, 3.77 mmol), and Boc2O (823 mg, 3.77 mmol) were added at 25°C, and the mixture was stirred at 40°C for 2 hours. The mixture was diluted with EtOAc and washed with saline. 3). The organic phase was dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by silica gel column chromatography to give the title compound (220 mg, 0.56 mmol, 44%) as a colorless oil. LCMS ( m / z ): 395.1 [M+H] + Step 3. 3-Chloro-4-methyl-2-(trifluoromethyl)-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (T70) CuI (106 mg, 0.56 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (161 mg, 0.84 mmol) were added to a solution of T69 (220 mg, 0.56 mmol) in DMF (1 mL). The mixture was stirred at 80 °C for 18 hours. The mixture was diluted with EtOAc and washed with brine (×3). The organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give the title compound (95 mg, 0.28 mmol, 51%) as a colorless oil. LCMS ( m / z ):337.1 [M+H] + Step 4. 3-Chloro-4-methyl-2-(trifluoromethyl)-6,7-dihydro-5- H -pyrrolo[3,4- b Synthesis of pyridine (T71) At 25°C, TFA (1 mL, 13.06 mmol) was added to a solution of T70 (95 mg, 0.28 mmol) in DCM (5 mL). The mixture was stirred for 1 hour. The mixture was purified by reversed-phase column chromatography to give the title compound (35 mg, 0.15 mmol, 52%) as a white solid. LCMS ( m / z ): 237.0 [M+H] + Preparation 31 3-(4-cyano-1-methyl-1- H (-pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T74) Step 1. 3-(4-iodo-1-methyl-1-) H Synthesis of methyl 1-pentane-1-carboxylate (T72) of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate NIS (4.36 g, 19.394 mmol) was added to a solution of P40 (2 g, 9.697 mmol) in MeCN (5 mL). The mixture was stirred at 50 °C for 2 hours. The mixture was filtered, concentrated, and purified by silica gel column chromatography to give the title compound (2.8 g, 8.430 mmol, 87%) as a white solid. LCMS ( m / z ): 333.1 [M+H] + Step 2. 3-(4-cyano-1-methyl-1- H Synthesis of methyl 1-pentane-1-carboxylate (T73) with pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate CuCN (269 mg, 3.010 mmol) was added to a solution of T72 (500 mg, 1.505 mmol) in DMF (5 mL). The mixture was heated to 140 °C for 3 hours. The reaction mixture was concentrated and purified by reversed-phase silica gel chromatography (H2O-MeCN containing 0.5% FA) to give the title compound (220 mg, 0.951 mmol, 63%) as a white solid. LCMS ( m / z ):232.1 [M+H] + Step 3. 3-(4-cyano-1-methyl-1- H Synthesis of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T74) The title compound was prepared primarily via a 4-step, 3-step method. LCMS ( m / z ): 218.1 [M+H] + Preparation of 32 3-(4-(methoxymethyl)-1-(methyl- d3 )-1 H (-pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T78) Step 1. 3-(4-formyl-1-(methyl- d3 )-1 H Synthesis of methyl 1-pentane-1-carboxylate (T75) of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate POCl3 (1 mL) was added to a solution of methyl 3-(2-(trideuterated methyl)pyrazol-3-yl)bicyclo[1.1.1]pentane-1-carboxylate (1.0 g, 4.779 mmol) in DMF (3 mL) at 80 °C, and the reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, concentrated, and purified by reversed-phase silica gel chromatography (water-MeCN containing 0.5% FA) to give the title compound (480 mg, 2.023 mmol, 42%). LCMS ( m / z ): 238.1 [M+H] + Step 2. 3-(4-(hydroxymethyl)-1-(methyl- d3 )-1 H Synthesis of methyl 1-pentane-1-carboxylate (T76) with pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate To a solution of T75 (440 mg, 1.854 mmol) in THF (8 mL) and DCM (2 mL), NaBH3CN (233.0 mg, 3.708 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, concentrated, and purified by reversed-phase silica gel chromatography (water-MeCN containing 0.5% FA) to give the title compound (180 mg, 0.752 mmol, 41%). LCMS ( m / z ): 240.1 [M+H] + Step 3. 3-(4-(methoxymethyl)-1-(methyl- d3 )-1 H Synthesis of methyl 1-pentane-1-carboxylate (T77) of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate H₂SO₄ (1 mL) was added to a solution of T76 (300 mg, 1.254 mmol) in MeOH (5 mL), and the reaction mixture was stirred at 70 °C for 1 hour. The reaction mixture was diluted with EA and brine. The organic layer was separated, washed with brine, and concentrated to give the crude title compound (280 mg, 1.105 mmol, 88%), which was used in the next step without further purification. LCMS ( m / z ): 254.2 [M+H] + Step 4. 3-(4-(methoxymethyl)-1-(methyl- d3 )-1 H Synthesis of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T78) The title compound was prepared primarily via a 4-step, 3-step method. LCMS ( m / z ): 240.1 [M+H] + Preparation of 33 3-(4-(difluoromethyl)-1-methyl-1 H (-pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T81) Step 1. 3-(4-formyl-1-methyl-1- H Synthesis of methyl 1-pentane-1-carboxylate (T79) with pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate At 0 °C, iPrMgCl (3M in THF, 1.13 mL, 2.258 mmol) was added to a solution of T72 (500 mg, 1.505 mmol) in THF (1 mL), and the reaction mixture was stirred at room temperature for 30 min. DMF (0.18 mL, 2.258 mmol) was added to the reaction mixture at 0 °C, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EA and water. The organic layer was collected, concentrated, and dried to give the crude title compound (200 mg, 0.854 mmol, 57%), which was used in the next step without further purification. LCMS ( m / z ): 253.2 [M+H] + Step 2. 3-(4-(difluoromethyl)-1-methyl-1 H Synthesis of methyl 1-pentane-1-carboxylate (T80) with pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate DAST (791.4 mg, 4.910 mmol) was added to a solution of T79 (230 mg, 0.491 mmol) in DCM (2 mL) at 0 °C, and the reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was diluted with DCM and saturated NaHCO3 solution. The organic layer was separated, washed with brine, concentrated, and purified by silica gel column chromatography to give the title compound (100 mg, 0.390 mmol, 79%). LCMS ( m / z ): 257.1 [M+H] + Step 3. 3-(4-(difluoromethyl)-1-methyl-1 H Synthesis of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T81) The title compound was prepared primarily via a 4-step, 3-step method. LCMS ( m / z ): 243.1 [M+H] + The following compounds were prepared basically according to the method used for preparing compound 33. Preparation of 34 3-(1-Methyl-4-(trifluoromethyl)-1 H (-pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T84) Step 1. 3-(1-Methyl-4-(trifluoromethyl)-1 H Synthesis of methyl 1-pentane-1-carboxylate (T83) with pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate Cu (172.2 mg, 2.71 mmol) and diphenyl(trifluoromethyl)thionium trifluoromethanesulfonate (730 mg, 1.81 mmol) were added to a solution of T72 (300 mg, 0.90 mmol) in DMF (1 mL), and the reaction mixture was stirred overnight at 60 °C. The reaction mixture was diluted with brine and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give the title compound (200 mg, 0.729 mmol, 81%) as a white solid. LCMS ( m / z ): 275.1 [M+H] + Step 2. 3-(1-Methyl-4-(trifluoromethyl)-1 H Synthesis of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T84) The title compound was prepared primarily via a 4-step, 3-step method. LCMS ( m / z ): 260.9 [M+H] + .

[0165] Preparation of 35 3-(4-(difluoromethoxy)-1-methyl-1 H (-pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T88) Step 1. 3-(4-(formyloxy)-1-methyl-1 H Synthesis of methyl 1-pentane-1-carboxylate (T85) of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate m-CPBA (4.86 g, 28.18 mmol) was added to a solution of T79 (2.2 g, 9.39 mmol) in MeCN (100 mL), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to give the crude title compound (5 g crude product), which was used in the next step without further purification. LCMS ( m / z ): 251.1 [M+H] + Step 2. 3-(4-hydroxy-1-methyl-1-yl) H Synthesis of methyl 1-pentane-1-carboxylate (T86) with pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate TEA (3.3 mL, 23.98 mmol) was added to a solution of T85 (5 g crude) in MeOH (20 mL), and the reaction mixture was stirred at 40 °C for 18 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was separated, washed with brine, concentrated, and purified by silica gel column chromatography to give the title compound (1.5 g, 5.4 mmol, 90%). LCMS ( m / z ): 223.2 [M+H] + Step 3. 3-(4-(difluoromethoxy)-1-methyl-1 H Synthesis of methyl 1-pentane-1-carboxylate (T87) of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate TMSCF2Br (571 mg, 2.81 mmol) was added to a solution of T86 (250 mg, 1.13 mmol) and K2CO3 (933 mg, 6.75 mmol) in DCM (6 mL) and H2O (6 mL) at 25 °C. The mixture was stirred at -25 °C for 2 hours. The reaction mixture was extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography to give the title compound (62 mg, 0.23 mmol, 20.2%) as a colorless gel. LCMS ( m / z ): 272.9 [M+H] + Step 4. 3-(4-(difluoromethoxy)-1-methyl-1 H Synthesis of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T88) The title compound was prepared primarily via a 4-step, 3-step method. LCMS ( m / z ): 259.1 [M+H] + The following compounds were prepared basically according to the method used for preparing 35. Preparation of 36 3-(4-cyclopropoxy-1-methyl-1-yl) H 5-pyrazole-5-yl)bicyclo[1.1.1]pentane-1-carboxylate (T91) Step 1. Methyl 3-(4-cyclopropoxy-1-methyl-1-methyl) H Synthesis of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T90) To a solution of T86 (200 mg, 0.90 mmol) in NMP (3 mL), KOH (101 mg, 1.80 mmol) and bromocyclopropane (544 mg, 4.50 mmol) were added, and the reaction mixture was stirred overnight at 120 °C. The reaction mixture was used in the next step without purification. LCMS ( m / z ): 263.1 [M+H] + Step 2. 3-(4-cyclopropoxy-1-methyl-1-yl) H Synthesis of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T91) The title compound was prepared primarily via a 4-step, 3-step method. LCMS ( m / z ): 249.0 [M+H] + Preparation of 37 3-(4-Cyclopropyl-1-methyl-1- H (-pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T93) Step 1. 3-(4-cyclopropyl-1-methyl-1-yl) H Synthesis of methyl 1-pentane-1-carboxylate (T92) of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylate Cyclopropylboronic acid (25.86 mg, 0.301 mmol), Pd(PPh3)4 (87.25 mg, 0.075 mmol), and K3PO4 (95.86 mg, 0.452 mmol) were added to a solution of T72 (50 mg, 0.151 mmol) in DMF (3 mL). After purging with N2, the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was separated, washed with brine, and concentrated to give the crude title compound (50 mg, 0.101 mmol, 67%), which was used in the next step without purification. LCMS ( m / z ): 247.2 [M+H] + Step 2. 3-(4-cyclopropyl-1-methyl-1-yl) H Synthesis of pyrazol-5-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T93) The title compound was prepared primarily via a 4-step, 3-step method. LCMS ( m / z ): 233.1 [M+H] + Preparation of 38 3-(2-methyl-2-)H (-Indazole-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T95) Step 1. 3-(2-methyl-2-) H Synthesis of methyl 1-pentane-1-carboxylate (T94) of (-indazole-3-yl)bicyclo[1.1.1]pentane-1-carboxylate At 25 °C, 4-DPAIPN (CAS No. 1846598-27-3, 15 mg, 0.02 mmol) and TFA (0.12 mL, 1.5 mmol) were added to a solution of P17 (238 mg, 0.76 mmol) in MeCN (5 mL). The mixture was stirred at 25 °C under a 405 nm lamp for 18 hours. The mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3. The mixture was extracted with DCM. The organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by reversed-phase column chromatography to give the title compound (50 mg, 0.20 mmol, 26%) as a brown solid. LCMS ( m / z ): 257.0 [M+H] + Step 2. 3-(2-methyl-2-) H Synthesis of 3-indazole-3-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (T95) The title compound was prepared primarily via a 4-step, 3-step method. LCMS ( m / z ): 243.1 [M+H] + .

[0166] The following compounds were prepared basically according to the method used to prepare 38. Preparation 39 3-((1-methyl-1 H -pyrazol-5-yl)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (T99) Step 1. 3-(1-methyl-1-yl) H Synthesis of methyl 1-pentane-1-carboxylate (T97) with pyrazole-5-carbonyl)-bicyclo[1.1.1]pentane-1-carboxylate At -20°C, 5-iodo-1-methyl-1 H A solution of pyrazole (300 mg, 1.44 mmol) was added dropwise to THF (5 mL). iPrMgCl (2M in THF, 1.11 mL, 2.22 mmol). The mixture was stirred at -20 °C for 10 min. This mixture was added at -78 °C to a solution of methyl 3-(methoxy(methyl)carbamoyl)-bicyclo[1.1.1]pentane-1-carboxylate (300 mg, 1.41 mmol) in THF (5 mL). The mixture was stirred at 0 °C for 18 h. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried, filtered, concentrated, and purified by silica gel column chromatography to give the title product (60 mg, 0.26 mmol, 23%) as a colorless oil. LCMS ( m / z ): 235.2 [M+H] + Step 2. 3-((1-methyl- ... H Synthesis of methyl pyrazol-5-yl)methyl)bicyclo-[1.1.1]pentane-1-carboxylate (T98) A solution of T97 (60 mg, 0.26 mmol) in TFA (2 mL) and triethylsilane (2 mL) was stirred at 80 °C for 18 hours. The mixture was concentrated under reduced pressure to give the crude title compound, which was used in the next step without further purification. LCMS ( m / z ): 221.1 [M+H] + Step 3. 3-((1-methyl- ... H Synthesis of pyrazol-5-yl)methyl)bicyclo[1.1.1]-pentane-1-carboxylic acid (T99) The title compound was prepared primarily via a 4-step, 3-step method. LCMS ( m / z ): 207.2 [M+H] + Preparation of 40 3-(difluoromethyl)-2,4-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridine (T108) Step 1. 2,4-Dimethyl-3-vinyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (T100). To a solution of P3 (200 mg, 0.71 mmol) in dioxane-water (10:1, v / v, 1 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (163 mg, 1.06 mmol), XPhos Pd G2 (56 mg, 0.07 mmol), and Cs2CO3 (461 mg, 1.42 mmol) were added. After purging with N2, the reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, concentrated, and purified by silica gel column chromatography to give the title compound (160 mg, 0.58 mmol, 82%). LCMS ( m / z ): 275.2 [M+H] + Step 2. 3-Formyl-2,4-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (T101). To a solution of T100 (120 mg, 0.44 mmol) in dioxane and water (1:1, v / v, 2 mL), NaIO4 (187 mg, 0.88 mmol) and K2OsO4 (32 mg, 0.09 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, concentrated, and purified by silica gel column chromatography to give the title compound (60 mg, 0.22 mmol, 50%). LCMS ( m / z ): 277.1 [M+H] + Step 3. 3-(difluoromethyl)-2,4-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (T102). DAST (58 mg, 0.36 mmol) was added to a solution of T101 (50 mg, 0.18 mmol) in DCM (2 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EA and water. The organic layer was separated, washed with brine, concentrated, and purified by silica gel column chromatography to give the title compound (65 mg) with low purity, which was used in the next step without further purification. LCMS ( m / z ): 299.1 [M+H] + Step 4. 3-(difluoromethyl)-2,4-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4-b Synthesis of pyridine (T103). HCl (4M in dioxane, 1 mL) was added to the T102 (55 mg, 0.18 mmol) in the flask. The reaction mixture was stirred at room temperature for 1 hour. The residue was concentrated and purified by reversed-phase preparative HPLC to give the title compound (15 mg, 0.08 mmol, 41%). LCMS ( m / z ): 199.1 [M+H] + Preparation 41 3-Methoxy-2,4-dimethyl-6,7-dihydro-5 H -Pyrrolo[3,4-b]pyridine hydrochloride (T106) Step 1. Synthesis of methyl 3-cyano-5-methoxy-4,6-dimethylpyridinecarboxylate (T104) XPhos PdG2 (350 mg, 0.45 mmol), MeONa (721 mg, 13.36 mmol), and MeOH (5 mL) were added to a solution of P1 (1.00 g, 4.45 mmol) in dioxane (15 mL) at room temperature. The mixture was stirred at 80 °C for 2 hours. The mixture was diluted with EtOAc, filtered, concentrated, and purified by silica gel column chromatography to give the title compound (180 mg, 0.82 mmol, 18%) as a colorless oil. LCMS ( m / z ): 221.1 [M+H] + Step 2. 3-Methoxy-2,4-dimethyl-5,6-dihydro-7 H -pyrrolo[3,4- b Synthesis of pyridin-7-one (T105). Reichelk nickel (100 mg, 1.70 mmol) was added to a solution of T104 (180 mg, 0.82 mmol) in DMF (5 mL) at room temperature. The mixture was stirred for 18 hours under a H2 atmosphere. The mixture was filtered, concentrated, and purified by reversed-phase column chromatography to give the title compound (40 mg, 0.208 mmol, 25%) as a colorless oil. LCMS ( m / z ): 193.1 [M+H] + Step 3. 3-Methoxy-2,4-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Synthesis of pyridine hydrochloride (T106). T105 (40 mg, 0.21 mmol) was added to BH3 The solution of Me₂S (2M in THF, 6 mL, 12.00 mmol) was stirred at 70 °C for 18 hours. The mixture was quenched with MeOH at 0 °C. The mixture was concentrated to give the crude title compound. The crude compound was diluted with 2M HCl solution. The mixture was stirred at 80 °C for 30 minutes. The mixture was concentrated to give the crude title compound (50 mg, 0.20 mmol, 96%) as a white solid, which was used directly in the next step without further purification. LCMS ( m / z ): 179.2 [M+H] + Preparation 42 3-Chloro-2-(methoxymethyl)-4-methyl-6,7-dihydro-5- H -pyrrolo[3,4- b Pyridine hydrochloride (T109) Step 1. 3-Chloro-2-(hydroxymethyl)-4-methyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (T107). 3-Chloroperoxybenzoic acid (1.8 g, 10.6 mmol) was added to a solution of P3 (1.0 g, 3.5 mmol) in DCM (20.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified directly by silica gel column chromatography to give a white solid. Acetic anhydride (6.3 mL) was added to the white solid, and the reaction mixture was stirred at 100 °C for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was dissolved in H2O (5.0 mL), MeOH (10.0 mL), and THF (5.0 mL). LiOH (453.1 mg, 10.8 mmol) was added to the solution, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by reversed-phase silica gel chromatography to give the title compound (190.7 mg, 0.64 mmol, 18.3%). LCMS ( m / z ): 299.1 [M+H] + Step 2. 3-Chloro-2-(methoxymethyl)-4-methyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (T108). Add NaH (10 mg, 0.25 mmol) to a solution of T107 (50 mg, 0.16 mmol) in THF (2 mL). Stir the reaction mixture at 0 °C for 30 min. Then add MeI (0.02 mL, 0.25 mmol). Stir the mixture at room temperature for 3 h. Filter the mixture, concentrate, and purify by silica gel column chromatography to give the title product (30 mg, 0.09 mmol, 57%) as a yellow solid. LCMS ( m / z ): 313.1 [M+H] + Step 3. 3-Chloro-2-(methoxymethyl)-4-methyl-6,7-dihydro-5- H -pyrrolo[3,4- b Synthesis of pyridine hydrochloride (T109). The title compound was prepared essentially following step 4 of preparation 1. LCMS ( m / z ): 213.1 [M+H] + Preparation 43 (3-Chloro-4-methyl-6,7-dihydro-5- H -pyrrolo[3,4- b 2-pyridinyl)methanol hydrochloride (T110) The title compound was prepared essentially following step 4 of preparation 1. LCMS ( m / z ): 199.1 [M+H] + Preparation of 44 3-Chloro-2-(difluoromethyl)-4-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridine hydrochloride (T113) Step 1. 3-Chloro-2-formyl-4-methyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (T111) MnO2 (250 mg, 2.876 mmol) was added to a solution of T107 (400 mg, 1.205 mmol) in DCM (4 mL), and the reaction mixture was stirred at 40 °C for 2 hours. The mixture was filtered, concentrated, and purified by silica gel column chromatography to give the title compound (300 mg, 1.011 mmol, 84%). LCMS ( m / z ): 297.1 [M+H] + Step 2. 3-Chloro-2-(difluoromethyl)-4-methyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of tert-butyl pyridine-6-carboxylate (T112). The title compound was prepared essentially according to the method described in step 2 of preparation 33. LCMS ( m / z ): 319.2 [M+H] + Step 3. 3-Chloro-2-(difluoromethyl)-4-methyl-6,7-dihydro-5- H -pyrrolo[3,4- b Synthesis of pyridine hydrochloride (T113). The title compound was prepared essentially following step 4 of preparation 1. LCMS ( m / z ): 219.1 [M+H] + Example 1 (3-Chloro-2,4-dimethyl-5,7-dihydro-6) H -pyrrolo[3,4-b]pyridin-6-yl)(3-(2-(trifluoromethyl)pyridin-4-yl)bicyclo[1.1.1]pent-1-yl) methyl ketone To a DMA (2.5 mL) solution of P4 (106.52 mg, 0.583 mmol) and P19 (100 mg, 0.389 mmol), EDCI (149.14 mg, 0.778 mmol), HOBT (105.13 mg, 0.778 mmol), and DIPEA (168.5 μL, 0.973 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase Prep-HPLC [column: XBridge BEH Shield RP18 5 μm 30 mm × 150 mm; mobile phase A: water (10 mM NH4HCO3), B: acetonitrile; 32% B to 58%) to give the title compound (37.1 mg, 0.088 mmol, 23%). 1 HNMR (400 MHz, CDCl3) δ 8.68 (d, J = 4.9 Hz, 1H), 7.51 (s, 1H), 7.34 (d, J=5.1, 2.6 Hz, 1H), 4.95 (s, 2H), 4.81 (s, 2H), 2.65 (s, 3H), 2.55 (s, 6H), 2.35 (s, 3H). LCMS ( m / z ): 421.8 [M+H] + The following compounds were prepared basically according to the method of Example 1. Examples 93 and 94 (3-Chloro-2,4-dimethyl-5,7-dihydro-6) H -pyrrolo[3,4- b Pyridin-6-yl)(3-(isoxazol-5-yl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Example 93) (3-Chloro-2,4-dimethyl-5,7-dihydro-6) H -pyrrolo[3,4- b Pyridin-6-yl)(3-(isoxazol-3-yl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Example 94) Step 1. ( E Synthesis of 3-(3-(dimethylamino)acryloyl)bicyclo[1.1.1]pentane-1-carboxylic acid (P160) The title compound was synthesized using P39 as the starting material, basically following step 3 of the preparation procedure. LC-MS (m / z): 210.0 [M+H] + Step 2. E )-1-(3-(3-chloro-2,4-dimethyl-6,7-dihydro-5- H Synthesis of pyrrolo[3,4-b]pyridin-6-carbonyl)bicyclo[1.1.1]pent-1-yl)-3-(dimethylamino)prop-2-en-1-one (P161) P4 (497.41 mg, 2.723 mmol), NMI (223.58 mg, 2.723 mmol), and TCFH (764.10 mg, 2.723 mmol) were added to a DMA (6 mL) solution of P160 (586 mg, 2.723 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc (20 mL) and water (15 mL), and the aqueous layer was extracted with EtOAc (2 × 20 mL). The organic layers were combined and washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by reversed-phase rapid chromatography [column, C18 silica gel; mobile phase A: water (0.5% NH4HCO3), B: acetonitrile, 10% to 70%] to obtain the title compound.

[0167] Step 3. (3-Chloro-2,4-dimethyl-5,7-dihydro-6) H -pyrrolo[3,4- b Synthesis of pyridin-6-yl)(3-(isoxazo-5-yl)bicyclo[1.1.1]pent-1-yl) methyl ketone (Example 93) and (3-chloro-2,4-dimethyl-5,7-dihydro-6-yl) H Synthesis of pyrrolo[3,4-b]pyridin-6-yl)(3-(isoxazo-3-yl)bicyclo[1.1.1]pent-1-yl) methyl ketone (Example 94) Hydroxylamine hydrochloride (78.1 mg, 1.123 mmol) was added to a methanol solution of P161 (210 mg, 0.562 mmol). The reaction mixture was stirred at 80 °C for 1 hour. The residue was purified by reversed-phase chromatography [column: YMCTriart C18 Ex 5 μm, 30 mm * 150 mm; mobile phase A: water (10 mM NH4HCO3), B: acetonitrile; gradient: 36% to 48%] to obtain Example 93 (first eluent) (31.2 mg, 0.091 mmol, 16%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.51 (t, J = 1.8 Hz, 1H), 6.39 (dd, J = 3.3, 1.8 Hz, 1H), 5.07 -4.83 (m, 2H), 4.74 - 4.49 (m, 2H), 2.55 (d, J = 1.9 Hz, 3H), 2.54 (s, 3H), 2.51 (s, 3H), 2.32 (d, J = 12.6 Hz, 3H). LCMS (m / z): 344.0 [M+H] + And Example 94 (Second eluate) (2.9 mg, 0.008 mmol, 2%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.87 (t, J = 1.6 Hz, 1H), 6.58 (dd, J =3.0, 1.7 Hz, 1H), 4.97 (m, 2H), 4.64 (m, 2H), 2.55(s, 3H), 2.50 (s, 3H), 2.47 (s, 3H), 2.32 (d, J = 11.6 Hz, 3H). LCMS (m / z):344.0 [M+H] + .

[0168] Examples 95 and 96 (3-Chloro-2,4-dimethyl-5,7-dihydro-6) H -pyrrolo[3,4-b]pyridin-6-yl)(3-(1-(difluoromethyl)-1 H -pyrazol-3-yl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Example 95) and (3-chloro-2,4-dimethyl-5,7-dimethyl-5,7-dihydro-6-yl) H -pyrrolo[3,4- b ]pyridin-6-yl)(3-(1-(difluoromethyl)-1 H (-pyrazol-5-yl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Example 96) Step 1. (3-(1) H -pyrazol-5-yl)bicyclo[1.1.1]pent-1-yl)(3-chloro-2,4-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of pyridin-6-yl)methyl ketone (P162) Hydrazine hydrochloride (39.94 mg, 0.583 mmol) was added to a solution of P161 (218 mg, 0.583 mmol) in MeOH (0.4 mL). The mixture was stirred at 80 °C for 1 hour. The solvent was removed, and the residue was purified by reversed-phase rapid chromatography [column, C18 silica gel; mobile phase, water (0.5% NH4HCO3), B: acetonitrile, 10% to 70%] to give the title compound (113 mg, 0.330 mmol, 57%). LCMS ( m / z ): 342.8 [M+H] + Step 2. (3-Chloro-2,4-dimethyl-5,7-dihydro-6) H -pyrrolo[3,4- b ]pyridin-6-yl)(3-(1-(difluoromethyl)-1 HSynthesis of (-pyrazol-3-yl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Example 95) and (3-chloro-2,4-dimethyl-5,7-dihydro-6-yl)-methyl ketone H -pyrrolo[3,4- b ]pyridin-6-yl)(3-(1-(difluoromethyl)-1 H Synthesis of pyrazol-5-yl)bicyclo[1.1.1]pent-1-yl)methyl ketone (Example 96) At room temperature and under N2, potassium fluoride (42.37 mg, 0.729 mmol) was added dropwise to a 2 mL solution of P162 (50 mg, 0.146 mmol) in acetonitrile (2 mL). Then, diethyl (bromodifluoromethyl)phosphonate (77.9 mg, 0.292 mmol) was added. The mixture was stirred at 30 °C for 2 hours. The mixture was diluted with water (100 mL) and EtOAc (20 mL), and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried over Na2SO4, filtered, concentrated, and purified by reversed-phase chromatography [column: YMC Triart C18 Ex 5 μm, 30 mm * 150 mm; mobile phase A: water (0.5% NH4HCO3), B: acetonitrile, 39% to 55%] to give Example 95 (first eluent) (6.5 mg, 0.013 mmol, 8%). 1 H NMR (400 MHz, CDCl3) δ 7.59 - 7.43 (m, 1H), 7.26 (s, 1H), 6.32 - 6.16 (m, 1H), 4.92 (d, J = 7.5 Hz, 2H), 4.79 (s, 2H), 2.63 (d, J = 6.2 Hz, 3H), 2.60 (s, 6H), 2.34 (s, 3H). 19 F NMR (376 MHz, CDCl3) δ -93.25, -93.30. LCMS: ( m / z ):392.9[M+H] + And Example 96 (Second eluate) (1.2 mg, 0.003 mmol, 2%). 1 H NMR (400 MHz, CDCl3) δ 7.59 - 7.43 (m, 1H), 7.26 (s, 1H), 6.32 - 6.16 (m, 1H), 4.92 (d, J=7.5 Hz, 2H), 4.79 (s, 2H), 2.63 (d, J = 6.2 Hz, 3H), 2.60 (s, 6H), 2.34 (s, 3H). 19 F NMR (376 MHz, chloroform-d) δ -93.25, -93.30. LCMS ( m / z ): 392.9 [M+H] + Example 97 ((1 s ,3 s )-3-(1 H -pyrazol-4-yl)cyclobutyl)(3-chloro-2,4-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- b pyridin-6-yl)methyl ketone TFA (1 mL, 13.059 mmol) was added to a 3 mL solution of DCM (120 mg, 0.289 mmol) from Example 53 at 0 °C. The mixture was then stirred at room temperature for 1 hour. The mixture was concentrated and purified by reversed-phase HPLC [column: XBridge BEH C18 OBD Prep column 130, 5 μm, 30 mm * 150 mm; mobile phase A: water (10 mM NH4HCO3), B: acetonitrile; 14% to 22% B] to give the title compound (10.2 mg, 0.028 mmol, 10%). 1 H NMR (400 MHz, CD3OD)δ 7.51 (s, 2H), 4.90 (s, 1H), 4.81 (t, J = 1.5 Hz, 1H), 4.75 (s, 1H), 4.69(d, J = 1.4 Hz, 1H), 3.43 (dtt, J = 23.0, 9.8, 7.8 Hz, 2H), 2.71 - 2.61 (m,2H), 2.60 (d, J = 1.1 Hz, 3H), 2.38 (d, J = 2.7 Hz, 3H), 2.36 - 2.28 (m, 2H). LCMS ( m / z ): 331.0 [M+H] + Example 98 (3-Chloro-2,4-dimethyl-5,7-dihydro-6) H -pyrrolo[3,4- b ]pyridin-6-yl)((1 s ,3 s )-3-(1-(methyl- d3 )-1 H -pyrazol-4-yl)cyclobutyl) ketone At 0 °C and N2, Example 97 (100 mg, 0.302 mmol) and iodomethane were subjected to... d 3 (43.82 mg, 0.302 mmol) of DMF (1 mL) solution was mixed with NaH (60% mineral oil, 8.71 mg, 0.363 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was poured into ice-cold NH4Cl solution (5 mL) and extracted with EtOAc (2 mL × 3). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by reversed-phase HPLC [column YMC Triart C18 Ex5 μm, 30 mm * 150 mm; mobile phase A: water (10 mM NH4HCO3), B: acetonitrile, 22% to 44%] to give the title compound (24.2 mg, 0.069 mmol, 23%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.50 (d, J = 1.4 Hz, 1H), 7.26 (s, 1H), 4.82 (s, 1H), 4.73 (s, 1H), 4.64 (s, 1H), 4.55 (s, 1H), 3.27 (d, J = 8.5 Hz,2H), 2.54 (s, 3H), 2.51 (s, 1H), 2.49 (s, 1H), 2.30 (s, 3H), 2.16 (d, J = 9.0Hz, 2H). LCMC ( m / z ): 348.1 [M+H] + The following compounds were prepared essentially according to the method of Example 95. Example 100 (3-Chloro-2,4-dimethyl-5,7-dihydro-6) H -pyrrolo[3,4- b]pyridin-6-yl)((1 s ,3 s )-3-(1-Cyclopropyl-1 H -pyrazol-4-yl)cyclobutyl) ketone At room temperature, copper diacetate hydrate (120.7 mg, 0.605 mmol), 1,10-phenanthroline (136.18 mg, 0.756 mmol), and K₂CO₃ (125.32 mg, 0.907 mmol) were added to a solution of Example 97 (100 mg, 0.302 mmol) and potassium cyclopropyltrifluoroborate (53.68 mg, 0.363 mmol) in acetonitrile (1 mL). After 1 hour, the mixture was poured into ice water (5 mL) and extracted with EtOAc (3 mL × 3). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by reversed-phase Prep-HPLC [column, YMC Triart C18 Ex 5 μm, 30 mm * 150 mm; mobile phase A: water (10 mM NH4HCO3), B: acetonitrile; 34% to 46%] to give the title compound (18.1 mg, 0.047 mmol, 15%). 1 H NMR (400 MHz, DMSO-d6) δ 7.58 (t, J = 1.2 Hz, 1H), 7.26 (t, J = 1.2 Hz, 1H), 4.81(s, 1H), 4.75 - 4.70 (m, 1H), 4.64 (s, 1H), 4.55 (d, J = 1.8 Hz, 1H), 3.63(ttd, J = 7.4, 3.9, 1.7 Hz, 1H), 3.27 (ddt, J = 10.1, 8.0, 1.9 Hz, 2H), 2.54(s, 3H), 2.52 (s, 1H), 2.49 (s, 1H), 2.30 (s, 3H), 2.16 (dtd, J = 11.4, 9.4,8.9, 4.2 Hz, 2H), 0.98 (dq, J = 6.5, 4.1, 3.2 Hz, 2H), 0.95 - 0.86 (m, 2H). LCMS ( m / z ): 370.9 [M+H] + Example 101 (3-Chloro-2,4-dimethyl-5,7-dihydro-6) H -pyrrolo[3,4- b ]pyridin-6-yl)(3-(1-methyl-1 H -pyrazol-4-yl)azacyclobutane-1-yl)methyl ketone Step 1. Synthesis of tert-butyl 3-(1-methyl-1H-pyrazole-4-yl)azacyclobutane-1-carboxylate (P163) tert-butyl 3-iodozacyclobutane-1-carboxylate (1.0 g, 3.532 mmol), Pd(PPh3)4 (0.41 g, 0.353 mmol), K3PO4 (2.25 g, 10.597 mmol) and (1-methyl-1 H A solution of pyrazol-4-yl)boronic acid (0.67 g, 5.298 mmol) in H2O (2 mL) and DMF (10 mL) was stirred at 60 °C under N2 for 2 h. The resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (3 × 15 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by reversed-phase rapid chromatography [column, C18 silica gel, mobile phase A: water (10 mM NH4HCO3, B: MeCN, 15% to 50%) to give the title compound (200 mg, 0.843 mmol, 24%). LCMS ( m / z ): 238.0 [M+H] + Step 2. Synthesis of 4-(azacyclobutane-3-yl)-1-methyl-1H-pyrazole hydrochloride (P164) A mixture of P163 (80 mg, 0.337 mmol) and HCl methanol solution (4 M, 0.5 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to give the crude title compound (80 mg), which could be used directly in the next step without further purification. LCMS: ( m / z ): 138.0 [M+H] + Step 3. Synthesis of 3-chloro-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carbonyl chloride (P165) Triphosgene (81.23 mg, 0.274 mmol) was added in portions to a stirred solution of P4 (50 mg, 0.274 mmol) in DCM (1 mL) at 0 °C. The resulting mixture was stirred at room temperature for 20 minutes. The mixture was then concentrated under vacuum to give the crude title compound (50 mg, 0.204 mmol, 75%), which could be used directly in the next step without further purification.

[0169] Step 4. Synthesis of (3-chloro-2,4-dimethyl-5,7-dihydro-6-hydropyrrolo[3,4-b]pyridin-6-yl)(3-(1-methyl-1-hydro-pyrazol-4-yl)azacyclobutane-1-yl) methyl ketone (Example 101) A solution of P165 (71.46 mg, 0.292 mmol), P164 (80 mg, 0.292 mmol), and TEA (0.12 mL, 0.875 mmol) in THF (1 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated and purified by reversed-phase Prep-HPLC [column: YMC Triart C18 ExRs 5 μm, 30 mm * 150 mm; mobile phase A: water (10 mM NH4HCO3), B: acetonitrile; 26% to 50%] to give the title compound (4.1 mg, 0.012 mmol, 4%). 1 H NMR (400 MHz, CD3OD) δ 7.62 (s, 1H), 7.49 (d, J = 0.9 Hz, 1H), 4.76 (s, 2H), 4.69 (t, J = 2.0 Hz, 2H), 4.47 (t, J = 8.3 Hz, 2H), 4.05 (dd, J = 7.9, 6.4 Hz, 2H), 3.87 (s, 3H), 3.85 - 3.77 (m, 1H), 2.59 (s, 3H), 2.36 (s, 3H). LCMS ( m / z ): 346.1 [M+H] + Example 102 racemic -((1 S ,2 S )-2-(1 H -pyrazol-4-yl)cyclopropyl)(3-chloro-2,4-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- bpyridin-6-yl)methyl ketone Step 1. Racemic - (1 R ,2 R )-2-(1-(tetrahydro-2 H -pyran-2-yl)-1 H Synthesis of 4-pyrazole-4-yl)cyclopropane-1-carboxylic acid ethyl ester (P166) racemic -((1) R ,2 R )-2-(ethoxycarbonyl)cyclopropyl)potassium trifluoroborate (714.14 mg, 3.245 mmol), 4-bromo-1-(tetrahydro-2) H -pyran-2-yl)-1 H A mixture of pyrazole (500 mg, 2.164 mmol), butyl[bis(tricyclo[3.3.1.13,7]dec-3-yl)]phosphine (155.16 mg, 0.433 mmol), Pd(OAc)2 (48.58 mg, 0.216 mmol), and Cs2CO3 (2114.89 mg, 6.491 mmol) in toluene (2 mL) / H2O (0.4 mL) was stirred at 90 °C for 2 hours under a N2 atmosphere. The resulting mixture was concentrated and purified by reversed-phase rapid chromatography [column, C18 silica gel; mobile phase A: water (0.5% NH4HCO3), B: MeCN, 10% to 50%] to give the title compound (300 mg, 0.851 mmol, 39%). LCMS ( m / z ):264.9 [M+H] + Step 2. Racemic - (1 R ,2 R )-2-(1-(tetrahydro-2H-pyran-2-yl)-1 H Synthesis of pyrazol-4-yl)cyclopropane-1-carboxylic acid (P167) To a solution of P166 (270 mg, 1.021 mmol) in THF (1 mL), a solution of LiOH (128.59 mg, 3.064 mmol) in H₂O (1 mL) and EtOH (1 mL) was added, and the mixture was stirred at 60 °C for 2 hours. The reaction mixture was concentrated under vacuum to obtain the crude title compound, which could be used in the next step without further purification. LCMS ( m / z ): 236.9[M+H] + Step 3. Racemic-(3-chloro-2,4-dimethyl-5,7-dihydro-6-) H-pyrrolo[3,4-b]pyridin-6-yl)((1 S ,2 S )-2-(1-(tetrahydro-2 H -pyran-2-yl)-1 H Synthesis of pyrazol-4-yl)cyclopropyl)methyl ketone (P168) To a solution of P167 (210 mg, 0.889 mmol) in DMA (5 mL), HATU (675.93 mg, 1.778 mmol), DIPEA (344.64 mg, 2.666 mmol), and P4 (162.34 mg, 0.889 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding H2O (3 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate (3 × 3 mL). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered, concentrated, and purified by reversed-phase rapid chromatography [column: C18 silica gel, mobile phase A: water (0.5% NH4HCO3), mobile phase B: MeCN, 10% to 50%] to give the title compound (120 mg, 0.299 mmol, 34%). LCMS ( m / z ): 401.5 [M+H] + Step 4. Racemic -((1 S ,2 S )-2-(1 H -pyrazol-4-yl)cyclopropyl)(3-chloro-2,4-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- b Synthesis of pyridin-6-yl)methyl ketone (Example 102) TFA (1 mL, 13.059 mmol) was added to a DCM (1 mL) solution of P168 (100 mg, 0.249 mmol), and the mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated and purified by reversed-phase Prep-HPLC [column: XBridgeBEH C18 OBD Prep column 130, 5 μm, 30 mm * 150 mm; mobile phase A: water (0.5% NH4HCO3), B: acetonitrile, 15% to 40%] to give the title compound (4.9 mg, 0.015 mmol, 6%). 1 H NMR (400 MHz, CD3OD) δ 7.52 (s, 2H), 5.09 (t, J =14.4 Hz, 1H), 5.02 - 4.90 (m, 1H), 4.77 (s, 1H), 4.71 (d, J = 1.5 Hz, 1H), 2.60 (s, 3H), 2.44 - 2.33 (m, 4H), 2.08 (dddd, J = 18.2, 8.2, 5.1, 4.1 Hz, 1H), 1.54 (ddd, J = 9.1, 5.1, 4.0 Hz, 1H), 1.28 (ddt, J = 8.3, 6.4, 4.2 Hz, 1H). LCMS ( m / z ): 317.0 [M+H] + The following compounds were prepared essentially according to the method of Example 99. Example 110 (3-Chloro-2,4-dimethyl-5,7-dihydro-6) H -pyrrolo[3,4- b ]pyridin-6-yl)(3-fluoro-3-(1-methyl-1 H -pyrazol-4-yl)cyclobutyl) ketone Step 1. (3-Chloro-2,4-dimethyl-5,7-dihydro-6) H -pyrrolo[3,4- b ]pyridin-6-yl)(3-hydroxy-3-(1-methyl-1 H Synthesis of pyrazol-4-yl)cyclobutyl) ketone (P169) A solution of P4 (150 mg, 0.821 mmol), P76 (161.14 mg, 0.821 mmol), TCFH (1152.12 mg, 4.106 mmol), and 1-methylimidazole (337.16 mg, 4.106 mmol) in DMA (2 mL) was stirred at room temperature for 1 hour. The reaction was quenched with H2O (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography (DCM:methanol, 20:1) to give the title compound (160 mg, 0.443 mmol, 54%). LCMS ( m / z ): 360.6 [M+H]+ Step 2. (3-Chloro-2,4-dimethyl-5,7-dihydro-6) H -pyrrolo[3,4- b ]pyridin-6-yl)(3-fluoro-3-(1-methyl-1 H Synthesis of pyrazol-4-yl)cyclobutyl) ketone (Example 110) Sulfur difluoro(N-morpholino)tetrafluoroborate (140.78 mg, 0.804 mmol) was added dropwise to a stirred solution of P169 (145 mg, 0.402 mmol) in DCM (5 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with a saturated aqueous solution of NaHCO3 (5 mL) at 0 °C. The mixture was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over Na2SO4, filtered, concentrated, and purified by reversed-phase Prep-HPLC [column: YMCTriart C18 Ex 5 μm, 30 mm * 150 mm; mobile phase A: water (10 mM NH4HCO3), B: MeCN; 35% to 42%] to give the title compound (6.2 mg, 0.017 mmol, 4%). 1 H NMR (400 MHz, DMSO-d6) δ 7.40 -7.31 (m, 1H), 6.39 (td, J = 2.3, 1.2 Hz, 1H), 4.85 (s, 1H), 4.77 (s, 1H), 4.64 (s, 1H), 4.55 (s, 1H), 3.85 - 3.75 (m, 3H), 3.75 - 3.62 (m, 1H), 3.06 -2.79 (m, 4H), 2.55 (d, J = 2.2 Hz, 3H), 2.37 - 2.24 (m, 3H). LCMS ( m / z ):363.0 [M+H] + Example 202 (3-(4-chloro-1,3-dimethyl-1) H -pyrazol-5-yl)bicyclo[1.1.1]pent-1-yl)(3-chloro-2,4-dimethyl-5,7-dihydro-6 H -pyrrolo[3,4- b pyridin-6-yl)methyl ketone Step 1. (3-Chloro-2,4-dimethyl-5,7-dihydro-6) H -pyrrolo[3,4- b ]pyridin-6-yl)(3-hydroxy-3-(1-methyl-1 H Synthesis of pyrazol-4-yl)cyclobutyl) ketone (Example 202) NCS (27.0 mg, 0.202 mmol) was added to the solution of Example 21 (50 mg, 0.135 mmol) in MeCN (2 mL), and the reaction mixture was stirred at 70 °C for 2 hours. The resulting mixture was directly purified by reversed-phase Prep-HPLC to give the title compound (22.6 mg, 0.055 mmol, 41%). 1 H NMR (400 MHz, DMSO-d6) δ 5.01 (s, 1H), 4.96 (s, 1H), 4.69 (s, 1H), 4.60 (s, 1H), 3.78 (d, 3H), 2.65 (d, 6H), 2.56 (s, 3H), 2.33 (d, 3H), 2.07 (d, 3H). LCMS ( m / z ): 405.2 [M+H] + Bioassay Measurement 1: Human M4 Calcium Mobility Measurement A stable cell line expressing human M4 mAChR was constructed using Flp-In-CHO cells (Pharmaron Flp-In-CHO-Gqi5-M4 Clone#57) expressing the chimeric Gq protein Gqi5. Cells were grown in a complete culture medium containing 90% Ham's F-12K (Hyclone SH30526.01), 10% fetal bovine serum (FBS, Ausgenex FBS500-S), 1× penicillin-streptomycin (PS, Gibco 15140122), 800 μg / mL hygromycin B (Sigma-Aldrich V900372), and 800 μg / mL G418 (Beyotime ST081).

[0170] The day before the assay, cells were washed with PBS (Solarbio P1020-500) and subjected to TrypLE when the cells were nearly confluent. TMCells were isolated using the Express enzyme (ThermoFisher Scientific 12604021). TrypLE was inactivated at a 1:3 dilution using assay medium (90% Ham's F-12K, 10% fetal bovine serum). TM Express enzyme. Centrifuge cells at 250x gravity for 3 minutes at room temperature. Remove the supernatant and resuspend the cell aggregates in assay medium at a concentration of 2.8 × 10⁻⁶. 5 Cells / mL. Cells were then added at 25 μL (7000 cells) per well to the assay plate (Corning 3764) and incubated overnight (20-24 hours) at 37°C in a humidified incubator with 5% carbon dioxide (CO2).

[0171] The next day, the culture medium was aspirated from the cell plate and replaced with 20 μL of assay buffer (1 × HBSS (Gibco 14025076) containing 20 mM HEPES (Gibco 15630080)). An equal volume of 2 × Ca2+ was added to each well. 2+ Indicator (FLIPR Calcium 6 Assay Kit, Molecular Devices R8191). Then cover the plate and incubate at 37°C in a humidified incubator with 5% carbon dioxide (CO2) for 2 hours, followed by FLIPR (Molecular Devices FLIPR) assay. Tetra The determination was carried out in ).

[0172] Compounds were prepared during incubation. The test compounds were dissolved in 100% dimethyl sulfoxide (DMSO, Sigma-Aldrich D8418) at a concentration of 10 mM. A 10-point intermediate dilution series was prepared using a liquid processing platform (Labcyte Echo 555) with 100% DMSO, 250 nL per well in a 384-well compound plate (Corning 3657). In the prepared serially diluted compound plates, 250 nL of 10 mM ACh (MCE HY-B0282, final 10 μM) or 250 nL of 100% DMSO (final 0.1%) was added to the positive and negative control wells, respectively. The compound plates were then diluted with 50 μL of assay buffer.

[0173] At the end of the 2-hour equilibration period, baseline signals were collected using FLIPR, once per second for 10 seconds before each compound addition, followed by 240 seconds of signal collection at 1-second intervals. For the first addition, 10 μL of the test compound, ACh, or DMSO was transferred from the compound plate to the cell plate. For the second and third additions, 10 μL of 6X EC was transferred, respectively. 20 ACh concentration or 10 μL 7 X EC 80 A concentration of ACh was transferred to cell plates. An ACh concentration-response curve was plotted to determine the EC50 before compound testing. 20 and EC 80 concentration.

[0174] Raw data files were exported from FLIPR ScreenWorks software. The maximum fold increase in fluorescence was determined by dividing the maximum fluorescence value obtained after compound addition by the average of the baseline values ​​before compound addition. The potency percentage of each compound concentration was calculated based on and relative to the maximum fold increase in fluorescence produced after the first addition in the positive and negative control wells on each plate. Positive control cells contained EC. 100 ACh concentrations were measured, with negative control wells containing only DMSO. Concentration and potency % values ​​were analyzed using GraphPad PRISM and fitted to a four-parameter logistic dose-response equation. The relative EC was then determined. 50 The maximum asymptote (potency) of the value (titer) and concentration response curve.

[0175] Table 3 below shows the test results for the exemplary compounds. Table 3. Relative EC values ​​of exemplary compounds 50 Value and effectiveness The above description is to be considered merely an illustration of the principles of this disclosure. Furthermore, since many modifications and variations will readily occur to those skilled in the art, it is not intended to limit the invention to the exact construction and process described above. Therefore, all suitable modifications and equivalents are to be considered to fall within the scope of the invention as defined in the following claims.

Claims

1. A compound having formula (I): (I) Or its pharmaceutically acceptable salt. in Each R 1 Independently selected from deuterium, halogen, cyano, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, cycloalkyl, -N(R) a (R) b ), -N(R a )C(=O)(R a -C(=O)N(R) a (R) b -OC(=O)-N(R) a (R) b -C(=O)R a and -C(=O)OR a The group consisting of wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, alkoxy, alkathioyl, haloalkyl, hydroxyalkyl, and cycloalkyl groups are independently and optionally influenced by one or more R groups. c replace; n1 is 0, 1, 2 or 3; Each R 2 Independently selected from deuterium, cyano, or optionally by one or more R c Substituted alkyl groups; n2 is 0, 1, 2, 3 or 4; Ring A is selected from , or The * end of ring A is connected to Y; X is selected from CH or N; m is 0, 1, or 2; q can be 0, 1, 2, 3, or 4; Each R 5 Independently selected from deuterium, halogens, and optionally by one or more R c Substituted alkyl or alkoxy; or R 5 One of them and R 3 Together with the intermediate atoms therein, they form an optional structure consisting of one or more R atoms. c Substituted cycloalkyl or heterocyclic groups; Each appearance is independent. ; Each time it appears, it is selected independently. or ; Each R 3 Independently selected from hydrogen or alkyl; n3 is 0, 1, or 2; n4 is either 0 or 1; L is selected from key, -O-, -S-, -N(R) a )-、 , , or ; i is 0, 1, or 2; j is 1, 2 is 3; k is 0, 1 is 2; Ring B is selected from the group consisting of cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Each R 4 Independently selected from deuterium, halogen, amino, cyano, hydroxyl, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclic, -N(R) a (R) b ), -N(R a )C(=O)(R a -C(=O)N(R) a (R) b -OC(=O)-N(R) a (R) b -C(=O)R a -OR a and -C(=O)OR a The group consisting of wherein the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, and heterocyclic groups are independently and optionally constituted by one or more R groups. c replace; n5 can be 0, 1, 2, 3, 4 or 5; R a and R b Each of the following groups is independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, or cycloalkyl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, and cycloalkyl groups are independently and optionally influenced by one or more R groups. c Replace; or R a and R b Together with the nitrogen atoms to which they are attached, they form cycloalkyl or heterocyclic groups optionally substituted with one or more groups independently selected from deuterium, halogen, amino, cyano, hydroxyl, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, alkoxy, alkathiol, haloalkyl, and hydroxyalkyl; and Each R c It is independently selected from the group consisting of deuterium, halogen, amino, cyano, hydroxyl, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, aryl, heteroaryl, -NH (alkyl) and -N (alkyl)2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently selected from the group consisting of deuterium, halogen, cyano, alkyl, heteroalkyl, haloalkyl, and hydroxyalkyl, wherein the alkyl, heteroalkyl, haloalkyl, and hydroxyalkyl are optionally influenced by one or more R c replace.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein each R 1 The group consisting of halogen, cyano, -CH3, -CD3, -CH2OH and -CH2OCH3 is selected independently.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n2 is 0.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n2 is 1.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 2 It is an alkyl group.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is... .

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein X is N.

9. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein X is CH.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein m is 0.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein q is 0.

12. The compound of claim 10 or 11 or a pharmaceutically acceptable salt thereof, wherein n3 and n4 are 0.

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 7 to 9, wherein m is 2.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein q is 0.

15. The compound of claim 13 or 14 or a pharmaceutically acceptable salt thereof, wherein n3 and n4 are 0.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 7 to 9, wherein m is 1.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein each R 5 It is independently selected from the group consisting of deuterium, halogen, alkyl and alkoxy groups.

18. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of: , , and .

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 16 to 18, wherein n3 and n4 are 0.

20. The compound according to any one of claims 7 to 9, or a pharmaceutically acceptable salt thereof, wherein n3 is 1 or 2, n4 is 0 or 1, and R 5 One of them and R 3 Together with the intercalated atoms, they form an array optionally formed by one or more R atoms. c Substituted cycloalkyl or heterocyclic groups.

21. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein... -CH2CH(R) 3 )-、-CH2N(R 3 )-、-CH2CH2CH(R 3 - or -CH2CH2N(R) 3 )-.

22. The compound according to claim 20 or 21, or a pharmaceutically acceptable salt thereof, wherein... Selected from , , , , , or , where the ** end is connected to L.

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is... .

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein ring A is... .

25. The compound of claim 23 or 24 or a pharmaceutically acceptable salt thereof, wherein n3 is 0 and n4 is 0.

26. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is... .

27. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein ring A is... .

28. The compound of claim 26 or 27 or a pharmaceutically acceptable salt thereof, wherein n3 is 0 and n4 is 0.

29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is -O-.

30. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is a bond.

31. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is... .

32. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein L is -CH2-, -CH2CH2- or -CH2CH2CH2-.

33. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is... .

34. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein L is -OCH2-, -CH2O-, -OCH2CH2-, -CH2OCH2- or -CH2CH2O-.

35. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is -N(R) a )-or .

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein L is -NH-, -N(CH3)-, -NHCH2-, -CH2NH-, -NHCH2CH2-, -CH2NHCH2- or -CH2CH2NH-.

37. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring B is a heteroaromatic ring.

38. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein ring B is selected from pyrazolyl, isothiazolyl, thiazolyl, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, triazolyl, oxazolyl, isoxazolyl, dihydropyrrolopyrazolyl, pyrazinyl, indazoleyl, pyrazolo[3,4-] b ]Pyridyl, 2,3-dihydro-1 H -pyrrolo[2,3- b ]pyridyl, 2,3-dihydro-1 H -pyrrolo[2,3- c ]pyridyl, 2,3-dihydro-1 H -pyrrolo[3,2- c ]pyridyl, 2,3-dihydro-1 H -pyrrolo[3,2- b ]pyridyl, 1 H -benzo[ d Imidazolyl or imidazo[1,2-] a ]Pyridyl.

39. The compound according to claim 37 or 38, or a pharmaceutically acceptable salt thereof, wherein each R 4 Independently selected from cyano, halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, heterocyclic and -OR a The group consisting of, wherein the alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclic groups are independently and optionally constituted by one or more R c replace.

40. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein each R c It is independently selected from deuterium, halogen, alkoxy, cycloalkyl, aryl, heteroaryl, -NH (alkyl) or -N (alkyl)2.

41. The compound according to claim 39 or 40, or a pharmaceutically acceptable salt thereof, wherein each R 4 It is independently selected from cyano, -F, -Cl, -CH3, -CD3, -CF3, -CF2H, -CH2CH3, -CD2CD3, -OCH3, -OCF2H, -CH2OCH3, -CH2-cyclopropyl, -O-cyclopropyl, -CH2-phenyl, -CH2CH2N(CH3)2, cyclopropyl, oxetane, tetrahydropyranyl, azirane, pyrrolidinyl or piperidinyl.

42. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein... Choose from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

43. The compound according to any one of claims 1 to 42, having a formula selected from the following: (him) (One) (Ic) (Id) (Ie) Or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

44. The compound according to claim 43, having a formula selected from the following: (I-1) (I-2) (I-3) (I-4) (Id-1) (Ie-1) Or its pharmaceutically acceptable salt.

45. The compound of claim 44 or a pharmaceutically acceptable salt thereof, wherein each R 1 Independently selected from the group consisting of halogen, cyano, alkyl, heteroalkyl, haloalkyl, and hydroxyalkyl, wherein the alkyl, heteroalkyl, haloalkyl, and hydroxyalkyl are independently and optionally derived from one or more R c Replace, and each R c It is independently selected from deuterium, halogen, hydroxyl or alkoxy.

46. ​​The compound of claim 44 or 45 or a pharmaceutically acceptable salt thereof, wherein L is a bond, O or -CH2-.

47. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 44 to 46, wherein ring B is a heteroaryl group.

48. The compound according to any one of claims 44 to 47, or a pharmaceutically acceptable salt thereof, wherein each R 4 Independently selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclic groups, wherein the alkyl, haloalkyl, alkoxy, cycloalkyl, and heterocyclic groups are independently and optionally influenced by one or more R groups. c Replace, and each R c It is independently selected from deuterium, halogen, alkoxy, cycloalkyl, aryl, heteroaryl, -NH (alkyl) or -N (alkyl)2.

49. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any of the compounds set forth in Table 1 or 2.

50. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 49 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

51. A method of treating a disease or medical condition by modulating M4 and / or M4-related cellular processes, comprising administering to a subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-49, or a pharmaceutical composition according to claim 50.

52. The method of claim 51, wherein the disease or medical condition treated by modulating M4 and / or M4-related cellular processes is selected from the group consisting of: schizophrenia, bipolar disorder, post-traumatic stress disorder (PTSD), autism, chronic or acute pain, addiction, sleep disorders, Alzheimer's disease, Lewy body dementia, Parkinson's disease dementia, frontotemporal dementia, and age-related TDP-43 with limbic system predominance. Encephalopathy, mild cognitive impairment, drug-induced motor difficulties, drug-induced psychotic symptoms, progressive supranuclear palsy, Huntington's disease, xerostomia, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, intestinal obstruction, intestinal stasis, inflammatory bowel disease, urinary incontinence, urinary retention, glaucoma, ocular hypertension, skin lesions, Down syndrome, cerebral amyloid angiopathy, Dutch hereditary cerebral hemorrhage with amyloidosis (HCHWA-D), Creutzfeldt-Jakob disease, Prion's disease, amyotrophic lateral sclerosis, inclusion body myositis, other forms of peripheral amyloidosis, diabetes, atherosclerosis, head trauma, stroke, alcoholic liver disease, pancreatitis.

53. The method of claim 52, wherein the disease or medical condition treated by regulating M4 and / or M4-related cellular processes is selected from the group consisting of: schizophrenia, bipolar disorder, chronic or acute pain, addiction, Alzheimer's disease, Huntington's disease, drug-induced motor difficulties, inflammatory bowel disease, and skin lesions.

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