1, 6-naphthyridine derivatives as muscarinic acetylcholine receptor M4 positive allosteric modulators useful for treatment of neurological and psychiatric disorders

Abstract

5, 6, 7, 8-tetrahydro-1, 6-naphthyridines and derivatives thereof, which are substituted in the 6 position with 6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one, furo [3, 4-b] pyridin-5 (7H)-one, 6, 7-dihydro-5H-cyclopenta [b] pyridin-5-one, or [1, 2, 4] triazolo [4, 3-a] pyrimidine-3 (2H)-one, are positive allosteric modulators of muscarinic acetylcholine receptor M4 (mAChR M4), and can be used for treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction.

Description

[0001] Cross-reference to related applications This application claims priority to U.S. Provisional Application No. 63 / 496,811, filed April 18, 2023, and U.S. Provisional Application No. 63 / 610,209, filed December 14, 2023, each of which is incorporated herein by reference in its entirety. Technical Field

[0002] This disclosure relates to compounds, compositions, and methods for treating neurological and mental disorders associated with muscarinic acetylcholine receptor dysfunction. Background Technology

[0003] Cholinergic neurotransmission involves the activation of nicotinic acetylcholine receptors (nAChR) or muscarinic acetylcholine receptors (mAChR) via the binding of the endogenous ortho-agonist acetylcholine (ACh). Conditions associated with cognitive impairment, such as Alzheimer's disease, are accompanied by a decrease in acetylcholine levels in the brain. This is thought to be a result of the degeneration of basal forebrain cholinergic neurons, which extensively innervate multiple brain regions, including the associative cortex and hippocampus, which play key roles in higher processes. Clinical data support that cholinergic dysfunction contributes to cognitive deficits in patients with schizophrenia. Efforts to increase acetylcholine levels have focused on increasing choline levels (the precursor to acetylcholine synthesis) and blocking acetylcholinesterase (AChE) (the enzyme that metabolizes acetylcholine). Therefore, acetylcholinesterase (AChE) inhibitors, which inhibit the hydrolysis of ACh, have been approved in the United States for palliative treatment of cognitive deficits in patients with AD, but not for disease-modifying therapy.

[0004] Attempts to enhance central cholinergic function through the administration of choline or phosphatidylcholine have not been successful. AChE inhibitors have shown therapeutic efficacy, but frequent cholinergic side effects, including abdominal cramps, nausea, vomiting, and diarrhea, have been observed due to peripheral acetylcholine stimulation. These gastrointestinal side effects have been observed in approximately one-third of treated patients. Furthermore, some AChE inhibitors, such as tacrine, have been found to cause significant hepatotoxicity, with elevated liver transaminases observed in approximately 30% of patients. The side effects of AChE inhibitors have severely limited their clinical application. An alternative pharmacological approach to targeting cholinergic dysfunction is to activate mAChR, which is widely expressed throughout the body.

[0005] mAChR is a member of the G protein-coupled receptor (GPCR) family A, and includes five subtypes, named M1-M5. Subtypes M1, M3, and M5 are primarily associated with G... q It couples with and activates phospholipase C, while the M2 and M4 isoforms are mainly associated with G. i / oCoupled with related effector systems. Five distinct mAChR subtypes have been identified in the mammalian central nervous system, where they are ubiquitous and differentially expressed. M1–M5 play different roles in cognition, sensation, motor function, and autonomic function. Therefore, without being bound by any particular theory, selective agonists of mAChR subtypes believed to regulate processes involved in cognitive function could prove to be excellent therapies for treating psychosis, schizophrenia, and related disorders. Muscarinic M4 receptors have been shown to play important roles in cognitive processes and are believed to play a significant role in the pathophysiology of psychotic disorders, including schizophrenia.

[0006] Evidence suggests that the most significant side effects of AChE inhibitors and other cholinergic agents are mediated by activation of peripheral M2 and M3 mAChRs, and include bradycardia, gastrointestinal upset, excessive salivation, and sweating. In contrast, M4 is considered the most likely subtype to mediate dysfunction of muscarinic acetylcholine receptors in psychotic disorders, including schizophrenia, cognitive impairment, and neuropathic pain. Therefore, considerable effort has been focused on developing selective M4 agonists for the treatment of these disorders. Unfortunately, these efforts have largely been unsuccessful due to the inability to develop compounds with high selectivity for mAChR M4. Consequently, mAChR agonists already tested in clinical studies induce a range of side effects by activating peripheral mAChRs. To fully understand the physiological roles of individual mAChR subtypes and further explore the therapeutic utility of mAChR ligands in psychosis, including schizophrenia, cognitive impairment, and other disorders, it may be important to develop compounds that act as highly selective activators of mAChR M4 and other individual mAChR subtypes.

[0007] Previous attempts to develop agonists with high selectivity for single mAChR isoforms have failed due to the highly conserved ortho-ACh binding site. To circumvent the problems associated with targeting highly conserved ortho-ACh binding sites, compounds that act at allosteric sites on the mAChR, which are distant from the ortho-site and less conserved, are believed to have been developed. This approach has proven highly successful in developing selective ligands for multiple GPCR isoforms. In the case of mAChR, the primary goal is to develop allosteric ligands that selectively increase the activity of mAChR M4 or other mAChR isoforms. Allosteric activators can include allosteric agonists, whose sites of action differ from the ortho-site, and which can directly activate the receptor in the absence of ACh; and positive allosteric modulators (PAMs), which do not directly activate the receptor but enhance the activation of the receptor by endogenous ortho-ACh agonists. Furthermore, a single molecule may possess both allosteric synergist and allosteric agonist activities.

[0008] Recently, muscarinic agonists (including xanthipone) have shown similar activity to known antipsychotics in animal models, but without causing static disorder (Bymaster et al.). Eur. J. Pharmacol. [European Journal of Pharmacology] 1998, 356, 109, Bymaster et al. Life Sci. [Life Sciences] 1999, 64, 527; Shannon et al., J. Pharmacol. Exp. Ther. [Journal of Pharmacology and Experimental Therapeutics] 1999, 290, 901; Shannon et al., Schizophrenia Res. [Schizophrenia Research] 2000, 42, 249. Furthermore, fenofibrillarine has been shown to reduce psychotic behavioral symptoms in Alzheimer's patients, such as delusions, paranoia, vocal outbursts, and hallucinations (Bodick et al., 2000). Arch. Neurol. [Neurology Literature] 1997, 54, 465), however, treatment-related side effects (such as gastrointestinal effects) have severely limited the clinical efficacy of this compound.

[0009] Despite progress in the study of muscarinic acetylcholine receptors, there remains a lack of potent, effective, and selective M4mAChR activators, as well as compounds effective in treating neurological and psychiatric disorders associated with cholinergic activity and diseases involving muscarinic M4 receptors. Summary of the Invention

[0010] On the one hand, compounds having formula (I) or pharmaceutically acceptable salts thereof are disclosed. in: G 1 yes X 1 It is NR 5 O or CR 5A R 5B ; X 2 It is CR 6 Or N; R 1 and R 3 Each is independently hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Fluoroalkyl, –OC 1-4 Alkyl, or –OC 1-4 fluoroalkyl; R 2 It is G 2 –NR b R c C1-6 Halogenated alkyl groups, halogens, cyano groups, NO2, C 1-6 Alkyl, C 2-6 alkenyl, –OR b –NR c C(O)R b –NR c SO2R a –N=S(O)(R a )2、–P(O)(R a )2、–C 1-3 Alkylene–G 2 –C 2-4 alkenyl–G 2 , or hydrogen; R a It is C independently each time it appears. 1-6 Alkyl, C 1-6 Haloalkyl, G 2 、or –C 1-3 Alkylene–G 2 ; Wherein, –N=S(O)(R a )2 or –P(O)(R a The two Rs in )2 a They are linked together to form a straight-chain alkylene chain, thus forming a 5- to 7-membered heterocycle; R b and R c Independently, it is hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl, G 2 、or –C 1-3 Alkylene–G 2 ; G 2 Each time it appears, it is independently a 5- to 12-membered heteroaryl, 6- to 12-membered aryl, 4- to 12-membered heterocyclic, or 3- to 12-membered carbocyclic, wherein each of the heteroaryl and heterocyclic groups contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and G 2 Selected arbitrarily from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, oxo, –OR x –N(R) x )2、–SR x –SO2R x –C(O)R x –C(O)OR x –C(O)N(R) x )2、–C 1-6 Alkylene – OR x –C 1-6alkylene–N(R) x )2、G 2a 、 and –C 1-3 Alkylene–G 2a The first substituent of the group is substituted, and optionally further independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and –OR x The group consists of 1-4 substituents; R x Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, –C 1-3 alkylene–C 3-6 cycloalkyl, phenyl, or –C 1-3 Alkylene-phenyl, wherein each cycloalkyl or phenyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of: halogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; G 2a It is a phenyl group, a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, or a 3- to 8-membered carbocyclic group, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 2a Each time it appears, it is independently and optionally substituted by 1-5 substituents selected independently from the following group: halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, –C 1-6 Alkylene –OH, oxo, OH, –OC 1-4 Alkyl, –OC 1-4 Haloalkyl, C 3-4 cycloalkyl and –C 1-3 alkylene–C 3-4 cycloalkyl; R 4A and R 4B Independently, it is hydrogen and C 1-4 Alkyl, C 3-4 cycloalkyl, or –C 1-3 alkylene–OH; R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 fluoroalkyl, –C 1-6 Alkylene–R y –C 1-6 Fluoride-R y G 5 、or –C 1-3 Alkylene–G5 ; R 5A and R 5B Independently, it is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkyl, or –C 1-4 alkylene–OH; R y Yes – OR 5a –N(R) 5a )2、–C(O)R 5a –C(O)OR 5a 、or –C(O)N(R) 5a )2; R 5a Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 fluoroalkyl, G 5 、or –C 1-3 Alkylene–G 5 ; G 5 It is a phenyl group, a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, or a C-shaped group. 3-8 Cycloalkyl groups, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 5 Optionally substituted by 1-4 substituents independently selected from the group consisting of: halogen, cyano, C 1-4 Alkyl, C 1-2 Fluoroalkyl, –OC 1-4 Alkyl, OH, and oxo; Alternatively, R 4A and R 4B Together with the carbon attached to them, they form C 3-6 cycloalkyl; or R 4B and R 5 Together with the atoms to which they are attached, they form 5- to 7-membered heterocycles that optionally contain an additional heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; R 6 It is hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 fluoroalkyl, C 2-4 alkenyl, –OR 6a –N(R) 6a )2、–C 1-3 Alkylene – OR 6a or C 3-6 cycloalkyl; R 6a Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4fluoroalkyl, C 3-4 cycloalkyl, or –C 1-3 alkylene–C 3-4 cycloalkyl; Alternatively, the two Rs 6a Together with the nitrogen to which they are attached, they form 4 to 8-membered heterocycles containing R 6a The attached nitrogen and optionally containing 1-2 additional heteroatoms, independently of O, N, or S, the heterocycle optionally being substituted by 1-4 substituents independently selected from the group consisting of: halogens, C 1-2 Alkyl and C 1-2 fluoroalkyl; R 7 It is C 1-4 Alkyl, hydrogen, halogen, cyano, C 1-4 fluoroalkyl, –OR 7a –C 1-3 Alkylene – OR 7a 、or G 7 ; Alternatively, R 6 and R 7 Together with the atoms to which they are attached, they form a 5- to 7-membered heterocycle or a 5- to 7-membered carbon ring containing one heteroatom, wherein the heteroatom is independently selected from the group consisting of N, O, and S, and the heterocycle and carbon ring are optionally substituted by 1 to 4 substituents independently selected from the group consisting of: C 1-4 Alkyl, halogen, –OC 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl and C 1-2 Alkylene-C 3-4 cycloalkyl; R 7a It is hydrogen, C 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or –C 1-3 alkylene–C 3-4 cycloalkyl; G 7 It is a phenyl group, a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, or a C-shaped group. 3-6 Cycloalkyl groups, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 5 Optionally substituted by 1-4 substituents independently selected from the group consisting of: halogen, cyano, C 1-4 Alkyl, C 1-2 Fluoroalkyl, –OC 1-4 Alkyl, OH, and oxo; R 8Each time it appears, it is independently halogen, C. 1-4 Alkyl, C 1-4 fluoroalkyl, or C 3-4 cycloalkyl; and n is 0, 1, 2, 3, or 4; Where R 6 R 6a R 7 R 7a and R 8 Each cycloalkyl group at the position is unsubstituted or independently selected from C10. 1-4 Alkyl groups (e.g., methyl) and halogens (e.g., fluorine) are substituted with 1 to 4 substituents.

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] On the other hand, methods are provided for treating neurological and / or mental disorders in mammals associated with dysfunction of muscarinic acetylcholine receptors, the methods comprising administering to the mammal a therapeutically effective amount of a compound having formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0013] On the other hand, compounds having formula (I), or pharmaceutically acceptable salts or compositions thereof, are provided for use in the treatment of neurological and / or mental disorders in mammals associated with dysfunction of muscarinic acetylcholine receptors.

[0014] On the other hand, the use of a compound having formula (I), or a pharmaceutically acceptable salt or composition thereof, in the preparation of a medicament for treating neurological and / or mental disorders in mammals associated with dysfunction of muscarinic acetylcholine receptors is provided.

[0015] In another aspect, the present invention provides a kit comprising a compound having formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use. Detailed Implementation

[0016] This article discloses positive allosteric modulators (i.e., synergists) of the muscarinic acetylcholine receptor M4 (mAChR M4), their preparation methods, pharmaceutical compositions comprising them, and methods of using them to treat neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. The compounds include naphthidine-substituted pyridazine compounds.

[0017] The human muscarinic acetylcholine receptor M4 (mAChR M4) is a 479-amino acid protein encoded by the CHRM4 gene. The unglycosylated protein has a molecular weight of approximately 54 kDa and is a transmembrane GPCR. As mentioned above, mAChR M4 is a member of the GPCRA family or a rhodopsin-like GPCR, characterized by structural features similar to rhodopsin, such as seven transmembrane segments. The N-terminus of the muscarinic acetylcholine receptor faces the extracellular membrane surface, while the C-terminus is located on the cytoplasmic surface.

[0018] Previous attempts to develop agonists with high selectivity for a single mAChR isotype have failed due to the highly conserved ortho-ACh binding site. To circumvent the problems associated with targeting highly conserved ortho-ACh binding sites, compounds are believed to have been developed that function at allosteric sites on the mAChR, which are distant from the ortho-site and less conserved. Without being bound by a specific theory, the disclosed compounds and products of the disclosed methods are believed to bind to allosteric sites different from the ortho-binding sites.

[0019] 1. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, this document (including the definitions) shall prevail. While similar or equivalent methods and materials to those described herein may be used in the practice or testing of the invention, preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0020] As used herein, the terms “comprise(s)”, “include(s)”, “having / has”, “can”, “contain(s)”, and variations thereof are intended as open-ended transitional phrases, terms, or words that do not exclude the possibility of additional actions or structures. Unless explicitly stated otherwise in the context, the singular forms “a / an” and “the” include a plural of indicators. This disclosure also contemplates other embodiments that “comprise”, “consist of,” and “substantially constitute” the embodiments or elements presented herein, whether or not explicitly stated.

[0021] The modifier “about” used with a quantity includes the value and has the meaning indicated by the context (e.g., it includes at least the degree of error associated with the measurement of a particular quantity). The modifier “about” should also be considered as disclosing a range defined by the absolute values ​​of the two endpoints. For example, the expression “about 2 to about 4” also discloses a range of “2 to 4”. The term “about” can refer to a positive or negative 10% of the indicated number. For example, “about 10%” can represent a range of 9% to 11%, and “about 1” can mean 0.9 to 1.1. Other meanings of “about” are apparent from the context, such as rounding; therefore, for example, “about 1” can also mean 0.5 to 1.4.

[0022] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified according to the periodic table, CAS edition, Handbook of Chemistry and Physics, 75th edition, inner cover, and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in... Organic Chemistry [Organic Chemistry], Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry [March's Advanced Organic Chemistry], 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations [Organic Functional Group Transformation], VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis [Some Modern Organic Synthesis Methods], 3rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of these are incorporated herein by reference.

[0023] As used herein, the term "alkoxy" refers to an alkyl group as defined herein, which is attached to a portion of a parent molecule by an oxygen atom. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.

[0024] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon chain. The terms "lower alkyl" or "C" refer to... 1-6 "Alkyl" refers to a straight-chain or branched hydrocarbon containing 1 to 6 carbon atoms. The term "C"... 1-4"Alkyl" refers to a straight-chain or branched saturated hydrocarbon containing 1 to 4 carbon atoms. Representative examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0025] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon chain containing at least one carbon-carbon double bond.

[0026] As used herein, the term "alkoxyalkyl" refers to an alkoxy group, as defined herein, attached to a portion of a parent molecule via an alkyl group as defined herein.

[0027] As used herein, the term "alkoxyfluoroalkyl" refers to an alkoxy group, as defined herein, attached to a portion of a parent molecule via a fluoroalkyl group as defined herein.

[0028] As used herein, the term "alkylene" refers to a divalent group derived from a straight-chain or branched saturated hydrocarbon (e.g., a straight-chain or branched saturated hydrocarbon having 1 to 6 carbon atoms). Representative examples of alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0029] As used herein, the term "alkylamino" means at least one alkyl group, as defined herein, attached to a portion of a parent molecule via an amino group as defined herein.

[0030] As used herein, the term "amide" means -C(O)NR- or -NRC(O)-, where R can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, or heteroalkyl.

[0031] As used herein, the term "aminoalkyl" means at least one amino group, as defined herein, attached to a portion of a parent molecule via an alkylene group as defined herein.

[0032] As used in this article, the term "amino" refers to –NR x R y , where R x and R y It can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, or heteroalkyl. In the case of an aminoalkyl group or any other part where the amino group is attached to two other parts, the amino group can be –NR. x –, where R xIt can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, or heteroalkyl.

[0033] As used herein, the term "aryl" refers to a phenyl group or a phenyl group attached to a parent molecule and fused to a cycloalkane group (e.g., the aryl group may be indan-4-yl), fused to a 6-membered aromatic group (i.e., the aryl group is naphthyl), or fused to a non-aromatic heterocycle (e.g., the aryl group may be benzo[d][1,3]m-dioxacyclopenten-5-yl). The term "phenyl" is used when referring to a substituent, and the term "6-membered aromatic" is used when referring to a fused ring. A 6-membered aromatic is monocyclic (e.g., benzene or benzo). The aryl group may be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic system).

[0034] As used herein, the term "cyanoalkyl" means at least one -CN group attached to a parent molecule portion via an alkylene group as defined herein.

[0035] As used herein, the term "cyanofluoroalkyl" means at least one -CN group attached to a parent molecule portion via a fluoroalkyl group as defined herein.

[0036] As used herein, the term "cycloalkoxy" refers to a cycloalkyl group as defined herein that is attached to a portion of the parent molecule via an oxygen atom.

[0037] As used herein, the term “cycloalkyl” or “cycloalkane” refers to a saturated ring system containing all carbon atoms as ring members and without double bonds. When present as a substituent, the term “cycloalkyl” as used herein refers to a cycloalkane. A cycloalkyl group can be a monocyclic cycloalkyl group (e.g., cyclopropyl), a fused bicyclic cycloalkyl group (e.g., decahydronaphthyl), or a bridged cycloalkyl group in which two non-adjacent atoms of the ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclic [2.2.1]heptyl). Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclic [1.1.1]pentyl.

[0038] As used herein, the term “cycloalkenyl” or “cycloalkene” refers to a non-aromatic monocyclic or polycyclic system containing all carbon atoms as ring members and at least one carbon-carbon double bond, and preferably having 5-10 carbon atoms per ring. When present as a substituent, the term “cycloalkenyl” as used herein refers to a cycloalkene. A cycloalkenyl can be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a fused bicyclic cycloalkenyl (e.g., octahydronaphthyl), or a bridged cycloalkenyl where two non-adjacent atoms of the ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclic [2.2.1]heptenyl). Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0039] The term "carbocyclic" refers to "cycloalkyl" or "cycloalkenyl". The term "carbocyclic" refers to "cycloalkanes" or "cycloalkenes". When present as a substituent, the term "carbocyclic" refers to a "carbocyclic ring".

[0040] As used herein, the term "fluoroalkyl" means an alkyl group as defined herein in which one, two, three, four, five, six, seven, or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkyl groups include, but are not limited to, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl, such as 3,3,3-trifluoropropyl.

[0041] As used herein, the term "fluoroalkylene" means an alkylene group as defined herein in which one, two, three, four, five, six, seven, or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkylene groups include, but are not limited to: –CF2–, –CH2CF2–, 1,2-difluoroethylene, 1,1,2,2-tetrafluoroethylene, 1,3,3,3-tetrafluoropropylene, 1,1,2,3,3-pentafluoropropylene, and perfluoropropylene, such as 1,1,2,2,3,3-hexafluoropropylene.

[0042] As used herein, the term "fluoroalkoxy" means at least one fluoroalkyl group as defined herein, which is attached to a portion of a parent molecule via an oxygen atom. Representative examples of fluoroalkoxy groups include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0043] As used in this article, the term "halogen" or "halo" refers to Cl, Br, I, or F.

[0044] As used herein, the term “halogenated alkyl” means an alkyl group as defined herein in which one, two, three, four, five, six, seven, or eight hydrogen atoms are replaced by a halogen.

[0045] As used herein, the term “haloalkoxy” means at least one haloalkyl group as defined herein that is attached to a portion of the parent molecule by an oxygen atom.

[0046] As used herein, the term “halocycloalkyl” means a cycloalkyl group in which one or more hydrogen atoms are replaced by a halogen, as defined herein.

[0047] As used herein, the term "heteroalkyl" means an alkyl group as defined herein in which one or more carbon atoms are replaced by a heteroatom selected from S, O, P, and N. Representative examples of heteroalkyl groups include, but are not limited to, alkyl ethers, secondary alkylamines, tertiary alkylamines, amides, and alkyl sulfides.

[0048] As used herein, the term "heteroaryl" refers to a ring containing an aromatic monocyclic heteroatom (monocyclic heteroaryl) or a bicyclic system containing at least one monocyclic heteroaromatic ring (bicyclic heteroaryl). When present as a substituent, the term "heteroaryl" as used herein refers to a heteroaromatic hydrocarbon. A monocyclic heteroaryl is a five- or six-membered ring containing at least one heteroatom independently selected from the group consisting of N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N). A five-membered aromatic monocyclic ring has two double bonds, and a six-membered aromatic monocyclic ring has three double bonds. Bicyclic heteroaryl groups are 8- to 12-membered ring systems and include fused bicyclic heteroaryl ring systems (i.e., 10π electron systems), such as monocyclic heteroaryl rings fused to 6-membered aromatic hydrocarbons (e.g., quinoline-4-yl, indole-1-yl), monocyclic heteroaryl rings fused to monocyclic heteroaryl hydrocarbons (e.g., naphthidyl), and phenyl groups fused to monocyclic heteroaryl hydrocarbons (e.g., quinoline-5-yl, indole-4-yl). Bicyclic heteroaryl / heteroaryl groups include 9-membered fused bicyclic heteroaryl ring systems having four double bonds and at least one heteroatom (contributing a lone pair of electrons to a fully aromatic 10π electron system), such as ring systems with a nitrogen atom at the ring junction (e.g., imidazopyridine) or benzoxadiazolyl. Bicyclic heteroaryl groups also include fused bicyclic systems consisting of a heteroaromatic ring and a non-aromatic ring, such as a monocyclic heteroaryl ring fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopentadienyl[b]pyridyl) or a monocyclic heteroaryl ring fused to a monocyclic heterocycle (e.g., 2,3-dihydrofuran[3,2-b]pyridyl). Bicyclic heteroaryl groups are attached to the parent molecule at the aromatic ring atom. Other representative examples of heteroaryl groups include, but are not limited to: indolyl (e.g., indol-1-yl, indol-2-yl, indol-4-yl), pyridyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrroleyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl Imidazolyl, thiazolyl (e.g., thiazolyl-4-yl), isothiazolyl, thiophene, benzimidazolyl (e.g., benzimidazol-5-yl), benzothiazolyl, benzooxazolyl, benzooxadiazolyl, benzothiaphene, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purine, isoindoleyl, quinoxolinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[1,2- a ]pyridyl (e.g., imidazo[1,2-a]pyridin-6-yl), naphridyl, pyridinoimidazoyl, thiazo[5,4- b ]pyridin-2-yl and thiazo[5,4- d]Pyrimidine-2-yl.

[0049] As used herein, the term "heterocyclic" or "of a heterocyclic ring" refers to a monocyclic, bicyclic, or tricyclic heterocyclic ring. When present as a substituent, the term "heterocyclic group" as used herein refers to a heterocycle. A monocyclic heterocycle is a ternary, quaternary, pentaneary, hexanal, septaneary, or octaneary ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A ternary or quaternary ring contains zero or one double bond and one heteroatom selected from the group consisting of O, N, and S. A pentaneary ring contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A hexanal ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A octaneary or octaneary ring contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocyclic groups include, but are not limited to: aziridine, aziridine-heptane, acridine, diaziridine-heptane, 1,3-dioxane, 1,3-dioxopentane, 1,3-dithiopentane, 1,3-dithiaalkyl, imidazolinyl, imidazolinyl, isothiazolinyl, isothiazolinyl, isoxazolinyl, isoxazolinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoaziridine-heptane-3-yl, oxadiazolinyl, oxadiazolinyl, oxazolinyl, oxazolinyl, oxazolinyl, oxaziridine, oxadiazolinyl, oxazolinyl, oxaziridine, oxadiazolinyl, oxaziridine, oxadiazolinyl, oxaziridine, oxadiazolinyl, oxaziridine, aziridine Alkyl, oxoheptanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolinyl, pyrrolinyl, pyrrolylyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl, thiazinanyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolinyl, thiomorpholinyl, 1,1-thiomorpholinyl dioxide (thiomorpholinone), thiaranyl, and trithiaranyl. Bicyclic heterocycles are monocyclic heterocycles fused to a 6-membered aromatic hydrocarbon, or fused to a monocyclic cycloalkanes, or fused to a monocyclic cycloalkenes, or fused to a monocyclic heterocycle, or fused to a monocyclic heteroaromatic hydrocarbon, or spirocyclic groups, or bridging monocyclic heterocyclic ring systems wherein two non-adjacent atoms of the ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or by an alkenylene bridge of two, 3, or 4 carbon atoms. The bicyclic heterocyclic group is attached to the parent molecule moiety at a non-aromatic ring atom (e.g., indoline-1-yl).Representative examples of bicyclic heterocyclic groups include, but are not limited to: chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzothiophene-2-yl, 1,2,3,4-tetrahydroisoquinoline-2-yl, 2-azaspiro[3.3]heptane-2-yl, 2-oxa-6-azaspiro[3.3]heptane-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), azabicyclo[3.1.0]hexyl (including 3-azabicyclo[3.1.0]hexane-3-yl), and 2,3-dihydro-1-yl. H -Indole-1-yl, isoindolin-2-yl, octahydrocyclopentadienyl[ c Pyrroloyl, octahydropyrrolopyridyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2.1]heptyl, hexahydro-2H-cyclopenta[b]furanyl, 2-oxaspiro[3.3]heptyl, 3-oxaspiro[5.5]undecyl, 6-oxaspiro[2.5]octane-1-yl, and 3-oxabicyclo[3.1.0]hexane-6-yl. Tricyclic heterocycles are exemplified by: bicyclic heterocycles fused to 6-membered aromatic hydrocarbons, or bicyclic heterocycles fused to monocyclic cycloalkanes, or bicyclic heterocycles fused to monocyclic cycloalkenes, or bicyclic heterocycles fused to monocyclic heterocycles, or bicyclic heterocycles wherein two non-adjacent atoms of the bicyclic are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms or by an alkenyl bridge of two, 3, or 4 carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxycyclopentadiene and hexahydro-2... H -2,5-bridged methylenecyclopentadiene[ b Furan, hexahydro-1 H -1,4-bridged methylenecyclopentadiene[ c Furan, aza-adamantane (1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). Monocyclic, bicyclic, and tricyclic heterocyclic groups are partially attached to the parent molecule at non-aromatic ring atoms.

[0050] As used in this article, the term "hydroxyl (hydroxyl or hydroxy)" refers to the -OH group.

[0051] As used herein, the term "hydroxyalkyl" means at least one -OH group attached to a parent molecule portion via an alkylene group as defined herein.

[0052] As used herein, the term "hydroxyfluoroalkyl" means at least one -OH group attached to a parent molecule portion via a fluoroalkyl group as defined herein.

[0053] Terms such as "alkyl", "cycloalkyl", and "alkylene" may be preceded by a designation indicating the number of atoms present in the group under specific conditions (e.g., "C"). 1-4 Alkyl", C 3-6 cycloalkyl, C 1-4 Alkylene). These designations are used as commonly understood by those skilled in the art. For example, a subscript number following "C" indicates the number of carbon atoms present in the subsequent group. Thus, "C3 alkyl" is an alkyl group having three carbon atoms (i.e., n-propyl, isopropyl). In the case of a given range, such as in "C 1-4 In the phrase "", the subsequent group members can have any number of carbon atoms falling within the range described. For example, "C 1-4 "Alkyl" is an alkyl group having 1 to 4 carbon atoms (regardless of the arrangement, i.e., straight chain or branched chain).

[0054] The term "parent molecule" or "parent molecule portion" refers to the entire molecule portion with the substituents attached, i.e., the remaining part of the molecule.

[0055] As used herein, the term "sulfonamide" refers to -S(O)2NR z -or–NR z S(O)-, where R z It can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, or heteroalkyl.

[0056] The term "substituent" refers to a group that "substitutes" on any atom of a group such as alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, or heterocyclic groups. Any atom can be substituted.

[0057] The term "substituted" refers to a group that can be further substituted by one or more non-hydrogen substituent groups. Substituent groups include, but are not limited to, halogens, =O (oxo), =S (thio), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketones, amides, carbamates, and acyl groups. In some embodiments, the group is optionally substituted. In some embodiments, the group is optionally substituted by 1, 2, 3, 4, or 5 substituents. In some embodiments, the aryl, heteroaryl, cycloalkyl, or heterocyclic group is optionally substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, the aryl, heteroaryl, cycloalkyl, or heterocyclic group may be independently unsubstituted or substituted with 1, 2, or 3 substituents.

[0058] For the compounds described herein, the groups and substituents may be selected based on the allowed valence of the atoms and substituents, such that selection and substitution produce stable compounds, for example, compounds that do not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, etc.).

[0059] As used in this article, the term "alternative site" refers to a ligand binding site that is topologically different from an orthogonal binding site.

[0060] As used herein, the term “modulator” refers to a molecular entity (e.g., but not limited to ligands and disclosed compounds) that modulates the activity of a target receptor protein.

[0061] As used herein, the term "ligand" refers to a natural or synthetic molecular entity capable of associating or binding with a receptor to form a complex and mediating, preventing, or altering biological effects. Therefore, the term "ligand" includes allosteric modulators, inhibitors, activators, agonists, antagonists, natural substrates, and analogues of natural substrates.

[0062] As used herein, the terms “natural ligand” and “endogenous ligand” are used interchangeably and refer to naturally occurring ligands that bind to receptors and are found in nature.

[0063] As used herein, the term "orthogonal site" refers to the primary binding site on a receptor that is recognized by the receptor's endogenous ligands or agonists. For example, the orthogonal site in the mAChR M4 receptor is the acetylcholine binding site.

[0064] As used herein, the term "mAChR M4 receptor positive allosteric modulator" refers to any exogenously administered compound or agent that, in the presence or absence of acetylcholine or another agonist, directly or indirectly enhances the activity of the mAChR M4 receptor in animals (particularly mammals, such as humans). For example, in the presence of extracellular acetylcholine, a mAChR M4 receptor positive allosteric modulator can increase the activity of the mAChR M4 receptor in cells. Cells can be Chinese hamster ovary (CHO-K1) cells transfected with human mAChRM4. Cells can be Chinese hamster ovary (CHO-K1) cells transfected with rat mAChR M4 receptor. Cells can be Chinese hamster ovary (CHO-K1) cells transfected with mammalian mAChR M4. The term "mAChR M4 receptor positive allosteric modulator" includes compounds that are "mAChR M4 receptor allosteric enhancers" or "mAChR M4 receptor allosteric agonists," as well as compounds with mixed activity, including the pharmacology of both "mAChR M4 receptor allosteric enhancers" and "mAChR M4 receptor allosteric agonists." The term "mAChR M4 receptor positive allosteric modulator" also includes compounds that are "mAChR M4 receptor allosteric enhancers."

[0065] As used herein, the term "mAChR M4 receptor allosteric enhancer" refers to any exogenously administered compound or agent that, when an endogenous ligand binds to the orthomeric site of the mAChR M4 receptor in an animal (particularly a mammal, such as a human), directly or indirectly enhances the response of an endogenous ligand (such as acetylcholine). Allosteric enhancers bind to sites other than the orthomeric site, i.e., allosteric sites, and positively enhance the receptor's response to an agonist or endogenous ligand. In some embodiments, the allosteric enhancer does not induce receptor desensitization, and the activity of compounds acting as mAChR M4 receptor allosteric enhancers offers advantages over the use of pure mAChR M4 receptor orthomeric agonists. Such advantages may include, for example, increased safety margins, greater tolerability, reduced likelihood of abuse, and reduced toxicity.

[0066] As used herein, the term "mAChR M4 receptor allosteric enhancer" refers to any exogenously administered compound or agent that directly or indirectly enhances the response of an animal (particularly mammals, such as humans) to an endogenous ligand (e.g., acetylcholine). In some embodiments, the allosteric enhancer increases the affinity of a natural ligand or agonist for the orthomeric site. In some embodiments, the allosteric enhancer increases the efficacy of the agonist. The mAChR M4 receptor allosteric enhancer binds to a site other than the orthomeric site, i.e., the allosteric site, and positively enhances the receptor's response to an agonist or endogenous ligand. The allosteric enhancer itself has no effect on the receptor and requires the presence of an agonist or natural ligand to exert its effect.

[0067] As used herein, the term "mAChR M4 receptor allosteric agonist" refers to any exogenously administered compound or agent that directly activates the activity of the mAChR M4 receptor in animals (particularly mammals, such as humans) in the absence of endogenous ligands (such as acetylcholine). mAChR M4 receptor allosteric agonists bind to a different site than the orthoacetylcholine site of the mAChR M4 receptor. Because the presence of an endogenous ligand is not required, compounds offer an advantage in activity as mAChR M4 receptor allosteric agonists if cholinergic tension at a given synapse is low.

[0068] As used herein, the term "mAChR M4 receptor neutral sex ligand" refers to any exogenously administered compound or agent that binds to an allosteric site without affecting the binding or function of the agonist or natural ligand at the orosteric site in animals (particularly mammals, such as humans). However, neutral sex ligands can block the action of other allosteric modulators that act via the same site.

[0069] In describing the numerical ranges in this article, every intermediate number with the same precision between the two is explicitly considered. For example, for the range 6–9, the numbers 7 and 8 are considered in addition to 6 and 9, and for the range 6.0–7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly considered.

[0070] abbreviation: AcOH is acetic acid; aq is an aqueous solution; ATM stands for Atmosphere; BINAP is 2,2′-bis(diphenylphosphine)-1,1′-binaphthyl; Boc stands for tert-butoxycarbonyl; Boc2O is ditert-butyl dicarbonate; B2pin2 is bis(pinacol)diboron; BrettPhos is 2-(dicyclohexylphosphine)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl; BrettPhos Pd G3 is [(2-di-cyclohexylphosphine-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate; Bu is butyl; t-BuOH is tert-butanol; CDI is 1,1'-carbonyldiimidazole; CD2O is deuterated formaldehyde; Celite® is diatomaceous earth; CSA is (1 S 4 R )-10-Camphorsulfonic acid; DCE is 1,2-dichloroethane; DCM stands for dichloromethane; DEA is diethylamine; DMAP is 4-dimethylaminopyridine; DMF is N , N -Dimethylformamide; DMP or Des Martin periodoyl is 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzyl-3-(1 H )-ketone; DIAD stands for diisopropyl azodicarbonate. DIPEA or DIEA is diisopropylethylamine; DMSO is dimethyl sulfoxide; Dowtherm™ A is a eutectic mixture of 26.5% diphenyl + 73.5% diphenyl oxide; D t BAD stands for di-tert-butyl azodicarbonate; eq or eq. means equivalent; EtOAC is ethyl acetate; (4,4′-dtbbpy)NiCl2 is 4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel(II) chloride; Et2O is diethyl ether; EtOH is ethanol; h or hr represents hours; Hex is hexane; HMPA is hexamethylphosphoramide; IPA stands for isopropanol; KOAc is potassium acetate; LAH stands for lithium aluminum hydride; LDA is lithium diisopropylamino; LiHMDS / LHMDS is a bis(trimethylsilyl)aminolithium; m CPBA is m-chloroperoxybenzoic acid; MeCN or ACN is acetonitrile; MeI stands for iodomethane / methyl iodide; MeOD is CD3OD (methanol-d4); MeOH is methanol; min means minutes; NaOAc is sodium acetate; NaOtBu is sodium tert-butoxide; NaOMe is sodium methoxide; NBS is N - Bromosuccinimide; NCS is N -Chlorosuccinimide; NH4OAc is ammonium acetate; NMO is 4-methylmorpholine N-oxide; NMP is N 2-Methyl-2-pyrrolidone; [Pd(allyl)(tBuBrettPhos)]OTf is allyl trifluoromethanesulfonate[(2-di-tert-butylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II); Pd2(dba)3 is tris(dibenzylacetone)dipalladium(0); Pd(dppf)Cl2 is [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II); Pd(OAc)2 is palladium(II) acetate; Pd(PPh3)4 is tetra(triphenylphosphine)palladium(0); PPA stands for polyphosphoric acid. PPh3 is triphenylphosphine; PPTS is pyridinium p-toluenesulfonate. rt is room temperature; sat. means saturated; sec is a second; SCX column or HF SCX column is a strong cation exchange column (i.e., Agilent part number 14256027). SFC stands for supercritical fluid chromatography. TBAC or TBACl is tetrabutylammonium chloride; t -BuXPhos is 2-di-tert-butylphosphine-2′,4′,6′-triisopropylbiphenyl; t -BuXPhos-Pd-G1 is [2-(di-tert-butylphosphine)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II) chloride; TCICA is trichloroisocyanuric acid; TEA or Et3N is triethylamine; TFA stands for trifluoroacetic acid; THF stands for tetrahydrofuran; TMB stands for trimethylboroxane; TosCl is p-toluenesulfonyl chloride; tosyl is a p-toluenesulfonyl group; Xantphos is 4,5-bis(diphenylphosphine)-9,9-dimethylxanthanium.

[0071] 2. Compounds In one aspect, the present invention provides a compound having formula (I), wherein R 1 R 2 R 3 R 8 G 1 , and n are as defined in this article.

[0072] Unsubstituted or substituted rings (i.e., optionally substituted), such as aryl, heteroaryl, etc., consist of a ring system and optional substituents of the ring system. Therefore, a ring system can be defined independently of its substituents, such that redefining the ring system preserves the presence of any previously optional substituents. For example, a 5- to 12-membered heteroaryl with optional substituents can be further defined by specifying the ring system of a 5- to 12-membered heteroaryl as a 5- to 6-membered heteroaryl (i.e., a 5- to 6-membered heteroaryl ring system), in which case the optional substituents of the 5- to 12-membered heteroaryl still exist on the 5- to 6-membered heteroaryl unless otherwise explicitly stated.

[0073] In the case where a heterocyclic and heteroaromatic ring system is defined as “containing” a specified heteroatom (e.g., 1-3 heteroatoms independently selected from the group consisting of O, N, and S), any ring atom in the heterocyclic and heteroaromatic ring system that is not one of the specified heteroatoms is a carbon atom.

[0074] The following describes numbered embodiments of the present invention. The first embodiment is designated E1, and subsequent embodiments are designated E1.1, E1.2, E2, E2.1, E3, E4, E4.1, E4.2, E4.3, E4.4, E4.5, E4.6, E4.7, E5, E5.1, etc.

[0075] E1. A compound having formula (I) or a pharmaceutically acceptable salt thereof, in: G 1 yes X 1 It is NR 5 O or CR 5A R 5B ; X 2 It is CR 6 Or N; R 1 and R 3 Each is independently hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Fluoroalkyl, –OC 1-4 Alkyl, or –OC 1-4 fluoroalkyl; R 2 It is G 2 –NR b R c C 1-6 Halogenated alkyl groups, halogens, cyano groups, NO2, C 1-6 Alkyl, C 2-6 alkenyl, –OR b –NR c C(O)R b –NR c SO2R a –N=S(O)(R a )2、–P(O)(R a )2、–C 1-3 Alkylene–G 2 –C 2-4 alkenyl–G 2 , or hydrogen; R a It is C independently each time it appears. 1-6 Alkyl, C 1-6 Halogenated alkyl, G 2 、or –C 1-3 Alkylene–G 2 ; Wherein, –N=S(O)(R a)2 or –P(O)(R a The two Rs in )2 a They are linked together to form a straight-chain alkylene chain, thus forming a 5- to 7-membered heterocycle; R b and R c Independently, it is hydrogen and C 1-6 Alkyl, C 1-6 Halogenated alkyl, G 2 、or –C 1-3 Alkylene–G 2 ; G 2 Each time it appears, it is independently a 5- to 12-membered heteroaryl, 6- to 12-membered aryl, 4- to 12-membered heterocyclic, or 3- to 12-membered carbocyclic, wherein each of the heteroaryl and heterocyclic groups contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and G 2 Selected arbitrarily from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, oxo, –OR x –N(R) x )2、–SR x –SO2R x –C(O)R x –C(O)OR x –C(O)N(R) x )2、–C 1-6 Alkylene – OR x –C 1-6 alkylene–N(R) x )2、G 2a 、 and –C 1-3 Alkylene–G 2a The first substituent of the group is substituted, and optionally further independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and –OR x The group consists of 1-4 substituents; R x Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, –C 1-3 alkylene–C 3-6 cycloalkyl, phenyl, or –C 1-3 Alkylene-phenyl, wherein each cycloalkyl or phenyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of: halogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; G 2aIt is a phenyl group, a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, or a 3- to 8-membered carbocyclic group, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 2a Each time it appears, it is independently and optionally substituted by 1-5 substituents selected independently from the following group: halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, –C 1-6 Alkylene –OH, oxo, OH, –OC 1-4 Alkyl, –OC 1-4 Haloalkyl, C 3-4 cycloalkyl and –C 1-3 alkylene–C 3-4 cycloalkyl; R 4A and R 4B Independently, it is hydrogen and C 1-4 Alkyl, C 3-4 cycloalkyl, or –C 1-3 alkylene–OH; R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 fluoroalkyl, –C 1-6 Alkylene–R y –C 1-6 Fluoride-R y G 5 、or –C 1-3 Alkylene–G 5 ; R 5A and R 5B Independently, it is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkyl, or –C 1-4 alkylene–OH; R y Yes – OR 5a –N(R) 5a )2、–C(O)R 5a –C(O)OR 5a 、or –C(O)N(R) 5a )2; R 5a Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 fluoroalkyl, G 5 、or –C 1-3 Alkylene–G 5 ; G 5It is a phenyl group, a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, or a C-shaped group. 3-8 Cycloalkyl groups, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 5 Optionally substituted by 1-4 substituents independently selected from the group consisting of: halogen, cyano, C 1-4 Alkyl, C 1-2 Fluoroalkyl, –OC 1-4 Alkyl, OH, and oxo; Alternatively, R 4A and R 4B Together with the carbon attached to them, they form C 3-6 cycloalkyl; or R 4B and R 5 Together with the atoms to which they are attached, they form 5- to 7-membered heterocycles that optionally contain an additional heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; R 6 It is hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 fluoroalkyl, C 2-4 alkenyl, –OR 6a –N(R) 6a )2、–C 1-3 Alkylene – OR 6a or C 3-6 cycloalkyl; R 6a Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or –C 1-3 alkylene–C 3-4 cycloalkyl; Alternatively, the two Rs 6a Together with the nitrogen to which they are attached, they form 4 to 8-membered heterocycles containing R 6a The attached nitrogen and optionally containing 1-2 additional heteroatoms, independently of O, N, or S, the heterocycle optionally being substituted by 1-4 substituents independently selected from the group consisting of: halogens, C 1-2 Alkyl and C 1-2 fluoroalkyl; R 7 It is C 1-4 Alkyl, hydrogen, halogen, cyano, C 1-4 fluoroalkyl, –OR 7a –C 1-3 Alkylene – OR 7a 、or G 7 ; Alternatively, R6 and R 7 Together with the atoms to which they are attached, they form a 5- to 7-membered heterocycle or a 5- to 7-membered carbon ring containing one heteroatom, wherein the heteroatom is independently selected from the group consisting of N, O, and S, and the heterocycle and carbon ring are optionally substituted by 1 to 4 substituents independently selected from the group consisting of: C 1-4 Alkyl, halogen, –OC 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl and C 1-2 Alkylene-C 3-4 cycloalkyl; R 7a It is hydrogen, C 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or –C 1-3 alkylene–C 3-4 cycloalkyl; G 7 It is a phenyl group, a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, or a C-shaped group. 3-6 Cycloalkyl groups, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 5 Optionally substituted by 1-4 substituents independently selected from the group consisting of: halogen, cyano, C 1-4 Alkyl, C 1-2 Fluoroalkyl, –OC 1-4 Alkyl, OH, and oxo; R 8 Each time it appears, it is independently halogen, C. 1-4 Alkyl, C 1-4 fluoroalkyl, or C 3-4 cycloalkyl; and n is 0, 1, 2, 3, or 4; Where R 6 R 6a R 7 R 7a and R 8 Each cycloalkyl group at the position is unsubstituted or independently selected from C10. 1-4 Alkyl groups (e.g., methyl) and halogens (e.g., fluorine) are substituted with 1 to 4 substituents.

[0076] E1.1. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 2 It is G 2 –NR b R c C1-6 Halogenated alkyl groups, halogens, cyano groups, NO2, C 1-6 Alkyl, –OR b –NR c C(O)R b –NR c SO2R a –N=S(O)(R a )2、–P(O)(R a )2、–C 1-3 Alkylene–G 2 , or hydrogen; G 2 Each time it appears, it is independently a 5- to 12-membered heteroaryl, 6- to 12-membered aryl, 4- to 12-membered heterocyclic, or 3- to 12-membered carbocyclic, wherein each of the heteroaryl and heterocyclic groups contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and G 2 Selected arbitrarily from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, oxo, –OR x –N(R) x )2、–C(O)R x –C(O)OR x –C(O)N(R) x )2、–C 1-6 Alkylene – OR x –C 1-6 alkylene–N(R) x )2、G 2a 、 and –C 1-3 Alkylene–G 2a The first substituent of the group is substituted, and optionally further independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and –OR x The group consists of 1-4 substituents; R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 fluoroalkyl, –C 1-6 Alkylene–R y G 5 、or –C 1-3 Alkylene–G 5 ; R 5a Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or –C 1-3 alkylene–C 3-4 cycloalkyl; G 5 It is a phenyl group, a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, or a C-shaped group. 3-6 Cycloalkyl groups, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 5 Optionally substituted by 1-4 substituents independently selected from the group consisting of: halogens, C 1-4 Alkyl, C 1-2 Fluoroalkyl, –OC 1-4 Alkyl, OH, and oxo; R 6 It is hydrogen, halogen, C1-4 alkyl, C 1-4 fluoroalkyl, –OR 6a –N(R) 6a )2、–C 1-3 Alkylene – OR 6a or C 3-6 cycloalkyl; and R 7 It is C 1-4 Alkyl, hydrogen, halogen, cyano, C 1-4 fluoroalkyl, –OR 7a –C 1-3 Alkylene – OR 7a or C 3-6 Cycloalkyl.

[0077] E1.2. A compound as described in E1 or E1.1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound having formula (IA): And n is 0, 1, or 2.

[0078] E2. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1, E1.1, or E1.2, wherein R 1 Is it hydrogen or C? 1-4 alkyl.

[0079] E2.1. The compound as described in E2 or a pharmaceutically acceptable salt thereof, wherein R 1 It is hydrogen.

[0080] E3. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E2.1, wherein R 3 It is hydrogen.

[0081] E4. The compound of any one of E1-E3 or a pharmaceutically acceptable salt thereof, wherein R 2 It is G 2 –NR b Rc C 1-6 Haloalkyl, C 2-6 alkenyl, cyano, hydrogen, or –C 2-4 alkenyl–G 2 .

[0082] E4.1. A compound as described in E4 or a pharmaceutically acceptable salt thereof, wherein R 2 It is G 2 –NR b R c or C 1-6 Halogenated alkyl groups.

[0083] E4.2. The compound as described in E4 or a pharmaceutically acceptable salt thereof, wherein R 2 It is hydrogen.

[0084] E4.3. The compound as described in E4 or a pharmaceutically acceptable salt thereof, wherein R 2 It is a cyano group.

[0085] E4.4. A compound as described in E4 or a pharmaceutically acceptable salt thereof, wherein R 2 It is C 2-6 alkenyl E4.5. A compound as described in E4.4 or a pharmaceutically acceptable salt thereof, wherein R 2 yes .

[0086] E4.6. A compound as described in E4 or a pharmaceutically acceptable salt thereof, wherein R 2 Yes –C 2-4 alkenyl–G 2 .

[0087] E4.7. A compound as described in E4.6 or a pharmaceutically acceptable salt thereof, wherein R 2 yes .

[0088] E5. A compound as described in E4 or E4.1, or a pharmaceutically acceptable salt thereof, wherein R 2 It is C 1-6 Halogenated alkyl groups.

[0089] E5.1. A compound as described in E5 or a pharmaceutically acceptable salt thereof, wherein R 2 It's CF3.

[0090] E6. A compound as described in E4 or E4.1, or a pharmaceutically acceptable salt thereof, wherein R 2 It is G 2 .

[0091] E7. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E4.6, E4.7 or E6, wherein G 2 It is a 5 to 12 heteroaryl group that is optionally substituted.

[0092] E7.1. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E4.6, E4.7, or E6-E7, wherein G 2 The ring system of the optionally substituted 5- to 12-membered heteroaryl group is a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S.

[0093] E7.2. The compound as described in E7.1 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 5 to 6 heteroaryl group is pyridyl, pyrazolyl, or isoxazolyl.

[0094] E7.3. The compound as described in E7.2 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 5- to 6-membered heteroaryl group is pyridin-2-yl, pyridin-3-yl, pyrazol-4-yl, pyrazol-5-yl, or isoxazol-4-yl.

[0095] E7.4. The compound or a pharmaceutically acceptable salt thereof as described in any one of E7-E7.3, wherein G 2 yes .

[0096] E7.5. The compound or a pharmaceutically acceptable salt thereof as described in any one of E7-E7.4, wherein G 2 yes .

[0097] E7.6. The compound or a pharmaceutically acceptable salt thereof as described in any one of E7-E7.5, wherein G 2 yes .

[0098] E7.7. A compound as described in E7.4 or a pharmaceutically acceptable salt thereof, wherein G 2 yes .

[0099] E7.8. A compound as described in E7.5 or E7.7, or a pharmaceutically acceptable salt thereof, wherein G 2 yes .

[0100] E7.9. A compound as described in E7.6 or E7.8 or a pharmaceutically acceptable salt thereof, wherein G 2 yes .

[0101] E7.10. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E4.6, E4.7, or E6-E7, wherein G 2 The ring system of the optionally substituted 5- to 12-membered heteroaryl group is a 9- to 10-membered heteroaryl group containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S.

[0102] E7.11. A compound as described in E7.10 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 9 to 10 heteroaryl group is quinolinyl, isoquinolinyl, or imidazopyridyl.

[0103] E7.12. A compound as described in E7.10 or E7.11, or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 9 to 10 heteroaryl groups is isoquinolinyl or imidazopyridyl.

[0104] E7.13. The compound as described in E7.11 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 9 to 10 heteroaryl group is quinoline-5-yl, isoquinoline-4-yl, isoquinoline-5-yl, or imidazo[1,2-a]pyridin-6-yl.

[0105] E7.14. A compound as described in E7.13 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 9 to 10 heteroaryl group is quinoline-5-yl, isoquinoline-5-yl, or imidazo[1,2-a]pyridin-6-yl.

[0106] E7.15. A compound as described in E7.12 or E7.14, or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 9 to 10 heteroaryl group is isoquinoline-5-yl or imidazo[1,2-a]pyridin-6-yl.

[0107] E7.16. A compound as described in E7.13 or a pharmaceutically acceptable salt thereof, wherein G 2 yes .

[0108] E7.17. A compound as described in E7.14 or E7.16, or a pharmaceutically acceptable salt thereof, wherein G 2 yes .

[0109] E7.18. A compound as described in E7.15 or E7.17, or a pharmaceutically acceptable salt thereof, wherein G 2 yes .

[0110] E7.19. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E4.6, E4.7, E6-E7.3 or E7.10-E7.15, wherein G 2 Selected arbitrarily from halogen, cyano, C 1-4 Alkyl, C 1-4 fluoroalkyl, –OR x and G 2a The first substituent of the group is substituted, and optionally further independently selected from halogens and C. 1-4 The group consisting of alkyl groups is substituted with 1-3 substituents.

[0111] E7.20. A compound as described in E7.19 or a pharmaceutically acceptable salt thereof, wherein G 2 Selected arbitrarily free of halogen, C 1-4 Alkyl, C 1-4 fluoroalkyl, –OR x and G 2a The first substituent of the group is substituted, and optionally further independently selected from halogens and C. 1-4 The group consisting of alkyl groups is substituted with 1-3 substituents.

[0112] E7.21. A compound as described in E7.19 or a pharmaceutically acceptable salt thereof, wherein G 2 Optionally selected from fluorine, cyano, methyl, isopropyl, CF3, CHF2, –OR x and G 2aThe first substituent of the group is substituted, and optionally further substituted by 1-3 substituents independently selected from the group consisting of fluorine and methyl.

[0113] E7.22. The compound as described in E7.20 or E7.21, or a pharmaceutically acceptable salt thereof, wherein G 2 Optionally selected free from fluorine, methyl, isopropyl, CF3, CHF2, –OR x and G 2a The first substituent of the group is substituted, and optionally further substituted by 1-3 substituents independently selected from the group consisting of fluorine and methyl.

[0114] E7.23. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E4.6, E4.7, E6-E7.5, E7.10-E7.15, or E7.19-E7.22, wherein R x Each time it appears, independently select from the following groups: C 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, –CH2–C 3-4 Cycloalkyl and –CH2–phenyl.

[0115] E7.24. A compound as described in E7.23 or a pharmaceutically acceptable salt thereof, wherein R x It is C 1-4 alkyl.

[0116] E7.25. A compound as described in E7.24 or a pharmaceutically acceptable salt thereof, wherein R x It is a methyl group.

[0117] E7.26. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E4.6, E4.7, E6-E7.5, E7.10-E7.15, or E7.19-E7.25, wherein G 2a It is C 3-6 Cycloalkyl.

[0118] E7.27. A compound as described in E7.26 or a pharmaceutically acceptable salt thereof, wherein G 2a It is cyclopropyl or cyclobutyl.

[0119] E8. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E4.6, E4.7 or E6, wherein G 2 It is a 6 to 12 aryl group that is optionally substituted.

[0120] E8.1. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E4.6, E4.7, E6, or E8, wherein G 2 The ring system of the optionally substituted 6 to 12 aryl groups is phenyl.

[0121] E8.2. The compound as described in E8.1 or a pharmaceutically acceptable salt thereof, wherein G 2 yes .

[0122] E8.3. The compound as described in E8.2 or a pharmaceutically acceptable salt thereof, wherein G 2 yes .

[0123] E8.4. The compound as described in E8.2 or a pharmaceutically acceptable salt thereof, wherein G 2 yes .

[0124] E8.5. A compound or a pharmaceutically acceptable salt thereof as described in E8.3 or E8.4, wherein G 2 yes .

[0125] E8.6. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E4.6, E4.7, E6, or E8-E8.1, wherein G 2 Selected arbitrarily from halogen, cyano, C 1-4 Alkyl, C 1-4 fluoroalkyl, –OR x –SR x –C(O)N(R) x )2, and G 2a The first substituent of the group is substituted, and optionally further independently selected from halogens and C. 1-4 The group consisting of alkyl groups is substituted with 1-4 substituents.

[0126] E8.7. A compound as described in E8.6 or a pharmaceutically acceptable salt thereof, wherein G 2 Selected arbitrarily free of halogen, C 1-4 Alkyl, C 1-4 fluoroalkyl, –OR x and G 2a The first substituent of the group is substituted, and optionally further independently selected from halogens and C. 1-4The group consisting of alkyl groups is substituted with 1-4 substituents.

[0127] E8.8. A compound as described in E8.6 or a pharmaceutically acceptable salt thereof, wherein G 2 Optionally selected from fluorine, cyano, methyl, isopropyl, tert-butyl, CF3, CHF2, CF3, –OR x –SR x –C(O)N(R) x )2, and G 2a The first substituent of the group is substituted, and optionally further substituted by 1-4 substituents independently selected from the group consisting of fluorine and methyl.

[0128] E8.9. A compound or a pharmaceutically acceptable salt thereof as described in E8.7 or E8.8, wherein G 2 Optionally selected free from fluorine, methyl, isopropyl, CF3, CHF2, –OR x and G 2a The first substituent of the group is substituted, and optionally further substituted by 1-4 substituents independently selected from the group consisting of fluorine and methyl.

[0129] E8.10. A compound or a pharmaceutically acceptable salt thereof as any one of E1-E4.1, E4.6, E4.7, E6-E7.6, E7.10-E7.15, E7.19-E7.22, E8-E8.3, or E8.6-E8.9, wherein R x Each time it appears, independently choose from the following groups: hydrogen, C 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, –CH2–C 3-4 Cycloalkyl and –CH2–phenyl.

[0130] E8.11. A compound as described in E8.10 or a pharmaceutically acceptable salt thereof, wherein R x Each time it appears, independently select from the following groups: C 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, –CH2–C 3-4 Cycloalkyl and –CH2–phenyl.

[0131] E8.12. A compound as described in E8.10 or a pharmaceutically acceptable salt thereof, wherein R x Each time it appears, it is independently either hydrogen or C. 1-4 alkyl.

[0132] E8.13. A compound as described in E8.12 or a pharmaceutically acceptable salt thereof, wherein R x It is hydrogen.

[0133] E8.14. The compound as described in E8.11 or E8.12 or a pharmaceutically acceptable salt thereof, wherein R x It is C 1-4 alkyl.

[0134] E8.15. A compound as described in E8.14 or a pharmaceutically acceptable salt thereof, wherein R x It is a methyl group.

[0135] E8.16. A compound as described in E8.11 or a pharmaceutically acceptable salt thereof, wherein R x It is –CH2–phenyl.

[0136] E8.17. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E4.6, E4.7, E6-E7.6, E7.10-E7.15, E7.19-E8.3, or E8.6-E8.16, wherein G 2a It is C 3-4 Cycloalkyl.

[0137] E9. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E4.6, E4.7 or E6, wherein G 2 It is a 4- to 12-membered heterocyclic group that is optionally substituted.

[0138] E9.1. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E4.6, E4.7, E6, or E9, wherein G 2 The ring system of the optionally substituted 4- to 12-membered heterocyclic group is a 4- to 6-membered heterocyclic group containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S.

[0139] E9.2. The compound as described in E9.1 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 4- to 6-membered heterocyclic group contains an oxygen atom.

[0140] E9.3. A compound as described in E9.2 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 4- to 6-membered heterocyclic group is 2,5-dihydrofuranyl or oxetane.

[0141] E9.4. A compound as described in E9.3 or a pharmaceutically acceptable salt thereof, wherein G 2The ring system of the optionally substituted 4- to 6-membered heterocyclic group is 2,5-dihydrofuran-3-yl or oxetane-3-yl.

[0142] E9.5. A compound as described in E9.3 or E9.4, or a pharmaceutically acceptable salt thereof, wherein G 2 yes .

[0143] E10. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E4.6, E4.7 or E6, wherein G 2 It is a 3 to 12-membered carbon cyclogroup that is optionally substituted.

[0144] E10.1. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E4.6, E4.7, E6, or E10, wherein G 2 The 3 to 12-membered carbon ring group that is optionally substituted at the location is C 3-6 Cycloalkyl.

[0145] E10.2. The compound as described in E10.1 or a pharmaceutically acceptable salt thereof, wherein G 2 It is cyclopropyl.

[0146] E10.3. A compound as described in E10.1 or a pharmaceutically acceptable salt thereof, wherein G 2 It is cyclobutyl or cyclopentyl.

[0147] E11. The compound or a pharmaceutically acceptable salt thereof as described in any one of E6-E10.3, wherein G 2 yes (a) Optionally substituted 5 to 12 heteroaryl groups, selected from the group consisting of: or (b) Optionally substituted 6- to 12-membered aryl groups, selected from the group consisting of: (c) Optionally substituted 4- to 12-membered heterocyclic groups, selected from the group consisting of: (d) Optionally substituted 3- to 12-membered carbocyclic groups, which are .

[0148] E11.1. The compound as described in E11 or a pharmaceutically acceptable salt thereof, wherein G 2 yes (a) Optionally substituted 5 to 12 heteroaryl groups, selected from the group consisting of: or (b) Optionally substituted 6- to 12-membered aryl groups, selected from the group consisting of: (c) Optionally substituted 4- to 12-membered heterocyclic groups, selected from the group consisting of: (d) Optionally substituted 3- to 12-membered carbocyclic groups, which are .

[0149] E11.2. The compound as described in E11.1 or a pharmaceutically acceptable salt thereof, wherein G 2 yes (a) Optionally substituted 5 to 12 heteroaryl groups, selected from the group consisting of: G 2 yes or (b) Optionally substituted 6- to 12-membered aryl groups, selected from the group consisting of: .

[0150] E12. The compound as described in E4 or E4.1, or a pharmaceutically acceptable salt thereof, wherein R 2 Yes – NR b R c ; R b It is C 1-6 Alkyl, G 2 、or –C 1-3 Alkylene–G 2 ;and R c Is it hydrogen or C? 1-6 alkyl.

[0151] E13. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1 or E12, wherein R b It is G 2 .

[0152] E14. The compound as described in E12 or E13, or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 5 to 12 heteroaryl group that is optionally substituted.

[0153] E14.1. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1 or E12-E14, wherein G 2 The ring system of the optionally substituted 5- to 12-membered heteroaryl group is a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S.

[0154] E14.2. The compound as described in E14.1 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 5- to 6-membered heteroaryl group is pyridyl.

[0155] E14.3. A compound as described in E14.2 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 5- to 6-membered heteroaryl group is pyridin-3-yl.

[0156] E14.4. A compound as described in E14.2 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted 5- to 6-membered heteroaryl group is pyridin-4-yl.

[0157] E14.5. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1 or E12-E14.4, wherein G 2 Selected arbitrarily free of halogen, C 1-4 Alkyl, C 1-2 fluoroalkyl, –OR x and G 2a The first substituent of the group is substituted, and optionally further independently selected from halogens and C. 1-4 The group consisting of alkyl groups is substituted with 1-3 substituents.

[0158] E14.6. A compound as described in E14.5 or a pharmaceutically acceptable salt thereof, wherein G 2 Optionally selected free from fluorine, methyl, isopropyl, CF3, CHF2, –OR x and G 2a The first substituent of the group is substituted, and optionally further substituted by 1-3 substituents independently selected from the group consisting of fluorine and methyl.

[0159] E14.7. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1 or E12-E14.6, wherein R xEach time it appears, independently select from the following groups: C 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, –CH2–C 3-4 Cycloalkyl and –CH2–phenyl.

[0160] E14.8. A compound as described in E14.7 or a pharmaceutically acceptable salt thereof, wherein R x It is C 1-4 alkyl.

[0161] E14.9. A compound as described in E14.8 or a pharmaceutically acceptable salt thereof, wherein R x It is a methyl group.

[0162] E14.10. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1 or E12-E14.9, wherein G 2a It is C 3-4 Cycloalkyl.

[0163] E14.11. The compound or a pharmaceutically acceptable salt thereof as described in any one of E12-E14.10, wherein G 2 Optionally substituted by 1-3 substituents independently selected from the group consisting of: halogens and C 1-4 alkyl.

[0164] E14.12. A compound as described in E14.11 or a pharmaceutically acceptable salt thereof, wherein G 2 Optionally substituted by 1-3 substituents selected independently from the group consisting of: fluorine and methyl.

[0165] E14.13. The compound or a pharmaceutically acceptable salt thereof as described in any one of E12-E14.11, wherein R 2 yes .

[0166] E14.14. A compound or a pharmaceutically acceptable salt thereof as described in E14.12 or E14.13, wherein R 2 yes .

[0167] E15. A compound as described in E12 or E13, or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 6 to 12 aryl group that is optionally substituted.

[0168] E15.1. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E12, E13, or E15, wherein G 2The ring system of the optionally substituted 6 to 12 aryl groups is phenyl.

[0169] E15.2. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E12-E13, or E15-E15.1, wherein G 2 Selected arbitrarily free of halogen, C 1-4 Alkyl, C 1-2 fluoroalkyl, –OR x and G 2a The first substituent of the group is substituted, and optionally further independently selected from halogens and C. 1-4 The group consisting of alkyl groups is substituted with 1-4 substituents.

[0170] E15.3. A compound as described in E15.2 or a pharmaceutically acceptable salt thereof, wherein G 2 Optionally selected free from fluorine, methyl, isopropyl, CF3, CHF2, –OR x and G 2a The first substituent of the group is substituted, and optionally further substituted by 1-4 substituents independently selected from the group consisting of fluorine and methyl.

[0171] E15.4. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E12-E13, or E15-E15.3, wherein R x Each time it appears, independently select from the following groups: C 1-4 Alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, –CH2–C 3-4 Cycloalkyl and –CH2–phenyl.

[0172] E15.5. A compound as described in E15.4 or a pharmaceutically acceptable salt thereof, wherein R x It is C 1-4 alkyl.

[0173] E15.6. A compound as described in E15.5 or a pharmaceutically acceptable salt thereof, wherein R x It is a methyl group.

[0174] E15.7. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1, E12-E13, or E15-E15.6, wherein G 2a It is C 3-4 Cycloalkyl.

[0175] E15.8. The compound or a pharmaceutically acceptable salt thereof as described in any one of E12-E13 or E15-E15.7, wherein G2 Optionally substituted by 1-3 substituents independently selected from the group consisting of: halogens and C 1-4 alkyl.

[0176] E15.9. A compound as described in E15.8 or a pharmaceutically acceptable salt thereof, wherein G 2 Optionally substituted by 1-3 substituents selected independently from the group consisting of: fluorine and methyl.

[0177] E15.10. A compound as described in E15.8 or a pharmaceutically acceptable salt thereof, wherein R 2 yes .

[0178] E15.11. The compound or a pharmaceutically acceptable salt thereof as described in any one of E15.8-E15.10, wherein R 2 yes .

[0179] E16. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4.1 or E12-E15.11, wherein R c It is hydrogen.

[0180] E17. The compound or a pharmaceutically acceptable salt thereof as described in any one of E12-E16, wherein R 2 yes .

[0181] E18. The compound of any one of E1-E17 or a pharmaceutically acceptable salt thereof, wherein R 4A and R 4B It is hydrogen.

[0182] E18.1. A compound as described in E18 or a pharmaceutically acceptable salt thereof, wherein R 4A and R 4B The hydrogen at that location is deuterium ( 2 H).

[0183] E19. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E18.1, wherein R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 fluoroalkyl, –C 1-6 Alkylene–R y G 5 、or –C 1-3 Alkylene–G 5 .

[0184] E19.1. A compound as described in E19 or a pharmaceutically acceptable salt thereof, wherein R 5It is hydrogen, C 1-6 Alkyl, –C 1-6 Alkylene–R y 、or –C 1-3 Alkylene–G 5 .

[0185] E19.2. A compound as described in E19 or E19.1, or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen, methyl, CD3, –C 1-6 Alkylene–R y G 5 、or –C 1-3 Alkylene–G 5 .

[0186] E19.3. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E19.2, wherein R 5 It is hydrogen.

[0187] E19.4. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E19.2, wherein R 5 It is C 1-6 alkyl.

[0188] E19.5. A compound as described in E19.4 or a pharmaceutically acceptable salt thereof, wherein R 5 It is methyl, ethyl, isobutyl, neopentyl, or CD3.

[0189] E19.6. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E18.1, wherein R 5 It is C 1-6 Fluoroalkyl groups.

[0190] E19.7. A compound as described in E19.6 or a pharmaceutically acceptable salt thereof, wherein R 5 It is 2-fluoro-2-methylpropyl.

[0191] E19.8. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E19.2, wherein R 5 Yes –C 1-6 Alkylene–R y .

[0192] E19.9. A compound as described in E19.8 or a pharmaceutically acceptable salt thereof, wherein R 5 It is –CH2CH2–R y Or –CH(CH3)CH2–R y .

[0193] E19.10. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E19 or E19.2, wherein R 5 It is G 5 .

[0194] E19.11. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E19.2, wherein R 5 Yes –C 1-3 Alkylene–G 5 .

[0195] E19.12. A compound as described in E19.21 or a pharmaceutically acceptable salt thereof, wherein R 5 It is –CH2–G 5 .

[0196] E19.13. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E19.2 or E19.8-E19.9, wherein R y Yes – OR 5a Or –C(O)OR 5a .

[0197] E19.14. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E19.2, E19.8-E19.9, or E19.13, wherein R 5a It is C independently each time it appears. 1-4 alkyl.

[0198] E19.15. A compound as described in E19.14 or a pharmaceutically acceptable salt thereof, wherein R 5a It is methyl or isopropyl.

[0199] E19.16. A compound as described in E19.15 or a pharmaceutically acceptable salt thereof, wherein R 5a It is a methyl group.

[0200] E19.17. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E19.2, E19.8-E19.9, or E19.13, wherein R 5a It is G 5 .

[0201] E19.18. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E19.17, wherein G 5 It is a 4- to 8-membered heterocyclic group that is optionally substituted, C 3-8 Cycloalkyl or phenyl.

[0202] E19.19. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E19.18, wherein G 5 The 4- to 8-membered heterocyclic group or C that is optionally substituted at the location 3-8 The cyclic system of cycloalkyl is oxacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolane-4-yl, 2-oxaspiro[3.3]heptane-6-yl, cyclopropyl, cyclobutyl, cyclopentyl, or bicyclo[2.2.1]heptane-2-yl.

[0203] E19.20. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E19.19, wherein G 5 It may be optionally substituted by 1-4 substituents independently selected from the group consisting of: fluorine, cyano, methyl, and –OCH3.

[0204] E19.21. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E19.18 or E19.20, wherein G 5 It is an optionally substituted 4- to 8-membered heterocyclic group or C 3-6 Cycloalkyl.

[0205] E19.22. The compound or a pharmaceutically acceptable salt thereof as described in any one of E19.19-E19.21, wherein G 5 It is an oxacyclobutane, tetrahydrofuranyl, cyclopropyl, or cyclopentyl.

[0206] E19.23. The compound or a pharmaceutically acceptable salt thereof as described in any one of E19-E19.22, wherein R 5 It is hydrogen, methyl, ethyl, isobutyl, neopentyl, CD3, 2-fluoro-2-methylpropyl, –CH(CH3)–C(O)OCH3, –CH2CH2OCH3, –CH(CH3)CH2OCH3, –CH2CH2OCH(CH3)2, cyclopropyl, cyclopentyl, bicyclo[2.2.1]heptane-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2 H -pyran-4-yl, .

[0207] E19.24. A compound as described in E19.23 or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen, methyl, CD3, –CH(CH3)–C(O)OCH3, –CH(CH3)CH2OCH3, cyclopropyl, cyclopentyl, tetrahydrofuran-3-yl, or oxacyclobutane-3-ylmethyl.

[0208] E20. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E17, wherein R 4B and R 5 Together with the atoms to which they are attached, they form 5 to 7-membered heterocycles.

[0209] E20.1. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E17 or E20, wherein R 4B and R 5 The 5- to 7-membered heterocycle formed is a piperazine.

[0210] E21. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E20.1, wherein R 6 It is hydrogen, halogen, C 1-4 Alkyl, C 1-4 fluoroalkyl, –OR 6a or C 3-6 Cycloalkyl.

[0211] E21.1. A compound as described in E21 or a pharmaceutically acceptable salt thereof, wherein R 6 It is hydrogen.

[0212] E21.2. The compound as described in E21 or a pharmaceutically acceptable salt thereof, wherein R 6 It is halogen.

[0213] E21.3. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21 or E21.2, wherein R 6 The halogen at that location is chlorine.

[0214] E21.4. A compound as described in E21 or a pharmaceutically acceptable salt thereof, wherein R 6 It is C 1-4 alkyl.

[0215] E21.5. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21 or E21.3-E21.4, wherein R 6 The C at that location 1-4 Alkyl is methyl.

[0216] E21.6. A compound as described in E21 or a pharmaceutically acceptable salt thereof, wherein R 6 It is C 1-4 Fluoroalkyl groups.

[0217] E21.7. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21, E21.3, or E21.5-E21.6, wherein R 6 The C at that location 1-4 Fluoroalkyl groups are –CHF2.

[0218] E21.8. A compound as described in E21 or a pharmaceutically acceptable salt thereof, wherein R 6 Yes – OR 6a .

[0219] E21.9. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21, E21.3, E21.5, or E21.7-E21.8, wherein R 6a It is C 1-4 alkyl.

[0220] E21.10. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21, E21.3, E21.5, or E21.7-E21.9, wherein R 6a The C at that location 1-4 Alkyl is methyl.

[0221] E21.11. A compound as described in E21 or a pharmaceutically acceptable salt thereof, wherein R 6 It is C 3-6 Cycloalkyl.

[0222] E21.12. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21, E21.3, E21.5, E21.7, or E21.9-E21.11, wherein R 6 The C at that location 3-6 The cycloalkyl group is cyclopropyl.

[0223] E22. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21.12, wherein R 7 It is C 1-4 Alkyl, halogen, cyano, or G 7 .

[0224] E22.1. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E22, wherein R 7 It is C 1-4 Alkyl, halogen, or cyano groups.

[0225] E22.2. A compound as described in E22.1 or a pharmaceutically acceptable salt thereof, wherein R 7 It is C 1-4 alkyl.

[0226] E22.3. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E22.2, wherein R 7 The C at that location 1-4 Alkyl is methyl.

[0227] E22.4. A compound as described in E22.1 or a pharmaceutically acceptable salt thereof, wherein R 7 It is a cyano group.

[0228] E22.5. A compound as described in E22.1 or a pharmaceutically acceptable salt thereof, wherein R 7 It is halogen.

[0229] E22.6. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E22.1, E22.3, or E22.5, wherein R 7 The halogen at that location is bromine.

[0230] E22.7. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E22.1, E22.3, or E22.5, wherein R 7 The halogen at that location is chlorine.

[0231] E22.8. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E22, wherein R 7 It is G 7 .

[0232] E22.9. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E22.1, E22.3, or E22.6-E22.8, wherein G 7 It is a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms that is optionally substituted.

[0233] E22.10. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E22.1, E22.3, or E22.6-E22.9, wherein G 7 The ring system of the optionally substituted 5- to 6-membered heteroaryl group is pyridyl.

[0234] E22.11. A compound as described in E22.10 or a pharmaceutically acceptable salt thereof, wherein G 7 yes .

[0235] E23 A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E22.11, wherein n is 0.

[0236] E24. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E23, wherein G 1 yes .

[0237] E25. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E24, wherein X 1 It is NR 5.

[0238] E26. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E18.1 or E21-E24, wherein X 1 It is O.

[0239] E27. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E18.1 or E21-E24, wherein X 1 It is CR 5A R 5B .

[0240] E27.1. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E18.1, E21-E24, or E27, wherein R 5A and R 5B It can be hydrogen, fluorine, or methyl on its own.

[0241] E27.2. A compound as described in E27.1 or a pharmaceutically acceptable salt thereof, wherein R 5A and R 5B It's fluorine.

[0242] E27.3. A compound as described in E27.1 or a pharmaceutically acceptable salt thereof, wherein R 5A and R 5B It is a methyl group.

[0243] E27.4. A compound as described in E27.1 or a pharmaceutically acceptable salt thereof, wherein R 5A and R 5B It is hydrogen.

[0244] E28. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E27.4, wherein X 2 It is CR 6 .

[0245] E29. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E27.4, wherein X 2 It is N.

[0246] E30. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E23, wherein G 1 yes .

[0247] E31. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E20.1 or E23-E30, wherein R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 5- to 7-membered heterocycles or 5- to 7-membered carbon rings.

[0248] E31.1. A compound as described in E31 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 5- to 7-membered heterocycles.

[0249] E31.2. A compound as described in E31.1 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 Together with the atoms to which they are attached, they form dihydrothiophene or dihydrofuran.

[0250] E31.3. The compound as described in E31.2 or a pharmaceutically acceptable salt thereof, wherein G 1 yes .

[0251] E31.4. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E20.1 or E23-30, wherein R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 5- to 7-membered carbon rings.

[0252] E31.5. A compound as described in E31.4 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 Together with the atoms to which they are attached, they form cyclopentene or cyclohexene.

[0253] E31.6. A compound as described in E31.5 or a pharmaceutically acceptable salt thereof, wherein G 1 yes .

[0254] E32. Compounds as described in E1, selected from the group consisting of: Or its pharmaceutically acceptable salt.

[0255] E33. A pharmaceutical composition comprising a compound as described in any one of E1-E32 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0256] E34. A method for treating neurological and / or mental disorders in mammals associated with dysfunction of muscarinic acetylcholine receptors, the method comprising administering to the mammal a therapeutically effective amount of a compound as described in any one of E1-E32 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in E33.

[0257] E35. The method as described in E34, wherein the impairment is associated with mAChR M4 dysfunction.

[0258] E36. The method as described in E34 or E35, wherein the disorder is a neurological and / or mental disorder associated with mAChR M4 dysfunction.

[0259] E37. The method of any one of E34-E36, wherein the disorder is selected from the group consisting of: Alzheimer's disease, schizophrenia, sleep disorders, pain disorders, and cognitive impairment.

[0260] E38. The method as described in E37, wherein the impairment is Alzheimer's disease.

[0261] E39. The method of any one of E34-E36, wherein the disorder is selected from the group consisting of: psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, anxiety psychotic episodes, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of intellectual disability, autism disorder, movement disorder, Tourette syndrome, akinesia-rigidity syndrome, movement disorder associated with Parkinson's disease, tardive dyskinesia, movement difficulties based on drug-induced and neurodegenerative changes, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

[0262] E40. A kit comprising a compound as described in any one of E1-E32 or a pharmaceutically acceptable salt thereof, and one or more of the following: (a) at least one known agent that increases mAChR M4 activity; (b) at least one known agent that decreases mAChR M4 activity; (c) at least one known agent that treats disorders related to cholinergic activity; (d) instructions for treating disorders related to cholinergic activity; (e) instructions for treating disorders related to mAChR M4 receptor activity; and (f) instructions for administering the compound in combination with cognitive or behavioral therapy.

[0263] E38. The compound of any one of E1-E32 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of E33, for use in the treatment of neurological and / or mental disorders in mammals associated with dysfunction of muscarinic acetylcholine receptors.

[0264] E39. Use of any compound of any one of E1-E32 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in E33 in the preparation of a medicament for treating neurological and / or mental disorders in mammals associated with dysfunction of muscarinic acetylcholine receptors.

[0265] Compounds can exist as stereoisomers with asymmetric or chiral centers. Stereoisomers are classified according to the configuration of the substituents surrounding the chiral carbon atom. R "or" S The term "" as used in this article R "and" S"This is the configuration as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry," Pure Appl. Chem., 1976, 45: 13-30. This disclosure considers various stereoisomers and mixtures thereof, and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. Individual stereoisomers of a compound may be prepared by synthesis from commercially available starting materials containing asymmetric or chiral centers, or by preparing a racemic mixture followed by a resolution method well known to those skilled in the art. These resolution methods are exemplified by (1) attaching a mixture of enantiomers to a chiral auxiliary, separating the resulting diastereomer mixture by recrystallization or chromatography, and optionally releasing an optically pure product from the auxiliary, such as Furniss, Hannaford, Smith and Tatchell, “Vogel’s Textbook of Practical Organic Chemistry”, 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, as described in (2) direct separation of a mixture of optical enantiomers on a chiral chromatographic column, or (3) stepwise recrystallization.

[0266] It should be understood that compounds may have tautomer forms and geometric isomers, and these also constitute embodiments of this disclosure.

[0267] In compounds having formula (I) and any sub-formula, any "hydrogen" or "H", whether explicitly enumerated or implicit in the structure, includes hydrogen isotopes. 1 H (protium) and 2 H (deuterium).

[0268] This disclosure also includes isotopically labeled compounds, which are the same as those described in formula (I), but in fact, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes suitable for inclusion in the compounds of this invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, but not limited to, correspondingly. 2 H, 3 H, 13 C 14 C 15N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, and 36 Cl. Using heavier isotopes such as deuterium (i.e., 2 H) substitution can yield certain therapeutic advantages stemming from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and is therefore preferred in some cases. The compound may contain a positron emission isotope for medical imaging and a positron emission tomography (PET) study for determining receptor distribution. Suitable positron emission isotopes that can be incorporated into compounds having formula (I) are 11 C 13 N、 15 O, and 18 F.

[0269] Isotopically enriched compounds having formula (I) or any subform can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using appropriate isotopically enriching reagents instead of non-isotopically enriching reagents. The degree of isotopic enrichment can be characterized as the percentage of a particular isotope incorporated at the isotopically labeled atom (e.g., deuterium incorporation % at a deuterium label).

[0270] a. Pharmaceutically acceptable salt The disclosed compounds may exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt or zwitterion of a compound that is water-soluble, oil-soluble, or dispersible, suitable for treating the disorder without unusual toxicity, irritation, or allergic reactions, commensurate with a reasonable benefit / risk ratio, and effective for its intended use. These salts may be prepared during the final separation and purification of the compound, or separately by reacting the amino group of the compound with a suitable acid. For example, the compound may be dissolved in a suitable solvent (e.g., but not limited to methanol and water) and treated with at least one equivalent of an acid (e.g., hydrochloric acid). The resulting salt may precipitate and be separated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide the salt. Representative salts include: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, butates, camphorates, camphorsulfonates, diglucose, glycerol phosphates, hemisulfates, heptahydrates, hexanoates, formates, hydroxyethyl sulfonates, fumarates, lactates, maleates, methanesulfonates, naphthalenesulfonates, nicotinates, oxalates, dihydroxynaphthalate, pectates, persulfates, 3-phenylpropionates, picrates, oxalates, maleates, neopentanoates, propionates, succinates, tartrates, trichloroacetates, trifluoroacetates, glutamates, p-toluenesulfonates, undecanoates, hydrochlorides, hydrobromates, sulfates, phosphates, etc. The amino groups of these compounds can be quaternized using alkyl chlorides, bromides, and iodides (e.g., methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, etc.).

[0271] Base addition salts can be prepared during the final separation and purification of the disclosed compounds by reacting the carboxyl group with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a metal cation (e.g., lithium, sodium, potassium, calcium, magnesium, or aluminum), or an organic primary, secondary, or tertiary amine. Quaternary ammonium salts, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, etc. N , N -Dimethylaniline, N -Methylpiperidine, N methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N -Dibenzylphenethylamine, 1-Diphenylhydroxymethylamine and N,N’ -Those like dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, etc.

[0272] b. General Synthesis Compounds having formula (I) can be prepared by synthetic or metabolic methods. The preparation of compounds by metabolic methods includes those that occur in the human or animal body (in vivo) or those that occur in vitro.

[0273] Compounds having formula (I) can be synthesized as shown in schemes 1-14.

[0274] Option 1 As shown in Scheme 1, an intermediate compound having formula P2 can be placed under standard nucleophilic substitution conditions with an intermediate having formula P1, a base (e.g., DIPEA), and a solvent (e.g., DMSO) and heated to approximately 90°C-160°C to provide a compound having formula P3.

[0275] Option 2 As shown in Scheme 2, the P4 type intermediate can be protected with di-tert-butyl carbonate under Boc protection conditions known in the art to provide a P5 type Boc protected intermediate. The P5 type intermediate can be coupled with an amine under Buchwald coupling conditions known in the art, and then deprotected to provide a P6 type product.

[0276] Option 3 Scheme 3 illustrates a general route for preparing intermediates having the formula P7. The P5-type intermediate can be coupled with boric acid or an ester under Suzuki coupling conditions known in the art, followed by deprotection to provide a compound having the formula P7, wherein R... 2 It is an alkyl group or G 2 And G 2 It is an optionally substituted aryl or heteroaryl ring system as defined herein. The coupling reaction can be carried out using a palladium catalyst (e.g., Pd(dppf)Cl2) and a base (e.g., K2CO3, Cs2CO3) in a solvent mixture of an organic solvent (e.g., DMF or 1,4-dioxane) and water, and heated to approximately 70°C–90°C. Microwave irradiation can promote the reaction.

[0277] Option 4 As shown in Scheme 4, the intermediate compound having formula P3a can be used with a base (e.g., NaH, LiHMDS, etc.), a solvent (e.g., DMSO), and R 5 -X (where X is a halogen, methanesulfonate or other leaving group) treatment to provide a compound having the formula P8.

[0278] Option 5 As shown in Scheme 5, ester intermediate P9 (where Y, Y) 1 and Y 2(Cl, Br or I) can be used with amines, bases (e.g. DIEA) and solvents (e.g. THF), and without heating or heated to 40°C-50°C to provide compound P1a.

[0279] Option 6 As shown in Scheme 6, an intermediate compound having formula P2 can be placed under standard nucleophilic substitution conditions with an intermediate having formula P1b (where Y is a halogen), a base (e.g., DIPEA), and a solvent (e.g., DMSO) and heated to approximately 90°C-120°C to provide a compound having formula P10.

[0280] Option 7 As shown in Scheme 7, an intermediate having the formula P10 (where Y is a halogen) can be coupled with boric acid or an ester under Suzuki coupling conditions known in the art. The coupling reaction can be carried out using a palladium catalyst (e.g., Pd(dppf)Cl2) and a base (e.g., K2CO3, Cs2CO3) in a solvent mixture of an organic solvent (e.g., DMF or 1,4-dioxane) and water, and heated to approximately 70°C–90°C. Microwave irradiation can promote the reaction.

[0281] Option 8 As shown in Scheme 8, an intermediate having formula P10 (where Y is a halogen) can be prepared using a catalyst (e.g., Pd(PPh3)4), a cyanide source (e.g., Zn(CN)2), and a solvent (e.g., DMF), and heated to 120°C–140°C to provide a compound having formula P11a. Microwave irradiation can promote the reaction.

[0282] Option 9 As shown in Scheme 9, the intermediate compound having formula P12 (where Y and Y) can be used. 1 A compound having the formula P13 is obtained by placing fluorine, chlorine, or bromine with an amine, a base (e.g., DIEA, Et3N, etc.) and a solvent (e.g., NMP, DMF) under standard nucleophilic substitution conditions.

[0283] Option 10 As shown in Scheme 10, an intermediate having formula P13 (where Y is a halogen) can be heated with hydrazine in a solvent (e.g., ethanol) to 70°C-80°C, then cyclized (e.g., CDI (CAS# 530-62-1)) and heated to 70°C-85°C to form a compound having formula P14.

[0284] Option 11 As shown in Scheme 11, a compound having formula P5 can be reacted with an alcohol under Ullman conditions known in the art, followed by deprotection with an acid (e.g., TFA) to provide a P15 type intermediate. Suitable Ullman conditions for coupling with phenol include using a base (e.g., Cs₂CO₃), 2,2,6,6-tetramethylheptane-3,5-dione, and a copper salt (e.g., cuprous iodide(I)) and heating in a solvent (e.g., NMP) to approximately 100°C–120°C.

[0285] Option 12 As shown in Scheme 12, compound P17 can be prepared from P16 by alkylation with a base (e.g., NaH) and a suitable alkylating agent (e.g., MeI).

[0286] Option 13 As shown in Scheme 13, compound P18 can react with compound P2 in the presence of a base (similar to Schemes 1 and 6) to provide P19. Reduction of the nitrile of P19 (e.g., Raney nickel, ammonia, and hydrogen (g)) can provide compound P20.

[0287] Option 14 As shown in Scheme 14, compound P21 can be derived from P14 by using a base (e.g., K2CO3) and a suitable alkylating agent (e.g., R). 5 It is prepared by alkylation of -X, where X is a halogen, toluenesulfonate, etc.

[0288] The above scheme can use the following intermediate to prepare compounds having formula (I): 3-bromo-2-chloro-6,7-dihydro-5- H -cyclopentadiene[ b Pyridin-5-one and 3-bromo-2-chloro-6,6-difluoro-6,7-dihydro-5 H -cyclopentadiene[ b ]Pyridin-5-one, described in WO 2018 / 118736.

[0289] Suitable boric acids / esters, amines, and alcohols used in the coupling reactions described herein can be readily obtained from commercial sources or prepared by standard methods well known to those skilled in the art.

[0290] Compounds and intermediates can be separated and purified using methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for separating and purifying compounds may include, but are not limited to: chromatography on a solid support (e.g., silica gel, alumina, or silica derived from alkylsilyl groups), recrystallization at high or low temperatures (optionally pretreated with activated carbon), thin-layer chromatography, distillation at various pressures, sublimation under vacuum, and grinding, as described, for example, in Vogel's Textbook of Practical Organic Chemistry, 5th Edition (1989), Furniss, Hannaford, Smith, and Tatchell, Longman Scientific & Technical, Essex CM20 2JE, England.

[0291] The disclosed compounds may have at least one basic nitrogen atom, thus allowing the compound to be treated with an acid to form a desired salt. For example, the compound may react with an acid at or above room temperature to provide the desired salt, which is then precipitated and collected by filtration upon cooling. Examples of acids suitable for the reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, as well as mandelic acid, arbutinic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, carbonic acid, fumaric acid, maleic acid, gluconic acid, acetic acid, propionic acid, salicylic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid, or glutamic acid.

[0292] The reaction conditions and time for each individual step can vary depending on the specific reactants used and the substituents present in the reactants. Specific procedures are provided in the Examples section. Reactions can be handled in a conventional manner, for example by removing the solvent from the residues and further purifying them according to methods generally known in the art, such as, but not limited to, crystallization, distillation, extraction, grinding, and chromatography. Unless otherwise stated, starting materials and reagents are commercially available or can be prepared from commercially available materials by those skilled in the art using methods described in the chemical literature. Starting materials (if not commercially available) can be prepared using procedures selected from standard organic chemistry techniques, techniques similar to those used for synthesizing compounds with known structural similarities, or techniques similar to those described in the Schemes or Synthesis Examples section above.

[0293] Routine experiments (including reaction conditions, reagents, the sequence of synthetic pathways, protection of any chemical functional groups incompatible with the reaction conditions, and appropriate deprotection procedures at suitable points in the reaction sequence of the method) are included within the scope of this invention. Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of them can be found in PGM Wuts and TW Greene, Greene's book entitled *Protective Groups in Organic Synthesis* (4th Edition), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. The synthesis of the compounds of this invention can be accomplished by methods similar to those described in the above synthetic schemes and specific examples.

[0294] When the optically active form of the disclosed compound is required, it can be obtained by using one of the procedures described herein with an optically active starting material (e.g., prepared by asymmetric induction via suitable reaction steps), or by resolving a mixture of stereoisomers of the compound or intermediate using standard procedures (e.g., chromatographic separation, recrystallization, or enzymatic resolution).

[0295] Similarly, when pure geometric isomers of a compound are required, they can be obtained by using pure geometric isomers as starting materials and performing one of the above procedures, or by using standard procedures such as chromatography to separate mixtures of geometric isomers of the compound or intermediate.

[0296] It is understood that the synthetic methods and specific examples are illustrative and should not be construed as limiting the scope of the invention as defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.

[0297] c. Muscarinic acetylcholine receptor M4 activity In some embodiments, the disclosed compound enhances the agonist response (e.g., acetylcholine) of mAChR M4. In some embodiments, the disclosed compound increases the response of mAChR M4 to non-maximum concentrations of agonists in the presence of the compound compared to the response to the agonist in the absence of the compound. The enhancement of mAChR M4 activity can be demonstrated by methods known in the art. For example, it can be demonstrated by measuring the response to Ca-loaded Ca. 2+Activation of mAChR M4 activity is determined by the calcium flux of cellular agonists (e.g., acetylcholine) co-expressed with chimeric or hybrid G ​​proteins, as indicated by sensitive fluorescent dyes (e.g., Fluo-4). In some embodiments, calcium flux is measured as an increase in the fluorescence static ratio. In some embodiments, positive allosteric modulator activity is analyzed as EC 20 Increased concentration dependence in acetylcholine response (i.e., response of mAChR M4 that produces 20% of the maximum response at acetylcholine concentrations).

[0298] In some embodiments, compared to the response of equivalent CHO-K1 cells in the absence of the compound, the disclosed compound activates the mAChR M4 response in the presence of the compound, manifested as decreased calcium fluorescence in mAChR M4-transfected CHO-K1 cells. In some embodiments, the disclosed compound activates the mAChR M4 response, whose EC50... 50 Less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. In some embodiments, CHO-K1 cells transfected with mAChR M4 are transfected with human mAChR M4. In some embodiments, CHO-K1 cells transfected with mAChR M4 are transfected with rat mAChR M4.

[0299] Compared to the response to acetylcholine in the absence of the compound, the disclosed compound, in the presence of the compound in CHO-K1 cells transfected with mAChR M4, can exhibit positive allosteric regulation of the mAChR M4 response to acetylcholine as an increase in the response to non-maximal concentrations of acetylcholine. In some embodiments, the disclosed compound exhibits positive allosteric regulation of the mAChR M4 response to acetylcholine, with an EC50 of [missing information]. 50 Less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, or less than about 100 nM. In some embodiments, positive allosteric regulation of EC was identified in CHO-K1 cells transfected with mAChR M4. 50 In some embodiments, mAChR M4 is transfected into human mAChR M4. In some embodiments, mAChR M4 is transfected into rat mAChR M4.

[0300] The disclosed compounds can exhibit selectivity for the mAChR M4 receptor relative to one or more of the mAChR M1, M2, M3, or M5 receptors. For example, the disclosed compounds can activate the mAChR M4 response in mAChR M4-transfected CHO-K1 cells, with EC5... 50One or more ECs smaller than mAChR M1, M2, M3, or M5 transfected CHO-K1 cells 50 In some embodiments, the disclosed compounds can activate the mAChR M4 response, with an EC50 greater effect than those activating the mAChR M1 response. 50 The reduction is approximately 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, or more than 500-fold. In some embodiments, the disclosed compound can activate the mAChR M4 response, and its EC50 is significantly reduced compared to activating the mAChR M2 response. 50 The reduction is approximately 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, or more than 500-fold. In some embodiments, the disclosed compound can activate the mAChR M4 response, and its EC50 is significantly reduced compared to activating the mAChR M3 response. 50 The reduction is approximately 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, or more than 500-fold. In some embodiments, the disclosed compound can activate the mAChR M4 response, and its EC5 ratio is significantly lower than that of the mAChR M5 response. 50 The reduction is approximately 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, or more than 500-fold. In some embodiments, the disclosed compound can activate the mAChR M4 response, with an EC5 ratio greater than that of the M2-M5 receptor response. 50 A 5-fold reduction, a 10-fold reduction, a 20-fold reduction, and a 30-fold reduction, compared to the activation of mAChR M1, M2, M3, or M5 receptor responses, resulted in lower ECGs. 50 The reduction is approximately 50 times, 100 times, 200 times, 300 times, 400 times, or more than 500 times.

[0301] The disclosed compound can activate the mAChR M4 response in M4-transfected CHO-K1 cells, and its EC50... 50 Less than about 10 μM, and exhibiting selectivity for the M4 receptor relative to one or more of the mAChR M1, M2, M3, or M5 receptors. For example, in some embodiments, the EC50 of the compound... 50The concentrations can be less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM; and the compound can also activate the mAChR M4 response, with an EC50 greater effect than that of activating the mAChR M1 response. 50 The reduction is approximately 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, or more than approximately 500-fold. In some embodiments, the EC50 of the compound... 50 The concentrations can be less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM; and the compound can also activate the mAChR M4 response, with an EC50 greater effect than that of activating the mAChR M2 response. 50 The reduction is approximately 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, or more than 500-fold. In some embodiments, the EC of the compound... 50 The concentrations can be less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM; and the compound can also activate the mAChR M4 response, with an EC50 greater effect than that of activating the mAChR M3 response. 50 The reduction is approximately 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, or more than 500-fold. In some embodiments, the EC of the compound... 50 The concentrations can be less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM; and the compound can also activate the mAChR M4 response, with an EC5 value lower than that activating the mAChR M5 response. 50 The reduction is approximately 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, or more than 500-fold. In some embodiments, the EC of the compound... 50 The concentrations can be less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM; and the compound can also activate the mAChR M4 response, with an EC5 value lower than that of the M2-M5 receptor response. 50 A 5-fold reduction, a 10-fold reduction, a 20-fold reduction, and a 30-fold reduction, compared to the activation of M2, M3, or M5 receptor responses, resulted in lower ECGs. 50A reduction of approximately 50-fold, 100-fold, 200-fold, 300-fold, or 400-fold, or compared to the activation of mAChR M1, M2, M3, or M5 receptor responses, its EC 50 It has been reduced by more than 500 times.

[0302] The in vivo efficacy of the disclosed compounds can be measured in many preclinical rat behavioral models, where known, clinically useful antipsychotic drugs show similar positive responses. For example, the disclosed compounds can reverse excitatory movement induced by oral administration of amphetamines at doses ranging from 1 to 100 mg / kg in male Spratly-Dowley rats.

[0303] 3. Pharmaceutical compositions and formulations The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to subjects (e.g., patients, which may be human or non-human). The disclosed compounds may also be provided as formulations (e.g., spray-dried dispersion formulations).

[0304] Pharmaceutical compositions and formulations may include agents of either a "therapeutic effective amount" or a "preventive effective amount." A "therapeutic effective amount" refers to an effective amount, measured in doses and sustained for the required period of time, to achieve the desired therapeutic outcome. Therapeutic effective amounts of a composition can be determined by those skilled in the art and can vary depending on various factors, such as an individual's disease state, age, sex, and weight, as well as the composition's ability to elicit a desired response in the individual. A therapeutic effective amount is also an amount in which any toxicity or adverse effect of the compounds of the present invention (e.g., compounds having formula (I)) does not exceed the amount of therapeutic benefit. A "preventive effective amount" refers to an effective amount, measured in doses and sustained for the required period of time, to achieve the desired preventive outcome. Typically, because preventive doses are administered to the subject before or early in the course of the disease, preventive effective amounts will be less than therapeutic effective amounts.

[0305] For example, the therapeutically effective amount of a compound having formula (I) may be about 1 mg / kg to about 1000 mg / kg, about 5 mg / kg to about 950 mg / kg, about 10 mg / kg to about 900 mg / kg, about 15 mg / kg to about 850 mg / kg, about 20 mg / kg to about 800 mg / kg, about 25 mg / kg to about 750 mg / kg, about 30 mg / kg to about 700 mg / kg, about 35 mg / kg to about 650 mg / kg, about 40 mg / kg to about 600 mg / kg, about 45 mg / kg to about 550 mg / kg, about 50 mg / kg to about 500 mg / kg, about 55 mg / kg to about 450 mg / kg, about 60 mg / kg to about 400 mg / kg, about 65 mg / kg to about 350 mg / kg, about 70 mg / kg to about 300 mg / kg, about 75 mg / kg to about 250 mg / kg, about 80 mg / kg to about 1000 mg / kg, about 50 mg / kg to about 950 mg / kg, about 10 mg / kg to about 900 mg / kg, about 15 mg / kg to about 850 mg / kg, about 200 mg / kg to about 800 mg / kg, about 400 mg / kg to about 600 mg / kg, about 45 mg / kg to about 550 mg / kg, about 65 mg / kg to about 350 mg / kg, about 70 mg / kg to about 300 mg / kg, about 75 mg / kg to about 250 mg / kg, about 800 mg / kg to about 1000 mg / kg, about 50 mg / kg to about 700 mg / kg, about 75 mg / kg to about 250 mg / kg to about 200 mg / kg, about 85 mg / kg to about 150 mg / kg, and about 90 mg / kg to about 100 mg / kg.

[0306] Pharmaceutical compositions and formulations may include pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or any type of formulation aid. Some examples of materials that can be used as pharmaceutically acceptable carriers are sugars, such as, but not limited to, lactose, glucose, and sucrose; starches, such as, but not limited to, corn starch and potato starch; cellulose and its derivatives, such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered astragalus gum; malt; gelatin; talc; excipients, such as, but not limited to, cocoa butter and suppository waxes; oils, such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; esters, such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffers, such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; and phosphate buffer solutions, as well as other non-toxic and compatible lubricants, such as, but not limited to, sodium dodecyl sulfate and magnesium stearate, and colorants, release agents, coating agents, sweeteners, flavoring agents, and flavoring agents. Preservatives and antioxidants may also be included in the composition at the discretion of the formulator.

[0307] Therefore, compounds and their pharmaceutically acceptable salts can be formulated for administration via, for example, solid dosage forms, eye drops, in topical oil-based formulations, injection, inhalation (through the mouth or nose), implantation, or for oral, oral, parenteral, or rectal administration. Technologies and formulations are generally available in Remington's Pharmaceutical Sciences (Meade Publishing Co., Easton, Pennsylvania). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.

[0308] The route of administration of the disclosed compound and the form of the composition determine the type of carrier to be used. The composition may be in a variety of forms suitable for, for example, systemic administration (e.g., oral, rectal, nasal, sublingual, oral, implant, or parenteral) or topical administration (e.g., skin, lung, nose, ear, eye, liposome delivery system, or iontophoresis).

[0309] Carriers for systemic application typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavorings, sweeteners, antioxidants, preservatives, flow aids, solvents, suspending agents, wetting agents, surfactants, and combinations thereof. All carriers are optional in the composition.

[0310] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; glycols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols such as glycerin; mannitol; and sorbitol. The amount of one or more diluents in a systemic or topical composition is typically from about 50% to about 90%.

[0311] Suitable lubricants include silica, talc, stearic acid and its magnesium and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter. The amount of one or more lubricants in a whole-body or topical composition is typically from about 5% to about 10%.

[0312] Suitable binders include polyvinylpyrrolidone; magnesium aluminum silicate; starch, such as corn starch and potato starch; gelatin; astragalus gum; and cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, microcrystalline cellulose, and sodium carboxymethyl cellulose. The amount of one or more binders in the whole-body composition is typically from about 5% to about 50%.

[0313] Suitable disintegrants include agar, alginate and its sodium salt, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium glycolate starch, clay, and ion exchange resins. The amount of one or more disintegrants in a systemic or topical composition is typically from about 0.1% to about 10%.

[0314] Suitable colorants include FD&C dyes and other colorants. When used, the amount of one or more colorants in a whole-body or topical composition is typically from about 0.005% to about 0.1%.

[0315] Suitable flavoring agents include menthol, peppermint, and fruit flavoring agents. When used, the amount of one or more flavoring agents in a whole-body or topical composition is typically from about 0.1% to about 1.0%.

[0316] Suitable sweeteners include aspartame and saccharin. The amount of one or more sweeteners in a systemic or topical composition is typically from about 0.001% to about 1%.

[0317] Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of one or more antioxidants in a systemic or topical composition is typically from about 0.1% to about 5%.

[0318] Suitable preservatives include benzalkonium chloride, methylparaben, and sodium benzoate. The amount of one or more preservatives in a systemic or topical composition is typically from about 0.01% to about 5%.

[0319] Suitable flow aids include silica. The amount of one or more flow aids in a systemic or topical composition is typically from about 1% to about 5%.

[0320] Suitable solvents include water, isotonic saline, ethyl oleate, glycerol, hydroxylated castor oil, alcohols (e.g., ethanol), and phosphate buffer solutions. The amount of one or more solvents in a systemic or topical composition is typically from about 0% to about 100%.

[0321] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation in Philadelphia, Pennsylvania) and sodium alginate. The amount of one or more suspending agents in a systemic or topical composition is typically from about 1% to about 8%.

[0322] Suitable surfactants include lecithin, polysorbate 80, and sodium lauryl sulfate, as well as TWEENS (from Atlas Powder Company, Wilmington, Delaware). Suitable surfactants include those disclosed in CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 15th edition, 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American edition, pp. 236-239. The amount of one or more surfactants in a systemic or topical composition is typically from about 0.1% to about 5%.

[0323] Although the amounts of components in a systemic composition can vary depending on the type of systemic composition being prepared, systemic compositions typically comprise 0.01% to 50% of the active compound (e.g., a compound having formula (I)) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically comprise 0.1% to 10% of the active ingredient and 90% to 99.9% of a carrier comprising a diluent and a solvent.

[0324] Compositions for oral administration can be in various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount (typically at least about 5%, more particularly about 25% to about 50%) of the active ingredient. Oral dosage compositions include about 50% to about 95% of a carrier, and more particularly, from about 50% to about 75%.

[0325] Tablets can be compressed, ground, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically comprise an active ingredient and a carrier containing an ingredient selected from diluents, lubricants, binders, disintegrants, colorants, flavorings, sweeteners, gliding agents, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginate and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners (e.g., aspartame and saccharin), or flavorings (e.g., menthol, peppermint, fruit flavorings), or combinations thereof.

[0326] Capsules (including implants, timed-release and sustained-release formulations) typically comprise an active compound (e.g., a compound having formula (I)) and a carrier comprising one or more diluents from the gelatin-containing capsules disclosed above. Particles typically comprise the disclosed compounds, preferably flow aids (e.g., silica) to improve flow properties. Implants may be biodegradable or non-biodegradable.

[0327] The selection of ingredients in the carrier for oral compositions depends on secondary considerations, such as taste, cost, and storage stability, which are not important to the purposes of this invention.

[0328] Solid compositions can be coated using conventional methods (typically pH- or time-dependent coating) to release the disclosed compound in the gastrointestinal tract near the desired application or at different points and times, thereby prolonging the desired action. Coatings typically comprise one or more components selected from the group consisting of: cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, EUDRAGIT® coating (available from Evonik Industries, Essen, Germany), waxes, and shellac.

[0329] Compositions for oral administration may be in liquid form. Suitable liquid forms include, for example, aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent particles, suspensions reconstituted from non-effervescent particles, effervescent formulations reconstituted from effervescent particles, elixirs, tinctures, syrups, etc. Liquid compositions for oral administration typically include the disclosed compounds and a carrier selected from diluents, colorants, flavoring agents, sweeteners, preservatives, solvents, suspending agents, and surfactants. Orally administered liquid compositions preferably include one or more components selected from colorants, flavoring agents, and sweeteners.

[0330] Other compositions for achieving systemic delivery of the subject compound include sublingual, oral, and nasal dosage forms. Such compositions typically comprise one or more soluble filler substances, such as diluents including sucrose, sorbitol, and mannitol; and binders such as gum arabic, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavoring agents, sweeteners, antioxidants, and flow aids.

[0331] The disclosed compounds can be applied topically. Topical compositions applicable to the skin can be in any form, including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-in and rinse-out conditioners, emulsions, cleansers, moisturizers, sprays, skin patches, etc. Topical compositions comprise: the disclosed compound (e.g., a compound having formula (I)) and a carrier. The carrier of the topical composition preferably facilitates penetration of the compound into the skin. The carrier may further comprise one or more optional components.

[0332] The amount of carrier used in combination with the disclosed compounds is sufficient to provide the actual amount of composition administered per unit dose of the compound. Techniques and compositions for preparing dosage forms that can be used in the methods of the present invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, edited by Banker and Rhodes (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd ed. (1976).

[0333] The carrier may comprise a single component or a combination of two or more components. In topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more components selected from: phosphate-buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristate propionate, dimethyl isosorbide, castor oil, and combinations thereof. More particularly, carriers for dermal applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate-buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0334] The carrier of the topical composition may further include one or more components selected from: emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0335] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl lauryl acid, hexyl lauryl acid, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients used on the skin include stearyl alcohol and polydimethylsiloxane. The amount of one or more emollients in a topical skin-based composition is typically from about 5% to about 95%.

[0336] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of one or more propellants in a localized composition is typically from about 0% to about 95%.

[0337] Suitable solvents include water, ethanol, dichloromethane, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethanol and homotopic alcohols. The amount of one or more solvents in the topical composition is typically from about 0% to about 95%.

[0338] Suitable moisturizers include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific moisturizers include glycerin. The amount of one or more moisturizers in a topical composition is typically from 0% to 95%.

[0339] The amount of one or more thickeners in a topical composition is typically from about 0% to about 95%.

[0340] Suitable powders include β-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, bleaching clay, kaolin, starch, gum, colloidal silica, sodium polyacrylate, tetraalkylammonium montmorillonite, trialkylarylammonium montmorillonite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymers, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of one or more powders in the topical composition is typically from 0% to 95%.

[0341] The amount of fragrance in the topical composition is typically from about 0% to about 0.5%, and particularly from about 0.001% to about 0.1%.

[0342] Suitable pH-adjusting additives include HCl or NaOH, in amounts sufficient to adjust the pH of the topical drug composition.

[0343] Pharmaceutical compositions or formulations can exhibit positive allosteric regulation of mAChR M4, with its EC50... 50 Less than about 10 µM, less than about 5 µM, less than about 1 µM, less than about 500 nM, or less than about 100 nM. Pharmaceutical compositions or formulations can exhibit positive allosteric regulation of mAChR M4, with EC50 values ​​of less than 10 µM. 50 Between approximately 10 µM and approximately 1 nM, between approximately 1 µM and approximately 1 nM, between approximately 100 nM and approximately 1 nM, or between approximately 10 nM and approximately 1 nM.

[0344] a. Spray-dried dispersion formulations The disclosed compounds can be formulated into spray-dried dispersions (SDDs). SDDs are single-phase, amorphous molecular dispersions of drugs in a polymer matrix. It is a solid solution in which the compound molecules are "dissolved" in the solid matrix. SDDs are obtained by dissolving the drug and polymer in an organic solvent and then spray-drying the solution. Using spray drying for pharmaceutical applications can produce amorphous dispersions with increased solubility for Biopharmaceutics Class II (high permeability, low solubility) and Class IV (low permeability, low solubility) drugs. Formulation and process conditions are selected to allow for rapid evaporation of the solvent from the droplets, resulting in insufficient time for phase separation or crystallization. SDDs have demonstrated long-term stability and manufacturability. For example, SDDs have demonstrated a shelf life exceeding 2 years. The advantages of SDDs include, but are not limited to, enhanced oral bioavailability of poorly water-soluble compounds, delivery using conventional solid dosage forms such as tablets and capsules, reproducible, controlled, and scalable manufacturing methods, and broad applicability to compounds with diverse physical properties and structural insolubility.

[0345] Therefore, in one embodiment, this disclosure may provide a spray-dried dispersion formulation comprising a compound having formula (I).

[0346] 4. How to use The disclosed compounds, pharmaceutical compositions, and formulations can be used in methods for treating disorders (e.g., neurological and / or mental disorders) associated with muscarinic acetylcholine receptor dysfunction. The disclosed compounds and pharmaceutical compositions can also be used in methods for enhancing muscarinic acetylcholine receptor activity in mammals, and in methods for enhancing mammalian cognition. These methods further include combined treatment methods for improving treatment outcomes in the context of cognitive or behavioral therapy. In the methods of use described herein, additional therapeutic agents may be administered concurrently or sequentially with the disclosed compounds and compositions.

[0347] a. Treatment barriers The disclosed compounds, pharmaceutical compositions, and formulations may be used in the treatment of disorders, or in methods of treating disorders (such as neurological and / or mental disorders) associated with dysfunction of muscarinic acetylcholine receptors. Treatment methods may include administering a therapeutically effective amount of a compound of formula (I) to a subject requiring such treatment, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I).

[0348] In some embodiments, this disclosure provides a method for enhancing mammalian cognition, the method comprising the steps of: administering to the mammal a therapeutically effective amount of a compound having formula (I), or a pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I).

[0349] The compounds and compositions disclosed herein can be used to treat, prevent, improve, control, or reduce the risk of various disorders associated with selective mAChR M4 receptor activation. For example, treatment may include selective mAChR M4 receptor activation to a degree that effectively affects cholinergic activity. Disorders may be related to cholinergic activity, such as cholinergic hypofunction. Therefore, a method for treating or preventing disorders in a subject is provided, the method comprising the step of administering to the subject at an amount effective in treating the subject's disorder at least one of the disclosed compounds or at least one of the disclosed pharmaceutical compositions.

[0350] A method for treating one or more disorders related to mAChR M4 receptor activity in a subject is also provided, the method comprising the steps of administering to the subject a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0351] In some embodiments, this disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in a method of treating a disorder related to the mAChR M4 receptor. In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in a method of treating a disorder related to the mAChR M4 receptor.

[0352] In some embodiments, this disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating disorders associated with the mAChR M4 receptor.

[0353] In some embodiments, this disclosure provides a method for treating a disorder in mammals associated with muscarinic acetylcholine receptor dysfunction, the method comprising the steps of: administering to the mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof.

[0354] In some embodiments, this disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in treating disorders in mammals associated with dysfunction of muscarinic acetylcholine receptors.

[0355] In some embodiments, this disclosure provides pharmaceutical compositions comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in treating disorders in mammals associated with dysfunction of muscarinic acetylcholine receptors.

[0356] In some embodiments, this disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating disorders in mammals associated with dysfunction of muscarinic acetylcholine receptors.

[0357] In some embodiments, the disclosed compounds and compositions may be used to treat a variety of neurological, psychiatric, and cognitive disorders associated with the mAChR M4 receptor, including one or more of the following conditions or diseases: schizophrenia, psychotic disorder NOS, transient psychotic disorder, schizophrenia-like disorder, schizoaffective disorder, paranoid disorder, common psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, mental breakdown, late-onset psychosis, myxedema psychosis, occupational psychosis, menstrual psychosis, secondary psychotic disorder, bipolar I disorder with psychotic features, and substance-induced psychotic disorder. In some embodiments, the psychotic disorder is a psychotic disorder associated with a condition selected from major depressive disorder, affective disorder, bipolar disorder, electrolyte imbalance, Alzheimer's disease, neurological disorder, hypoglycemia, AIDS, lupus, and post-traumatic stress disorder.

[0358] In some embodiments, this disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in methods of treating neurological, mental, or cognitive disorders related to the mAChR M4 receptor, particularly the disorders described herein. In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in methods of treating neurological, mental, or cognitive disorders related to the mAChR M4 receptor, particularly the disorders described herein. In some embodiments, this disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in manufacturing a medicament for treating neurological, mental, or cognitive disorders related to the mAChR M4 receptor, particularly the disorders described herein.

[0359] In some embodiments, the disorder is a neurological disorder selected from brain tumors, Lewy body dementia, multiple sclerosis, sarcoidosis, Lyme disease, syphilis, Alzheimer's disease, Parkinson's disease, and anti-NMDA receptor encephalitis.

[0360] In some embodiments, the disorder is a psychotic disorder selected from schizophrenia, transient psychotic disorder, schizophrenia-like disorder, schizoaffective disorder, delusional disorder, and common psychotic disorder. In some embodiments, schizophrenia is selected from catastrophic schizophrenia, catatonic schizophrenia, paranoid schizophrenia, residual schizophrenia, disintegrative schizophrenia, and undifferentiated schizophrenia. In some embodiments, the disorder is selected from schizotypal personality disorder, schizotypal personality disorder, and paranoid personality disorder. In some embodiments, the psychotic disorder is due to a general medical condition and is substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamines and other psychotropic drugs, and cocaine).

[0361] In some embodiments, this disclosure provides a method for treating cognitive impairment, the method comprising administering an effective amount of the disclosed compound or composition to a patient in need. In some embodiments, cognitive impairment includes dementia (as associated with Alzheimer's disease, ischemic stroke, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Kreutzfeldt-Jacob's disease, perinatal hypoxia, other general medical conditions or substance abuse), delirium, amnesia, substance-induced persistent delirium, dementia caused by HIV disease, dementia caused by Huntington's disease, dementia caused by Parkinson's disease, Parkinson's syndrome-ALS dementia complex, Alzheimer's dementia, age-related cognitive decline, and mild cognitive impairment.

[0362] The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington, D.C.) provides a diagnostic tool that includes cognitive impairments, including dementia, delirium, amnesia, and age-related cognitive decline. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (2013, American Psychiatric Association, Washington, D.C.) provides a diagnostic tool for neurocognitive disorders (NCDs), including delirium, followed by syndromic severe NCD, mild NCD, and their etiological subtypes. Subtypes of severe or mild NCD include NCD caused by Alzheimer's disease, vascular NCD, Lewy body NCD, NCD caused by Parkinson's disease, frontotemporal NCD, NCD caused by traumatic brain injury, NCD caused by HIV infection, substance / drug-induced NCD, NCD caused by Huntington's disease, NCD caused by prion diseases, NCD caused by other medical conditions, NCD caused by multiple etiologies, and unspecified NCD. The NCD categories in DSM-5 encompass a group of disorders in which the primary clinical deficit is cognitive function and is acquired rather than developmental. As used herein, the term "cognitive impairment" includes those cognitive impairments and treatments of mental cognitive impairments as described in DSM-IV-TR or DSM-5. Those skilled in the art will recognize that alternative nomenclature, disease taxonomy, and classification systems exist for mental disorders, and that these systems have evolved with advances in medicine and science. Therefore, the term "cognitive impairment" is intended to include similar impairments described in other diagnostic sources.

[0363] In some embodiments, this disclosure provides a method for treating schizophrenia or psychosis, the method comprising administering an effective amount of the disclosed compound or composition to a patient in need. Specific pathotypes of schizophrenia or psychosis are paranoid, disintegrative, catatonic, or undifferentiated schizophrenia and substance-induced psychotic disorders. The DSM-IV-TR provides a diagnostic tool that includes paranoid, disintegrative, catatonic, undifferentiated, or residual schizophrenia and substance-induced psychotic disorders. The DSM-5 eliminates subtypes of schizophrenia, replacing them with a dimensional approach to assess the severity of core symptoms of schizophrenia to capture the heterogeneity in the types and severity of symptoms manifested in individuals with psychotic disorders. As used herein, the term “schizophrenia or psychosis” includes the treatment of those mental disorders as described in the DSM-IV-TR or DSM-5. Those skilled in the art will recognize that alternative nomenclature, disease taxonomy, and classification systems exist for mental disorders, and that these systems have evolved with advances in medicine and science. Therefore, the term “schizophrenia or psychosis” is intended to include similar disorders described in other diagnostic sources.

[0364] In some embodiments, this disclosure provides a method for treating pain, the method comprising administering an effective amount of the disclosed compound or composition to a patient in need. Specific examples of pain include bone and joint pain (osteoarthritis), repetitive motion pain, toothache, cancer pain, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecological surgery), chronic pain, and neuropathic pain.

[0365] The compounds and compositions may be further used in methods for the prevention, treatment, control, improvement, or reduction of the risk of the diseases, disorders, and conditions described herein. The compounds and compositions may also be further combined with other pharmaceutical agents for use in methods for the prevention, treatment, control, improvement, or reduction of the risk of the aforementioned diseases, disorders, and conditions.

[0366] In the treatment of conditions requiring activation of mAChR M4, appropriate dose levels can be from about 0.01 to 500 mg / kg patient body weight / day, which can be administered as a single dose or multiple doses. Dosage levels can be from about 0.1 to about 250 mg / kg / day, or from about 0.5 to about 100 mg / kg / day. Suitable dose levels can be from about 0.01 to 250 mg / kg / day, from about 0.05 to 100 mg / kg / day, or from about 0.1 to 50 mg / kg / day. Within this range, the dose can be 0.05 to 0.5, 0.5 to 5, or 5 to 50 mg / kg / day. For oral administration, the composition can be provided in tablet form containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 mg of the active ingredient, to adjust the dosage according to the symptoms of the patient being treated. The compound can be administered in a regimen of 1 to 4 times daily, preferably once or twice daily. This dosage regimen can be adjusted to provide the best therapeutic response. However, it should be understood that the specific dose level and frequency of administration for any particular patient can vary and depends on a variety of factors, including the activity of the particular compound used, the metabolic stability and duration of action of the compound, age, weight, general health condition, sex, diet, route and time of administration, excretion rate, drug combination, severity of the specific condition, and the host being treated.

[0367] Therefore, in some embodiments, this disclosure relates to a method for activating mAChR M4 receptor activity in at least one cell, the method comprising the step of: contacting the at least one cell with at least one disclosed compound, or at least one product of the disclosed method, in an amount that effectively activates mAChR M4 in the at least one cell. In some embodiments, the cell is mammalian, such as human. In some embodiments, the cell has been isolated from a subject prior to the contact step. In some embodiments, the contact is performed via administration to a subject.

[0368] In some embodiments, the present invention relates to a method for activating mAChR M4 activity in a subject, the method comprising the step of administering to the subject at a dose and amount sufficient to effectively activate the subject's mAChR M4 activity at least one disclosed compound, or at least one product of the disclosed method. In some embodiments, the subject is a mammal, such as a human. In some embodiments, prior to the administration step, the mammal has been diagnosed as requiring mAChR M4 agonism. In some embodiments, prior to the administration step, the mammal has been diagnosed as requiring mAChR M4 activation. In some embodiments, the method further comprises the step of identifying subjects requiring mAChR M4 agonism.

[0369] In some embodiments, the present invention relates to a method for treating a disorder in mammals associated with selective mAChR M4 activation (e.g., a disorder associated with cholinergic activity), the method comprising the step of administering to the mammal at a dose and amount effective for treating the disorder, at least one disclosed compound, or at least one product of the disclosed method. In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed as needing treatment for the disorder prior to the administration step. In some embodiments, the method further comprises the step of identifying a subject who needs treatment for the disorder.

[0370] In some embodiments, the disorder may be selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, anxiety psychotic episodes, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of intellectual disability, autism disorder, movement disorder, Tourette syndrome, akinesia-rigid syndrome, movement disorder associated with Parkinson's disease, tardive dyskinesia, movement difficulties based on drug-induced and neurodegenerative changes, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

[0371] In some embodiments, the obstacle is Alzheimer's disease.

[0372] b. Enhanced activity of muscarinic acetylcholine receptors In some embodiments, this disclosure relates to a method for enhancing the activity of muscarinic acetylcholine receptors in mammals, the method comprising the steps of: administering to the mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof.

[0373] In some embodiments, this disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in a method of enhancing the activity of muscarinic acetylcholine receptors in mammals. In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in a method of enhancing the activity of muscarinic acetylcholine receptors in mammals.

[0374] In some embodiments, this disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament that enhances the activity of mammalian muscarinic acetylcholine receptors.

[0375] In some embodiments, enhanced activity of muscarinic acetylcholine receptors increases muscarinic acetylcholine receptor activity. In some embodiments, enhanced activity of muscarinic acetylcholine receptors is a partial agonist effect of muscarinic acetylcholine receptors. In some embodiments, enhanced activity of muscarinic acetylcholine receptors is a positive allosteric regulation of muscarinic acetylcholine receptors.

[0376] In some embodiments, the applied compound exhibits an enhancement of mAChR M4, whose EC50 50 Less than about 10 µM, less than about 5 µM, less than about 1 µM, less than about 500 nM, or less than about 100 nM. In some embodiments, the applied compound exhibits enhancement of mAChR M4, whose EC50... 50 Between approximately 10 µM and approximately 1 nM, between approximately 1 µM and approximately 1 nM, between approximately 100 nM and approximately 1 nM, or between approximately 10 nM and approximately 1 nM.

[0377] In some embodiments, the mammal is a human. In some embodiments, prior to the administration step, the mammal has been diagnosed as needing enhanced muscarinic acetylcholine receptor activity. In some embodiments, the method further includes the step of: identifying mammals needing enhanced muscarinic acetylcholine receptor activity. In some embodiments, the enhancement of muscarinic acetylcholine receptor activity treats a disorder in mammals associated with muscarinic acetylcholine receptor activity. In some embodiments, the muscarinic acetylcholine receptor is mAChR M4.

[0378] In some embodiments, enhanced activity of muscarinic acetylcholine receptors in mammals is associated with the treatment of neurological and / or psychiatric disorders (e.g., those disclosed herein) that are associated with muscarinic receptor dysfunction. In some embodiments, the muscarinic receptor is mAChR M4.

[0379] In some embodiments, this disclosure provides a method for enhancing the activity of muscarinic acetylcholine receptors in cells, the method comprising the step of contacting the cells with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the cells are mammalian (e.g., human). In some embodiments, the cells have been isolated from the mammal prior to the contact step. In some embodiments, the contact is performed via administration to the mammal.

[0380] c. Enhance cognition In some embodiments, the present invention relates to a method for enhancing mammalian cognition, the method comprising the steps of: administering to the mammal an effective amount of at least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.

[0381] In some embodiments, this disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in methods of enhancing mammalian cognition. In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in methods of enhancing mammalian cognition.

[0382] In some embodiments, this disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for enhancing mammalian cognition.

[0383] In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed with a need for cognitive enhancement prior to the administration step. In some embodiments, the method further includes the step of: identifying the mammal requiring cognitive enhancement. In some embodiments, the need for cognitive enhancement is associated with muscarinic receptor dysfunction. In some embodiments, the muscarinic receptor is mAChR M4.

[0384] In some embodiments, cognitive enhancement is a statistically significant increase in novel object recognition. In some embodiments, cognitive enhancement is a statistically significant increase in performance on the Wisconsin Card Sorting Test.

[0385] d. Combination therapy The present invention further relates to the administration of selective mAChR M4 activators for improving therapeutic outcomes in a cognitive or behavioral therapy context. Specifically, in some embodiments, the present invention relates to a combination therapy comprising the steps of administering to a mammal an effective amount and dose of at least one disclosed compound or a pharmaceutically acceptable salt thereof.

[0386] In some embodiments, this disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in combination therapy of cognitive or behavioral therapies in mammals. In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in combination therapy of cognitive or behavioral therapies in mammals.

[0387] In some embodiments, this disclosure provides a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in a medicament for the manufacture of a combination therapy for cognitive or behavioral therapies in mammals.

[0388] In some embodiments, administration improves treatment outcomes in the context of cognitive or behavioral therapy. Administration in conjunction with cognitive or behavioral therapy can be continuous or intermittent. Administration does not need to be concurrent with therapy and can be administered before, during, and / or after therapy. For example, cognitive or behavioral therapy may be provided 1, 2, 3, 4, 5, 6, or 7 days before or after administration of the compound. As another example, cognitive or behavioral therapy may be provided 1, 2, 3, or 4 weeks before or after administration of the compound. As yet another example, cognitive or behavioral therapy may be provided before or after administration for a period of time, within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the administered compound.

[0389] It should be understood that the disclosed combination therapy can be used in conjunction with the disclosed compounds, compositions, kits and uses.

[0390] e. Combination therapy In the methods of use described herein, additional therapeutic agents may be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, one or more additional therapeutic agents may be administered with the disclosed compounds in the same composition. In other embodiments, a time interval may exist between the administration of the additional therapeutic agent and the disclosed compounds. In some embodiments, administering the additional therapeutic agent together with the disclosed compounds may allow for lower doses and / or administration at lower frequency intervals of the other therapeutic agents. When used in combination with one or more other active ingredients, the compounds of the present invention, as well as the other active ingredients, may be used at lower doses than when used alone. Therefore, the pharmaceutical compositions of the present invention include those pharmaceutical compositions that, in addition to containing a compound having formula (I), also contain one or more other active ingredients. The above combinations include not only combinations of the compounds of the present invention with one other active compound, but also combinations of the compounds of the present invention with two or more other active compounds.

[0391] The disclosed compound may be used as a single agent or in combination with one or more other drugs to treat, prevent, control, improve, or reduce the risk of the aforementioned diseases, disorders, and conditions to which the compound or the other drug is effective, wherein the combination of drugs is safer or more effective than either drug alone. One or more other drugs may be administered concurrently or sequentially with the disclosed compound via a route and in amounts normally used. When the disclosed compound is used concurrently with one or more other drugs, a pharmaceutical composition containing a unit dosage form of such drug and the disclosed compound may be used. However, combination therapies may also be administered on overlapping schedules. It is also envisioned that combinations of one or more active ingredients with the disclosed compound may be more effective than either as a single agent. Therefore, when used in combination with one or more other active ingredients, the disclosed compound and other active ingredients may be administered at lower doses than when used individually.

[0392] The pharmaceutical compositions and methods of the present invention may further include other therapeutically active compounds mentioned herein, which are commonly used to treat the aforementioned pathological conditions.

[0393] The combinations described above include not only combinations of the disclosed compounds with one other active compound, but also combinations with two or more other active compounds. Similarly, the disclosed compounds can be combined with other pharmaceuticals for the prevention, treatment, control, improvement of diseases or conditions for which the disclosed compounds can be used, or reduction of the risk of such diseases or conditions. Such other pharmaceuticals may be administered simultaneously or sequentially with the compounds of the present invention via a route and in amounts typically used. When the compounds of the present invention are used simultaneously with one or more other pharmaceuticals, pharmaceutical compositions containing these other pharmaceuticals besides the disclosed compounds are preferred. Accordingly, pharmaceutical compositions include those containing one or more other active ingredients in addition to the compounds of the present invention.

[0394] The weight ratio of the disclosed compound to the second active ingredient can vary and will depend on the effective dosage of each ingredient. Typically, the effective dosage of each ingredient will be used. Therefore, for example, when the compound of the present invention is combined with another pharmaceutical agent, the weight ratio of the disclosed compound to that other pharmaceutical agent will generally be in the range of about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of the compound of the present invention with other active ingredients will also generally be within the above range, but in each case, the effective dosage of each active ingredient should be used.

[0395] In such combinations, the disclosed compounds and other active agents can be applied alone or in combination. Furthermore, the application of one element can be performed before, simultaneously with, or subsequently of one or more other agents.

[0396] Therefore, the disclosed compound may be used alone or in combination with other agents known to be beneficial in the subject's indication or with other drugs that affect receptors or enzymes, which may increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the disclosed compound. The subject compound and other agents may be administered together as concomitant therapy or in a fixed combination.

[0397] In some embodiments, the compound may be used in combination with anti-Alzheimer's agents, β-secretase inhibitors, cholinergic agents, γ-secretase inhibitors, HMG-CoA reductase inhibitors, M1 allosteric agonists, M1 positive allosteric modulators, NSAIDs (including ibuprofen), vitamin E, and anti-amyloid antibodies. In another embodiment, the subject compound may be used in combination with: sedatives, hypnotics, anxiolytics, antipsychotics (typical and atypical), anxiolytics, cyclopyrrolidones, imidazopyridines, pyrazolopyrimidines, weak tranquilizers, melatonin agonists and antagonists, melatoninizers, benzodiazepines, barbiturates, 5HT-2 antagonists, etc., such as: adidazolam, allobarbital, allomidone, alprazolam, amisupipride, amitriptyline, amoxapine, amoxapine, and aripiprazole. Azoxystrobin, Benzodiazepam, Benzodamine, Bromotezolam, Bupropion, Buspirone, Butabarbital, Butabarbital, Capourea, Carbochlor, Chloral Betaine, Chloral Hydrate, Clomipramine, Clonazepam, Clopidogrel, Clorazidone, Cloradic Acid, Librium, Chlorethidate, Chlorpromazine, Clozapine, Ciprozepam, Desipramine, Declamo, Diazepam, Chlorpyrifos, Divalproic Acid, Diphenhydramine, Doxepin, Estazolam, Ecclovirol, Etomidate, Fenoban, Flunitrazepam, Flupentixol, Fluphenazine, Flufenazate Zepam, Fluvoxamine, Fluoxetine, Furazepam, Grumitol, Halazepam, Haloperidol, Hydroxyzine, Imipramine, Lithium, Lorazepam, Chlormethazine, Maprotiline, Methaqualone, Melatonin, Toluidine, Methaqualone, Midazolam, Nefazodone, Nissodium, Nitrosamide, Nortriptyline, Olanzapine, Oxazepam, Paraaldehyde, Paroxetine, Pentobarbital, Piperabine, Perphenazine, Phenylehniail, Phenobarbital, Prazepam, Promethazine, Propofol, Protriptyline, Quazepam Quetiapine, reclozepam, risperidone, loremide, secobarbital, sertraline, suprofen, temazepam, thioridazine, tevothixone, tracarzolate, transphenylcyclopropionamide, trazodone, triazolam, tramipapane, trimethoxyphenylacetamide, triclophosphamide, trifluralazine, trimetazine, trimethapamine, udazepam, venlafaxine, zaleplon, ziprasidone, zoprazepam, zolpidem, and their salts, and combinations thereof, or the subject compound may be used in combination with physical methods (e.g., phototherapy or electrical stimulation).

[0398] In some embodiments, the compound may be used in combination with: levodopa (with or without a selective extracerebral decarboxylase inhibitor, such as carbidopa or benserazide), anticholinergics (such as biperiden (optionally as its hydrochloride or lactate) and trihexyphenidyl (benhexol) hydrochloride), COMT inhibitors (such as entacapone), MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists, and dopamine receptor agonists (such as alentemoxine, bromocriptine, fenodopam, ergothione, nagolide, pergolide, and pramipexole). It is understood that dopamine agonists may be in pharmaceutically acceptable salt forms, such as alentemoxine hydrobromide, bromocriptine mesylate, fenodopam mesylate, nagolide hydrochloride, and pergolide mesylate. Ergothione and pramipexole are typically used in non-salt forms.

[0399] In some embodiments, the compound may be used in combination with compounds derived from phenothiazines, thioxanthates, heterocyclic dibenzozazepines, butyrophenones, diphenylbutylpiperidine, and indoleone antipsychotics. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acephenanthracene, fluphenazine, perphenazine, and trifluralin. Suitable examples of thioxanthates include cloprothioxanthate and tevothioxanthate. An example of a dibenzozazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indoleone is morolindona. Other antipsychotics include loxapine, sulpiride, and risperidone. It is understandable that antipsychotic drugs, when used in combination with the subject compound, may be in pharmaceutically acceptable salt forms, such as chlorpromazine hydrochloride, mesoridazine benzylsulfonate, thioridazine hydrochloride, acephenanthracene maleate, fluphenanthracene hydrochloride, fluphenanthracene heptaate, fluphenanthracene decanoate, trifluoperazine hydrochloride, tevothixol hydrochloride, haloperidol decanoate, loxapine succinate, and morpholinone hydrochloride. Perphenazine, chlorpromazine, clozapine, haloperidol, pimozide, and risperidone are typically used in non-salt forms. Therefore, the subject compound can be used in combination with the following: acephenanol, alentemoxol, aripiprazole, amisupiride, benztropine, bromocriptine, biperiden, chlorpromazine, cloprothioxan, clozapine, diazepam, fenodopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, ergot urea, loxapine, mesoridazine, morpholino, nagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, buphenazine, trihexyphenidyl, thioridazine, tevothioxan, trifluralin, or ziprasidone.

[0400] In some embodiments, the compound may be used in combination with the following: antidepressants or anxiolytics, including norepinephrine reuptake inhibitors (including tertiary and secondary tricyclic amines), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible monoamine oxidase inhibitors (RIMAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), corticotropin-releasing factor (CRF) antagonists, alpha-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists (especially partial 5-HT1A agonists), and corticotropin-releasing factor (CRF) antagonists. Specific formulations include: amitriptyline, clomipramine, doxepin, imipramine, and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline, and protriptyline; fluoxetine, fluvoxamine, paroxetine, and sertraline; isocarboxazid, phenelzine, tranylcypromine, and selegiline; moclobemide; venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone, and veloxacin; alprazolam, nitrazepam, clonazepam, dipotassium chlordiazepoxide, diazepam, halazepam, lorazepam, oxazepam, and plaszepam; buspirone, fluocinolone, gepiron, and ixaprone, and their pharmaceutically acceptable salts.

[0401] In some embodiments, the compound may be co-administered with an ortho-muscarinic agonist, a muscarinic potentiator, or a cholinesterase inhibitor. In some embodiments, the compound may be co-administered with GlyT1 inhibitors, such as, but not limited to, risperidone, clozapine, haloperidol, fluoxetine, prazolam, fenofibrate, lithium, phenobarbital, and their salts, and combinations thereof.

[0402] f. Method of application Methods of treatment may include administering any amount of the disclosed composition. Administration methods may include tablets, pills, sugar-coated pills, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions (e.g., oil-in-water emulsions), liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions, or dispersible powders. To prepare a pharmaceutical composition for oral administration, the pharmaceutical agent may be mixed with adjuvants and excipients commonly known and used, such as gum arabic, talc, starch, sugars (e.g., mannose, methylcellulose, lactose), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, crosslinking agents, dispersants, emulsifiers, lubricants, preservatives, flavoring agents (e.g., ether oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol), or bioavailability enhancers (e.g., Gelucire™). In the pharmaceutical composition, the pharmaceutical agent may also be dispersed in microparticles (e.g., nanoparticle compositions).

[0403] For parenteral administration, the agent can be dissolved or suspended in a physiologically acceptable diluent, such as water, buffer solution, oil with or without solubilizer, surfactant, dispersant, or emulsifier. Oils, such as, but not limited to, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil, and sesame oil, can be used. More generally, for parenteral administration, the agent can be in the form of an aqueous, lipid, oily, or other type of solution or suspension, or even in the form of liposomes or nanosuspensions.

[0404] As used in this article, the term "parenteral" refers to administration methods including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intra-articular injections and infusions.

[0405] 5. Reagent kit In one respect, this disclosure provides kits containing at least one of the disclosed compounds or a pharmaceutically acceptable salt thereof, and one or more of the following: (a) At least one known agent that increases mAChR M4 activity; (b) At least one known agent that reduces mAChR M4 activity; (c) At least one known medicine for treating disorders related to cholinergic activity; (d) Instructions for use in the treatment of disorders related to cholinergic activity; (e) Instructions for use in treating disorders related to M4 receptor activity; or (f) Instructions for use of compounds in combination with cognitive or behavioral therapy.

[0406] In some embodiments, the at least one disclosed compound and the at least one pharmaceutical agent are co-formulated. In some embodiments, the at least one disclosed compound and the at least one pharmaceutical agent are co-packaged. The kit may also contain compounds and / or products co-packaged, co-formulated, and / or co-delivered with other components. For example, pharmaceutical manufacturers, pharmaceutical distributors, physicians, compounding shops, or pharmacists may provide kits containing disclosed compounds and / or products for delivery to patients and another component.

[0407] The disclosed kit can be used in conjunction with the disclosed instructions for use.

[0408] The kit may further include information, instructions, or both regarding the use of the kit to provide treatment for medical conditions in mammals, particularly humans. The information and instructions may be in the form of text, images, or both. Additionally or alternatively, the kit may contain a compound, a composition, or both; and information, instructions, or both regarding the application of the compound or composition (e.g., its benefits in treating or preventing medical conditions in mammals, such as humans).

[0409] The compounds and methods of the present invention will be better understood by referring to the following examples, which are intended to illustrate rather than limit the scope of the invention.

[0410] 6. Examples All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer. 1H chemical shifts are reported as δ values ​​in ppm low field, with deuterated solvent as an internal standard. Data are reported as follows: chemical shifts, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet, m = multiply, ABq = AB quartet), coupling constant, and integral. Reversed-phase LCMS analysis was performed using an Agilent 1200 system with the following parameters. This system consists of a binary pump with degassing, a high-performance autosampler, a temperature-controlled column chamber, a C18 column, a diode array detector (DAD), and an Agilent 6150 MSD. Gradient conditions were 5% to 95% acetonitrile in 1.4 min, with the aqueous phase being 0.1% TFA in water, held in 95% acetonitrile for 0.1 min, 0.5 mL / min, 55°C (“90-second method”). Samples were separated at a rate of 0.5 mL / min on a Waters Acquity UPLC BEH C18 column (1.7 µm, 1.0 x 50 mm) with column and solvent temperatures maintained at 55°C. The DAD was set to scan from 190 nm to 300 nm, and signals were used at 220 nm and 254 nm (both with a bandwidth of 4 nm). The MS detector was configured with an electrospray ionization source, and low-resolution mass spectra were acquired as follows: scan range from 140 to 700 AMU, step size 0.2 AMU, at 0.13 cycles / sec, peak width 0.008 min. The drying gas flow rate was set to 13 L / min at 300°C, and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set to 3000 V, and the fragmentation voltage was set to 100 V. Data acquisition was performed using Agilent Chemstation and Analytical Studio Reviewer software.

[0411] a. Preparation of intermediates 5-Bromo-6-hydroxy-2-methylnicotinic acid ethyl ester. At 0°C, ethyl-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (10 g, 55.2 mmol) was slowly added in portions to a solution of ethyl-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate in DMF (185 mL). N - Bromosuccinimide (10.8 g, 60.7 mmol). Removed from the ice bath. After 18 h, saturated sodium bisulfite (aq) was added to the reaction and stirred for 30 min. The reaction was filtered, and the collected solid was dried in a vacuum oven to give the title compound (14.2 g). 1HNMR (400 MHz, DMSO) δ 8.15 (s, 1H), 4.20 (q,J= 7.1 Hz, 2H), 3.32 (s, 3H), 2.55 (s, 1H), 1.27 (t,J= 7.1 Hz, 3H); ES-MS [M+1]+: 260.0 / 262.0.

[0412] 5-Bromo-6-chloro-2-methylnicotinic acid ethyl ester. 5-Bromo-6-hydroxy-2-methylnicotinic acid ethyl ester (14.2 g, 54.6 mmol) in MeCN (300 mL) was added to a 500 mL round-bottom flask, followed by phosphorus oxychloride (V) (29.4 mL, 316 mmol). The reaction mixture was fitted with a condenser and heated to 85°C. After 18 h, the mixture was cooled to room temperature and concentrated. The residue was dissolved in DCM (10 mL) and slowly added dropwise to a stirred solution of saturated NaHCO3 aqueous solution while maintaining pH > 7. Additional DCM (25 mL) was added, and the mixture was stirred for 30 min. The organic layer was separated, and the aqueous layer was re-extracted with 3:1 chloroform / IPA (3 x 20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0%-25% EtOAc / hexane) to obtain the title compound (12 g). 1 H NMR (400 MHz, CDCl3) δ 8.40(s, 1H), 4.38 (q,J= 7.1 Hz, 2H), 2.76 (s, 3H), 1.40 (t,J= 7.1 Hz, 3H); ES-MS[M+1]+: 277.9 / 279.9.

[0413] 5-Bromo-2-(bromomethyl)-6-chloronicotinic acid ethyl ester. N-bromosuccinimide (8.43 g, 47.4 mmol) was added fractionally to a solution of 5-bromo-6-chloro-2-methylnicotinic acid ethyl ester (12 g, 43.1 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.71 g, 4.3 mmol) in carbon tetrachloride (287 mL). After 30 min, the reaction was heated to 80°C. After 18 h, the reaction was cooled to room temperature, diluted with water, and the organic layers were separated. The aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0%–4% EtOAc / hexane) to give the title compound (13.6 g).1 H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 4.91 (s, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H); ES-MS [M+1] + : 357.9 / 359.9.

[0414] 3-Bromo-2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. At 0°C, a 2.0 M solution of methylamine (17.5 mL, 35.0 mmol) was added to a solution of ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate (2.5 g, 6.99 mmol) in THF (140 mL), and the reaction was stirred for 30 min. The reaction was concentrated at room temperature and purified by normal-phase chromatography (0%–30% EtOAc / DCM) to give the title compound. 1 H NMR (400 MHz, DMSO) δ 8.49 (s,1H), 4.50 (s, 2H), 3.09 (s, 3H); ES-MS [M+1] + : 261.1 / 263.1.

[0415] ( S )-3-bromo-2-chloro-6-(1-methoxypropane-2-yl)-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one. Add ( ) to a solution of 5-bromo-2-(bromomethyl)-6-chloronicotinic acid ethyl ester (201 mg, 0.3 mmol) in THF (2.5 mL). S )-(+)-1-methoxy-2-propylamine (0.11 mL, 1.0 mmol), and the reaction was stirred at room temperature for 18 hr. Additional ( S )-(+)-1-methoxy-2-propane (0.11 mL, 1.0 mmol). After 12 h, the mixture was concentrated under vacuum and purified by normal-phase column chromatography (0%-80% EtOAc / hexane) to give the title compound (138 mg). 1 H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 4.68 (pd, J= 6.9, 4.5 Hz, 1H), 4.42 (q, J = 18.4 Hz, 3H), 3.60 – 3.48 (m, 3H), 3.33 (s, 4H), 1.32 (d, J = 7.0 Hz, 4H). ES-MS [M+1] + :319.0 / 321.0.

[0416] ( R )-3-bromo-2-chloro-6-(1-methoxypropane-2-yl)-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one. With ( S )-3-bromo-2-chloro-6-(1-methoxypropane-2-yl)-6,7-dihydro-5 H -pyrrolo[3,4- b It was prepared in the same manner as pyridin-5-one. 1 H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 4.68 (pd, J = 6.9, 4.5Hz, 1H), 4.42 (q, J = 18.4 Hz, 3H), 3.60 – 3.48 (m, 3H), 3.33 (s, 4H), 1.32 (d, J = 7.0 Hz, 4H). ES-MS [M+1] + : 319.0 / 320.9.

[0417] 5-Bromo-6-chloro-2-carboxyethyl nicotinate. 4-Methylmorpholine N-oxide (893 µL, 8.6 mmol) was added to a solution of 5-bromo-2-(bromomethyl)-6-chloronicotinate (1.36 g, 3.8 mmol) in MeCN (21.5 mL), and the mixture was stirred at ambient temperature for 2 hr. The solution was diluted with EtOAc and washed with water. The organic layer was separated, dried (MgSO4), filtered, and concentrated. The crude product was purified by normal-phase column chromatography (0%–30% EtOAc / hexane) to give the title compound (668 mg). ES-MS [M+1] + : 292 / 294; 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H),8.34 (d, J = 0.5 Hz, 1H), 4.45 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).

[0418] 3-Bromo-2-chlorofurano[3,4- b ]Pyridine-5(7 H )-Ketone. Sodium borohydride (27 mg, 0.70 mmol) was added to a solution of 5-bromo-6-chloro-2-formylnicotinic acid ethyl ester (668 mg, 1.76 mmol) in THF (8.8 mL) at -40°C. The reaction was stirred at -40°C for 45 minutes. Water was added to the reaction mixture, and the reaction was heated to room temperature. The reaction mixture was extracted with EtOAc (3x), and the combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was dissolved in 1,4-dioxane (4 mL), and then hydrochloric acid (879 µL, 3.52 mmol; 4) was added. M In 1,4-dioxane), and the mixture was heated to 50°C for 18 hours. Additional 4% of the mixture was added to the 1,4-dioxane. M The mixture was heated to 50°C with HCl (400 µL, 1.6 mmol). After 4 hr, the mixture was concentrated under vacuum, and the residue was dissolved in DCM. The solution was washed with saturated NaHCO3 aqueous solution. The organic layer was separated, dried (MgSO4), and concentrated. The crude residue was purified by normal-phase column chromatography (0%–0.5% MeOH / DCM) to give the title compound. ES-MS [M+1] + : 248 / 250; 1 H NMR (400 MHz, CDCl3) δ 8.42 (t, J = 0.5 Hz, 1H), 5.28 (d, J = 0.5 Hz, 2H).

[0419] 3-Bromo-6,7-Dihydro-5 H -cyclopentadiene[ b ]Pyridine-2-ol. At 15°C, add 6,7-dihydro-5-pyridine to a vial. H -cyclopentadiene[ bPyridine-2-ol (500 mg, 3.7 mmol) and acetic acid (5.3 mL) were added. Bromine (150 µL, 2.9 mmol) was added. The reaction mixture was allowed to return to room temperature for 3 h. The reaction mixture was then concentrated under vacuum. 。 EtOAc was added to the residue, and the mixture was quenched with saturated sodium thiosulfate solution and neutralized with saturated aqueous sodium carbonate solution. The mixture was extracted with EtOAc (3x), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by normal-phase column chromatography (0%–10% DCM / MeOH, containing 1% NH4OH) to give the title compound (493 mg). 1 H NMR (400MHz, CDCl3) δ 7.74 (s, 1H), 2.91 (tt, J = 8.1, 1.2 Hz, 2H), 2.79 – 2.70 (m, 2H), 2.21 – 2.09 (m, 2H). ES-MS [M+1] + : 214 / 216.

[0420] 3-Bromo-2-chloro-6,7-dihydro-5 H -cyclopentadiene[ b Pyridine. 3-Bromo-6,7-dihydro-5-pyridine in POCl3 (1.2 mL, 13.2 mmol) H -cyclopentadiene[ b Pyridine-2-ol (493 mg, 2.3 mmol). The solution was heated to 90°C for 18 h. The reaction mixture was concentrated. Aqueous saturated sodium carbonate was slowly added to the residue. The mixture was extracted with DCM (3x). The organic layers were combined and washed with water (3x). The organic matter was dried over sodium sulfate, filtered, and concentrated. The crude material was purified by normal-phase column chromatography (0% - 60% EtOAc / hexane) to yield the title compound (316 mg). 1 H NMR (400 MHz, CDCl3) δ 7.72 (t, J = 1.2 Hz, 1H), 3.00 – 2.88 (m, 4H), 2.17 (p, J = 7.7 Hz, 2H). ES-MS [M+1] + : 232 / 234.

[0421] 3-Bromo-2-chloro-6,7-dihydro-5 H-cyclopentadiene[ b Pyridin-5-one. Add 3-bromo-2-chloro-6,7-dihydro-5-one to a solution of magnesium sulfate (833 mg, 6.8 mmol), potassium permanganate (430 mg, 2.7 mmol) in water (1.7 mL) and tert-butanol (5 mL). H -cyclopentadiene[ b Pyridine (316 mg, 1.36 mmol). The mixture was stirred at 40°C for 3 h. The reaction mixture was then subjected to Celite... ® Filter and wash with EtOAc and MeOH. Concentrate the filtrate and treat with water / EtOAc (2x). Wash the combined organic layers with brine (2x), filter, concentrate under reduced pressure, and purify by normal-phase column chromatography (0%-60% EtOAc / hexane) to give the title compound (40 mg). 1 H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 3.26 – 3.18 (m, 2H), 2.87 – 2.80 (m, 2H). ES-MS [M+1] + : 246 / 248.

[0422] 5-Chloro-6-hydroxy-2-methylnicotinic acid ethyl ester. At 0°C, ethyl-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (1 g, 5.5 mmol) was slowly added in portions to a solution of ethyl-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate in DMF (37 mL). N -Chlorosilicate (814 mg, 6.1 mmol). After removing the ice bath and heating to room temperature, the mixture was heated to 50°C for 22 h. After cooling to ambient temperature, saturated sodium bisulfite (aq) was added to the reaction, and the mixture was stirred for 30 min. The mixture was then further diluted with water (50 mL) and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to give the title compound. ES-MS [M+1]+: 216; 1 H NMR (400 MHz, CDCl3) δ 8.19(s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.74 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H).

[0423] 5,6-Dichloro-2-methylnicotinic acid ethyl ester. Prepared in a similar manner to 5-bromo-6-chloro-2-methylnicotinic acid ethyl ester, to give the title compound. ES-MS [M+1] + : 234 / 236; 1 H NMR (400 MHz, CDCl3) δ 8.27 (s,1H), 4.39 (q, J = 7.1 Hz, 2H), 2.80 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H).

[0424] 2-(bromomethyl)-5,6-dichloronicotinic acid ethyl ester. Prepared in a similar manner to 5-bromo-2-(bromomethyl)-6-chloronicotinic acid ethyl ester, to give the title compound. ES-MS [M+1] - : 314; 1 H NMR (400 MHz, CDCl3) δ 8.34(s, 1H), 4.94 (s, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H).

[0425] 2,3-Dichloro-6-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one. With 3-bromo-2-chloro-6-methyl-6,7-dihydro-5- H -pyrrolo[3,4- b The pyridin-5-one was prepared in a similar manner to give the title compound. ES-MS [M+1] - : 217 / 219; 1 H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 4.41 (s, 2H), 3.23 (s, 3H).

[0426] 3,5-Dichloro-6-methyl-2 H-1,4-Oxazin-2-one. Under an inert atmosphere, at 0°C, a solution of DL-lactonitrile (10 g, 140.7 mmol) in chlorobenzene (11 mL) was added dropwise to a cooled solution of oxalyl chloride (49.1 mL, 563 mmol) in chlorobenzene (75 mL). The solution was then heated to 90°C, and triethylamine hydrochloride (1.43 g, 10.4 mmol) was added in portions at 90°C. The resulting mixture was then stirred for 3 hours, cooled to ambient temperature, and concentrated under vacuum. The resulting solution was then diluted with Et2O (approximately 300 mL), and the solid was filtered off. The filtrate was concentrated and purified by silica gel normal-phase column chromatography (0%–15% EtOAc / Hex) to give 16.8 g of the title compound. 1 H NMR (400 MHz, CDCl3) δ 2.38 (s, 1H).

[0427] 5-Chloro-3-iodo-6-methyl-2- H -1,4-oxazin-2-one. Under an inert atmosphere, to 3,5-dichloro-6-methyl-2- H -1,4-oxazin-2-one (16.8 g, 93.4 mmol) in a solution of acetone (359 mL) was supplemented with sodium iodide (56.4 g, 374 mmol) and (1 S 4 R 10-Camphorsulfonic acid (1.52 g, 6.5 mmol). The mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated, diluted with water, and extracted with DCM (3x). The combined organic matter was washed successively with saturated Na2S2O3 aqueous solution and brine, dried (MgSO4), filtered, and concentrated to give 22 g of the title compound. The material was used without further purification. 1 H NMR (400 MHz, CDCl3) δ 2.30 (s, 3H); ES-MS [M+1] + : 272.

[0428] 6-Chloro-2-iodo-5-methylnicotinic acid methyl ester. 5-Chloro-3-iodo-6-methyl-2- HA solution of 1,4-oxazin-2-one (22 g, 81.1 mmol) and methyl propynate (21.6 mL, 243 mmol) in toluene (80 mL) was heated to 80°C for 42 h. The reaction was cooled to ambient temperature, and the volatiles were removed under reduced pressure. Normal-phase silica gel column chromatography (0%–10% EtOAc / hexane, second eluent from the column) yielded 15.0 g of the title compound. 1 H NMR (400 MHz, CDCl3) δ7.86 (d, J = 0.8 Hz, 1H), 3.95 (s, 3H), 2.36 (d, J = 0.8 Hz, 3H); ES-MS [M+1] + :312.

[0429] 6-Chloro-2-cyano-5-methylnicotinic acid methyl ester. A solution of 6-chloro-2-iodo-5-methylnicotinic acid methyl ester (15.0 g, 48.2 mmol) and cuprous(I) cyanide (6.48 g, 72.3 mmol) in DMF (112 mL) was heated at 100°C for 1 hour. After cooling to ambient temperature, the mixture was subjected to Celite... ® Filter and wash with EtOAc. Add the filtrate to a saturated NaHCO3 aqueous solution (approximately 150 mL) and extract with EtOAc (3x). Then wash the combined organic matter sequentially with a saturated NH4Cl aqueous solution (100 mL) and brine. Dry the organic matter (MgSO4), filter, and concentrate. Perform silica gel normal-phase column chromatography (0%–40% EtOAc / hexane) to give 8.1 g of the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 0.9 Hz,1H), 4.04 (s, 3H), 2.52 (d, J = 0.8 Hz, 3H); ES-MS [M+1] + : 211.

[0430] 2-(aminomethyl)-6-chloro-5-methylnicotinic acid methyl ester. Platinum oxide (IV) (1.48 g, 6.5 mmol) was added to a round-bottom flask under nitrogen atmosphere. Next, a solution of 6-chloro-2-cyano-5-methylnicotinic acid methyl ester (8.1 g, 38.5 mmol) in ethanol / chloroform (240 mL; 3:1) was added. The flask was evacuated under vacuum and purged with H2 (g) (3x). The mixture was stirred under a hydrogen atmosphere (balloon) for 36 hours. The solids were then passed through Celite. ® The residue was removed by filtration, washed with DCM, and the filtrate was concentrated. The material was then dissolved in MeOH and evenly distributed into eight Agilent Bond Elut SCX columns (10 g columns). The columns were washed with MeOH (approximately 80 mL per column), and the eluent was concentrated to give 5.46 g of 2-(aminomethyl)-6-chloro-5-methylnicotinic acid methyl ester. 1 H NMR (400 MHz, MeOD) δ 8.38 (d, J = 0.8 Hz,1H), 4.62 (s, 2H), 3.96 (s, 3H), 2.47 (q, J = 0.7 Hz, 3H). ES-MS [M+1] + : 215.

[0431] 2-Chloro-3-methyl-6,7-dihydro-5 H -Pyrrolo[3,4-b]pyridin-5-one. A solution of 2-(aminomethyl)-6-chloro-5-methylnicotinic acid methyl ester (5.46 g, 25.4 mmol) and triethylamine (17.7 mL, 127 mmol) in methanol (127 mL) was added to a vial. The solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated by half under vacuum, and the solids were removed by vacuum filtration and washed with MeOH to give 1.99 g of the desired product. The filtrate was concentrated to Celite under reduced pressure. ® The material was purified by silica gel normal-phase column chromatography (0%–3.5% MeOH / DCM with 1% NH4OH additive) to give 138 mg of the desired product. The materials were combined to give 2.13 g of the title compound. 1 H NMR (400 MHz, DMSO) δ8.82 (s, 1H), 8.11 (d, J = 0.9 Hz, 1H), 4.39 (s, 2H), 2.42 (d, J= 0.8 Hz, 3H); ES-MS [M+1] + : 183.

[0432] 3-Bromo-7,8-dihydro-1,6-naphthidine-6(5) H 3-Tetrahydro-1,6-Naphthyl dihydrochloride (10 g) was added to a suspension of 3-bromo-5,6,7,8-tetrahydro-1,6-naphthyl dihydrochloride in DCM (150 mL) at ambient temperature, followed by the slow addition of DIEA (24.4 mL). The mixture was stirred at room temperature for 18 h and concentrated under reduced pressure. Purification was performed using normal-phase chromatography (0%–50% EtOAc / hexane) to provide 10.7 g of the title compound. 1 H NMR (400 MHz, CDCl3) δ8.49 (d, J = 2.2 Hz, 1H), 7.60 (s, 1H), 4.59 (s, 2H), 3.74 (t, J = 6.0 Hz, 2H), 2.98 (t, J = 6.0 Hz, 2H), 1.49 (s, 9H); ES-MS [M+1] + : 313.3 / 315.3.

[0433] 3-(6,7-dihydropyrazolo[1,5- a ]Pyrimidine-4(5 H )-yl)-7,8-dihydro-1,6-naphthidine-6(5 H 3-Bromo-7,8-dihydro-1,6-naphthyl-6(5)-butyl formate. H 4,5,6,7-Tetrahydropyrazolo[1,5- a Pyrimidine (1.66 g), NaO t Bu (1.73 g) t BuXPhos (382 mg), and t BuXPhos-Pd-G1 (619 mg) in 1,4-dioxane (15 mL) and t-The solution of BuOH (45 mL) was uniformly added to three microwave-safe vials. The solutions were purged with nitrogen and stirred at 100°C for 4 h. After cooling to ambient temperature, the mixture was filtered through a Celite® pad and washed thoroughly with EtOAc / DCM. The filtrate was concentrated under vacuum, and the resulting residue was dissolved in DMSO / DMF (1:1) (36 mL). After passing through a syringe filter, the solution was purified by RP-HPLC (10%–50% MeCN / 0.1% aqueous TFA) to give the title compound (3.71 g). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.49 (d, J = 2.6 Hz, 1H), 7.86 (d, J =2.6 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 5.80 (d, J = 2.1 Hz, 1H), 4.61 (s, 2H), 4.13 (t, J = 6.2 Hz, 2H), 3.91 – 3.70 (m, 2H), 3.67 (t, J = 5.9 Hz, 2H), 2.91 (t, J = 5.9 Hz, 2H), 2.21 (p, J = 6.1 Hz, 2H), 1.43 (s, 9H); ES-MS [M+1-TFA] + : 356.5.

[0434] 3-(6,7-dihydropyrazolo[1,5- a ]Pyrimidine-4(5 H )-yl)-5,6,7,8-tetrahydro-1,6-naphthylidine dihydrochloride. To 3-(6,7-dihydropyrazolo[1,5- a ]Pyrimidine-4(5 H )-yl)-7,8-dihydro-1,6-naphthidine-6(5 H 3.72 g of tert-butyl formate was added to a solution of tert-butyl formate (50 mL) in DCM (10 mL), and the solution was stirred at ambient temperature for 2 h. The reaction mixture was concentrated under vacuum, and the crude material was suspended in THF (10 mL). 4-Dioxane was added to a solution of tert-butyl formate (20 mL). MThe mixture was prepared with HCl solution and stirred for 30 minutes, then concentrated under vacuum. The residue was then azeotropically reacted with MeOH (3x) to remove excess solvent. The solid was dried in a vacuum oven to provide 1.85 g of the title compound, which was used without further purification. ES-MS [M+1-2·HCl] + : 256.2.

[0435] 1-(5,6,7,8-tetrahydro-1,6-naphthid-3-yl)-2,3-dihydro-1 H -pyrido[2,3- b [1,4]Oxazine. 3-Bromo-7,8-dihydro-5 H 1,6-Naphthyl-6-carboxylic acid tert-butyl ester (2.82 g, 9.0 mmol), 8-azabenzimorpholine (1.47 g, 10.8 mmol), sodium tert-butoxide (1.73 g, 18 mmol). t -BuXPhos Palladacycle Gen 1 (928 mg, 1.35 mmol), t -BuXPhos (573 mg, 1.35 mmol), 1,4-dioxane (9.0 mL) and t -BuOH (27 mL) was combined in vials and degassed (3x). The reaction was heated at 100°C for 2.5 h. The reaction was filtered through Celite®, washed with DCM, and concentrated. The crude oil was purified by reversed-phase chromatography (5%-45% MeCN / water / 0.1% aqueous TFA). The desired fraction was concentrated, and the residue was dissolved in DCM (40 mL) and TFA (2.07 mL). After 2 h, the solvent was removed, diluted with MeOH, and loaded onto an SCX column (HF bond). The column was washed with MeOH and eluted with 7 N NH3 in MeOH to yield the title compound (1.2 g). ES-MS [M + H] + = 269.5.

[0436] 3-(2-methyl-6,7-dihydropyrazolo[1,5-) a ]Pyrimidine-4(5 H )-(5,6,7,8-tetrahydro-1,6-naphthidine). Combined with 1-(5,6,7,8-tetrahydro-1,6-naphthidine-3-yl)-2,3-dihydro-1 H -pyrido[2,3- b Prepared in a similar manner to [1,4]oxazine. ES-MS [M + H]+ = 270.4.

[0437] 3-(2-fluorophenoxy)-5,6,7,8-tetrahydro-1,6-naphthidine. Add 3-bromo-7,8-dihydro-5-naphthidine to a microwave-safe vial. H 1,6-Naphthyl-6-carboxylic acid tert-butyl ester (3.0 g, 9.58 mmol), 2-fluorophenol (2.15 g, 19.2 mmol), cesium carbonate (6.28 g, 19.2 mmol), dineopentylmethane (200 µL, 0.96 mmol), and cuprous iodide (I) (91.2 mg, 0.48 mmol). The solids were degassed, and then NMP (48 mL) was added. The resulting solution was stirred at 140°C for 18 h. The reaction was filtered through Celite®, washed with DCM, and concentrated. The resulting solution was purified by reversed-phase HPLC (5%–45% MeCN / 0.1% aqueous TFA) through a syringe filter. The desired fraction was concentrated, and the residue was dissolved in DCM (48 mL) and TFA (7.34 mL, 95.8 mmol). After 1 h, the reaction was concentrated and purified by SCX column (10 G), washed with MeOH, and eluted with 7 N NH3 / MeOH to yield the title compound (950 mg). ES-MS [M + H] + =245.4.

[0438] 8-Methyl-3-(trifluoromethyl)-7,8-dihydro-5 H 1,6-Naphthyl-6-carboxylic acid tert-butyl ester. To N -Boc-3-methyl-4-piperidinone (400 mg) was added dropwise to a solution of 1 M bis(trimethylsilyl)aminolithium in THF (8 mL) at -15°C. The reaction was heated to room temperature for 1.5 h, and then added to [( Z[-3-(dimethylamino)-2-(trifluoromethyl)prop-2-enylidene]-dimethyl-hexafluorophosphate ammonium (638 mg) was in suspension in THF (5 mL). The resulting mixture was stirred at -15°C for 2 h, then acetic acid (0.161 mL) was added, and the mixture was heated to room temperature. After 1 h, ammonium acetate (413 mg) was added, and the mixture was heated at 65°C for 2 h. The mixture was cooled, diluted with water, and extracted with diethyl ether. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude residue was purified by silica gel normal-phase chromatography (0%-50% EtOAc / hexane) to give the title compound (60 mg). ES-MS [M+1] + : 317.2.

[0439] 8-Methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthidine; 2,2,2-trifluoroacetic acid. Add 8-methyl-3-(trifluoromethyl)-7,8-dihydro-5-naphthidine to the vial. H 1,6-Naphthyl-6-carboxylic acid tert-butyl ester (60 mg), DCM (0.9 mL), and trifluoroacetic acid (0.15 mL). The reaction was stirred for 1 hr and concentrated to give the title compound (75 mg). ES-MS [M+1] + :217.2.

[0440] 1-(2,4-Dimethoxybenzyl)piperidine-2,2,6,6- d 4,4-Alcohol. Deuterated formaldehyde (7.58 mL, 55.0 mmol) was added to 2,4-dimethoxybenzylamine (3.64 mL, 23.9 mmol). Trifluoroacetic acid (1.83 mL, 23.9 mmol) was then added. The resulting mixture was sonicated for 10 min and then stirred at room temperature for 1 h. Allyltrimethylsilane (4.18 mL, 26.3 mmol) was added to the resulting solution, and the reaction was heated at 40°C for 18 h. The reaction mixture was diluted with water (8 mL) and DCM (8 mL), and solid potassium carbonate (1.67 g, 12.0 mmol) was added. The mixture was stirred for 10 min and then extracted with 3:1 CHCl3 / IPA (5x). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude oil was purified by silica gel chromatography (0%–20% MeOH / DCM) to give the title compound. 1 H NMR (400 MHz, MeOD) δ 7.22 (d, J= 8.6Hz, 1H), 6.58 (d, J = 2.3, 1H), 6.53 (dd, J = 8.3, 2.4 Hz, 1H), 3.84 (s, 3H), 3.83-3.80 (m, 5H), 3.35 (s, 1H), 1.89 (dd, J = 13.7, 3.7 Hz, 2H), 1.65 (dd, J =13.6, 8.1 Hz, 2H); ES-MS [M+1] + : 256.2.

[0441] 4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester-2,2,6,6- d 4. To 1-(2,4-dimethoxybenzyl)piperidine-2,2,6,6- d 4-4-ol (3.5 g, 13.7 mmol) was added to a degassed solution in methanol (300 mL) with palladium hydroxide (0.29 g, 2.1 mmol) and 10% palladium supported on activated carbon (0.22 g, 2.1 mmol). H₂ was introduced into the reaction mixture and the mixture was stirred at 50°C and 50 psi for 48 h. The reaction mixture was filtered through a Celite® filter, washed with methanol, and concentrated under reduced pressure. The solid was then reacted with 1,4-dioxane (45 mL), acetonitrile (45 mL), and... N , N - Diisopropylethylamine (2.9 mL, 16.4 mmol) was combined. Di-tert-butyl dicarbonate (4.7 mL, 20.5 mmol) was added to the solution, and the reaction was stirred at room temperature. After 3 h, the reaction was concentrated, and the crude oil was purified by normal-phase chromatography (0%–20% MeOH / DCM) to give the title compound (2.18 g). 1 H NMR (400MHz, MeOD) δ 3.79-3.71 (m, 1H), 1.79 (dd, J = 13.1, 3.8 Hz, 2H), 1.45 (s, 9H), 1.39-1.34 (m, 2H).

[0442] 4-Oxoperidin-1-tert-butyl carboxylate-2,2,6,6- d 4. To tert-butyl 4-hydroxypiperidine-1-carboxylate-2,2,6,6- d4. Des Martin periodane (6.75 g, 15.9 mmol) was added to a solution in DCM (30 mL). The reaction was stirred at room temperature for 18 h. The reaction was concentrated by Celite® and purified by normal phase chromatography (0%-50% EtOAc / hexane) to give the title compound (1.69 g). 1 H NMR (400 MHz, CDCl3) δ 2.42 (s, 4H), 1.49 (s, 9H).

[0443] 3-Methyl-7,8-dihydro-1,6-naphthidine-6(5) H 5,5,7,7- tert-butyl formate d 4. Combine equal amounts of 1-methyl-3,5-dinitro-2-pyridone (1.0 g, 5.1 mmol) and 4-oxopiperidinium-1-carboxylic acid tert-butyl ester-2,2,6,6- in four separate microwave-safe vials. d 4 (1.0 g, 5.1 mmol), and 2 M Ammonia-methanol solution (20.2 mL). The mixture was heated in a microwave reactor at 120°C for 20 min. The reaction was concentrated by Celite® and purified by normal-phase chromatography (0%-30% EtOAc / hexane) to give the title compound (1.23 g). 1 H NMR (400 MHz, CDCl3) δ 9.25 (d, J = 2.5Hz, 1H), 8.23 ​​(d, J = 2.5, 1H), 3.11 (s, 2H), 1.50 (s, 9H); ES-MS [M+1] + : 284.1.

[0444] 3-Amino-7,8-dihydro-1,6-naphthidine-6(5) H 5,5,7,7- tert-butyl formate d 4. To 3-methyl-7,8-dihydro-1,6-naphthidine-6(5 H 5,5,7,7- tert-butyl formate d4. 10% palladium supported on activated carbon (527 mg, 4.9 mmol) was added to a solution of ethanol (10 mL) and THF (10 mL). The mixture was degassed and placed under a H2 balloon at 1 atm for 3 h. The reaction was filtered through Celite®, washed with EtOH, and the filtrate was concentrated to give the title compound (1.03 g). 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 2.6 Hz, 1H), 6.73 (d, J = 2.6,1H), 3.60 (s, 2H), 2.87 (s, 2H), 1.48 (s, 9H); ES-MS [M+1] + : 254.1.

[0445] 3-Bromo-7,8-dihydro-1,6-naphthidine-6(5) H 5,5,7,7- tert-butyl formate d 4. Copper bromide (767 mg, 3.4 mmol) was added to 3-amino-7,8-dihydro-1,6-naphthyl-6 (5... H 5,5,7,7- tert-butyl formate d 4 (580 mg, 2.3 mmol) was added in a solution of MeCN (8 mL). The reaction was cooled to 0°C, followed by the dropwise addition of tert-butyl nitrite (0.33 mL, 2.8 mmol). The reaction was stirred at 0°C for 1 h, then at room temperature for 5 h. The mixture was diluted with water and 3:1 CHCl3 / IPA. The layers were separated, and the aqueous layer was re-extracted with 3:1 CHCl3 / IPA (2x). The combined organic phases were washed with brine (2x), dried (MgSO4), filtered, and concentrated. The crude oil was purified by normal-phase chromatography (0%–40% EtOAc / hexane) to give the title compound (520 mg). 1 H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 2.2 Hz, 1H), 7.56 (d, J = 2.2, 1H), 2.93 (s, 2H), 1.48 (s, 9H); ES-MS [M+1] + : 317.1 / 319.1.

[0446] 3-((3-Fluoropyridin-4-yl)amino)-7,8-dihydro-1,6-naphthyl-6(5) H 5,5,7,7- tert-butyl formate d 4. Combine 4-bromo-3-fluoropyridine hydrochloride (415 mg, 1.9 mmol) and 3-amino-7,8-dihydro-1,6-naphthyl-6 (5 mg, 1.9 mmol) in a vial. H 5,5,7,7- tert-butyl formate d 4 (330 mg, 1.3 mmol), tris(dibenzylacetone)palladium(O) (119 mg, 0.1 mmol), Xantphos (113 mg, 0.2 mmol), and cesium carbonate (1.7 g, 5.2 mmol) were added to 1,4-dioxane (6.5 mL). The reaction mixture was degassed and heated at 100°C for 2 h. The mixture was cooled and passed through Celite. ® The sample was filtered through a pad and washed with 3:1 CHCl3 / IPA. The solvent was removed, and the crude product was purified by normal-phase chromatography (0%–5% MeOH / DCM) to give the title compound (314 mg). 1 H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 2.5 Hz, 1H), 8.32 (d, J = 2.9 Hz, 1H), 8.13 (d, J = 5.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 6.94 (dd, J =7.0, 5.8, 1H), 6.24 (s, 1H), 3.00 (s, 2H), 1.50 (s, 9H); ES-MS [M+1] + : 349.3.

[0447] N -(3-Fluoropyridin-4-yl)-5,6,7,8-Tetrahydro-1,6-Naphthidine-5,5,7,7- d 4-3-amine. Combined in vials 3-((3-fluoropyridin-4-yl)amino)-7,8-dihydro-1,6-naphthyl-6(5-) H 5,5,7,7- tert-butyl formate d 4 (314 mg, 0.9 mmol), trifluoroacetic acid (1.07 mL, 14.0 mmol), and DCM (4 mL). The reaction was stirred at room temperature for 2 h. The reaction was concentrated and passed through an SCX column (using 2...N Purification was performed by elution with NH3 / MeOH solution. The solvent was removed to give the title compound (178 mg). 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 2.5 Hz, 1H), 8.23 ​​(s, 1H), 8.17 (d, J =5.7 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H), 6.79 (d, J = 5.6, 1H), 5.68 (s, 1H), 2.94(s, 2H); ES-MS [M+1] + : 249.3.

[0448] 3-((3-methylpyridin-4-yl)amino)-7,8-dihydro-1,6-naphthidine-6(5) H 5,5,7,7- tert-butyl formate d 4. Combine 4-bromo-3-methylpyridine hydrochloride (407 mg, 1.95 mmol) and 3-amino-7,8-dihydro-1,6-naphthyl-6 (5 mg, 1.95 mmol) in a vial. H 5,5,7,7- tert-butyl formate d 4 (330 mg, 1.3 mmol), tris(dibenzylacetone)palladium(O) (119 mg, 0.13 mmol), xantphos (113 mg, 0.2 mmol), and cesium carbonate (1700 mg, 5.21 mmol) were added to 1,4-dioxane (6.5 mL). The mixture was heated at 100°C for 2 h. The mixture was cooled and passed through Celite. ® The sample was filtered through a filter pad and washed with 3:1 CHCl3 / IPA. The solvent was removed, and the crude product was purified by normal-phase chromatography (0%–10% MeOH / DCM) to give the title compound (366 mg). ES-MS [M+1] + : 345.3.

[0449] N -(3-methylpyridin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthidine-5,5,7,7- d 4-3-amine. Combined in vials 3-((3-methylpyridin-4-yl)amino)-7,8-dihydro-1,6-naphthyl-6(5-) H5,5,7,7- tert-butyl formate d 4 (366 mg, 1.06 mmol), trifluoroacetic acid (1.30 mL, 17.0 mmol), and DCM (4 mL). The reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with a 3:1 CHCl3:IPA solution and saturated Na2CO3. The layers were separated, and the aqueous layer was extracted (2x). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the title compound (258 mg). 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.6 Hz, 1H), 8.26 – 8.21 (m, 1H), 8.18 (d, J = 5.6 Hz, 1H), 7.22 (d, J = 2.6 Hz, 1H), 6.80 (d, J = 5.7 Hz, 1H), 5.69 (s, 1H), 2.95 (s, 2H), 2.25 (s, 3H); ES-MS [M+1] + : 245.3.

[0450] 3-(3,5-Dimethylisoxazol-4-yl)-7,8-dihydro-1,6-naphthidine-6(5 H 5,5,7,7- tert-butyl formate d 4. 3-Bromo-7,8-dihydro-1,6-naphthidine-6 ​​(5 H 5,5,7,7- tert-butyl formate d 4 (200 mg, 0.63 mmol), 3,5-dimethylisoxazole-4-boronic acid pinacol ester (169 mg, 0.76 mmol), cesium carbonate (413 mg, 1.26 mmol), and Pd(dppf)Cl2 (69 mg, 0.09 mmol) were combined in 1,4-dioxane (2.5 mL) and water (0.5 mL) and degassed (3x). The reaction was heated at 100°C for 2.5 h. The mixture was filtered through a Celite® pad, washed with EtOAc / DCM, and the filtrate was concentrated under reduced pressure. The oil was purified by normal-phase chromatography (0%–4% MeOH / DCM) to give the title compound (202 mg). 1 H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.0 Hz, 1H), 7.31 (d, J= 2.1 Hz, 1H), 3.04(s, 2H), 2.41 (s, 3H), 2.27 (s, 3H), 1.51 (s, 9H); ES-MS [M+1] + : 334.1.

[0451] 3,5-Dimethyl-4-(5,6,7,8-tetrahydro-1,6-naphthid-3-yl-5,5,7,7- d 4) Isoxazole. 3-(3,5-dimethylisoxazol-4-yl)-7,8-dihydro-1,6-naphthidine-6(5-) H 5,5,7,7- tert-butyl formate d 4 (200 mg, 0.6 mmol) was combined with DCM (3 mL) and trifluoroacetic acid (0.69 mL, 9.0 mmol). After 2 h, the reaction was complete and concentrated under vacuum. The crude oil was passed through an SCX column (washed with MeOH, and the compound was subjected to 7... N Purification was performed by elution with NH3 / MeOH solution. The solvent was removed to give the title compound (114 mg). 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 2.98 (s, 2H), 2.39 (s, 3H), 2.25 (s, 3H); ES-MS [M+1] + :234.3.

[0452] 3-((2-fluorophenyl)amino)-7,8-dihydro-1,6-naphthidine-6(5 H 5,5,7,7- tert-butyl formate d 4. Combine xantphos (86 mg, 0.15 mmol), 2-fluorobromobenzene (0.16 mL, 1.48 mmol), and 3-amino-7,8-dihydro-1,6-naphthyl-6 (5 mg) in vials. H 5,5,7,7- tert-butyl formate d 4 (250 mg, 0.99 mmol), tris(dibenzylacetone)palladium(O) (90 mg, 0.1 mmol), and cesium carbonate (1294 mg, 3.95 mmol) were placed in 1,4-dioxane (6.5 mL). The container was degassed (3x) and heated at 100°C for 2 h. The mixture was cooled and passed through Celite.® The sample was filtered through a filter and washed with 3:1 CHCl3 / IPA. The solvent was removed, and the crude product was purified by normal-phase chromatography (0%–7% MeOH / DCM) to give the title compound (407 mg). ES-MS [M+1] + : 348.4.

[0453] N -(2-Fluorophenyl)-5,6,7,8-Tetrahydro-1,6-Naphthidine-5,5,7,7- d 4-3-amine. Combined in vials 3-((2-fluorophenyl)amino)-7,8-dihydro-1,6-naphthidine-6(5 H 5,5,7,7- tert-butyl formate d 4 (407 mg, 1.17 mmol), trifluoroacetic acid (1.39 mL, 18.2 mmol), and DCM (4.7 mL). The reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with a 3:1 CHCl3:IPA solution and saturated Na2CO3. The layers were separated, and the aqueous layer was extracted (2x). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the title compound (241 mg). 1 H NMR (400 MHz, CDCl3) δ8.26 (d, J = 2.7 Hz, 1H), 7.23 – 6.96 (m, 5H), 6.92 – 6.82 (m, 1H), 5.71 (s,1H), 2.90 (s, 2H); ES-MS [M+1] + : 248.2.

[0454] 3-(1-methyl-1-yl) H -pyrazol-5-yl)-7,8-dihydro-1,6-naphthyl-6(5 H 5,5,7,7- tert-butyl formate d 4. 3-Bromo-7,8-dihydro-1,6-naphthidine-6 ​​(5 H 5,5,7,7- tert-butyl formate d4 (170 mg, 0.54 mmol), 1-methylpyrazole-5-boronic acid pinacol ester (133 mg, 0.64 mmol), cesium carbonate (351 mg, 1.07 mmol), and Pd(dppf)Cl2 (59 mg, 0.08 mmol) were combined in 1,4-dioxane (2.5 mL) / water (0.5 mL). The container was degassed, and the reaction was heated at 100°C for 2.5 h. After cooling, the mixture was passed through a Celite tube. ® The sample was filtered through a filter pad and washed thoroughly with EtOAc / DCM. The filtrate was concentrated under reduced pressure. The residue was purified by normal-phase chromatography (0%–5% MeOH / DCM) to give the title compound (109 mg). ES-MS [M+1] + : 319.3.

[0455] 3-(1-methyl-1-yl) H -pyrazol-5-yl)-5,6,7,8-tetrahydro-1,6-naphthyl-5,5,7,7- d 4. 3-(1-methyl-1-yl) H -pyrazol-5-yl)-7,8-dihydro-1,6-naphthyl-6(5 H 5,5,7,7- tert-butyl formate d 4 (109 mg, 0.34 mmol) was combined with DCM (2.3 mL) and trifluoroacetic acid (0.39 mL, 5.1 mmol). The reaction was concentrated after 2 h. The crude residue was passed through an SCX column (washed with MeOH and 7...) N Purification was performed by elution with NH3 / MeOH solution. The solvent was removed to give the title compound (71 mg). ES-MS [M+1] + : 219.1.

[0456] 3-(1,3-dimethyl-1 H -pyrazol-5-yl)-7,8-dihydro-1,6-naphthyl-6(5 H 3-Tetrabutyl formate. In a vial, mix cesium carbonate (942 mg, 2.9 mmol) and 3-bromo-7,8-dihydro-1,6-naphthyl-6 (5... H 1,3-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1 H1,4-Dioxane / water (11 mL; 5:1) was prepared with pyrazole (532 mg, 2.4 mmol) and Pd(dppf)Cl2 (70 mg, 0.10 mmol). The mixture was stirred at 80°C for 20 h. After cooling to ambient temperature, the reaction mixture was subjected to a Celite reaction. ® The sample was filtered, washed with DCM / MeOH, and concentrated. Purified by silica gel normal-phase column chromatography (0%–60% MeOH / DCM) to give 292 mg of the title compound. ES-MS [M+1] + : 329.

[0457] 3-(1,3-dimethyl-1 H 3-Pyrazol-5-yl)-5,6,7,8-tetrahydro-1,6-naphthylidine hydrochloride. To 3-(1,3-dimethyl-1 H -pyrazol-5-yl)-7,8-dihydro-1,6-naphthyl-6(5 H tert-butyl formate (314 mg, 0.96 mmol) was added to a solution of hydrochloric acid (4 mmol) in DCM (4.8 mL). M In 1,4-dioxane (1.2 mL, 4.78 mmol), the mixture was stirred for 18 h and then concentrated under vacuum. 。 The material was used without further purification. ES-MS [M+1] + : 229.

[0458] 3-(2-(difluoromethyl)pyridin-3-yl)-7,8-dihydro-1,6-naphthidine-6(5 H 3-Tetrabutyl formate. In a vial, mix cesium carbonate (942 mg, 2.9 mmol) and 3-bromo-7,8-dihydro-1,6-naphthyl-6 (5... H tert-butyl formate (300 mg, 0.96 mmol), 2-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyridine (489 mg, 1.9 mmol), and Pd(dppf)Cl2 (70 mg, 0.10 mmol) were added to 1,4-dioxane / water (11 mL; 5:1). The mixture was stirred at 90°C for 18 h. After cooling to ambient temperature, the reaction mixture was subjected to a Celite reaction. ® Filter, wash with chloroform / IPA (3:1), and concentrate. Purify by silica gel normal-phase column chromatography (0%–80% EtOAc / DCM) to give 318 mg of the title compound. ES-MS [M+1]+ 362; 1 H NMR (400 MHz, MeOD) δ 8.72 (dd, J = 4.8, 1.6 Hz, 1H), 8.39 (d, J = 2.2 Hz, 1H), 7.93 – 7.89 (m, 1H), 7.74 – 7.60 (m, 2H), 6.72 (t, J =53.9 Hz, 1H), 4.70 (s, 2H), 3.82 (t, J = 6.0 Hz, 2H), 3.04 (t, J = 6.0 Hz, 2H), 1.51 (s, 9H).

[0459] 3-(2-(difluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydro-1,6-naphthidine. To 3-(2-(difluoromethyl)pyridin-3-yl)-7,8-dihydro-1,6-naphthidine-6(5 H tert-butyl formate (346 mg, 0.96 mmol) was added to a solution of trifluoroacetic acid (730 μL) in DCM (3.2 mL), and the mixture was stirred for 18 h and then concentrated under vacuum. 。 The material was dissolved in MeOH and purified by strong cation exchange chromatography to obtain the title compound. ES-MS [M+1] + : 262; 1 H NMR (400 MHz, MeOD) δ 8.71 (dd, J = 4.8, 1.6 Hz, 1H), 8.36 (d, J = 2.2 Hz, 1H), 7.90(ddt, J = 7.9, 1.6, 0.8 Hz, 1H), 7.67 (ddt, J = 7.9, 4.7, 0.9 Hz, 1H), 7.59 (d, J =2.2 Hz, 1H), 4-Fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1 H -Pyrazole. Add 5-bromo-4-fluoro-1-methyl-1-pyrazole to the vial containing 1,4-dioxane (11 mL). H-Pyrazole (375 mg, 2.1 mmol), potassium acetate (617 mg, 6.29 mmol), bis(pinacol)diboron (798 mg, 3.14 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (154 mg, 0.21 mmol). The vials were heated to 85°C for 18 hours. After cooling to room temperature, the mixture was diluted with EtOAc and then passed through Celite. ® Filter and concentrate. The material is then used without further purification. ES-MS [M+1] + : 145.1.

[0460] 3-(4-fluoro-1-methyl-1- H (-pyrazol-5-yl)-5,6,7,8-tetrahydro-1,6-naphthidine. Add 3-bromo-7,8-dihydro-5-yl) to the vial. H 1,6-Naphthyl-6-carboxylic acid tert-butyl ester (532 mg, 1.7 mmol), 4-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyrazole (461 mg, 2.0 mmol), cesium carbonate (1.67 g, 5.1 mmol), and Pd(dppf)Cl2 (125 mg, 0.17 mmol) were mixed in 1,4-dioxane (7 mL) and water (0.7 mL). The mixture was stirred at 90°C for 18 hr and subjected to Celite. ® Filter and wash with EtOAc (50 mL). The organic matter was then washed with saturated NaHCO3 and concentrated. The crude residue was purified by silica gel chromatography (0%-100% MeOH / DCM). The intermediate was dissolved in DCM (7 mL) and trifluoroacetic acid (1.3 mL) was added. After 18 h, the reaction was concentrated at room temperature. The crude residue was purified using an SCX column (HF bond) (loaded and washed with MeOH, using 2... N Purification (elution with NH3). The solvent was removed to give the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 2.1 Hz, 1H), 7.44 – 7.39(m, 2H), 4.14 (s, 2H), 3.83 (d, J = 0.7 Hz, 3H), 3.33 (t, J = 6.1 Hz, 2H), 3.07(t, J= 6.0 Hz, 2H). ES-MS [M+1] + : 233.3.

[0461] 3-((3-methylpyridin-4-yl)amino)-7,8-dihydro-1,6-naphthidine-6(5) H 3-Bromo-7,8-dihydro-5-methyl tert-butyl formate. Add 3-bromo-7,8-dihydro-5-methyl tert-butyl formate to a microwave-safe vial containing 1,4-dioxane (4 mL). H 1,6-Naphthyl-6-carboxylic acid tert-butyl ester (250 mg, 0.8 mmol), 4-amino-3-methylpyridine (129 mg, 1.2 mmol), cesium carbonate (785 mg, 2.39 mmol), tris(dibenzylacetone)palladium(0) (73 mg, 0.08 mmol), and xantphos (69 mg, 0.12 mmol). The reaction was degassed (3x) and heated at 100°C for 18 h. The reaction was cooled and passed through Celite. ® The mixture was filtered, washed with 3:1 CHCl3 / IPA, and concentrated. The crude residue was purified by normal-phase chromatography to give the title compound (265 mg). 1 H NMR (400 MHz, CDCl3) δ8.35 (d, J = 2.5 Hz, 1H), 8.23 ​​(d, J = 25.8 Hz, 2H), 7.32 (d, J = 2.5 Hz, 1H), 6.83(s, 1H), 6.05 (s, 1H), 4.61 (s, 2H), 3.78 (t, J = 6.0 Hz, 2H), 3.01 (t, J = 6.0Hz, 2H), 2.28 (s, 3H), 1.50 (s, 9H); ES-MS [M+1] + : 341.2.

[0462] N -(3-methylpyridin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthidium-3-amine. 3-[(3-methylpyridin-4-yl)amino]-7,8-dihydro-5 H1,6-Naphthyl-6-carboxylic acid tert-butyl ester (204 mg, 0.6 mmol) was combined with DCM (3 mL) and trifluoroacetic acid (0.69 mL). The reaction was concentrated after 2 h. The crude residue was passed through an SCX column (washed with MeOH and precipitated with 7... N Purification was performed by elution with NH3 / MeOH solution. The solvent was removed to give the title compound (158 mg). ES-MS [M+1] + :241.2.

[0463] 2-(3-bromo-7,8-dihydro-1,6-naphthidine-6(5) H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one. Prepared in a similar manner to compound 2 to give the desired compound. ES-MS [M+1] + : 359 / 361; 1 H NMR (400 MHz, MeOD) δ 8.46 (d, J = 2.2 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 0.9 Hz, 1H), 4.34 (s, 2H), 3.67 (t, J = 5.9 Hz, 2H), 3.35 (s, 2H), 3.10 (t, J = 5.9 Hz, 2H), 2.45 (d, J = 0.8 Hz, 3H).

[0464] 3-Methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-7,8-dihydro-1,6-naphthidium-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one. Combine 2-(3-bromo-7,8-dihydro-1,6-naphthyl-6(5-)-one in a vial. H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- bPyridin-5-one (80 mg, 0.22 mmol), bis(pinacol)diboron (85 mg, 0.33 mmol), Pd(dppf)Cl2 (16 mg, 0.02 mmol), and potassium acetate (66 mg, 0.67 mmol). After rinsing the vial with nitrogen, degassed 1,4-dioxane (1.1 mL) was added, and the reaction was heated at 90°C for 18 h. The reaction was then subjected to Celite... ® Filter, wash with 3:1 CHCl3 / IPA, and concentrate. The material was used without further purification. ES-MS [M+1] + 325 (mass of boric acid).

[0465] 2-(3-bromo-7,8-dihydro-1,6-naphthidine-6(5) H )-3,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one. Prepared in a similar manner to compound 8 to give the title compound. ES-MS [M+1] + : 373 / 375; 1 H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.84 (s, 1H), 7.80 (s, 1H), 4.56 (s, 2H), 4.29 (s, 2H), 3.59 (t, J = 5.9 Hz, 2H), 3.32 – 3.24 (m, 2H), 3.19 (s, 3H), 2.40 (s, 3H).

[0466] 3-Bromo-2-(3-(2-(difluoromethyl)pyridin-3-yl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)furano[3,4- b ]Pyridine-5(7 H )-ketone (intermediate A). 3-(2-(difluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydro-1,6-naphthidine (49 mg, 0.19 mmol), 3-bromo-2-chlorofurano[3,4- b ]Pyridine-5(7 H )-keto (36 mg, 0.14 mmol), and N, NA solution of diisopropylethylamine (252 μL, 1.45 mmol) in NMP (0.5 mL) was heated at 160°C for 16 h. Afterward, the reaction mixture was cooled to ambient temperature and then added to water. A precipitate formed, and the solid was collected by vacuum filtration to give 61 mg of the title compound. The material was used without further purification. ES-MS [M+1] + : 473 / 475.

[0467] 3-Bromo-2-(3-(4-fluoro-1-methyl-1-) H -pyrazol-5-yl)-7,8-dihydro-1,6-naphthyl-6(5 H )-yl)furano[3,4- b ]Pyridine-5(7 H )-Ketone. Add 3-bromo-2-chloro-7- ketone to a solution of 3-(4-fluoro-2-methylpyrazol-3-yl)-5,6,7,8-tetrahydro-1,6-naphthidine (19 mg, 0.08 mmol) in NMP (0.5 mL). H -furano[3,4- b Pyridin-5-one (20 mg, 0.07 mmol) and N , N -Diisopropylethylamine (0.04 mL, 0.22 mmol). The mixture was heated at 50°C for 18 hours. The reaction mixture was added to water and extracted with EtOAc (3x). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The material was used without further purification. ES-MS [M+1] + : 444.1.

[0468] 3-Bromo-2-(3-(2-(difluoromethyl)pyridin-3-yl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-6-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one. Prepared in a similar manner to intermediate A to give the title compound. ES-MS [M+1] + : 486 / 488; 1 H NMR (400 MHz, MeOD) δ 8.73 (dd, J = 4.8, 1.6 Hz, 1H), 8.42 (d, J= 2.2 Hz, 1H), 8.20 (s, 1H), 8.05 – 7.87 (m, 1H), 7.73 (d, J =2.2 Hz, 1H), 7.68 (dd, J = 7.9, 4.8 Hz, 1H), 6.73 (t, J = 53.9 Hz, 1H), 4.76 (s,2H), 4.41 (s, 2H), 3.93 (t, J = 5.8 Hz, 2H), 3.18 (s, 3H) (CH2 group in solvent).

[0469] 3-Bromo-6-cyclopropyl-2-(3-(2-(difluoromethyl)pyridin-3-yl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one. Prepared in a similar manner to intermediate A to give the title compound. ES-MS [M+1] + : 512 / 514.

[0470] ( S )-3-bromo-6-(1-methoxypropane-2-yl)-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one. To ( S )-3-bromo-2-chloro-6-(1-methoxypropane-2-yl)-6,7-dihydro-5 H -pyrrolo[3,4- b ] A solution of pyridin-5-one (30 mg, 0.09 mmol) in DMSO (0.5 mL) was supplemented with 7-(trifluoromethyl)-2,5-diazanaphthalene dihydrochloride (28.4 mg, 0.1 mmol) and N , N-Diisopropylethylamine (98 µL, 0.56 mmol). The mixture was heated to 70°C for 48 hr. After cooling to room temperature, the mixture was poured into water and extracted with EtOAc (3x). The organic compounds were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by reversed-phase HPLC (20%–60% MeCN / 0.05% aqueous NH4OH). The fraction containing the desired product was concentrated to give the title compound (26 mg). 1 H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 2.0 Hz, 1H), 8.21 (s, 1H), 7.70(d, J = 2.2 Hz, 1H), 4.73 – 4.63 (m, 1H), 4.68 (s, 2H), 4.34 (q, 2H), 3.85 (t, J = 5.8 Hz, 2H), 3.60 – 3.46 (m, 2H), 3.34 (s, 3H), 3.34 – 3.30 (m, 2H), 1.31(d, J = 7.0 Hz, 3H). ES-MS [M+1] + : 485.2 / 487.2.

[0471] ( R )-3-bromo-6-(1-methoxypropane-2-yl)-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one. With ( S )-3-bromo-6-(1-methoxypropane-2-yl)-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-6,7-dihydro-5H-pyrrolo[3,4- b Prepared in the same manner as pyridin-5-one. ES-MS [M+1] + : 485.2 / 487.2.

[0472] 3-Bromo-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -cyclopentadiene[b ]Pyridin-5-one. To 3-bromo-2-chloro-6,7-dihydro-5 H -cyclopentadiene[ b ] A solution of pyridin-5-one (13 mg, 0.05 mmol) in DMSO (0.5 mL) was supplemented with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthidine (10 mg, 0.06 mmol) and N , N -Diisopropylethylamine (55 µL, 0.32 mmol). The mixture was heated to 50°C for 18 h. The mixture was poured into water and extracted with EtOAc (3x). The organic compounds were combined, dried over MgSO4, filtered, and concentrated. The crude residue was purified by normal-phase column chromatography (0%–5% MeOH / DCM, containing 1% NH4OH) to give the title compound (19 mg). 1 HNMR (400 MHz, CDCl3) δ 8.73 (d, J = 2.2 Hz, 1H), 8.11 (s, 1H), 7.73 (d, J = 2.3Hz, 1H), 4.80 (s, 2H), 3.97 (t, J = 5.9 Hz, 2H), 3.35 (t, J = 5.9 Hz, 2H), 3.11 –3.04 (m, 2H), 2.79 – 2.72 (m, 2H). [M+1] + : 412 / 414.

[0473] 2-Iodo-5-methyl-6-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyl dihydrochloride (662 mg, 2.4 mmol) was added to a solution of 6-chloro-2-iodo-5-methylnicotinic acid methyl ester (500 mg, 1.6 mmol) in DMF (7 mL). N,N -Diisopropylethylamine (1.7 mL, 9.6 mmol). The mixture was heated to 50°C for 48 h. The reaction mixture was diluted with water (approximately 100 mL) and extracted with EtOAc (3x). The combined organic matter was dried (MgSO4), filtered, and concentrated. Purified by silica gel normal-phase column chromatography (0%–30% EtOAc / Hex) to give 239 mg of the title compound. ES-MS [M+1] +: 478.

[0474] 5-Methyl-2-(pyrazin-2-yl)-6-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl) nicotinic acid methyl ester. To 2-iodo-5-methyl-6-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H 2-(tributyltinyl) methyl nicotinate (239 mg, 0.5 mmol) and 2-(tributyltinyl)pyrazine (277 mg, 0.75 mmol) in a solution of toluene (7.7 mL) were supplemented with tetrakis(triphenylphosphine)palladium(O) (58 mg, 0.05 mmol). The reaction mixture was stirred at 100°C under an inert atmosphere for 18 h. The mixture was cooled to room temperature and an additional 2-(tributyltinyl)pyrazine (277 mg, 0.75 mmol) was added, and the reaction was heated to 100°C for 16 h. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with EtOAc (3x). The combined organics were washed with water (20 mL x 3), dried (MgSO4), filtered, and concentrated. Purification was performed by silica gel normal-phase column chromatography (0%-60% EtOAc / Hex) to give 140 mg of the title compound. ES-MS [M+1] + :430; 1 H NMR (400 MHz, CDCl3) δ 9.13 (d, J = 1.5 Hz, 1H), 8.81 (s, 1H), 8.60 (d, J =2.6 Hz, 1H), 8.60 – 8.54 (m, 1H), 8.17 (s, 1H), 7.90 (s, 1H), 4.78 (s, 2H), 3.76 (s, 3H), 3.69 (t, J = 5.8 Hz, 2H), 3.66 – 3.51 (m, 2H), 2.44 (s, 3H).

[0475] 3-Bromo-6-(2-chloro-5-methylpyrimidin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthidine (Intermediate B). Triethylamine (2.2 mL, 16.0 mmol) and 2,4-dichloro-5-methylpyrimidin (575 mg, 3.5 mmol) were added to a solution of 3-bromo-5,6,7,8-tetrahydro-1,6-naphthidine hydrochloride (800 mg, 3.2 mmol) in DMF (9.7 mL). The mixture was stirred at ambient temperature for 18 hours. The mixture was then diluted with water, and the precipitate was collected by vacuum filtration to give 857 mg of the title compound. ES-MS [M+1] + : 339 / 341; 1 H NMR (400 MHz, MeOD) δ 8.47 (d, J = 2.2 Hz, 1H), 8.01 (d, J = 0.9 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 4.81 (s, 2H), 3.94 (t, J = 5.9Hz, 2H), 3.09 (t, J = 5.9 Hz, 2H), 2.35 (d, J = 0.9 Hz, 3H).

[0476] 6-(2-Chloro-5-methylpyrimidin-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthidine. Prepared in a manner similar to intermediate B, to give the title compound. ES-MS [M+1] + : 329; 1 H NMR (400 MHz, CDCl3) δ8.73 (d, J = 1.2 Hz, 1H), 8.05 (q, J = 0.8 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 4.78(s, 2H), 3.87 (t, J = 5.9 Hz, 2H), 3.26 (t, J = 5.9 Hz, 2H), 2.32 (d, J = 0.9 Hz, 3H).

[0477] 6-(2,6-dichloro-5-methylpyrimidin-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthidine. Add 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthidine (139 mg, 0.54 mmol) to a solution of 2,4,6-trichloro-5-methylpyrimidin (110 mg, 0.55 mmol) in DMSO (1.5 mL) and N , N -Diisopropylethylamine (352 µL, 2.52 mmol). The mixture was heated to 70°C for 18 h. The mixture was poured into water and extracted with EtOAc (3x). The organic compounds were combined, dried over MgSO4, filtered, and concentrated. The crude residue was purified by normal-phase column chromatography (0%–80% EtOAc / hexane) to give the title compound (140 mg).

[0478] 3-Bromo-6-(2-hydrazino-5-methylpyrimidin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthidine (intermediate C). Hydrazine (370 µL, 11.8 mmol) was added to a solution of 3-bromo-6-(2-chloro-5-methylpyrimidin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthidine (200 mg, 0.59 mmol) in ethanol (4.0 mL), and the mixture was stirred at 80°C for 4 hours. After cooling to ambient temperature, the mixture was concentrated under vacuum without further purification and used. ES-MS [M+1] + : 335 / 337.

[0479] 6-(2-hydrazino-5-methylpyrimidin-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthidine: prepared in a manner similar to intermediate C, to give the title compound. ES-MS [M+1] + : 325.

[0480] 6-(6-chloro-2-hydrazino-5-methylpyrimidin-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthidine. Add 6-(2,6-dichloro-5-methylpyrimidin-4-yl)-3-(trifluoromethyl)-7,8-dihydro-5-naphthidine to the vial containing ethanol (10 mL). HHydrazine (0.17 mL, 5.51 mmol) was added to 1,6-naphthylidine (100 mg, 0.28 mmol), and the mixture was stirred at 40°C for 6 h. After cooling to ambient temperature, the mixture was concentrated under vacuum without further purification and used. ES-MS [M+1] + :335 / 337.

[0481] 7-(3-bromo-7,8-dihydro-1,6-naphthidine-6(5) H )-yl)-6-methyl-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-Ketone (Intermediate D). 1,1'-carbonyldiimidazole (431 mg, 2.7 mmol) was added to a solution of 3-bromo-6-(2-hydrazino-5-methylpyrimidin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthidine (557 mg, 1.7 mmol) in 1,4-dioxane (2.9 mL). The reaction was heated to 80°C for 18 hours, after which the mixture was cooled to ambient temperature. The mixture was then diluted with water, and the precipitate was collected by vacuum filtration to give 425 mg of the title compound. ES-MS [M+1] + : 361 / 363; 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 2.2 Hz, 1H), 8.50 (s, 1H), 7.69 (d, J =1.4 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 4.71 (s, 2H), 3.81 (t, J = 5.9 Hz, 2H), 3.16 (t, J = 5.9 Hz, 2H), 2.31 (d, J = 1.3 Hz, 3H).

[0482] 7-(3-bromo-7,8-dihydro-1,6-naphthidine-6(5) H )-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-ketone (intermediate E). To 7-(3-bromo-7,8-dihydro-1,6-naphthidine-6(5 H)-yl)-6-methyl-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H The 200 mg (0.55 mmol) ketone was dissolved in DMF (5.5 mL) with potassium carbonate (155 mg, 1.11 mmol), followed by methyl iodide (52 µL, 0.83 mmol). The mixture was heated to 50°C for 18 hours. After cooling to ambient temperature, the reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were dried (MgSO4), filtered, and concentrated to give 170 mg of the title compound. The material was used without further purification. ES-MS [M+1] + :375 / 377; 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 2.3 Hz, 1H), 7.68 (q, J = 1.3 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 4.69 (s, 2H), 3.79 (t, J = 5.9 Hz, 2H), 3.58 (s,3H), 3.15 (t, J = 5.8 Hz, 2H), 2.30 (d, J = 1.2 Hz, 3H).

[0483] 2,4-Dichloro-6-cyclopropyl-5-methylpyrimidine. A solution of 2,4-dichloro-5-methylpyrimidine (1.0 g, 6.1 mmol), silver nitrate (521 mg, 3.1 mmol), and cyclopropanecarboxylic acid (1.47 mL, 18.4 mmol) in water (31 mL) was heated to 72°C. Ammonium persulfate (2.1 g, 9.2 mmol) was added in portions over 15 minutes. After reheating at 72°C for 20 minutes, sulfuric acid (491 µL, 9.2 mmol) was added, and the mixture was heated to 90°C for 1 h. After cooling to ambient temperature, the reaction mixture was slowly poured into a solution of saturated aqueous bicarbonate and DCM and stirred for another 20 minutes. The organic layer was separated, and the aqueous layer was further extracted with DCM (3x). The combined organic layers were dried (MgSO4), filtered, and concentrated. Purified by normal-phase column chromatography (0%–25% EtOAc / hexane) to give the title compound (872 mg). ES-MS [M+1]+: 203 / 205; 1H NMR (400 MHz, CDCl3) δ 2.45 (s, 3H), 2.11 (tt, J = 7.9, 4.6 Hz, 1H), 1.29 – 1.23 (m, 2H), 1.18 – 1.12 (m, 2H).

[0484] 6-(2-chloro-5,6-dimethylpyrimidin-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthidine. Prepared in a manner similar to intermediate B, to give the title compound. ES-MS [M+1]+: 343; 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.72 (s, 1H), 4.65 (s, 2H), 3.69 (t, J = 5.9 Hz, 2H), 3.27 (t, J = 5.9 Hz, 2H), 2.44 (s, 3H), 2.22 (s, 3H).

[0485] 6-(2-chloro-6,7-dihydro-5-) H -cyclopentadiene[ d Pyrimidin-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthidine. Prepared in a manner similar to intermediate B, to give the title compound. ES-MS [M+1]+: 355; 1 HNMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.74 (s, 1H), 4.98 (s, 2H), 4.07 (t, J =6.0 Hz, 2H), 3.20 (t, J = 6.0 Hz, 2H), 3.11 (t, J = 7.3 Hz, 2H), 2.89 (t, J = 7.9Hz, 2H), 2.13 (p, J = 7.7 Hz, 2H).

[0486] 6-(2-chloro-6-cyclopropyl-5-methylpyrimidin-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthidine. Prepared in a manner similar to intermediate B, to give the title compound. ES-MS [M+1]+: 369;1 H NMR (400 MHz, CDCl3) δ 8.72 (dd, J = 2.2, 0.8 Hz, 1H), 7.71 (dd, J = 2.0, 0.9 Hz, 1H), 4.62 (s,2H), 3.66 (t, J = 5.9 Hz, 2H), 3.27 (t, J = 5.9 Hz, 2H), 2.33 (s, 3H), 2.07 –1.96 (m, 1H), 1.24 – 1.14 (m, 2H), 1.08 – 0.99 (m, 2H).

[0487] 6-(2-hydrazino-5,6-dimethylpyrimidin-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthidine. Prepared in a manner similar to intermediate C, to give the title compound. ES-MS [M+1]+: 339.

[0488] 6-(2-hydrazino-6,7-dihydro-5-) H -cyclopentadiene[ d ]pyrimidin-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthidine. Prepared in a manner similar to intermediate C, to give the title compound. ES-MS [M+1]+: 351.

[0489] 6-(6-cyclopropyl-2-hydrazino-5-methylpyrimidin-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthidine. Prepared in a manner similar to intermediate C, to give the title compound. ES-MS [M+1]+: 365.

[0490] 2,4,5-Trimethylpyridin-3-yl trifluoromethanesulfonic acid. A solution of 2,4,5-trimethylpyridin-3-ol (1.0 g, 7.29 mmol), triethylamine (2.03 mL, 14.6 mmol), and 4-dimethylaminopyridine (178 mg, 1.46 mmol) in DCM (21 mL) was cooled to 0°C and then added... N2.76 g, 7.73 mmol phenylbis(trifluoromethanesulfonylimide). The solution was heated to ambient temperature and stirred for 18 hours. The reaction mixture was concentrated in Celite. ® The sample was purified by normal phase chromatography (0%-15% EtOAc / Hex) to provide the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 2.57 (s, 3H), 2.30 (s, 3H), 2.28 (s, 3H). ES-MS [M+1] + : 270.

[0491] 2,4,5-Trimethylnicotinic acid ethyl ester. Triethylamine (9.8 mL, 70.6 mmol), 1,3-bis(diphenylphosphine)propane (437 mg, 1.06 mmol), and palladium(II) acetate (240 mg, 1.06 mmol) were added to a solution of 2,4,5-trimethylpyridin-3-yl trifluoromethanesulfonate (1.9 g, 7.06 mmol) in ethanol (12 mL) and DMSO (6 mL). The mixture was placed under a CO(g) atmosphere (50 psi) and heated to 80°C for 18 hours. The reaction mixture was then subjected to Celite... ® The mixture was filtered through a pad, washed with DCM / MeOH, and concentrated. The residue was then diluted with water (approximately 150 mL) and extracted with EtOAc (4x). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0%–60% EtOAc / Hex) to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H),2.49 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). ES-MS [M+1] + :194.

[0492] 2-(chloromethyl)-4,5-dimethylnicotinic acid ethyl ester. Trichloroisocyanuric acid (1085 mg, 4.67 mmol) was added to a stirred solution of 2,4,5-trimethylnicotinic acid ethyl ester (752 mg, 3.89 mmol) in DCM (19.5 mL), and the mixture was stirred at ambient temperature for 12 h. Additional TCICA (226 mg, 0.97 mmol) was added and the mixture was stirred for another 18 h. Additional TCICA (300 mg, 1.29 mmol) was added, and the mixture was stirred for 3 h. The pH was adjusted to 8 with a saturated aqueous solution of Na₂CO₃. The organic layer was separated, and the aqueous layer was further extracted with DCM (3x). The combined organic matter was dried (MgSO₄), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0%–5% MeOH / DCM) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 4.71 (s, 2H), 4.46 (q, J = 7.2 Hz, 2H), 2.29(s, 3H), 2.28 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H). ES-MS [M+1] + : 228.

[0493] 2-(chloromethyl)-3-(ethoxycarbonyl)-4,5-dimethylpyridine 1-oxide. At 0°C, 3-chloroperoxybenzoic acid (285 mg, 1.65 mmol) was added in portions to a solution of 2-(chloromethyl)-4,5-dimethylnicotinic acid ethyl ester (216 µL, 1.38 mmol) in DCM (6.9 mL). After removing the ice bath and allowing the mixture to stand at room temperature for 18 hours, it was directly concentrated into Celite. ® The compound was purified by normal phase chromatography (0%-80% EtOAc / DCM, then 0%-10% MeOH / DCM) to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 4.84 (s, 2H), 4.48 (q, J = 7.2 Hz,2H), 2.25 (s, 3H), 2.22 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H). ES-MS [M+1] + : 244.

[0494] 6-Chloro-2-(chloromethyl)-4,5-dimethylnicotinic acid ethyl ester. Phosphorus oxychloride (V) (348 µL, 3.73 mmol) was added to a solution of 2-(chloromethyl)-3-(ethoxycarbonyl)-4,5-dimethylpyridine 1-oxide (182 mg, 0.75 mmol) in MeCN (1.6 mL). The vial was sealed, and the mixture was heated to 90°C for 20 hours. After cooling to ambient temperature, the reaction mixture was slowly added to a stirred solution of saturated aqueous NaHCO3 while maintaining the pH at alkaline. DCM was added, and the mixture was stirred for 30 minutes. The organic layers were separated, and the aqueous layer was back-extracted with chloroform / IPA (3:1) (3x). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0%–15% EtOAc / hexane) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ 4.66 (s, 2H), 4.46 (q, J = 7.2Hz, 2H), 2.39 (s, 3H), 2.33 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). ES-MS [M+1] + :262 / 264.

[0495] 2-Chloro-3,4,6-trimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one. Add methylamine (2.0 mg / mL) to a solution of 6-chloro-2-(chloromethyl)-4,5-dimethylnicotinic acid ethyl ester (68 mg, 0.26 mmol) in THF (1.3 mL). M The solution was prepared in THF (650 µL, 1.3 mmol), and the reaction was heated to 30°C for 18 hours. The reaction was then concentrated under vacuum to give the title compound. 1 H NMR (400 MHz, CDCl3) δ 4.29 (s, 3H), 3.18 (s, 2H), 2.73 (s, 3H), 2.39 (s, 3H). ES-MS [M+1] + : 211.

[0496] 6-Hydroxy-4,5-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxynitrile. Ethyl 2-methyl-3-oxobutyrate (3.37 mL, 23.89 mmol) and potassium hydroxide (2.04 g, 35.7 mmol) were added to a solution of 2-cyanoacetamide (2.0 g, 23.8 mmol) dissolved in methanol (30 mL). The mixture was then stirred at 65°C for 4 hours, followed by cooling to 4°C. The solid was collected by vacuum filtration and washing with MeOH. The solid was dissolved in approximately 175 mL of hot water (70°C). The solution was then dissolved in aqueous HCl (5... M Adjust the pH to approximately 1 and observe the precipitate. Collect the solid by vacuum filtration and rinsing with water to give the title compound. 1 H NMR (400 MHz, DMSO) δ 2.23 (s, 1H), 1.90 (s, 1H). ES-MS[M+1] + : 165.

[0497] 2,6-Dichloro-4,5-dimethylnicotinonitrile. A solution of 6-hydroxy-4,5-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxynitrile (2.28 g, 13.88 mmol) in phosphorus oxychloride (v) (10 mL) was heated to 180°C. After 6 hours, the heat source was removed, and the reaction mixture was poured into ice water (100 mL) at room temperature. The precipitate was collected by vacuum filtration to give the title compound. 1 H NMR (400 MHz, CDCl3) δ 2.58 (s, 3H), 2.39 (s, 3H). ES-MS [M+1] + :201 / 203.

[0498] 2,6-Dichloro-4,5-dimethylnicotinic acid. A stirred solution of 2,6-dichloro-4,5-dimethylnicotinonitrile (1.48 g, 7.36 mmol) in sulfuric acid (2.0 mL) was heated to 110°C for 1 hour. After cooling to ambient temperature, the reaction mixture was cooled to 0°C, and an aqueous solution of sodium nitrite (671 mg, 9.58 mmol) was added dropwise over 15 minutes. M (In water), resulting in the release of heat and brown gas. The mixture was then heated to ambient temperature for 15 minutes, followed by heating to 60°C for 18 hours. After cooling to ambient temperature, the reaction mixture was cooled again to 0°C, and sodium nitrite (186 mg, 2.66 mmol) was added dropwise over 15 minutes. MAn aqueous solution (in water) was prepared. The mixture was then heated to ambient temperature for 15 minutes, followed by heating to 60°C for 18 hours. After cooling to room temperature, the reaction mixture was added to ice water, and the precipitate was collected by vacuum filtration to give the title compound. 1 H NMR (400 MHz, DMSO) δ 2.32 (s, 3H), 2.31 (s, 3H). ES-MS [M+1] + : 220 / 222.

[0499] 2,6-Dichloro-4,5-dimethylnicotinic acid methyl ester. Potassium carbonate (918 mg, 6.54 mmol) and methyl iodoform (543 µL, 8.73 mmol) were added to a solution of 2,6-dichloro-4,5-dimethylnicotinic acid (960 mg, 4.36 mmol) in DMF (14.5 mL). The mixture was stirred at ambient temperature for 1 hour, then diluted with water and extracted with EtOAc (3x). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0%–10% EtOAc / Hex) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ 3.97 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H). ES-MS [M+1] + : 234 / 236.

[0500] 6-Chloro-2-cyano-4,5-dimethylnicotinic acid methyl ester. A solution of 2,6-dichloro-4,5-dimethylnicotinic acid methyl ester (868 mg, 3.71 mmol) in NMP (4.4 mL) and cuprous cyanide (I) (498 mg, 5.56 mmol) was stirred for 3 hours at 180°C under an inert atmosphere. After cooling to ambient temperature, the reaction mixture was poured into ice water, and the solid was removed by filtration and washed with EtOAc. The filtrate was then extracted with EtOAc (3x), and the combined organic matter was dried (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0%–40% EtOAc / Hex) to give the title compound. ES-MS [M+1] + : 225.

[0501] 2-(aminomethyl)-6-chloro-4,5-dimethylnicotinic acid methyl ester. Platinum oxide (IV) (38 mg, 0.17 mmol) was added to a solution of 6-chloro-2-cyano-4,5-dimethylnicotinic acid methyl ester (219 mg, 0.98 mmol) in ethanol (4.6 mL) / chloroform (1.5 mL) (3:1). The flask was evacuated and purged with hydrogen (the process was repeated three times). The mixture was stirred under a hydrogen atmosphere (balloon) for 25 hours. The reaction mixture was then subjected to Celite... ® Filter, wash with DCM / MeOH, and concentrate the filtrate for continued use without further purification. ES-MS [M+1] + : 229.

[0502] 2-Chloro-3,4-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one. Add a solution of 2-(aminomethyl)-6-chloro-4,5-dimethylnicotinic acid methyl ester (236 mg, 0.97 mmol) and triethylamine (680 µL, 4.88 mmol) in methanol (4.9 mL) to a vial. Stir the solution at ambient temperature for 18 hours, then concentrate in Celite. ® The compound was purified by normal phase chromatography (0%-3% MeOH / DCM) to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ 6.06 (s, 1H), 4.38 (s, 2H), 2.74 (s, 3H), 2.41 (s, 3H). ES-MS [M+1] + : 197.

[0503] 6-Hydroxy-2,4-dimethylnicotinic acid ethyl ester. To ( Z 3-Aminobutyric acid ethyl ester (1.96 mL, 15.5 mmol) was added to a solution of toluene (11.6 mL) with hydrochloric acid solution (4 mmol / L). M The reaction was carried out in dioxane (7.74 mL, 30.9 mmol) and heated to 115°C for 18 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under vacuum, and the crude residue was purified by normal-phase chromatography (0%-90% EtOAc / DCM) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ 6.25 (s, 1H), 4.34 (q, J= 7.1 Hz, 2H), 2.46 (s, 3H), 2.29(s, 3H), 1.37 (t, J = 7.1 Hz, 3H). ES-MS [M+1] + : 196.

[0504] 5-Bromo-6-hydroxy-2,4-dimethylnicotinic acid ethyl ester. Prepared in a similar manner to 5-bromo-6-hydroxy-2-methylnicotinic acid ethyl ester. 1 H NMR (400 MHz, CDCl3) δ 4.36 (q, J = 7.1 Hz, 2H), 2.43 (s, 3H), 2.42 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). ES-MS [M+1] + : 274 / 276.

[0505] 5-Bromo-6-chloro-2,4-dimethylnicotinic acid ethyl ester: prepared in a similar manner to 5-bromo-6-chloro-2-methylnicotinic acid ethyl ester. 1 H NMR (400 MHz, CDCl3) δ 4.43 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 2.43(s, 3H), 1.40 (t, J = 7.1 Hz, 3H). ES-MS [M+1] + : 292 / 294.

[0506] 5-Bromo-2-(bromomethyl)-6-chloro-4-methylnicotinic acid ethyl ester: prepared in a similar manner to 5-bromo-2-(bromomethyl)-6-chloronicotinic acid ethyl ester. 1 H NMR (400 MHz, CDCl3) δ 4.53 (s, 2H), 4.48 (q, J = 7.2 Hz,2H), 2.48 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). ES-MS [M+1] + : 370 / 372 / 374.

[0507] 3-Bromo-2-chloro-4,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one: with 3-bromo-2-chloro-6-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b It can be prepared in a similar manner to pyridin-5-one. 1 H NMR (400 MHz, DMSO) δ 4.43 (s, 2H), 3.07 (s, 3H), 2.75 (s, 3H). ES-MS [M+1] + : 275 / 277.

[0508] 3-Bromo-2-(3-cyclopropyl-7,8-dihydro-1,6-naphthidine-6(5) H )-4,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one. To 3-cyclopropyl-5,6,7,8-tetrahydro-1,6-naphthylidine (51 mg, 0.29 mmol) and 3-bromo-2-chloro-4,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one (40 mg, 0.15 mmol) was added to a solution of N,N-diisopropylethylamine (126 µL, 0.73 mmol) in DMSO (0.5 mL). The reaction was heated to 100°C for 18 hours. After cooling, the reaction mixture was added to water (about 10 mL), and the solid was collected by vacuum filtration to give the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 2.2 Hz, 1H), 7.07 (d, J =2.2 Hz, 1H), 4.53 (s, 2H), 4.22 (s, 2H), 3.74 (t, J = 5.8 Hz, 2H), 3.23 (t, J =5.8 Hz, 2H), 3.17 (s, 3H), 2.79 (s, 3H), 1.88 (tt, J = 8.5, 5.1 Hz, 1H), 1.06 –0.91 (m, 2H), 0.69 (dt, J = 6.6, 4.8 Hz, 2H). ES-MS [M+1]+ : 414.

[0509] b. Synthesis of representative compounds of the present invention 3-Methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound 2). To 2-chloro-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ] A solution of pyridin-5-one (100 mg, 0.55 mmol) in DMSO (1.8 mL) was supplemented with 7-(trifluoromethyl)-2,5-diazanaphthalene dihydrochloride (226 mg, 0.82 mmol) and N,N -Diisopropylethylamine (572 µL, 3.3 mmol). Heat the mixture to 120°C for 18 h. Add additional... N,N- Diisopropylethylamine (572 µL, 3.3 mmol) was used, and the mixture was heated to 120°C for 18 h. After cooling to ambient temperature, the mixture was poured into water (approximately 30 mL), and a precipitate formed. The solid was collected by vacuum filtration and dried under a nitrogen stream to give the title compound. ES-MS [M+1] + : 349; 1 H NMR (400MHz, CDCl3) δ 8.76 (s, 1H), 7.89 (d, J = 0.9 Hz, 1H), 7.86 (s, 1H), 5.99 (s,1H), 4.66 (s, 2H), 4.39 (s, 2H), 3.66 (t, J = 5.8 Hz, 2H), 3.39 (t, J = 5.8 Hz, 2H), 2.43 (d, J = 0.8 Hz, 3H).

[0510] 3,6-Dimethyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b]Pyridin-5-one (compound 1). At ambient temperature, to 3-methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ] A solution of pyridin-5-one (15 mg, 0.04 mmol) in DMSO (0.62 mL) was supplemented with lithium bis(trimethylsilyl)amino (43 µL, 0.04 mmol) (1 M (In THF). The reaction was stirred for 20 min, then iodomethane (2.7 µL, 0.04 mmol) was added. The reaction was stirred for 4 h, and the mixture was purified directly by RP-HPLC (5%–60% ACN / 0.05% aqueous NH4OH) to give the title compound. ES-MS [M+1] + :363; 1 H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.29 (s, 1H), 8.00 (s, 1H), 4.91(s, 2H), 4.46 (s, 2H), 3.87 – 3.72 (m, 2H), 3.76 – 3.66 (m, 2H), 3.23 (s,3H), 2.48 (s, 3H).

[0511] 2-(3-methyl-5-oxo-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5-) H )-yl)-5,7-dihydro-6 H -pyrrolo[3,4- b Methyl pyridin-6-yl)propionate (compound 3). Prepared in a similar manner to compound 1 to give the title compound. ES-MS [M+1] + : 435; 1 H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.88 (s, 2H), 5.20 (q, J = 7.5 Hz, 1H), 4.67 (s, 2H), 4.51 (d, J = 17.0 Hz, 1H), 4.35(d, J = 17.1 Hz, 1H), 3.73 (s, 3H), 3.66 (t, J= 5.8 Hz, 2H), 3.45 – 3.30 (m,0H), 2.43 (d, J = 0.9 Hz, 3H), 1.58 (d, J = 7.5 Hz, 3H).

[0512] 3-Methyl-2-(3-(1-methyl-1-yl) H -pyrazol-4-yl)-7,8-dihydro-1,6-naphthyl-6(5) H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound 4). To 2-chloro-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ] Pyridin-5-one (15 mg, 0.08 mmol) in a solution of DMSO (0.5 mL) was supplemented with 3-(1-methyl-1-yl) H -pyrazol-4-yl)-5,6,7,8-tetrahydro-1,6-naphthylidine hydrochloride (39 mg, 0.12 mmol) and N,N -Diisopropylethylamine (86 μL, 0.49 mmol). The mixture was heated to 120°C for 18 h. After cooling to ambient temperature, the crude mixture was purified by RP-HPLC (5%–45% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and then extracted with 3:1 chloroform / IPA (3x). The combined organics were passed through a phase separator and the solvent was concentrated to give 11.4 mg of the title compound. ES-MS [M+1] + 361; 1 H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 2.2 Hz, 1H), 7.85 (d, J = 0.9 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 7.65 (s, 1H), 7.53 (d, J = 2.2Hz, 1H), 5.96 (s, 1H), 4.58 (s, 2H), 4.38 (s, 2H), 3.97 (s, 3H), 3.63 (t, J =5.9 Hz, 2H), 3.22 (t, J= 5.8 Hz, 2H), 2.44 (s, 3H).

[0513] 2-(3-(6-fluoro-4-methylpyridin-3-yl)-7,8-dihydro-1,6-naphthidine-6(5-yl) H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one (compound 5). Prepared in a similar manner to compound 4 to give the title compound. ES-MS [M+1] + : 390; 1 H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 2.2 Hz, 1H), 8.05(s, 1H), 7.87 (d, J = 0.9 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 6.89 (d, J = 2.0 Hz,1H), 5.98 (s, 1H), 4.62 (s, 2H), 4.39 (s, 2H), 3.66 (t, J = 5.9 Hz, 2H), 3.29(t, J = 5.9 Hz, 2H), 2.50 (s, 3H), 2.34 (s, 3H).

[0514] 3-Methyl-6-(methyl- d 3)-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound 8). At 0°C, to 3-methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidium-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b [Pyridin-5-one (10 mg, 0.03 mmol) was added to a solution of diisopropylaminolithium (35 μL, 0.03 mmol) in THF (400 μL) and HMPA (100 μL) (1) M (In THF). The reaction was heated to ambient temperature and stirred for 30 minutes, then iodomethane was added.d 3 (4.3 μL, 0.04 mmol). The reaction was stirred for 50 min, then water was added, and the mixture was extracted with EtOAc (3x). The organic matter was dried (MgSO4), filtered, and concentrated. The crude product was dissolved in DMSO (2 mL) and purified by RP-HPLC (5%–60% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and then extracted with 3:1 chloroform / IPA (3x). The combined organic matter was passed through a phase separator, and the solvent was concentrated to give the title compound. ES-MS [M+1] + 366; 1 HNMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.83 (s, 1H), 7.71 (d, J = 1.9 Hz, 1H), 4.58 (s, 2H), 4.29 (s, 2H), 3.61 (t, J = 5.9 Hz, 2H), 3.27 (t, J = 5.9 Hz, 2H), 2.41 (s, 3H).

[0515] 3-Methyl-6-(oxetane-3-ylmethyl)-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4-b]pyridin-5-one (compound 9). Prepared in a similar manner to compound 8 to give the title compound. ES-MS [M+1] + : 419.

[0516] 2-(3-(1,3-dimethyl-1-yl) H -pyrazol-5-yl)-7,8-dihydro-1,6-naphthyl-6(5 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one (compound 24). Prepared in a similar manner to compound 4 to give the title compound. ES-MS [M+1] + 375; 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 2.1 Hz, 1H), 7.87 (d,J = 0.9 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 6.14 (s, 1H), 5.99 (s, 1H), 4.61 (s, 2H), 4.39 (s, 2H), 3.84 (s, 3H), 3.64 (t, J = 5.9 Hz, 2H), 3.26 (s, 2H), 2.44 (s, 3H), 2.31 (s, 3H).

[0517] 3-Methyl-2-(3-(1-methyl-1-yl) H -pyrazol-5-yl)-7,8-dihydro-1,6-naphthyl-6(5 H )-base-5,5,7,7- d 4)-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound 10). To 2-chloro-3-methyl-6,7-dihydropyrrolo[3,4- b Pyridin-5-one (15 mg, 0.08 mmol) and N , N 3-(1-methyl-1-diisopropylethylamine) (0.07 mL, 0.41 mmol) was added to a solution of DMSO (0.8 mL). H -pyrazol-5-yl)-5,6,7,8-tetrahydro-1,6-naphthyl-5,5,7,7- d 4 (18 mg, 0.08 mmol). The reaction was heated at 120°C for 18 h. The reaction was purified by reversed-phase HPLC (5%-45% MeCN / water / 0.05% NH4OH) to give the title compound (3.2 mg). 1 H NMR (400 MHz, CDCl3) δ 8.54 (d, J =2.2 Hz, 1H), 7.87 (d, J = 0.9 Hz, 1H), 7.54 (dd, J = 9.6, 2.1 Hz, 2H), 6.36 (d, J =1.9 Hz, 1H), 6.06 (s, 1H), 4.38 (s, 2H), 3.92 (s, 3H), 3.27 (s, 2H), 2.44 (d, J = 0.8 Hz, 3H); ES-MS [M+1]+ : 365.5.

[0518] 2-(3-(3,5-dimethylisoxazol-4-yl)-7,8-dihydro-1,6-naphthidine-6-(5-yl) H )-base-5,5,7,7- d 4)-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound 11). To 2-chloro-3-methyl-6,7-dihydropyrrolo[3,4- b Pyridin-5-one (15 mg, 0.08 mmol) and N , N 3,5-Dimethyl-4-(5,6,7,8-tetrahydro-1,6-naphthid-3-yl-5,5,7,7-)diisopropylethylamine (0.07 mL, 0.41 mmol) was added to a solution of DMSO (0.8 mL). d 4) Isoxazole (19 mg, 0.08 mmol). The reaction was heated at 120°C for 18 h. The reaction was purified by reversed-phase HPLC (5%–45% MeCN / water / 0.05% NH4OH) to give the title compound (5.7 mg). ES-MS [M+1] + 380.5; 1 H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 2.1 Hz, 1H), 7.87 (s, 1H), 7.52 (s, 1H), 6.33(s, 1H), 4.38 (s, 2H), 3.37 (s, 2H), 2.61 (s, 3H), 2.44 (s, 3H), 2.29 (s,3H).

[0519] 2-(3-(6-methoxypyridin-3-yl)-7,8-dihydro-1,6-naphthidine-6(5) H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one (compound 20). In a vial, cesium carbonate (41 mg, 0.13 mmol), 2-(3-bromo-7,8-dihydro-1,6-naphthyl-6(5...)... H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- bPyridin-5-one (15 mg, 0.04 mmol), (6-methoxypyridin-3-yl)boronic acid (13 mg, 0.08 mmol), and Pd(dppf)Cl2 (3.1 mg, 0.004 mmol) were added to 1,4-dioxane (350 μL) / water (70 μL) (5:1). The mixture was stirred at 80°C for 16 h. After cooling to ambient temperature, the reaction mixture was subjected to Celite... ® Filter, wash with DCM / MeOH, and concentrate. Dissolve the crude product in DMSO (2 mL) and purify by RP-HPLC (5%–50% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and then extracted with 3:1 chloroform / IPA (3x). The combined organic compounds were passed through a phase separator, and the solvent was concentrated to give the title compound. ES-MS [M+1] + 388; 1 H NMR (400 MHz, CDCl3) δ8.69 (d, J = 2.1 Hz, 1H), 8.42 (dd, J = 2.8, 0.6 Hz, 1H), 7.91 (s, 1H), 7.78 (dd, J = 8.7, 2.7 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 5.96 (s, 1H), 4.74 (s, 2H), 4.37(s, 2H), 4.08 – 3.91 (m, 4H), 3.68 (s, 3H), 2.43 (d, J = 0.8 Hz, 3H).

[0520] 2-(3-(5-fluoro-2-methylpyridin-3-yl)-7,8-dihydro-1,6-naphthidine-6(5-) H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound 33). In a vial, cesium carbonate (55 mg, 0.17 mmol), 3-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-7,8-dihydro-1,6-naphthidium-6(5... H )-6,7-dihydro-5 H -pyrrolo[3,4- bPyridin-5-one (23 mg, 0.06 mmol), 3-bromo-5-fluoro-2-methylpyridine (21 mg, 0.11 mmol), and Pd(dppf)Cl2 (4.1 mg, 0.01 mmol) were added to 1,4-dioxane (350 μL) / water (70 μL) (5:1). The mixture was stirred at 90°C for 18 h and then cooled to ambient temperature. The reaction mixture was subjected to Celite... ® Filter and wash with 3:1 CHCl3 / IPA. The organic matter was then washed with saturated aqueous NaHCO3, passed through a phase separator, and concentrated. The crude residue was dissolved in DMSO (1.5 mL) and purified by RP-HPLC (5%–45% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and then extracted with 3:1 chloroform / IPA (3x). The combined organic matter was passed through a phase separator, and the solvent was concentrated to give the title compound. ES-MS [M+1] + : 390; 1 H NMR (400MHz, CDCl3) δ 8.45 (d, J = 2.2 Hz, 1H), 8.42 (d, J = 2.9 Hz, 1H), 7.87 (d, J = 0.9Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.28 (dd, J = 8.6, 2.9 Hz, 1H), 6.00 (s, 1H), 4.62 (s, 2H), 4.39 (s, 2H), 3.66 (t, J = 5.9 Hz, 2H), 3.30 (t, J = 5.9 Hz, 2H), 2.50 (d, J = 1.2 Hz, 3H), 2.45 (s, 3H).

[0521] 2-(3-(4-fluoro-1-methyl-1-) H -pyrazol-5-yl)-7,8-dihydro-1,6-naphthyl-6(5 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one (compound 37). Prepared in a similar manner to compound 33 to give the title compound. ES-MS [M+1] +379; 1 H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 2.1 Hz, 1H),7.87 (s, 1H), 7.58 – 7.53 (m, 1H), 7.44 (d, J = 4.5 Hz, 1H), 6.01 (s, 1H), 4.63(s, 2H), 4.39 (s, 2H), 3.87 (s, 3H), 3.65 (t, J = 5.9 Hz, 2H), 3.29 (t, J = 5.9Hz, 2H), 2.45 (s, 3H).

[0522] 2-(3-(2-(difluoromethyl)pyridin-3-yl)-7,8-dihydro-1,6-naphthidine-6(5) H )-yl)-3-methylfurano[3,4- b ]Pyridine-5(7 H )-ketone (compound 38). 3-bromo-2-(3-(2-(difluoromethyl)pyridin-3-yl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)furano[3,4- b ]Pyridine-5(7 H 1,4-Dioxane (30 mg, 0.05 mmol), cesium carbonate (46 mg, 0.14 mmol), trimethylboroxane (50% wt in THF) (40 μL, 0.14 mmol), Pd(dppf)Cl2 (7.0 mg, 0.01 mmol), and 1,4-dioxane (0.5 mL) were placed in vials. The mixture was evacuated and purged with nitrogen, then stirred at 80°C for 18 h. After cooling to ambient temperature, the reaction was passed through a Celite tube. ® The sample was filtered through a filtration mat and thoroughly washed with DCM / MeOH. The solvent was removed, and the crude sample was dissolved in DMSO (1.5 mL) and purified by RP-HPLC (30%–50% ACN / 0.05% aqueous NH4OH). The fraction containing the desired product was concentrated to give 6.5 mg of the title compound. ES-MS [M+1] + :409.

[0523] 2-(3-(4-fluoro-1-methyl-1-) H -pyrazol-5-yl)-7,8-dihydro-1,6-naphthyl-6(5H )-yl)-3-methylfurano[3,4- b ]Pyridine-5(7 H )-ketone (compound 44). 3-bromo-2-[3-(4-fluoro-2-methylpyrazol-3-yl)-7,8-dihydro-5-yl] H -1,6-Naphthid-6-yl]-7 H -furano[3,4- b Pyridin-5-one (15 mg, 0.03 mmol), cesium carbonate (33 mg, 0.1 mmol), trimethylborooxane (50% wt in THF) (0.03 mL, 0.1 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloro(II) (5.0 mg, 0.01 mmol), and 1,4-dioxane (0.5 mL) were placed in vials. The vials were evacuated and purged with nitrogen (3x) and heated to 80°C for 18 hours. The reaction was passed through a Celite tube. ® The sample was filtered through a filter pad and thoroughly washed with EtOAc. The solvent was removed under vacuum, and the crude residue was purified by RP-HPLC (15%–55% MeCN / water / 0.1% TFA). The desired fraction was treated with saturated NaHCO3, extracted with CHCl3 / iPA (3:1), and the organic layer was concentrated to give the title compound. ES-MS [M+1] + : 423.

[0524] 2-(3-(2-(difluoromethyl)pyridin-3-yl)-7,8-dihydro-1,6-naphthidine-6(5) H )-yl)-5-oxo-5,7-dihydrofurano[3,4- b ]Pyridine-3-carboxylonitrile (compound 42). 3-Bromo-2-[3-[2-(difluoromethyl)pyridin-3-yl]-7,8-dihydro-5 H -1,6-Naphthid-6-yl]-7 H -furano[3,4- bPyridin-5-one (25 mg, 0.05 mmol) and zinc cyanide (9.3 mg, 0.08 mmol) were suspended in DMF (0.5 mL). The mixture was degassed with nitrogen, and then tetrakis(triphenylphosphine)palladium(0) (9.0 mg, 0.01 mmol) was added. The reaction was heated to 80°C for 5 hr. The reaction mixture was diluted with EtOAc. The organic phase was washed with saturated NaHCO3(aq) (2x) and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0%–10% NH4OH / MeOH / DCM) to give the title compound. ES-MS [M+1] + : 420.3.

[0525] 2-(3-(2-(difluoromethyl)pyridin-3-yl)-7,8-dihydro-1,6-naphthidine-6(5) H )-3,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one (compound 39). Prepared in a similar manner to compound 38 to give the title compound. ES-MS [M+1] + : 422; 1 H NMR (400 MHz, CDCl3) δ 8.76 (dd, J = 4.7, 1.6Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 0.9 Hz, 1H), 7.76 – 7.69 (m, 1H), 7.53 (m, 2H), 6.64 (t, J = 54.2 Hz, 1H), 4.60 (s, 2H), 4.30 (s, 2H), 3.64 (t, J =5.9 Hz, 2H), 3.29 (t, J = 5.9 Hz, 2H), 3.20 (s, 3H), 2.44 (s, 1H).

[0526] 3-Methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one-7,7-d 2 (Compound 12). 3-Methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5... H )-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one (41 mg, 0.12 mmol) was dissolved in THF (780 μL) and deuterium oxide (410 μL). Next, sodium deuterium oxide (40 wt% in D2O) was added, and the resulting mixture was stirred at 35°C for 16 h. The mixture was extracted with DCM (3x), and the combined extracts were passed through a phase separator and concentrated. The crude material was subjected a second reaction under the same conditions as above. After 16 h, the reaction mixture was extracted with DCM (3x), and the combined extracts were passed through a phase separator and concentrated. Purification was performed using silica gel normal-phase chromatography (0%–80% EtOAc / DCM, then 0%–1% MeOH / DCM) to obtain the title compound. The material was further purified using RP-HPLC (5%–55% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3, followed by extraction with 3:1 chloroform / IPA (3:1) (3x). The combined organic compounds were passed through a phase separator, and the solvent was concentrated to give the title compound. ES-MS [M+1] + : 351 (HRMS determination shows approximately 98% deuterium doping); 1 H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 7.98 (s, 1H), 7.91 (s, 1H), 5.96 (s, 1H), 4.71 (s, 2H), 3.68 (t, J = 5.8 Hz, 2H), 3.49 (t, J = 5.6 Hz, 2H), 2.44 (d, J = 0.8 Hz, 3H).

[0527] 3-Methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-base)-8,9,10,10 a -Tetrahydropyridino[2',3':3,4]pyrrolo[1,2- a ]Pyrazine-5(7 H)-ketone (compound 6). 5-methyl-2-(pyrazin-2-yl)-6-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5-methyl)-ketone (compound 6)-ketone was added to an autoclave reactor in ethanol (5 mL). H The reaction mixture consisted of methyl nicotinic acid (40 mg, 0.09 mmol), palladium supported on activated carbon (19.8 mg, 0.02 mmol), and platinum(IV) oxide (2.1 mg, 0.01 mmol). The reaction was stirred at 52 psi under hydrogen while being heated to 60°C for 20 h. The mixture was then cooled to ambient temperature and subjected to Celite... ® Filter and wash with EtOAc. Concentrate the organic matter and dissolve the crude residue in DMSO (2 mL) and purify using RP-HPLC (5%–50% ACN / 0.05% aqueous NH4OH). Concentrate the fraction containing the desired product to give the title compound. ES-MS [M+1] + : 404.

[0528] 3-Methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -cyclopentadiene[ b ]Pyridin-5-one (compound 50). 3-bromo-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -cyclopentadiene[ b Pyridin-5-one (19 mg, 0.05 mmol), cesium carbonate (45 mg, 0.14 mmol), trimethylboroxane (50% wt in THF) (35 µL, 0.04 mmol), Pd(dppf)Cl2 (7.0 mg, 0.009 mmol), and 1,4-dioxane (0.5 mL) were placed in vials. The mixture was evacuated and purged with nitrogen and stirred at 80°C for 18 h. The reaction mixture was diluted with EtOAc and purified by Celite. ® Filter and concentrate. Dissolve the crude residue in DMSO (1.5 mL) and purify using reversed-phase chromatography (10%–50% MeCN / 0.1% aqueous TFA). Alkalinize the fraction containing the desired product with saturated NaHCO3 (aq) and extract with 3:1 chloroform / IPA (3x). Pass the combined organics through a hydrophobic phase separator and concentrate the solvent to give the title compound (4.3 mg). 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.73 (s, 2H), 4.70 (s, 2H), 3.72 (t, J = 5.9 Hz, 2H), 3.29 (t, J = 6.0 Hz, 2H),3.12 – 3.05 (m, 2H), 2.75 – 2.68 (m, 2H), 2.39 (d, J = 0.9 Hz, 3H). [M+1] + :348.2.

[0529] ( S )-6-(1-methoxypropane-2-yl)-3-methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound 51). ( S )-3-bromo-6-(1-methoxypropane-2-yl)-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one (26 mg, 0.05 mmol), cesium carbonate (52 mg, 0.16 mmol), trimethylboroxane (50% wt in THF) (0.04 mL, 0.16 mmol), Pd(dppf)Cl2 (8.0 mg, 0.01 mmol), and 1,4-dioxane (0.5 mL) were placed in vials. The mixture was evacuated and purged with nitrogen and stirred at 80°C for 18 h. The reaction mixture was diluted with EtOAc and purified by Celite. ® Filter and concentrate. Purify the crude residue using reversed-phase HPLC (20%–60% MeCN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organic compounds were passed through a hydrophobic phase separator, and the solvent was concentrated to give the title compound (8.5 mg). ES-MS [M+1] - :421.4.

[0530] ( R)-6-(1-methoxypropane-2-yl)-3-methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one (compound 52). Prepared in the same manner as compound 51. ES-MS [M+1] + : 421.4.

[0531] 3-Chloro-6-methyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one (compound 55). Prepared in a similar manner to intermediate A to give the title compound. ES-MS [M+1] + : 383; 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.00 (s, 1H), 7.71 (s, 1H), 4.72 (s, 2H), 4.30 (s, 2H), 3.89 (t, J = 5.8 Hz, 2H), 3.31 (t, J = 5.9Hz, 2H), 3.19 (s, 3H).

[0532] 2-(3-((3-fluoropyridin-4-yl)amino)-7,8-dihydro-1,6-naphthyl-6(5-) H )-base-5,5,7,7- d 4)-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound A2). To 2-chloro-3-methyl-6,7-dihydropyrrolo[3,4- b Pyridin-5-one (15 mg, 0.08 mmol) and N , N - Diisopropylethylamine (0.07 mL, 0.41 mmol) was added to a solution of DMSO (0.8 mL). N -(3-Fluoropyridin-4-yl)-5,6,7,8-Tetrahydro-1,6-Naphthidine-5,5,7,7- d4-3-amine (25 mg, 0.1 mmol). The reaction was heated at 120°C for 18 h. The reaction was purified by reversed-phase HPLC (5%–45% MeCN / water / 0.05% NH4OH) to give the title compound (3.5 mg). 1 H NMR (400 MHz, CDCl3) δ 8.41 (d, J =2.6 Hz, 1H), 8.32 (d, J = 3.0 Hz, 1H), 8.13 (d, J = 5.6 Hz, 1H), 7.86 (s, 1H), 7.40 (d, J = 2.6 Hz, 1H), 6.96 (dd, J = 7.4, 5.5 Hz, 1H), 6.21 (d, J = 5.1 Hz, 2H), 4.38 (s, 2H), 3.21 (s, 2H), 2.44 (s, 3H); ES-MS [M+1] + : 395.5.

[0533] 3-Methyl-2-(3-((3-methylpyridin-4-yl)amino)-7,8-dihydro-1,6-naphthidine-6(5 H )-base-5,5,7,7- d 4)-6,7-dihydro-5 H -pyrrole[3,4- b ]Pyridin-5-one (compound A3). To 2-chloro-3-methyl-6,7-dihydropyrrolo[3,4- b Pyridin-5-one (15 mg, 0.08 mmol) and N , N - Diisopropylethylamine (0.07 mL, 0.41 mmol) was added to a solution of DMSO (0.8 mL). N -(3-methylpyridin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthidine-5,5,7,7- d 4-3-amine (24 mg, 0.1 mmol). The reaction was heated at 120°C for 18 h. The reaction was purified by reversed-phase HPLC (5%–45% MeCN / water / 0.05% NH4OH) to give the title compound (3.7 mg). 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J=2.6 Hz, 1H), 8.25 (s, 1H), 8.18 (d, J = 5.7 Hz, 1H), 7.85 (s, 1H), 7.38 (d, J =2.6 Hz, 1H), 6.85 (d, J ES-MS [M+1] + : 391.5.

[0534] 2-(3-((2-fluorophenyl)amino)-7,8-dihydro-1,6-naphthidine-6-(5-) H )-base-5,5,7,7- d 4)-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound A6). To 2-chloro-3-methyl-6,7-dihydropyrrolo[3,4- b Pyridin-5-one (15 mg, 0.08 mmol) and N , N - Diisopropylethylamine (0.07 mL, 0.41 mmol) was added to a solution of DMSO (0.8 mL). N -(2-Fluorophenyl)-5,6,7,8-Tetrahydro-1,6-Naphthidine-5,5,7,7- d 4-3-amine (20 mg, 0.08 mmol). The reaction was heated at 120°C for 18 h. The reaction was purified by reversed-phase HPLC (5%–45% MeCN / water / 0.05% NH4OH) to give the title compound (8.3 mg). ES-MS [M+1] + : 394.1; 1 H NMR (400 MHz, CDCl3)δ 8.32 (d, J = 2.6 Hz, 1H), 7.83 (d, J= 1.0 Hz, 1H), 7.26 – 7.20 (m, 2H), 7.16 –7.00 (m, 2H), 6.97 – 6.88 (m, 1H), 6.56 (s, 1H), 6.06 (s, 1H), 4.36 (s, 2H), 3.18 (s, 2H), 2.41 (s, 3H).

[0535] 3-Methyl-2-(3-((3-methylpyridin-4-yl)amino)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound A7). To 2-chloro-3-methyl-6,7-dihydropyrrolo[3,4- b Pyridin-5-one (15 mg, 0.08 mmol) and N , N - Diisopropylethylamine (0.07 mL, 0.41 mmol) was added to a solution of DMSO (0.8 mL). N -(3-methylpyridin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthidine-3-amine (20 mg, 0.08 mmol). The reaction was heated at 120°C for 18 h. The reaction was purified by reversed-phase HPLC (5%–35% MeCN / water / 0.05% NH4OH) to give the title compound (3.3 mg). 1 H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 2.5 Hz, 1H),8.25 (s, 1H), 8.19 (d, J = 5.7 Hz, 1H), 7.86 (d, J = 0.9 Hz, 1H), 7.38 (d, J = 2.5Hz, 1H), 6.85 (d, J = 5.7 Hz, 1H), 6.09 (s, 1H), 5.75 (s, 1H), 4.56 (s, 2H), 4.38 (s, 2H), 3.62 (t, J = 5.9 Hz, 2H), 3.22 (t, J = 5.9 Hz, 2H), 2.46 – 2.42 (m,3H), 2.27 (s, 3H); ES-MS [M+1]+ : 387.4.

[0536] 2-(3-((3-fluoropyridin-4-yl)amino)-7,8-dihydro-1,6-naphthyl-6(5-) H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound A4). To 2-chloro-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Add pyridin-5-one (15 mg, 0.08 mmol) to a solution of DMSO (0.5 mL). N -(3-Fluoropyridin-4-yl)-5,6,7,8-tetrahydro-1,6-naphthyl-3-amine dihydrochloride (39 mg, 0.12 mmol) and N , N -Diisopropylethylamine (86 μL, 0.49 mmol). The mixture was heated to 120°C for 40 h and then cooled to ambient temperature. Purification by RP-HPLC (5%–45% ACN / 0.05% aqueous NH4OH) yielded the title compound, which was confirmed by LC-MS to still contain impurities. The material was subjected to a second RP-HPLC purification (5%–35% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and then extracted with 3:1 chloroform / IPA (3:1) (3x). The combined organics were passed through a phase separator, and the solvent was concentrated to obtain the title compound. ES-MS [M+1] + : 391; 1 H NMR (400 MHz, CDCl3) δ8.41 (d, J = 2.5 Hz, 1H), 8.32 (d, J = 3.1 Hz, 1H), 8.13 (d, J = 5.5 Hz, 1H), 7.87(d, J = 0.9 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 6.96 (dd, J = 7.4, 5.5 Hz, 1H), 6.16(d, J = 3.2 Hz, 1H), 5.98 (s, 1H), 4.58 (s, 2H), 4.38 (s, 2H), 3.63 (t,J = 5.9Hz, 2H), 3.23 (t, J = 5.9 Hz, 2H), 2.44 (d, J = 0.9 Hz, 3H).

[0537] 2-(3-((3-fluoro-2-methylpyridin-4-yl)amino)-7,8-dihydro-1,6-naphthidine-6(5 H )-3,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound A8). Add 2-(3-bromo-7,8-dihydro-1,6-naphthyl-6(5-dioxane) in 1,4-dioxane (0.5 mL) (degassed) to a vial. H )-3,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one (15 mg, 0.04 mmol), 3-fluoro-2-methylpyridin-4-amine (7.6 mg, 0.06 mmol), cesium carbonate (40 mg, 0.12 mmol), Xantphos (3.5 mg, 0.01 mmol), and tris(dibenzylacetone)palladium(0) (3.7 mg, 0.004 mmol). The mixture was heated to 80°C for 16 h under a nitrogen atmosphere. The mixture was then cooled to ambient temperature and passed through a Celite tube. ® The sample was filtered through a pad, thoroughly washed with MeOH / DCM, and concentrated. The residue was dissolved in DMSO (2 mL) and purified by RP-HPLC (5%–40% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and then extracted with 3:1 chloroform / IPA (3x). The combined organic compounds were passed through a phase separator, and the solvent was concentrated to give the title compound. ES-MS [M+1] + : 419.

[0538] 6-Methyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-Ketone (compound B1). Prepared in a similar manner to intermediate D to give the title compound. ES-MS [M+1] + : 351.

[0539] 7-(3-(3,5-dimethylisoxazol-4-yl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-6-methyl-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-ketone (compound B2). Add cesium carbonate (82 mg, 0.25 mmol) and 7-(3-bromo-7,8-dihydro-1,6-naphthidine-6(5-)-ketone to the vial. H )-yl)-6-methyl-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H A mixture of 1,4-dioxane (30 mg, 0.08 mmol), 3,5-dimethylisoxazole-4-boronate pinacol ester (37 mg, 0.17 mmol), and Pd(dppf)Cl2 (6 mg, 0.01 mmol) in 1,4-dioxane (460 µL) / water (93 µL) (5:1) was prepared. The mixture was stirred at 80°C for 18 hours. Additional 3,5-dimethylisoxazole-4-boronate pinacol ester (37 mg, 0.17 mmol) was added, and the mixture was reheated to 80°C for 2.5 hours. After cooling to room temperature, the mixture was subjected to Celite... ® The mixture was filtered and washed with chloroform / IPA (3:1). The organic matter was then washed with saturated NaHCO3 and passed through a phase separator, followed by concentration. The residue was purified using RP-HPLC (5%–40% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organic matter was passed through a phase separator, and the solvent was concentrated to give the title compound. ES-MS [M+1] + : 378; 1 H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.39(d, J = 2.2 Hz, 1H), 7.71 (q, J = 1.2 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 4.79 (s,2H), 3.86 (t, J = 5.9 Hz, 2H), 3.26 (t, J = 5.9 Hz, 2H), 2.43 (s, 3H), 2.34 (d, J=1.3 Hz, 3H), 2.28 (s, 3H).

[0540] 7-(3-(3,5-dimethylisoxazol-4-yl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-ketone (compound B10). Add cesium carbonate (40 mg, 0.12 mmol) and 7-(3-bromo-7,8-dihydro-5-ethylhexane) to a vial. H -1,6-naphthid-6-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3- a A mixture of pyrimidin-3-one (15 mg, 0.04 mmol), 3,5-dimethylisoxazol-4-boronic acid (14 mg, 0.1 mmol), and Pd(dppf)Cl2 (3.0 mg, 0.004 mmol) in 1,4-dioxane (0.5 mL) / water (0.1 mL) (5:1). The mixture was stirred at 80°C for 16 hr and then subjected to Celite. ® Filter, wash with EtOAc, and concentrate. Purify the crude residue using RP-HPLC (5%–50% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated NaHCO3 and then extracted with 3:1 chloroform / IPA (3x). The combined organic compounds were passed through a phase separator, and the solvent was concentrated to provide the title compound. ES-MS [M+1] + :392.3. 1 H NMR (400 MHz, DMSO) δ 8.43 (d, J = 2.2 Hz, 1H), 7.99 (d, J = 1.4Hz, 1H), 7.78 (d, J = 2.2 Hz, 1H), 4.72 (s, 2H), 3.83 (t, J = 5.8 Hz, 2H), 3.41(s, 3H), 3.12 (t, J = 5.8 Hz, 2H), 2.43 (s, 3H), 2.29 (d, J = 1.2 Hz, 3H), 2.25 (s, 3H).

[0541] 7-(3-(4-methoxy-2,5-dimethylphenyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-Ketone (compound B11). Prepared in a similar manner to compound B10 to give the title compound. ES-MS [M+1] + 430.5; 1 H NMR (400 MHz, DMSO) δ 8.34 (d, J = 2.2Hz, 1H), 7.98 (d, J = 1.3 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.01 (s, 1H), 6.89(s, 1H), 4.71 (s, 2H), 3.88 – 3.82 (m, 2H), 3.82 (s, 3H), 3.40 (s, 3H), 3.11(t, J = 5.8 Hz, 2H), 2.29 (d, J = 1.3 Hz, 3H), 2.24 (s, 3H), 2.14 (s, 3H).

[0542] 7-(3-(2,4-dimethylphenyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-6-methyl-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-Ketone (compound B12). Prepared in a similar manner to compound B2 to give the title compound. ES-MS [M+1] + 387.2; 1 H NMR (400 MHz, DMSO) δ 8.35 (d, J = 2.2 Hz, 1H), 7.94(d, J = 1.3 Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 12.3, 4.7 Hz, 3H),4.70 (s, 2H), 3.82 (t, J = 5.8 Hz, 3H), 3.12 (t, J= 6.2 Hz, 3H), 2.32 (s, 3H), 2.28 (d, J = 1.2 Hz, 3H), 2.23 (s, 3H).

[0543] 7-(3-(4-methoxy-2-methylphenyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-6-methyl-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-Ketone (compound B13). Prepared in a similar manner to compound B2 to give the title compound. ES-MS [M+1] + 417.3; 1 H NMR (400 MHz, DMSO) δ 8.33 (d, J = 2.2 Hz, 1H), 7.94(d, J = 1.5 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.01 (s, 1H), 6.89 (s, 1H), 4.69 (s, 2H), 3.86 – 3.79 (m, 5H), 3.11 (t, J = 5.9 Hz, 2H), 2.28 (d, J = 1.3 Hz, 3H), 2.24 (s, 3H), 2.14 (s, 3H).

[0544] 2,6-Dimethyl-7-[3-(trifluoromethyl)-7,8-dihydro-5- H -1,6-naphthid-6-yl]-[1,2,4]triazolo[4,3- a Pyrimidine-3-one (compound B24). To 6-methyl-7-[3-(trifluoromethyl)-7,8-dihydro-5 H -1,6-Naphthid-6-yl]-2 H -[1,2,4]triazolo[4,3- aPyrimidine-3-one (15 mg, 0.043 mmol) was dissolved in DMF (0.7 mL) with potassium carbonate (12 mg, 0.086 mmol), followed by methyl iodide (3.9 µL, 0.064 mmol). The mixture was heated to 60°C for 2.5 h. After cooling to ambient temperature, the reaction mixture was further dissolved in DMF (1 mL), filtered, and purified by RP-HPLC (10%–60% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organics were passed through a hydrophobic phase separator, and the solvent was concentrated to give the title compound. ES-MS [M+1] + 365; 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H),7.70 (d, J = 1.3 Hz, 2H), 4.76 (s, 2H), 3.83 (t, J = 5.9 Hz, 2H), 3.58 (s, 3H), 3.27 (t, J = 5.9 Hz, 2H), 2.31 (d, J = 1.2 Hz, 3H).

[0545] 2-Ethyl-6-methyl-7-[3-(trifluoromethyl)-7,8-dihydro-5- H -1,6-naphthid-6-yl]-[1,2,4]triazolo[4,3- a Pyrimidine-3-one (compound B25). To 6-methyl-7-[3-(trifluoromethyl)-7,8-dihydro-5 H -1,6-Naphthid-6-yl]-2 H -[1,2,4]triazolo[4,3- aPyrimidine-3-one (15 mg, 0.043 mmol) was dissolved in DMF (0.7 mL) with potassium carbonate (12 mg, 0.086 mmol), followed by the addition of bromoethane (4.8 µL, 0.064 mmol). The mixture was heated to 60°C for 2.5 h. After cooling to ambient temperature, the reaction mixture was further dissolved in DMF (1 mL), filtered, and purified by RP-HPLC (10%–65% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organics were passed through a hydrophobic phase separator, and the solvent was concentrated to give the title compound. ES-MS [M+1] + 379; 1 H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H),8.00 (d, J = 1.3 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H), 4.87 (s, 2H), 4.12 (q, J = 7.2Hz, 2H), 3.99 (t, J = 5.9 Hz, 2H), 3.32 (t, J = 6.0 Hz, 2H), 2.40 (s, 3H), 1.46(t, J = 7.2 Hz, 3H).

[0546] 5,6-Dimethyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-Ketone (compound B26). Prepared in a similar manner to intermediate D, to give the title compound. ES-MS [M+1]+: 365; 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.51 (s, 1H), 7.70 (s, 1H), 4.66 (s, 2H), 3.67 (t, J = 5.9 Hz, 2H), 3.28 (t, J = 6.0 Hz, 2H), 2.81 (d, J = 1.0 Hz, 3H), 2.17 (d, J = 1.0 Hz, 3H).

[0547] 5-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-2,6,7,8-tetrahydro-1 H -cyclopentadiene[ e [1,2,4]triazolo[4,3- a Pyrimidin-1-one (compound B27). Prepared in a similar manner to intermediate D, to give the title compound. ES-MS [M+1]+: 377; 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.37 (s, 1H), 7.71 (s, 1H), 4.99 (s, 2H), 4.06 (t, J = 5.9 Hz, 2H), 3.38 (t, J = 7.8Hz, 2H), 3.22 (t, J = 6.0 Hz, 2H), 3.04 (t, J = 7.3 Hz, 2H), 2.25 (p, J = 7.7 Hz, 2H).

[0548] 1-[[6-methyl-3-oxo-7-[3-(trifluoromethyl)-7,8-dihydro-5- H -1,6-naphthid-6-yl]-[1,2,4]triazolo[4,3- a [Pyrimidin-2-yl]methyl]cyclopropane-1-carboxynitrile (compound B47). To 6-methyl-7-[3-(trifluoromethyl)-7,8-dihydro-5 H -1,6-Naphthid-6-yl]-2 H -[1,2,4]triazolo[4,3- aPyrimidine-3-one (13 mg, 0.037 mmol) was dissolved in DMF (0.5 mL) with potassium carbonate (10.4 mg, 0.074 mmol), followed by the addition of 1-(bromomethyl)cyclopropane-1-carboxynitrile (5.6 µL, 0.056 mmol). The mixture was heated to 60°C for 2.5 h. After cooling to ambient temperature, the reaction mixture was further dissolved in DMF (1 mL), filtered, and purified by RP-HPLC (20%–70% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organics were passed through a hydrophobic phase separator, and the solvent was concentrated to give the title compound. ES-MS [M+1] + :430; 1 H NMR (400 MHz, MeOD) δ 8.70 (d, J = 1.2 Hz, 1H), 8.06 (d, J = 1.0 Hz, 1H), 7.85 (q, J = 1.2 Hz, 1H), 4.86 (s, 2H), 4.00 (s, 2H), 3.97 (t, J = 5.9 Hz, 2H), 3.27 (t, J = 6.0 Hz, 2H), 2.38 (d, J = 1.3 Hz, 3H), 1.34 – 1.32 (m, 2H), 1.31 –1.28 (m, 2H).

[0549] 2,5,6-Trimethyl-7-[3-(trifluoromethyl)-7,8-dihydro-5 H -1,6-naphthid-6-yl]-[1,2,4]triazolo[4,3- a ]Pyrimidin-3-one (compound B53). To 5,6-dimethyl-7-[3-(trifluoromethyl)-7,8-dihydro-5 H -1,6-Naphthid-6-yl]-2 H -[1,2,4]triazolo[4,3- aPyrimidine-3-one (13 mg, 0.036 mmol) was dissolved in DMF (0.7 mL) with potassium carbonate (10 mg, 0.071 mmol), followed by methyl iodide (3.5 µL, 0.054 mmol). The mixture was heated to 60°C for 18 hours. After cooling to ambient temperature, the reaction mixture was further dissolved in DMF (1 mL), filtered, and purified by RP-HPLC (15%–65% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organics were passed through a hydrophobic phase separator, and the solvent was concentrated to give the title compound. ES-MS [M+1] + 379; 1 H NMR (400 MHz, CDCl3) δ 8.71 (s,1H), 7.68 (s, 1H), 4.64 (s, 2H), 3.66 (t, J = 5.9 Hz, 2H), 3.55 (s, 3H), 3.26(t, J = 5.9 Hz, 2H), 2.82 (d, J = 0.9 Hz, 3H), 2.16 (d, J = 1.0 Hz, 3H).

[0550] 5-Chloro-6-methyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-Ketone (compound B55). Triphosgene (8.3 mg, 0.03 mmol) was added to a solution of 6-(6-chloro-2-hydrazino-5-methylpyrimidin-4-yl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthidine (10 mg, 0.03 mmol) in 1,4-dioxane (0.2 mL) at 25°C. After 2 h, the reaction mixture was concentrated, and the crude residue was purified by reversed-phase chromatography (20%–50% MeCN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated NaHCO3 and then extracted with 3:1 chloroform / IPA (3x). The combined organics were passed through a hydrophobic phase separator, and the solvent was concentrated to give the title compound (4 mg). ES-MS [M+1] + : 385.1 / 387.1.

[0551] 5-Chloro-2,6-dimethyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-ketone (compound B56). At room temperature, to 5-chloro-6-methyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H Iodimethane (4 µL, 0.06 mmol) was added to a solution of 15 mg (0.04 mmol) and potassium carbonate (11 mg, 0.08 mmol) in DMF (0.5 mL), and the mixture was stirred at 60°C for 18 h. The mixture was further dissolved in DMF (1 mL), filtered, and purified by reversed-phase chromatography (30%–60% MeCN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organics were passed through a hydrophobic phase separator and concentrated to give the title compound (9 mg). 1 H NMR (400 MHz, DMSO) δ 8.78 (s, 1H), 8.17 (dd, J = 2.4, 1.0 Hz, 1H), 4.68 (s, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.38 (s, 3H), 3.17 (t, J = 5.8 Hz, 2H), 2.23 (s, 3H). ES-MS [M+1] + : 399.3 / 401.2.

[0552] 2-(cyclopropylmethyl)-6-methyl-7-[3-(trifluoromethyl)-7,8-dihydro-5- H -1,6-naphthid-6-yl]-[1,2,4]triazolo[4,3- a ]Pyrimidin-3-one (compound B74). To 6-methyl-7-[3-(trifluoromethyl)-7,8-dihydro-5 H -1,6-Naphthid-6-yl]-2 H -[1,2,4]triazolo[4,3- aPyrimidine-3-one (13 mg, 0.037 mmol) was dissolved in DMF (0.5 mL) with potassium carbonate (10.4 mg, 0.074 mmol), followed by (bromomethyl)cyclopropane (5.4 µL, 0.056 mmol). The mixture was heated to 60°C for 18 hours. After cooling to ambient temperature, the reaction mixture was further dissolved in DMF (1 mL), filtered, and purified by RP-HPLC (20%–75% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organics were passed through a hydrophobic phase separator and concentrated to give the title compound. ES-MS [M+1] + : 405; 1 H NMR (400 MHz, CDCl3) δ 8.73(d, J = 2.2 Hz, 1H), 7.71 (q, J = 1.2 Hz, 1H), 7.69 (s, 1H), 4.77 (s, 2H), 3.82(t, J = 5.9 Hz, 2H), 3.78 (d, J = 7.1 Hz, 2H), 3.27 (t, J = 5.9 Hz, 2H), 2.31 (d, J =1.3 Hz, 3H), 1.37 – 1.26 (m, 1H), 0.61 – 0.50 (m, 2H), 0.42 (dt, J = 6.2, 4.6Hz, 2H).

[0553] 2-(cyclopropylmethyl)-5,6-dimethyl-7-[3-(trifluoromethyl)-7,8-dihydro-5- H -1,6-naphthid-6-yl]-[1,2,4]triazolo[4,3- a ]Pyrimidin-3-one (compound B80). To 5,6-dimethyl-7-[3-(trifluoromethyl)-7,8-dihydro-5 H -1,6-Naphthid-6-yl]-2 H -[1,2,4]triazolo[4,3- aPyrimidine-3-one (13 mg, 0.036 mmol) was dissolved in DMF (0.5 mL) with potassium carbonate (10 mg, 0.071 mmol), followed by (bromomethyl)cyclopropane (5.2 µL, 0.054 mmol). The mixture was heated to 60°C for 5 hours. After cooling to ambient temperature, the reaction mixture was further dissolved in DMF (1.0 mL), filtered, and purified by RP-HPLC (20%–80% ACN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organics were passed through a hydrophobic phase separator, and the solvent was concentrated to give the title compound. ES-MS [M+1] + : 419; 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.67 (s, 1H), 4.65 (s, 2H), 3.74 (d, J = 7.1 Hz, 2H), 3.65 (t, J = 5.9 Hz, 2H), 3.27 (t, J = 5.9 Hz, 2H), 2.82 (d, J = 0.9 Hz, 3H), 2.16(d, J = 1.0 Hz, 3H), 1.37 – 1.23 (m, 1H), 0.61 – 0.50 (m, 2H), 0.46 – 0.38 (m, 2H).

[0554] 5-Methoxy-2,6-dimethyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-ketone (compound B85). At 0°C, 5-chloro-2,6-dimethyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5-)-ketone was added to a solution of sodium methoxide (60 µL, 0.03 mmol) in methanol (0.20 mL). H )-yl)-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H)-Ketone (6 mg, 0.02 mmol). The reaction mixture was removed by ice bath and concentrated after 30 min at room temperature. The residue was purified by reversed-phase chromatography (5%–40% MeCN / 0.05% aqueous NH4OH). The fraction containing the desired product was concentrated to give impure products. The impure products were further purified by reversed-phase chromatography (10%–40% MeCN / 0.1% aqueous TFA). The fraction containing the desired product was alkalized with saturated NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organics were passed through a hydrophobic phase separator and the solvent was concentrated to give the title compound (5 mg). 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.69 (s, 1H), 4.70 (s, 2H), 4.14 (s, 3H), 3.75 (t, J = 5.9 Hz, 2H), 3.54 (s, 3H), 3.26 (t, J =5.9 Hz, 2H), 2.17 (s, 3H). ES-MS [M+1] + : 395.3.

[0555] 5-Cyclopropyl-6-methyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-ketone (compound B93). Prepared in a similar manner to intermediate D, to give the title compound. ES-MS [M+1]+: 391; 1 H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.38 (s, 1H), 7.69 (s, 1H), 4.67 (s, 2H), 3.68 (t, J = 5.9 Hz, 2H), 3.26 (t, J = 5.9 Hz, 2H), 2.29 (d, J = 1.3 Hz, 3H), 2.27 – 2.15 (m, 1H), 1.39 – 1.28 (m, 2H), 0.89 (q, J =5.8 Hz, 2H).

[0556] 5-Cyclopropyl-2,6-dimethyl-7-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-yl)-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-ketone (compound B94). Prepared in a similar manner to intermediate E, to give the title compound. ES-MS [M+1]+: 405; 1 H NMR (400 MHz, CDCl3) δ 8.71 (dd, J = 2.1, 0.8 Hz, 1H), 7.68 (dd, J = 2.4, 1.0 Hz, 1H), 4.65 (s, 2H), 3.67 (t, J = 5.9 Hz, 2H), 3.55(s, 3H), 3.25 (t, J = 5.9 Hz, 2H), 2.28 (d, J = 1.3 Hz, 3H), 2.24 – 2.15 (m, 1H), 1.40 – 1.28 (m, 2H), 0.95 – 0.83 (m, 2H).

[0557] 2,5,6-Trimethyl-7-[3-(oxecyclobutane-3-yl)-7,8-dihydro-5-yl] H -1,6-naphthid-6-yl]-[1,2,4]triazolo[4,3- a ]Pyrimidin-3-one (compound B140) and 7-(7,8-dihydro-5 H -1,6-naphthid-6-yl)-2,5,6-trimethyl-[1,2,4]triazolo[4,3- a Pyrimidine-3-one (compound B141). To 7-(3-bromo-7,8-dihydro-5- H -1,6-naphthid-6-yl)-2,5,6-trimethyl-[1,2,4]triazolo[4,3- a[Pyrimidin-3-one (30 mg, 0.077 mmol)] was added to a solution of 3-bromooxetane (19.2 µL, 0.231 mmol), tris(trimethylsilyl)silane (35.7 µL, 0.116 mmol), lithium hydroxide (5.5 mg, 0.231 mmol), and (Ir[dF(CF3)ppy]2(dtbpy))PF6 (4.3 mg, 0.0039 mmol) in DME (1.0 mL). Nitrogen was bubbled through the reaction mixture for 10 min, and then [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine]nickel(II) dichloride (1.5 mg, 0.0039 mmol) was added. Nitrogen was bubbled through the reaction mixture again for 5 min, the mixture was sonicated under an inert atmosphere, sealed with plastic wrap, and stirred at room temperature under a blue LED. After 18 hours, the ratio of compounds B140 to B141 was observed to be 1:1 by LCMS. The reaction mixture was concentrated and purified by RP-HPLC (0%–50% ACN / 0.1% aqueous TFA). Fractions containing each desired product were alkalized with saturated aqueous NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organic layers were passed through a hydrophobic phase separator, and the solvent was concentrated to give the title compounds separately. [Reference: Zhang et al.] J. Am. Chem. Soc. [Journal of the American Chemical Society] 2016, 138 , 8084-8087].

[0558] Compound B140: ES-MS [M+1] + 367; 1 H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 2.2Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 5.11 (dd, J = 8.3, 6.1 Hz, 2H), 4.73 (t, J = 6.3Hz, 2H), 4.61 (s, 2H), 4.22 (tt, J = 8.3, 6.5 Hz, 1H), 3.65 (t, J = 5.9 Hz, 2H),3.54 (s, 3H), 3.19 (t, J = 5.9 Hz, 2H), 2.81 (d, J = 1.0 Hz, 3H), 2.16 (d, J = 1.0Hz, 3H); Compound B141: ES-MS [M+1] + : 311; 1 H NMR (400 MHz, CDCl3) δ 8.46 (dd, J =4.8, 1.6 Hz, 1H), 7.46 (dd, J = 7.7, 1.6 Hz, 1H), 7.15 (dd, J = 7.8, 4.8 Hz, 1H), 4.59 (s, 2H), 3.63 (t, J = 5.9 Hz, 2H), 3.54 (s, 3H), 3.21 (t, J = 5.9 Hz, 2H), 2.80 (d, J = 0.9 Hz, 3H), 2.16 (d, J = 1.0 Hz, 3H).

[0559] 3,4,6-Trimethyl-2-(3-(trifluoromethyl)-7,8-dihydro-1,6-naphthidine-6(5 H )-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one. Prepared in a manner similar to intermediate A. 1 H NMR (400 MHz, CDCl3) δ8.71 (dd, J = 2.2, 0.9 Hz, 1H), 7.70 (dd, J = 2.1, 1.0 Hz, 1H), 4.52 (s, 2H), 4.23 (s, 2H), 3.52 (t, J = 5.9 Hz, 2H), 3.27 (t, J = 5.9 Hz, 2H), 3.17 (s, 3H), 2.67 (s, 3H), 2.29 (s, 3H). ES-MS [M+1] + : 377.

[0560] 3,4-Dimethyl-2-(3-(t...

Claims

1. A compound having formula (I) or a pharmaceutically acceptable salt thereof, in: G 1 yes X 1 It is NR 5 O or CR 5A R 5B ; X 2 It is CR 6 Or N; R 1 and R 3 Each is independently hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Fluoroalkyl, –OC 1-4 Alkyl, or –OC 1-4 fluoroalkyl; R 2 It is G 2 –NR b R c C 1-6 Halogenated alkyl groups, halogens, cyano groups, NO2, C 1-6 Alkyl, C 2-6 alkenyl, –OR b –NR c C(O)R b –NR c SO2R a –N=S(O)(R a )2、–P(O)(R a )2、–C 1-3 Alkylene–G 2 –C 2-4 alkenyl–G 2 , or hydrogen; R a It is C independently each time it appears. 1-6 Alkyl, C 1-6 Haloalkyl, G 2 、or –C 1-3 Alkylene–G 2 ; Wherein, –N=S(O)(R a )2 or –P(O)(R a The two Rs in )2 a They are linked together to form a straight-chain alkylene chain, thus forming a 5- to 7-membered heterocycle; R b and R c Independently, it is hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, G 2 、or –C 1-3 Alkylene–G 2 ; G 2 Each time it appears, it is independently a 5- to 12-membered heteroaryl, 6- to 12-membered aryl, 4- to 12-membered heterocyclic, or 3- to 12-membered carbocyclic, wherein each of the heteroaryl and heterocyclic groups contains 1-4 heteroatoms independently selected from the group consisting of O, N, and S, and G 2 Selected arbitrarily from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, oxo, –OR x –N(R) x )2、–SR x –SO2R x –C(O)R x –C(O)OR x –C(O)N(R) x )2、–C 1-6 Alkylene – OR x –C 1-6 Alkylene–N(R) x )2、G 2a 、 and –C 1-3 Alkylene–G 2a The first substituent of the group is substituted, and optionally further independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and –OR x The group consists of 1-4 substituents; R x Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 cycloalkyl, –C 1-3 alkylene–C 3-6 cycloalkyl, phenyl, or –C 1-3 Alkylene-phenyl, wherein each cycloalkyl or phenyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of: halogen, C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; G 2a It is a phenyl group, a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, or a 3- to 8-membered carbocyclic group, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 2a Each time it appears, it is independently and optionally substituted by 1-5 substituents selected independently from the following group: halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, –C 1-6 Alkylene –OH, oxo, OH, –OC 1-4 Alkyl, –OC 1-4 Haloalkyl, C 3-4 cycloalkyl and –C 1-3 alkylene–C 3-4 cycloalkyl; R 4A and R 4B Independently, it is hydrogen and C 1-4 Alkyl, C 3-4 cycloalkyl, or –C 1-3 alkylene–OH; R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 fluoroalkyl, –C 1-6 Alkylene–R y –C 1-6 Fluoride-R y G 5 、or –C 1-3 Alkylene–G 5 ; R 5A and R 5B Independently, it is hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkyl, or –C 1-4 alkylene–OH; R y is –OR 5a 、–N(R 5a )2, –C(O)R 5a 、–C(O)OR 5a 、or –C(O)N(R 5a )2; R 5a Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 fluoroalkyl, G 5 、or –C 1-3 Alkylene–G 5 ; G 5 It is a phenyl group, a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, or a C-shaped group. 3-8 Cycloalkyl groups, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 5 Optionally substituted by 1-4 substituents independently selected from the group consisting of: halogen, cyano, C 1-4 Alkyl, C 1-2 Fluoroalkyl, –OC 1-4 Alkyl, OH, and oxo; Alternatively, R 4A and R 4B Together with the carbon attached to them, they form C 3-6 cycloalkyl; or R 4B and R 5 Together with the atoms to which they are attached, they form 5- to 7-membered heterocycles that optionally contain an additional heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur; R 6 It is hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 fluoroalkyl, C 2-4 alkenyl, –OR 6a –N(R) 6a )2、–C 1-3 Alkylene – OR 6a or C 3-6 cycloalkyl; R 6a Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or –C 1-3 alkylene–C 3-4 cycloalkyl; Alternatively, the two Rs 6a Together with the nitrogen to which they are attached, they form 4 to 8-membered heterocycles containing R 6a The attached nitrogen and optionally containing 1-2 additional heteroatoms, independently of O, N, or S, the heterocycle optionally being substituted by 1-4 substituents independently selected from the group consisting of: halogens, C 1-2 Alkyl and C 1-2 fluoroalkyl; R 7 It is C 1-4 Alkyl, hydrogen, halogen, cyano, C 1-4 fluoroalkyl, –OR 7a –C 1-3 Alkylene – OR 7a 、 or G 7 ; Alternatively, R 6 and R 7 Together with the atoms to which they are attached, they form a 5- to 7-membered heterocycle or a 5- to 7-membered carbon ring containing one heteroatom, wherein the heteroatom is independently selected from the group consisting of N, O, and S, and the heterocycle and carbon ring are optionally substituted by 1 to 4 substituents independently selected from the group consisting of: C 1-4 Alkyl, halogen, –OC 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl and C 1-2 Alkylene-C 3-4 cycloalkyl; R 7a It is hydrogen, C 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or –C 1-3 alkylene–C 3-4 cycloalkyl; G 7 It is a phenyl group, a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, or a C-shaped group. 3-6 Cycloalkyl groups, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 5 Optionally substituted by 1-4 substituents independently selected from the group consisting of: halogen, cyano, C 1-4 Alkyl, C 1-2 Fluoroalkyl, –OC 1-4 Alkyl, OH, and oxo; R 8 Each time it appears, it is independently halogen, C. 1-4 Alkyl, C 1-4 fluoroalkyl, or C 3-4 cycloalkyl; and n is 0, 1, 2, 3, or 4; Where R 6 R 6a R 7 R 7a and R 8 Each cycloalkyl group at the position is unsubstituted or independently selected from C10. 1-4 Alkyl and halogen substituents of 1-4.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Is it hydrogen or C? 1-4 alkyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 It is hydrogen.

4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, R 2 It is G 2 –NR b R c C 1-6 Haloalkyl, C 2-6 alkenyl, cyano, hydrogen, or –C 2-4 alkenyl–G 2 .

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 2 It is C 1-6 Halogenated alkyl groups.

6. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 2 It is G 2 .

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 5 to 12 heteroaryl group that is optionally substituted.

8. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 6 to 12 aryl group that is optionally substituted.

9. The compound of any one of claims 1-4 or 6, or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 4- to 12-membered heterocyclic group that is optionally substituted.

10. The compound of any one of claims 1-4 or 6, or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 3 to 12-membered carbon cyclogroup that is optionally substituted.

11. The compound of any one of claims 6-10, or a pharmaceutically acceptable salt thereof, wherein G 2 yes (a) Optionally substituted 5 to 12 heteroaryl groups, selected from the group consisting of: or (b) Optionally substituted 6- to 12-membered aryl groups, selected from the group consisting of: (c) Optionally substituted 4- to 12-membered heterocyclic groups, selected from the group consisting of: (d) Optionally substituted 3- to 12-membered carbocyclic groups, which are .

12. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein... R 2 Yes – NR b R c ; R b It is C 1-6 Alkyl, G 2 、or –C 1-3 Alkylene–G 2 ;and R c Is it hydrogen or C? 1-6 alkyl.

13. The compound of any one of claims 1-4 or 12, or a pharmaceutically acceptable salt thereof, wherein R b It is G 2 .

14. The compound of claim 12 or 13 or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 5 to 12 heteroaryl group that is optionally substituted.

15. The compound of claim 12 or 13 or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 6 to 12 aryl group that is optionally substituted.

16. The compound of any one of claims 1-4 or 12-15, or a pharmaceutically acceptable salt thereof, wherein R c It is hydrogen.

17. The compound of any one of claims 12-16 or a pharmaceutically acceptable salt thereof, wherein R 2 yes .

18. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein R 4A and R 4B It is hydrogen.

19. The compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen, C 1-6 Alkyl, C 1-6 fluoroalkyl, –C 1-6 Alkylene–R y G 5 、or –C 1-3 Alkylene–G 5 .

20. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein R 4B and R 5 Together with the atoms to which they are attached, they form 5 to 7-membered heterocycles.

21. The compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, wherein R 6 It is hydrogen, halogen, C 1-4 Alkyl, C 1-4 fluoroalkyl, –OR 6a or C 3-6 Cycloalkyl.

22. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, wherein R 7 It is C 1-4 Alkyl, halogen, cyano, or G 7 .

23. The compound of any one of claims 1-22 or a pharmaceutically acceptable salt thereof, wherein n is 0.

24. The compound of any one of claims 1-23 or a pharmaceutically acceptable salt thereof, wherein G 1 yes .

25. The compound of any one of claims 1-24 or a pharmaceutically acceptable salt thereof, wherein X 1 It is NR 5 .

26. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-18 or 21-24, wherein X 1 It is O.

27. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-18 or 21-24, wherein X 1 It is CR 5A R 5B .

28. The compound of any one of claims 1-27 or a pharmaceutically acceptable salt thereof, wherein X 2 It is CR 6 .

29. The compound of any one of claims 1-27 or a pharmaceutically acceptable salt thereof, wherein X 2 It is N.

30. The compound of any one of claims 1-23 or a pharmaceutically acceptable salt thereof, wherein G 1 yes .

31. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-20 or 23-30, wherein R 6 and R 7 Together with the atoms to which they are attached, they form optionally substituted 5- to 7-membered heterocycles or 5- to 7-membered carbon rings.

32. The compound of claim 1, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salt.

33. A pharmaceutical composition comprising the compound of any one of claims 1-32 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

34. The compound of any one of claims 1-32 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 33, for use in the treatment of neurological and / or mental disorders, wherein the disorder is selected from Alzheimer's disease, schizophrenia, sleep disorders, pain disorders, and cognitive impairment.

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