Pyrrolopyridine derivatives as positive allosteric modulators of muscarinic acetylcholine receptor M4

Abstract

The present invention relates to 6, 7-dihydrothiazolo [5, 4-c] pyridines substituted in the 5 position with 6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-5-one or furo [3, 4-b] pyridin-5 (7H)-one, are positive allosteric modulators of muscarinic acetylcholine receptor M4 (mAChR M4), and are useful in the treatment of neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction.

Description

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Application No. 63 / 496,806, filed April 18, 2023, and U.S. Provisional Application No. 63 / 610,184, 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 Science. [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: X 1 It is NR 5 O or CR 5A R 5B ; R 2 It is G 2 –NR 2a R 2b Halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, –OR 2a –NR 2a C(O)R 2b –C(O)OR 2a –C(O)NR 2a R 2b , or hydrogen; R 2a and R 2b Independently, it is hydrogen and C 1-6 Alkyl, C1-6 Haloalkyl, G 2 、or –C 1-3 Alkylene–G 2 ; G 2 Each time it appears, it is independently a 5- to 6-membered heteroaryl group containing 1-4 heteroatoms, a phenyl group, a 4- to 7-membered heterocyclic group containing 1-2 heteroatoms, or a 3- to 7-membered carbocyclic group, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 2 Optionally and independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 fluoroalkyl, 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 group consists of 1-5 substituents; R x Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, or –C 1-3 alkylene–C 3-6 cycloalkyl; G 2a It is C 3-6 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; or R 4A and R 4B Together with the carbon attached to them, they form C 3-6 cycloalkyl; 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 fluoroalkyl, 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, C 3-4 cycloalkyl, or –C 1-3 alkylene–C 3-4 cycloalkyl; G 5 It is a phenyl group, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, a 5- to 6-membered heteroaryl group containing 1-4 heteroatoms, or a C-type heterocyclic 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 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 3-4 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 6aThe attached nitrogen and optionally contain one additional heteroatom, which is O, N, or S, and the heterocycle is optionally 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, C 2-4 alkenyl, –OR 7a –C 1-3 Alkylene – OR 7a CO2R 7a COR 7a or C 3-6 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; 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 x G 2a R 6 R 6a R 7 R 7a and R 8 Each cycloalkyl group at the position is independently 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 rhodopsin-like structural features, 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 ed., 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 x It 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: AIBN is 2,2'-azobis(2-methylpropionitrile); aq is an aqueous solution; BINAP is 2,2′-bis(diphenylphosphine)-1,1′-binaphthyl; Boc stands for tert-butoxycarbonyl; 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; t-BuOH is tert-butanol; Celite ® It is diatomaceous earth; 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; EtOH is ethanol; h or hr represents hours; Hex is hexane; IPA stands for isopropanol; KOAc is potassium acetate; LAH stands for lithium aluminum hydride; Lawson's reagent is 2,4-bis(4-methoxyphenyl)-2,4-dithio-1,3,2,4-dithiodiphosphine heterocyclic butane; m CPBA is m-chloroperoxybenzoic acid; MeCN or ACN is acetonitrile; MeOH is methanol; min means minutes; NaOAc is sodium acetate; NaOMe is sodium methoxide; NBS is N - Bromosuccinimide; NCS is N -Chlorosuccinimide; 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); 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; TEA or Et3N is triethylamine; TFA stands for trifluoroacetic acid; THF stands for tetrahydrofuran; TMB stands for trimethylboroxane; TosCl is p-toluenesulfonyl chloride; and tosyl is a p-toluenesulfonyl group.

[0071] 2. Compounds In one aspect, the present invention provides a compound having formula (I), wherein R 2 R 4A R 4B R 6 R 7 R 8 X1 , 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, E3, E4, E4.1, etc.

[0075] E1. A compound having formula (I) or a pharmaceutically acceptable salt thereof, in: X 1 It is NR 5 O or CR 5A R 5B ; R 2 It is G 2 –NR 2a R 2b Halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, –OR 2a –NR 2a C(O)R 2b –C(O)OR 2a –C(O)NR 2a R 2b , or hydrogen; R 2a and R 2b Independently, it is hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, G 2 、or –C 1-3 Alkylene–G2 ; G 2 Each time it appears, it is independently a 5- to 6-membered heteroaryl group containing 1-4 heteroatoms, a phenyl group, a 4- to 7-membered heterocyclic group containing 1-2 heteroatoms, or a 3- to 7-membered carbocyclic group, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 2 Optionally and independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 fluoroalkyl, 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 group consists of 1-5 substituents; R x Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, or –C 1-3 alkylene–C 3-6 cycloalkyl; G 2a It is C 3-6 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; or R 4A and R 4B Together with the carbon attached to them, they form C 3-6 cycloalkyl; 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 5BIndependently, it is hydrogen, halogen, C 1-4 Alkyl, C 1-4 fluoroalkyl, 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, C 3-4 cycloalkyl, or –C 1-3 alkylene–C 3-4 cycloalkyl; G 5 It is a phenyl group, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, a 5- to 6-membered heteroaryl group containing 1-4 heteroatoms, or a C-type heterocyclic 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 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 3-4 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 contain one additional heteroatom, which is O, N, or S, and the heterocycle is optionally substituted by 1-4 substituents independently selected from the group consisting of: halogens, C1-2 Alkyl and C 1-2 fluoroalkyl; R 7 It is C 1-4 Alkyl, hydrogen, halogen, cyano, C 1-4 fluoroalkyl, C 2-4 alkenyl, –OR 7a –C 1-3 Alkylene – OR 7a CO2R 7a COR 7a or C 3-6 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; 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 x G 2a R 6 R 6a R 7 R 7a and R 8 Each cycloalkyl group at the position is independently 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 as described in E1 or a pharmaceutically acceptable salt thereof, wherein G 5 It is a phenyl group, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, a 5- to 6-membered heteroaryl group containing 1-4 heteroatoms, or a C-type heterocyclic 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.

[0077] E1.2. A compound as described in E1 or E1.1, or a pharmaceutically acceptable salt thereof, wherein X 1It is NR 5 Or O.

[0078] E2. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E1.2, wherein R 2 It is G 2 –NR 2a R 2b Halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, –OR 2a –C(O)OR 2a –C(O)NR 2a R 2b , or hydrogen.

[0079] E3. A compound as described in E2 or a pharmaceutically acceptable salt thereof, wherein R 2 It is G 2 .

[0080] E4. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E3, wherein G 2 It is a 3- to 7-membered carbon cyclogroup that is optionally substituted.

[0081] E4.1. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E4, wherein G 2 The ring system of the optionally substituted 3 to 7-membered carbon cyclic group is C 3-7 Cycloalkyl.

[0082] E4.2. The compound as described in E4.1 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the 3 to 7-membered carbon cyclic group that is optionally substituted is cyclopropyl or cyclobutyl.

[0083] E4.3. The compound or a pharmaceutically acceptable salt thereof as described in any one of E4-E4.2, wherein G 2 Optionally substituted by 1-4 substituents independently selected from the group consisting of: C 1-4 Alkyl groups and halogens.

[0084] E4.4. A compound as described in E4.3 or a pharmaceutically acceptable salt thereof, wherein G 2 Optionally, it may be substituted by 1-4 substituents selected independently from the group consisting of: methyl and fluorine.

[0085] E4.5. A compound as described in E4.4 or a pharmaceutically acceptable salt thereof, wherein G 2 yes , , , ,or .

[0086] E5. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E3, wherein G 2 It is a 5- to 6-membered heteroaryl group that is optionally substituted.

[0087] E5.1. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E3 or E5, wherein G 2 The ring system of the optionally substituted 5- to 6-membered heteroaryl group is a 5-membered heteroaryl group.

[0088] E5.2. The compound as described in E5 or E5.1 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted heteroaryl group contains 1-2 heteroatoms independently selected from the group consisting of N and S.

[0089] E5.3. The compound as described in E5.2 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted heteroaryl group is thienyl or pyrazolyl.

[0090] E5.4. A compound as described in E5.3 or a pharmaceutically acceptable salt thereof, wherein G 2 The ring system of the optionally substituted heteroaryl group is thiophene-2-yl or pyrazol-5-yl.

[0091] E5.5. The compound or a pharmaceutically acceptable salt thereof as described in any one of E5-E5.4, wherein G 2 Optionally substituted by 1-4 substituents independently selected from the group consisting of: C 1-4 Alkyl groups and halogens.

[0092] E5.6. A compound as described in E5.5 or a pharmaceutically acceptable salt thereof, wherein G 2 Optionally, it may be substituted by 1-4 substituents selected independently from the group consisting of: methyl and fluorine.

[0093] E5.7. A compound as described in E5.6 or a pharmaceutically acceptable salt thereof, wherein G 2 yes or .

[0094] E6. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E5.7, wherein G 2 yes , , , , , ,or .

[0095] E7. A compound as described in E2 or a pharmaceutically acceptable salt thereof, wherein R 2 Yes – NR 2a R 2b .

[0096] E8. A compound as described in E2 or a pharmaceutically acceptable salt thereof, wherein R 2 It is C 1-6 alkyl.

[0097] E8.1. A compound as described in E8 or a pharmaceutically acceptable salt thereof, wherein R 2 It is methyl or tert-butyl.

[0098] E9. A compound as described in E2 or a pharmaceutically acceptable salt thereof, wherein R 2 It is halogen.

[0099] E9.1. A compound as described in E9 or a pharmaceutically acceptable salt thereof, wherein R 2 It is chlorine.

[0100] E10. A compound as described in E2 or a pharmaceutically acceptable salt thereof, wherein R 2 It is hydrogen.

[0101] E11. A compound as described in E2 or a pharmaceutically acceptable salt thereof, wherein R 2 It is –C(O)OR 2a .

[0102] E12. A compound as described in E2 or a pharmaceutically acceptable salt thereof, wherein R 2 It is –C(O)NR 2a R 2b .

[0103] E13. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1, E1.1, E1.2, E2, E4.1-E4.4, E5.1-E5.6, E7, or E11-E12, wherein R 2a Is it hydrogen or C? 1-6 alkyl.

[0104] E13.1. A compound as described in E13 or a pharmaceutically acceptable salt thereof, wherein R 2a It is hydrogen.

[0105] E13.2. A compound as described in E13 or a pharmaceutically acceptable salt thereof, wherein R 2a It is C 1-4 alkyl.

[0106] E13.3. A compound as described in E13.2 or a pharmaceutically acceptable salt thereof, wherein R 2a It is an ethyl group.

[0107] E14. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1, E1.1, E1.2, E2, E4.1-E4.4, E5.1-E5.6, E7, or E12-E13.3, wherein R 2b It is hydrogen.

[0108] E15. The compound of any one of E1-E14 or a pharmaceutically acceptable salt thereof, wherein R 4A and R 4B It is hydrogen.

[0109] E15.1. A compound as described in E15 or a pharmaceutically acceptable salt thereof, wherein R 4A and R 4B The hydrogen at that location is deuterium ( 2 H).

[0110] E16. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E15.1, wherein X 1 It is NR 5 .

[0111] E17. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E16, wherein R 5 It is hydrogen, C 1-6 Alkyl, G 5 、or –C 1-3 Alkylene–G 5 .

[0112] E17.1. A compound as described in E17 or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen, C 1-6 Alkyl, or G 5 .

[0113] E17.2. A compound as described in E17.1 or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen.

[0114] E17.3. A compound as described in E17.1 or a pharmaceutically acceptable salt thereof, wherein R 5 It is C 1-6 alkyl.

[0115] E17.4. A compound as described in E17.3 or a pharmaceutically acceptable salt thereof, wherein R 5 It is C 1-3 alkyl.

[0116] E17.5. A compound as described in E17.4 or a pharmaceutically acceptable salt thereof, wherein R 5 It is a methyl group.

[0117] E17.6. A compound as described in E17.1 or a pharmaceutically acceptable salt thereof, wherein R 5 It is G 5 .

[0118] E17.7. A compound as described in E17 or a pharmaceutically acceptable salt thereof, wherein R 5 Yes –C 1-3 Alkylene–G 5 .

[0119] E17.8. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E17.1 or E17.6-E17.7, wherein G 5 C is arbitrarily replaced 3-6 Cycloalkyl.

[0120] E17.9. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E17.1 or E17.6-E17.8, wherein G 5 The C that can be arbitrarily replaced at this location 3-6 The cyclic system of cycloalkyl groups is cyclopropyl, cyclobutyl, or cyclopentyl.

[0121] E17.10. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E17.1 or E17.6-E17.9, wherein G 5 The C at that location 3-6 The cycloalkyl group is optionally substituted by one or two substituents independently selected from the group consisting of: halogen, cyano, and C. 1-4 alkyl.

[0122] E17.11. A compound as described in E17.10 or a pharmaceutically acceptable salt thereof, wherein G 5 The C at that location 3-6 The cycloalkyl group is optionally substituted by one or two substituents independently selected from the group consisting of fluorine, cyano, and methyl.

[0123] E17.12. A compound as described in E17.11 or a pharmaceutically acceptable salt thereof, wherein G 5 It is cyclopropyl or cyclopentyl.

[0124] E17.13. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E17.1 or E17.6-E17.7, wherein G 5 It is an optionally substituted phenyl group.

[0125] E17.14. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E17.1, E17.6-E17.7, or E17.13, wherein G 5 The phenyl group at the position is optionally substituted by one or two substituents independently selected from the group consisting of: fluorine, chlorine, cyano, methyl, and –OCH3.

[0126] E17.15. A compound as described in E17.14 or a pharmaceutically acceptable salt thereof, wherein G 5 It is 2,4-dimethoxyphenyl.

[0127] E18. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E15.1, wherein X 1 It is O.

[0128] E19. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E15.1, wherein X 1 It is CR 5A R 5B .

[0129] E19.1. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E15.1 or E19, wherein R 5A and R 5B It is hydrogen.

[0130] E20 The compound of any one of E1-E19.1 or a pharmaceutically acceptable salt thereof, wherein R 6 It is hydrogen.

[0131] E20.1. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E19.1, wherein R 6 It is C 1-4 alkyl.

[0132] E20.2. A compound as described in E20.1 or a pharmaceutically acceptable salt thereof, wherein R 6 It is a methyl group.

[0133] E21. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E20.2, wherein R 7 It is C 1-4 Alkyl, halogen, cyano, C 2-4 alkenyl, CO2R 7a or unsubstituted or substituted C 3-6 Cycloalkyl.

[0134] E21.1. A compound as described in E21 or a pharmaceutically acceptable salt thereof, wherein R 7 It is C 1-4Alkyl, halogen, cyano, or unsubstituted or substituted C 3-6 Cycloalkyl.

[0135] E21.2. A compound as described in E21.1 or a pharmaceutically acceptable salt thereof, wherein R 7 It is C 1-4 alkyl.

[0136] E21.3. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21.2, wherein R 7 The C at that location 1-4 Alkyl is methyl.

[0137] E21.4. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21.2, wherein R 7 The C at that location 1-4 The alkyl group is ethyl.

[0138] E21.5. A compound as described in E21.1 or a pharmaceutically acceptable salt thereof, wherein R 7 It is a cyano group.

[0139] E21.6. A compound as described in E21.1 or a pharmaceutically acceptable salt thereof, wherein R 7 It is unreplaced C 3-6 Cycloalkyl.

[0140] E21.7. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21.1 or E21.6, wherein R 7 It is cyclopropyl.

[0141] E21.8. A compound as described in E21.1 or a pharmaceutically acceptable salt thereof, wherein R 7 It is halogen.

[0142] E21.9. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21.1, E21.3, E21.4, or E21.8, wherein R 7 The halogen at that location is bromine.

[0143] E21.10. A compound as described in E21 or a pharmaceutically acceptable salt thereof, wherein R 7 It is C 2-4 Alkenyl group.

[0144] E21.11. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21, E21.3, E21.4, E21.9, or E21.10, wherein R 7 The C at that location 2-4 The alkenyl group is vinyl or prop-1-en-2-yl.

[0145] E21.12. A compound as described in E21 or a pharmaceutically acceptable salt thereof, wherein R 7 It is CO2R 7a .

[0146] E21.13. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21, E21.3, E21.4, E21.9, E21.10, E21.11, or E21.12, wherein R 7a It is C 1-4 alkyl.

[0147] E21.14. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21, E21.3, E21.4, E21.9, E21.10, E21.11, or E21.12-E21.13, wherein R 7a The C at that location 1-4 Alkyl is methyl.

[0148] E21.15. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E20.2, wherein R 7 It is hydrogen.

[0149] E22 A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E21.15, wherein n is 0.

[0150] E23. Compounds as described in E1, selected from the group consisting of: 2-(6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 3-Methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 3-Methyl-2-(2-(thien-2-yl)-6,7-dihydrothiazo[5,4-]c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 5-(3-methyl-5-oxo-6,7-dihydro-5-) H -pyrrolo[3,4- b ]pyridin-2-yl)-4,5,6,7-tetrahydrothiazo[5,4- c ]Ethyl pyridine-2-carboxylate; 3-Methyl-2-(2-methyl-6,7-dihydrothiazo[5,4-]) c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 3-Methyl-2-(2-(1-methyl-1-yl) H -pyrazol-5-yl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-amino-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-chloro-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-(tert-butyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4-b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 3,6-Dimethyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 6-Cyclopropyl-2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-]) c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 6-Cyclopropyl-3-methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 6-Cyclopentyl-2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-]) c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 6-Cyclopentyl-3-methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 6-Cyclopropyl-2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 6-Cyclopentyl-2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclobutyl-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-3,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclobutyl-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-yl)-3-methylfurano[3,4- b ]Pyridine-5(7 H )-ketone; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 3-Methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)furano[3,4- b ]Pyridine-5(7 H )-ketone; 2-(2-Cyclobutyl-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 3-Cyclopropyl-2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-]) c ]Pyridine-5(4H )-yl)-6-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-6-methyl-5-oxo-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridine-3-carboxynitrile; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-6-methyl-3-vinyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-6-methyl-3-(prop-1-en-2-yl)-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-6-methyl-5-oxo-6,7-dihydro-5 H -pyrrolo[3,4- b ] Methyl pyridine-3-carboxylic acid ester; 5-(3-methyl-5-oxo-6,7-dihydro-5-) H -pyrrolo[3,4- b ]pyridin-2-yl)-4,5,6,7-tetrahydrothiazo[5,4- c ]Pyridine-2-carboxamide; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6-(2,4-dimethoxybenzyl)-3-ethyl-6,7-dihydro-5 H-pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-ethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -cyclopentadiene[ b ]Pyridin-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3,4-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-4-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3,4,6-trimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; Or its pharmaceutically acceptable salt.

[0151] E24. A pharmaceutical composition comprising a compound as described in any one of E1-E23 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0152] E25. 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-E23 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in E24.

[0153] E26. The method as described in E25, wherein the impairment is associated with mAChR M4 dysfunction.

[0154] E27. The method as described in E25 or E26, wherein the disorder is a neurological and / or mental disorder associated with mAChR M4 dysfunction.

[0155] E28. The method of any one of E25-E27, wherein the disorder is selected from the group consisting of: Alzheimer's disease, schizophrenia, sleep disorders, pain disorders, and cognitive impairment.

[0156] E29. The method as described in E28, wherein the impairment is Alzheimer's disease.

[0157] E30. The method of any one of E25-E27, 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.

[0158] E31. A kit comprising a compound as described in any one of E1-E23 or a pharmaceutically acceptable salt thereof, and one or more of the following: (a) at least one agent known to increase mAChR M4 activity; (b) at least one agent known to decrease mAChR M4 activity; (c) at least one agent known to treat 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.

[0159] E32. The compound of any one of E1-E23 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of E24, for use in the treatment of neurological and / or mental disorders in mammals associated with dysfunction of muscarinic acetylcholine receptors.

[0160] E33. Use of any compound of any one of E1-E23 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of E24 in the preparation of a medicament for treating neurological and / or mental disorders in mammals associated with dysfunction of muscarinic acetylcholine receptors.

[0161] 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 the paper, or (2) direct separation of a mixture of optical enantiomers on a chiral chromatographic column, or (3) stepwise recrystallization.

[0162] It should be understood that compounds may have tautomer forms and geometric isomers, and these also constitute embodiments of this disclosure.

[0163] 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) and2 H (deuterium).

[0164] 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 15 N、 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.

[0165] 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).

[0166] a. Pharmaceutically acceptable salts 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.).

[0167] 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.

[0168] 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.

[0169] Compounds having formula (I) can be synthesized as shown in schemes 1-10.

[0170] Option 1 As shown in Scheme 1, tert-butyl 3-bromo-4-oxopiperidin-1-carboxylic acid (i) can be heated with a thioamide in a solvent (e.g., ethanol) to approximately 70°C-80°C to provide intermediate (ii). Intermediate (iii) can be formed by treating intermediate (ii) with an acid (e.g., TFA, HCl, etc.).

[0171] Option 2 As shown in Scheme 2, 2-bromo-6,7-dihydrothiazo[5,4-c]pyridine-5(4 H tert-butyl formate (iv) can be reacted with a suitable substituted boric acid or ester reagent and a palladium catalyst (e.g., Pd(PPh3)4, Pd(dppf)Cl2) under Suzuki reaction conditions in the presence of a base (e.g., sodium carbonate, cesium carbonate) and a solvent (e.g., dioxane or a dioxane / water mixture). Subsequent deprotection under acidic conditions (e.g., TFA, HCl) can form an intermediate compound (iii).

[0172] Option 3 As shown in Scheme 3, the intermediate compound having formula (iii) can be reacted with 2-chloro-3-methyl-6,7-dihydro-5- H -pyrrolo[3,4- b Pyridin-5-one (vi), a base (e.g., DIPEA), and a solvent (e.g., DMSO) are placed under standard nucleophilic substitution conditions and heated to approximately 90°C–120°C to provide a compound having formula (vii).

[0173] Option 4 As shown in scheme 4, ester intermediate (viii) (where Y, Y 1 and Y 2 (Is 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 (ix).

[0174] Option 5 As shown in Scheme 5, intermediate compound (iii) can be placed with intermediate (x) (where Y is a halogen), base (e.g., DIPEA), and solvent (e.g., DMSO) under standard nucleophilic substitution conditions and heated to about 90°C-120°C to provide a compound having formula (xi).

[0175] Option 6 As shown in Scheme 6, an intermediate having formula (xi) (where Y is a halogen) can be coupled with boric acid or an ester (e.g., trimethylboroxane) under Suzuki coupling conditions known in the art to provide (xii). 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.

[0176] Option 7 As shown in Scheme 7, an intermediate having formula (xi) (where Y is a halogen) can be treated with 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 obtain a compound having formula (xiii).

[0177] Option 8 As shown in Scheme 8, the intermediate (xiv) can be coupled with an amine under Buchwald coupling conditions known in the art to provide the product (xv). A similar reaction can be performed on the intermediate (iv) to provide –NR. 2a R 2b Substituted intermediate compounds.

[0178] Option 9 As shown in Scheme 9, intermediate (xiv) can be coupled with an alkoxide reagent in a suitable solvent to provide product (xvi). A similar reaction can be carried out on intermediate (iv) to provide –OR 2a Substituted intermediate compounds.

[0179] Option 10 As shown in Scheme 10, intermediate (xiv) can be reacted with zinc metal and Zn(CN)2 in a palladium catalyst (e.g., Pd(dppf)Cl2) and heated in a suitable solvent to provide (xvii). Intermediate (iv) can be reacted similarly to provide a cyano-substituted intermediate compound.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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).

[0186] 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.

[0187] 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.

[0188] c. Activity of muscarinic acetylcholine receptor M4 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).

[0189] 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.

[0190] 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. 50In some embodiments, mAChR M4 is transfected into human mAChR M4. In some embodiments, mAChR M4 is transfected into rat mAChR M4.

[0191] 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... 50 One or more ECs smaller than mAChR M1, M2, M3, or M5 transfected in 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.

[0192] 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... 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 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... 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 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. 50 A 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.

[0193] 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.

[0194] 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).

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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).

[0200] 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.

[0201] 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%.

[0202] 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%.

[0203] 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%.

[0204] 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%.

[0205] 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%.

[0206] 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%.

[0207] 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%.

[0208] 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%.

[0209] 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%.

[0210] 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%.

[0211] 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%.

[0212] 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%.

[0213] 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%.

[0214] 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.

[0215] 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%.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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).

[0224] 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.

[0225] 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.

[0226] 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%.

[0227] 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%.

[0228] 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%.

[0229] 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%.

[0230] The amount of one or more thickeners in a topical composition is typically from about 0% to about 95%.

[0231] 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%.

[0232] 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%.

[0233] Suitable pH-adjusting additives include HCl or NaOH, in amounts sufficient to adjust the pH of the topical drug composition.

[0234] 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.

[0235] 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.

[0236] Therefore, in one embodiment, this disclosure may provide a spray-dried dispersion formulation comprising a compound having formula (I).

[0237] 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.

[0238] 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).

[0239] 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).

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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).

[0252] 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.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] In some embodiments, the obstacle is Alzheimer's disease.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] It should be understood that the disclosed combination therapy can be used in conjunction with the disclosed compounds, compositions, kits and uses.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] 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).

[0289] 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.

[0290] 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.

[0291] 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.

[0292] 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.

[0293] f. Application method 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).

[0294] 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.

[0295] As used in this article, the term "parenteral" refers to administration methods including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intra-articular injections and infusions.

[0296] 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 the compound in combination with cognitive or behavioral therapy.

[0297] 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.

[0298] The disclosed kit can be used in conjunction with the disclosed instructions for use.

[0299] 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).

[0300] 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.

[0301] 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.

[0302] a. Preparation of intermediates 1-Methylcyclopropanethioformamide. Lawson's reagent (4.5 g, 11.1 mmol) was added to a suspension of 1-methylcyclopropaneformamide (1.1 g, 11.1 mmol) and sodium carbonate (1.2 g, 11.1 mmol) in THF (55 mL), and the reaction mixture was heated to 70 °C. After 2 h, the reaction mixture was concentrated, and the resulting residue was diluted with EtOAc and washed with water (2x) and brine. The organic layer was concentrated and dried under high vacuum to give the title compound (1.2 g). ES-MS [M+1] + : 116.9.

[0303] 1-Fluorocyclopropane-1-thiocarboxamide. Lawson's reagent (1.96 g, 4.85 mmol) was added to a suspension of 1-fluorocyclopropanecarboxamide (500 mg, 4.85 mmol) and sodium carbonate (524 mg, 4.85 mmol) in THF (24 mL). The resulting mixture was heated to 70 °C. After 36 hr, the reaction mixture was concentrated, and the resulting residue was diluted with EtOAc and washed with water (2x) and brine. The organic layer was concentrated to give the desired compound, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO) δ 9.74 (d, J = 194.7 Hz, 2H), 1.63 (td, J = 8.7,5.2 Hz, 2H), 1.49 – 1.38 (m, 2H).

[0304] 2-(1-Methylcyclopropyl)-4,5,6,7-Tetrahydrothiazo[5,4- c Pyridine. Add to a suspension of 1-methylcyclopropanethioformamide (1.0 g, 9.0 mmol) in ethanol (46 mL). N -Boc-3-bromo-4-oxoperididine (2.5 g, 9.0 mmol) was reacted, and the reaction was subsequently heated to 80 °C for 48 h. The crude reaction mixture was concentrated under vacuum. DCM (25 mL) and TFA (6.9 mL) were added to the residue. After 1 h at room temperature, the reaction mixture was concentrated. The residue was dissolved in EtOAc and saturated Na2CO3 solution. The mixture was separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by normal-phase column chromatography (0%-70% EtOAc / hexane, followed by a 0%-10% DCM:MeOH:1% NH4OH gradient) to give the title compound (1.59 g). 1 H NMR (400MHz, CDCl3) δ 4.00 (t, J = 1.8 Hz, 2H), 3.71 (t, J = 5.8 Hz, 2H), 2.80-2.76 (m,2H), 1.54 (s, 3H), 1.23 (dd, J = 6.8, 4.4 Hz, 2H), 0.91 (dd, J = 6.5, 4.1 Hz,2H); ES-MS [M+1]+ : 295.1 and 195.1.

[0305] 2-Cyclopropyl-4,5,6,7-Tetrahydrothiazo[5,4-] c Pyridine hydrochloride. Cyclopropanethioformamide (1.8 g, 18.0 mmol) in ethanol (30 mL) and N -Boc-3-bromo-4-oxoperididine (5.0 g, 18.0 mmol) was stirred at 80 °C for 2 h. The solution was concentrated, and then 1,4-dioxane (8 mL) and 4 mmol were added to 1,4-dioxane (40 mL). M Hydrochloric acid solution. After 1 h at room temperature, the solution was concentrated under vacuum to give the title compound (4.0 g). 1 H NMR (400 MHz, DMSO-d6) δ4.30 (s, 2H), 2.91 (t, J = 6.0 Hz, 2H), 2.59 (t, J = 6.5 Hz, 2H), 2.41-2.35 (m,1H), 1.13-1.08 (m, 2H), 0.95-0.91 (m, 2H); ES-MS [M+1] + : 181.4.

[0306] 2-(2,2-Dimethylcyclopropyl)-4,5,6,7-Tetrahydrothiazo[5,4- c Pyridine. In a vial, 2,2-dimethylcyclopropanethiocarboxamide (232 mg, 1.8 mmol) and N -Boc-3-bromo-4-oxoperididine (500 mg, 1.8 mmol) was combined in ethanol (2 mL). After 2 h at 80 °C, the reaction mixture was concentrated. DCM (2 mL) and trifluoroacetic acid (1.38 mL) were added to the crude residue. After 1 h at room temperature, the solution was concentrated, diluted with a saturated aqueous solution of Na₂CO₃, and extracted with DCM (3x). The combined organic layers were passed through a hydrophobic phase separator and concentrated to give the title compound (195 mg). 1 H NMR (400MHz, DMSO) δ 3.83 (d, J = 1.8 Hz, 2H), 2.96 (t, J = 5.8 Hz, 2H), 2.61 (t, J = 4.1.2H), 2.14 (dd,J = 8.4, 5.6 Hz, 1H), 1.17 (s, 3H), 1.11 – 1.01 (m, 2H), 0.97(s, 3H); ES-MS [M+1] + : 209.3.

[0307] 2-Isopropyl-4,5,6,7-Tetrahydrothiazo[5,4-] c Pyridine. The mixture contained 2-methylpropanethioamide (185 mg, 1.8 mmol) in ethanol (2 mL) and N The vial of -Boc-3-bromo-4-oxoperididine (500 mg, 1.8 mmol) was heated at 80 °C for 2 h. The reaction mixture was concentrated. DCM (2 mL) and trifluoroacetic acid (1.38 mL) were added to the crude residue. After 1 h, the solution was concentrated, diluted with saturated Na₂CO₃ solution, and the aqueous layer was extracted with DCM (3x). The combined organic layers were passed through a hydrophobic phase separator and concentrated to give the title compound (372 mg). 1 H NMR (400 MHz, CDCl3) δ 4.40 (s,2H), 3.53 (t, J = 6.1 Hz, 2H), 3.29 (p, J = 6.9 Hz, 1H), 3.17 (t, J = 5.8 Hz, 2H), 1.38 (d, J = 6.9 Hz, 6H); ES-MS [M+1] + : 183.2.

[0308] 2-(tert-butyl)-4,5,6,7-tetrahydrothiazo[5,4- c Pyridine. The mixture contained 2,2-dimethylpropanethioamide (211 mg, 1.8 mmol) in ethanol (2 mL) and N The vial of 3-bromo-4-oxoperpiperidine (500 mg, 1.8 mmol) was heated at 80 °C for 2 h. The solution was concentrated. DCM (2 mL) and trifluoroacetic acid (1.4 mL) were added to the crude residue. After 1 h at room temperature, the reaction mixture was concentrated and purified by an SCX column. N After elution with NH3 / MeOH solution, the solvent was removed to give the title compound (238 mg). 1H NMR (400 MHz, DMSO) δ 3.83 (t, J = 1.9 Hz, 2H), 2.96(t, J = 5.8 Hz, 2H), 2.61 (t, J = 5.8, 1.9 Hz, 2H), 1.34 (s, 9H); ES-MS [M+1] + :197.1.

[0309] 2-(1-Fluorocyclopropyl)-4,5,6,7-Tetrahydrothiazo[5,4- c Pyridine. 1-Fluorocyclopropane-1-thiocarboxamide (114 mg, 0.72 mmol) in ethanol (2.3 mL) and N -boc-3-bromo-4-oxoperididine (200 mg, 0.72 mmol) was heated to 80 °C for 18 h. The reaction mixture was concentrated, and the residue was purified by normal-phase column chromatography (0%-80% EtOAc / hexane). At room temperature, DCM and trifluoroacetic acid (2.0 mL; 2:1) were added to the intermediate residue. After 3 hr, the solution was concentrated, and the material was purified using an SCX column. N After elution with NH3 / MeOH solution, the solvent was removed to obtain the title compound. ES-MS [M+1] + : 199; 1 H NMR (400 MHz, DMSO) δ 3.92 (t, J = 1.9 Hz, 2H), 2.99 (t, J = 5.8 Hz, 2H), 2.63 (tt, J = 5.9, 1.9 Hz, 2H), 1.70 – 1.55 (m, 2H), 1.40 – 1.28 (m, 2H).

[0310] 2-Cyclobutyl-4,5,6,7-Tetrahydrothiazo[5,4-] c Pyridine. Cyclobutane thiocarboxamide (203 mg, 1.76 mmol) in ethanol (4.5 mL) and N-boc-3-bromo-4-oxoperididine (490 mg, 1.76 mmol) was stirred at 80 °C for 2 hr. The solution was concentrated, and then DCM (4.0 mL) and trifluoroacetic acid (1.35 mL) were added at room temperature for 1 hr. The solution was concentrated and then diluted with EtOAc and saturated Na2CO3 solution. The layers were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the title compound (300 mg). ES-MS [M+1] + : 195; 1 HNMR (400 MHz, CDCl3) δ 4.21 (s, 2H), 3.83 – 3.72 (m, 2H), 3.33 (t, J = 6.0 Hz, 2H), 2.94 (t, J = 5.8 Hz, 2H), 2.49 – 2.37 (m, 2H), 2.37 – 2.24 (m, 2H), 2.12 –1.84 (m, 2H).

[0311] 2-(thien-2-yl)-4,5,6,7-tetrahydrothiazo[5,4-] c ]Pyridine. In a vial, thiophene-2-boronic acid (105 mg, 0.82 mmol), 2-bromo-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H tert-butyl formate (175 mg, 0.55 mmol), sodium carbonate (148 mg, 1.37 mmol), and tetrakis(triphenylphosphine)palladium(0) were combined in 1,4-dioxane (2 mL) and water (0.5 mL). The reaction was purged with nitrogen (3x) and heated to 80 °C for 2 h. The reaction was then subjected to a Celite reaction. ® Filter and use the Celite ® Wash with DCM (2 x 25 mL). Concentrate the filtrate and purify by normal-phase chromatography (0%-40% EtOAc / hexane) to obtain the desired Boc-protected amine. Dissolve the Boc-protected amine in DCM (2 mL) and trifluoroacetic acid (0.59 mL). After 1 h, concentrate the reaction, alkalize with saturated Na2CO3, extract with DCM (3x), pass through a hydrophobic phase separator, and concentrate to obtain the title compound (112 mg). 1 H NMR (400 MHz, CDCl3) δ 7.44 (dd, J= 3.7, 1.2 Hz, 1H), 7.36 (dd, J = 5.1, 1.2 Hz, 1H), 7.06 (dd, J = 5.1, 3.7 Hz, 1H), 4.10(s, 2H), 3.24 (t, J = 5.9 Hz, 2H), 2.90 (ddd, J = 6.0, 4.1, 1.8 Hz, 2H); ES-MS [M+1] + : 223.1.

[0312] 2-(1-methyl-1 H -pyrazol-5-yl)-4,5,6,7-tetrahydrothiazo[5,4- c ]Pyridine. 2-Bromo-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H tert-butyl formate (300 mg, 0.94 mmol), cesium carbonate (924 mg, 2.82 mmol), Pd(dppf)Cl2 (69 mg, 0.09 mmol), and pinacol 1-methylpyrazole-5-boronate (391 mg, 1.88 mmol) were heated at 100 °C for 18 h. The mixture was then passed through a Celite filter. ® The mixture was filtered through a pad, and the filtrate was concentrated. The residue was purified by normal-phase chromatography (0%–40% EtOAc / hexane) to obtain Boc-amine, which was dissolved in DCM (2 mL) and trifluoroacetic acid (1.1 mL). After 1 h, the reaction was concentrated, alkalized with saturated Na2CO3 solution, extracted with DCM (3x), passed through a hydrophobic phase separator, and concentrated to obtain the title compound (162 mg). 1 H NMR (400MHz, CDCl3) δ 7.47 (d, J = 2.0 Hz, 1H), 6.60 (d, J = 2.1 Hz, 1H), 4.26 (d, J = 1.6Hz, 2H), 4.22 (s, 3H), 3.39 (t, J = 5.9 Hz, 2H), 3.10 – 3.01 (m, 2H); ES-MS [M+1] + : 221.2.

[0313] tert-Butyl-5-(tert-Butoxycarbonyl)-4,5,6,7-Tetrahydrothiazo[5,4- c ]Pyridine-2-carboxylic acid. To 6,7-dihydrothiazolyl[5,4- c ]Pyridine-2,5(4 H 5-(tert-butyl)-2-ethyl dicarboxylic acid (300 mg, 0.96 mmol) was dissolved in ethanol (4.8 mL) with NaOH (384 µL, 1.92 mmol) in 5% ethanol solution. M Aqueous solution. After 3 h, the reaction mixture was concentrated and used without further purification. ES-MS [M + H] + = 285.

[0314] 2-Carbamoyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazo[5,4- c Add pyridine-2-carboxylic acid (273 mg, 0.96 mmol) to a solution of THF (3.2 mL). N,N -Diisopropylethylamine (1.7 mL, 9.6 mmol), HATU (1.09 g, 2.88 mmol), and NH4Cl (285 mg, 5.76 mmol). The mixture was heated to 75 °C for 18 hours. At room temperature, the reaction mixture was diluted with water and extracted with chloroform / IPA (3:1) (3x). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude material was purified by normal-phase column chromatography (0%–2% MeOH / DCM). 1 H NMR (400 MHz, CDCl3) δ 7.01 (s, 1H), 5.46 (s,1H), 4.71 (s, 2H), 3.77 (t, J = 5.3 Hz, 2H), 2.90 (t, J = 5.1 Hz, 2H), 1.49 (s,9H); ES-MS [M + H] + = 284.

[0315] 4,5,6,7-Tetrahydrothiazolyl[5,4- c ]Pyridine-2-carboxamide. To 2-carbamoyl-6,7-dihydrothiazo[5,4- c]Pyridine-5(4 H 272 mg (0.96 mmol) of tert-butyl formate was added to a solution of TFA (735 µL, 9.6 mmol) in DCM (6.4 mL). After 18 hours at room temperature, the reaction was concentrated and dissolved in MeOH and loaded onto an SCX column (HF bond). After rinsing the column with MeOH, the solution was used to prepare a 7-dimethyl formate solution. N The column was eluted with NH3 / MeOH solution. The solvent was removed under vacuum to obtain the title compound. 1 H NMR (400 MHz, DMSO) δ 7.15 (s, 1H), 6.80 (s, 1H), 3.05 (t, J =1.7 Hz, 2H), 2.10 (t, J = 5.8 Hz, 2H), 1.83 (ddd, J = 7.4, 3.8, 1.5 Hz, 2H); ES-MS [M + H] + = 184.

[0316] 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). 1 HNMR (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.

[0317] 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 chloroform / IPA at a ratio of 3:1 (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) δ8.40 (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.

[0318] 5-Bromo-2-(bromomethyl)-6-chloronicotinic acid ethyl ester. At 50 °C, 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) were added in portions 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). N - Bromosuccinimide (8.43 g, 47.4 mmol). 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 layer was 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.

[0319] 3-Bromo-2-chloro-6-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one. At 0°C, 2.0 g of methylamine was added to a solution of 2.5 g (6.99 mmol) of 5-bromo-2-(bromomethyl)-6-chloronicotinic acid ethyl ester in THF (140 mL). M The solution was prepared (17.5 mL, 35.0 mmol), 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 (948 mg). 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.

[0320] 3-Bromo-2-(2-cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-6-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one. To 3-bromo-2-chloro-6-methyl-7 H -pyrrolo[3,4- b Pyridin-5-one (262 mg, 1.0 mmol) and N , N 2-Cyclopropyl-4,5,6,7-Tetrahydro-[1,3]thiazo[5,4-]diisopropylethylamine (0.87 mL, 5.0 mmol) was added to a solution of NMP (3.7 mL). c Pyridine (271 mg, 1.5 mmol). The reaction was heated to 160 °C. After 18 h, the reaction was cooled to room temperature and water was added to form a precipitate. The suspension was filtered, washed with water, and dried under N2. The residue was purified by normal-phase chromatography (0%–5% MeOH / DCM / 0.1% NH4OH) to give the title compound (225 mg). 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 4.60 (s, 2H), 4.25 (s, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.42 – 3.32 (m, 2H), 2.84 (s, 3H), 2.36 (q, J = 9.0 Hz, 2H), 2.29 (dt, J = 8.4, 4.8 Hz, 1H), 2.08 – 1.95 (m, 2H); ES-MS [M+1] + : 405.1 / 407.1.

[0321] 3-Bromo-2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-6-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one. To 3-bromo-2-chloro-6-methyl-7 H -pyrrolo[3,4- b Pyridin-5-one (30 mg, 0.11 mmol) and N , N 2-(1-fluorocyclopropyl)-4,5,6,7-tetrahydrothiazo[5,4-]diisopropylethylamine (0.1 mL, 0.57 mmol) was added to a solution of DMSO (0.57 mL). c Pyridine (27.0 mg, 0.14 mmol). The reaction was heated to 70 °C for 18 h. The reaction was purified by reversed-phase HPLC (18%–58% MeCN / water / 0.05% NH4OH) to give the title compound. ES-MS [M+1] + : 425 / 426; 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 1.5 Hz, 1H), 4.68 (q, J = 1.8 Hz, 2H), 4.26 (d, J = 1.5 Hz, 2H), 3.82 (td, J = 5.7, 1.6 Hz, 2H), 3.19 (d, J = 1.5 Hz, 3H), 3.09 (ddd,J = 7.6, 3.8, 1.8 Hz, 2H), 1.65 – 1.54 (m, 2H), 1.51 – 1.41 (m, 2H).

[0322] 3-Bromo-2-chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one. 2,4-Dimethoxybenzylamine (2.1 mL, 14.0 mmol) was slowly added to a solution of 5-bromo-2-(bromomethyl)-6-chloronicotinic acid ethyl ester (1300 mg, 2.8 mmol) in THF (55 mL), and the reaction was stirred at room temperature for 30 min. Triethylamine (0.58 mL, 4.2 mmol) was then added. After 18 h at room temperature, the reaction was concentrated with Celite® and purified by normal-phase chromatography (0%–25% EtOAc / DCM) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.22(dd, J = 7.8, 0.7 Hz, 1H), 6.46-6.43 (m, 2H), 4.74 (s, 2H), 4.30 (s, 2H), 3.82(s, 3H), 3.79 (s, 3H). ES-MS [M+1] + : 397 / 399.

[0323] 3-Bromo-2-(2-cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one. To 3-bromo-2-chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one (888 mg, 2.2 mmol) and N , N 2-Cyclopropyl-4,5,6,7-Tetrahydro-[1,3]thiazo[5,4-]diisopropylethylamine (1.94 mL, 11.2 mmol) was added to a solution of NMP (5.6 mL). cPyridine (604 mg, 3.4 mmol). The reaction was heated to 120 °C. After 18 h, water was added, and the precipitate was filtered, washed with water, and dried under N2 to give the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.20(d, J = 8.1 Hz, 1H), 6.45-6.43 (m, J = 2.4 Hz, 2H), 4.72 (s, 2H), 4.56 (s, 2H), 4.16 (s, 2H), 3.83 (s, 3H), 3.81-3.75 (s, 5H), 3.05 (td, J = 5.6, 1.9 Hz, 2H), 2.25 (tt, J = 8.2, 4.9 Hz, 1H), 1.13 – 1.07 (m, 2H), 1.03 – 0.97 (m, 2H). ES-MS[M+1] + : 541 / 543.

[0324] 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-6-(2,4-dimethoxybenzyl)-3-vinyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one. 3-Bromo-2-(2-cyclopropyl-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H )-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5 H -pyrrolo[3,4- b A mixture of pyridin-5-one (200 mg, 0.37 mmol), pinacol vinylborate (0.09 mL, 0.55 mmol), Pd(dppf)Cl2 (14 mg, 0.02 mmol), and cesium carbonate (363 mg, 1.11 mmol) in THF (2.2 mL) and water (0.22 mL) was microwave-treated at 130 °C for 30 min. The reaction mixture was filtered through Celite®, washed with 3:1 CHCl3 / IPA, and the solvent was removed under vacuum. The crude sample was purified by reversed-phase chromatography (15%–65% MeCN / water / 0.05% NH4OH) to obtain the title compound. ES-MS [M+1]+ : 489.

[0325] 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; 1 H 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).

[0326] 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 min. 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. MHCl (400 µL, 1.6 mmol) was added, and the mixture was heated to 50 °C. 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).

[0327] 3-Bromo-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)furano[3,4- b ]Pyridine-5(7 H )-ketone. To 3-bromo-2-chlorofuran[3,4- b ]Pyridine-5(7 H 3-bromo-2-chloro-7-one (40 mg, 0.13 mmol) was added to a solution of NMP (1 mL). H -furano[3,4- b Pyridine-5-one hydrochloride (40 mg, 0.13 mmol) and N , N -Diisopropylethylamine (0.07 mL, 0.39 mmol). The mixture was heated at 50 °C for 18 hr. The mixture was cooled to ambient temperature, diluted with water, and extracted with EtOAc (3x). The combined organic layers were dried (MgSO4), filtered, and concentrated. The product was used without further purification. ES-MS [M+1] + : 406 / 408.

[0328] 3-Bromo-6,7-Dihydro-5 H -cyclopentadiene[ b ]Pyridine-2-ol. At 0°C, to a mixture containing 6,7-dihydro-5 H -cyclopentadiene[ bBromine (150 µL, 2.9 mmol) was added to vials of pyridine-2-ol (500 mg, 3.7 mmol) and acetic acid (5.3 mL). The reaction mixture was allowed to return to room temperature for 3 h. The reaction mixture was concentrated under vacuum, and the residue was added to a saturated sodium thiosulfate solution and neutralized with a saturated aqueous sodium carbonate solution. The mixture was extracted with EtOAc (3x). 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 with 1% NH4OH additive) to give the desired compound (493 mg). 1 H NMR (400 MHz, CDCl3) δ7.74 (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.

[0329] 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. A saturated aqueous sodium carbonate solution was slowly added to the residue. The mixture was extracted with DCM (3x). The combined organic layers were washed with water (3x). The organic matter was dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by normal-phase column chromatography (0% - 60% EtOAc / hexane) to yield the title compound (316 mg). 1 H NMR (400MHz, 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.

[0330] 3-Bromo-2-chloro-6,7-dihydro-5 H -cyclopentadiene[ bPyridin-5-one. Add 3-bromo-2-chloro-6,7-dihydro-5-one to a solution of magnesium sulfate (833 mg, 6.8 mmol) and 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 filtered through Celite® and washed with EtOAc and MeOH. The filtrate was concentrated. The residue was dissolved in water / EtOAc (1:1; 50 mL). The organic layers were separated, and the aqueous layer was re-extracted with EtOAc (2x). The combined organic layers were washed with brine, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase column chromatography (0%-60% EtOAc / hexane) to give the title compound. ES-MS [M+1] + : 246 / 248; 1 H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 3.26– 3.18 (m, 2H), 2.87 – 2.80 (m, 2H).

[0331] 3-Bromo-2-(2-cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6,7-dihydro-5 H -cyclopentadiene[ b ]Pyridin-5-one. To 3-bromo-2-chloro-6,7-dihydro-5 H -cyclopentadiene[ b ]Pyridin-5-one (13 mg, 0.05 mmol) was added to a solution of 2-cyclopropyl-4,5,6,7-tetrahydro-[1,3]thiazo[5,4- c Pyridine (10 mg, 0.06 mmol) and N , N -Diisopropylethylamine (55 µL, 0.32 mmol). The mixture was heated to 120 °C. After 18 h, the mixture was decanted into water and extracted with EtOAc (3x). The combined organic layers were 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. [M+1] + :390 / 392.

[0332] 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.

[0333] 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.

[0334] 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.

[0335] 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.

[0336] 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.

[0337] 3-Bromo-2-chloro-4-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one: Add ammonia (7 mg) to a solution (15.4 mL) of 5-bromo-2-(bromomethyl)-6-chloro-4-methylnicotinic acid ethyl ester (320 mg, 0.86 mmol) in methanol. N In MeOH (615 µL, 4.31 mmol), the reaction was stirred at room temperature for 18 hours. Additional ammonia (7...) was added. N The reaction was carried out in MeOH (615 µL, 4.31 mmol) and stirred for another 18 hours. The reaction was concentrated under vacuum and then resuspended in IPA. The solution was sonicated and the precipitate was collected by vacuum filtration to obtain the title compound. 1 H NMR (400MHz, DMSO) δ 8.93 (s, 1H), 4.33 (d, J = 1.2 Hz, 2H), 2.75 (s, 3H). ES-MS [M+1]+ :261 / 263.

[0338] 3-Bromo-2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-4,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one. With 3-bromo-2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H )-yl)-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, CDCl3) δ 4.63 (d, J = 1.9 Hz, 2H), 4.20 (s, 2H), 3.75 (t, J =5.6 Hz, 2H), 3.17 (s, 3H), 3.12 – 3.07 (m, 2H), 2.78 (s, 3H), 1.65 – 1.58 (m,2H), 1.50 – 1.40 (m, 2H). ES-MS [M+1] + : 437 / 439.

[0339] 3-Bromo-2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-4-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one. With 3-bromo-2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H )-yl)-6-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b It can be prepared in a similar manner to pyridin-5-one. 1 HNMR (400 MHz, CDCl3) δ 5.90 (s, 1H), 4.65 (t, J = 1.8 Hz, 2H), 4.28 (d, J= 1.1Hz, 2H), 3.78 (t, J = 5.6 Hz, 2H), 3.11 (t, J = 5.7 Hz, 2H), 2.79 (s, 3H), 1.65 –1.58 (m, 2H), 1.49 – 1.42 (m, 2H). ES-MS [M+1] + : 423 / 425.

[0340] Table 1. Commercial Starting Materials name CAS# supplier 6,7-Dihydrothiazo[5,4-]pyridine-5(4)-carboxylic acid tert-butyl ester 165948-24-3 Modular Block Co., Ltd. 6,7-Dihydrothiazo[5,4-]pyridine-2,5(4)-dicarboxylic acid 5-(tert-butyl)2-ethyl ester 1053656-51-1 J&W PharmLab 4,5,6,7-Tetrahydrothiazo[5,4-]pyridine 165948-23-2 Enamine 2-Chloro-6,7-dihydrothiazo[5,4-c]pyridine-5(4)-carboxylic acid tert-butyl ester 1221931-40-3 Modular Block Co., Ltd. 2-Amino-6,7-dihydrothiazo[5,4-c]pyridine-5(4)-carboxylic acid tert-butyl ester 365996-05-0 Modular Block Co., Ltd. 4,5,6,7-Tetrahydrothiazo[5,4-]pyridine-2-carboxylic acid ethyl ester hydrochloride 1186663-33-1 AstaTech, Inc. 2-Bromo-4,5,6,7-Tetrahydrothiazo[5,4-]pyridine hydrochloride 949922-52-5 Synthonix 2-Methyl-4,5,6,7-tetrahydrothiazo[5,4-]pyridine 124458-27-1 Aurum Pharmatech 2-Bromo-6,7-dihydrothiazo[5,4-c]pyridine-5(4)-carboxylic acid tert-butyl ester 365996-06-1 Modular Block Co., Ltd. 1,2,5,6,7-Cyclopentadieno[]pyridin-2-one 88499-85-8 Enamine 1-Fluorocyclopropaneformamide 1445686-01-7 eNovation Chemicals

[0341] b. Representative synthesis of the compounds of this invention 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound 2). To 2-chloro-3-methyl-6,7-dihydropyrrolo[3,4- b Pyridin-5-one (15 mg, 0.08 mmol) and N , N 2-Cyclopropyl-4,5,6,7-Tetrahydro-[1,3]thiazo[5,4-]diisopropylethylamine (0.07 mL, 0.41 mmol) was added to a solution of DMSO (0.8 mL). c Pyridine; hydrochloride (21 mg, 0.10 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). The desired fraction was concentrated to give the title compound (2.1 mg). 1 H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 6.50 (s, 1H), 4.52 (s, 2H), 4.35 (s, 2H), 3.57 (t, J = 5.6 Hz, 2H), 3.02 (t, J = 5.6Hz, 2H), 2.40 (s, 3H), 2.30-2.23 (m, 1H), 1.14-1.09 (m, 2H), 1.04-1.00 (m,2H); ES-MS [M+1] + : 327.0.

[0342] 3-Methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound 3). To 2-chloro-3-methyl-6,7-dihydropyrrolo[3,4- b Pyridin-5-one (15 mg, 0.08 mmol) and N , N 2-(1-methylcyclopropyl)-4,5,6,7-tetrahydro-[1,3]thiazo[5,4-]diisopropylethylamine (0.07 mL, 0.41 mmol) was added to a solution of DMSO (0.8 mL). c Pyridine (19 g, 0.10 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). The desired fraction was concentrated to give the title compound (9.4 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.37(s, 1H), 7.77 (s, 1H), 4.49 (s, 2H), 4.25 (s, 2H), 3.54 (t, J = 5.5 Hz, 2H), 2.91 (t, J = 5.4 Hz, 2H), 2.37 (s, 3H), 1.50 (s, 3H), 1.13 (dd, J = 6.7, 2.6 Hz, 2H), 0.96 (dd, J = 6.3, 3.7 Hz, 2H); ES-MS [M+1] - : 341.0.

[0343] 2-(2-Cyclopropyl-6,7-Dihydro-4- H -[1,3]thiazo[5,4- c ]pyridin-5-yl)-3,6-dimethyl-7 H -pyrrolo[3,4- b ]Pyridin-5-one (compound 12). 3-Bromo-2-(2-cyclopropyl-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H)-yl)-6-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one (225 mg, 0.56 mmol), cesium carbonate (543 mg, 1.67 mmol), trimethylboroxane (50% wt in THF) (0.47 mL, 1.67 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloro(II) (81 mg, 0.11 mmol), and 1,4-dioxane (2.9 mL) were placed in vials. The mixture was evacuated and purged with nitrogen and stirred at 80 °C for 18 h. The reaction was then passed through a Celite tube. ® The sample was filtered through a filtration mat and thoroughly washed with 3:1 CHCl3 / IPA. The solvent was removed, and the crude sample was purified by reversed-phase chromatography (5%–40% MeCN / water / 0.1% TFA). The desired fraction was alkalized with saturated NaHCO3, extracted with 3:1 CHCl3 / IPA, and concentrated to give the title compound (36 mg). 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 4.50 (s, 2H), 4.26 (s, 2H), 3.55(t, J = 5.6 Hz, 2H), 3.18 (s, 3H), 3.06 – 2.99 (m, 2H), 2.39 (s, 3H), 2.31 (d, J = 4.7 Hz, 1H), 1.14 (dd, J = 7.9, 3.1 Hz, 2H), 1.09 – 1.00 (m, 2H).; ES-MS [M+1] + : 341.2.

[0344] 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound 23). 3-Bromo-2-[2-(1-fluorocyclopropyl)-6,7-dihydro-4- H -[1,3]thiazo[5,4- c ]pyridin-5-yl]-6-methyl-7 H -pyrrolo[3,4- bPyridin-5-one (21.0 mg, 0.05 mmol), cesium carbonate (48.0 mg, 0.15 mmol), trimethylboroxane (50% wt in THF) (40.0 µL, 0.15 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloro(II) (7.0 mg, 0.01 mmol), and 1,4-dioxane (0.5 mL) were placed in microwave-safe vials. The mixture was evacuated and purged with nitrogen and stirred at 80 °C for 18 h. The reaction was then passed through a Celite tube. ® Filter with a pad and wash thoroughly with EtOAc. Remove the solvent and purify the crude sample by reversed-phase chromatography (15%–55% MeCN / water / 0.1% TFA). The desired fraction was alkalized with saturated NaHCO3, extracted with 3:1 CHCl3 / IPA, and concentrated to give the title compound. ES-MS [M+1] + : 359.2; 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 0.9 Hz, 1H), 4.57 (t, J = 1.9 Hz, 2H), 4.27 (s, 2H), 3.56 (t, J = 5.7 Hz, 2H), 3.18 (s,3H), 3.02 (tt, J = 5.7, 1.8 Hz, 2H), 2.40 (d, J = 0.9 Hz, 3H), 1.65 – 1.52 (m, 2H), 1.52 – 1.41 (m, 2H).

[0345] 3-Methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)furano[3,4- b ]Pyridine-5(7 H )-ketone (compound 24). 3-bromo-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H )-yl)furano[3,4- b ]Pyridine-5(7 HA solution of 1,4-dioxane (1 mL) was prepared in a vial containing 57 mg (0.13 mmol) of cesium carbonate (126 mg, 0.39 mmol), 50% wt. trimethylborooxane in THF (108 µL, 0.39 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichlorodi ... After 4 h, the mixture was cooled to ambient temperature, and additional cesium carbonate (126 mg, 0.39 mmol), trimethylborooxane (50% wt. in THF) (108 µL, 0.39 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichlorodi ... ® The product was filtered through a pad, thoroughly washed with DCM / MeOH, and then concentrated. The crude product was purified by reversed-phase chromatography (10%–60% MeCN / water / 0.1% TFA), and the desired fraction was alkalized with saturated NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The organic compounds were combined, passed through a phase separator, and concentrated. The product was then purified by normal-phase column chromatography (0%–70% EtOAc / hexane) to give the title compound. ES-MS [M+1] + :342.

[0346] 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-6-methyl-5-oxo-6,7-dihydro-5 H -pyrrolo[3,4- b ] Pyridine-3-carboxylic acid methyl ester (compound 31). To 3-bromo-2-(2-cyclopropyl-6,7-dihydrothiazo[5,4- c ]pyridin-5(4H)-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4- bXantphos (14 mg, 0.02 mmol) and palladium(II) acetate (2.8 mg, 0.01 mmol) were added to a solution of pyridin-5-one (50 mg, 0.12 mmol) in triethylamine (0.4 mL, 2.8 mmol) and methanol (0.05 mL, 1.2 mmol), and the resulting reaction vial was sealed. The vial was purged under a CO atmosphere. The reaction was then heated at 70 °C under a CO balloon for 16 h. Upon cooling to room temperature, the crude reaction was diluted with 3:1 CHCl3 / IPA, filtered, and concentrated. The crude oil was purified by reversed-phase chromatography (10%–60% MeCN / water / 0.1% TFA). The desired fraction was post-treated with an alkaline solution to give the title compound (3.9 mg). 1 H NMR (400MHz, CDCl3) δ 8.39 (s, 1H), 4.51 (s, 2H), 4.27 (s, 2H), 3.94-3.91 (m, 5H), 3.16 (s, 3H), 3.03 (td, J = 5.5, 2.1 Hz, 2H), 2.26 (tt, J = 8.2, 4.9 Hz, 1H), 1.15 – 1.07 (m, 2H), 1.06 – 0.97 (m, 2H). ES-MS [M+1] + : 385.

[0347] 5-(3-methyl-5-oxo-6,7-dihydro-5-) H -pyrrolo[3,4- b ]pyridin-2-yl)-4,5,6,7-tetrahydrothiazo[5,4- c ]Pyridine-2-carboxamide (compound 32). To 4,5,6,7-tetrahydrothiazo[5,4- c Pyridine-2-carboxamide (23 mg, 0.12 mmol) and 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 NMP (0.5 mL). N,N-Diisopropylethylamine (72 µL, 0.41 mmol), and the reaction was heated to 160 °C for 18 h. The crude residue was purified by RP-HPLC (5%–50% ACN / 0.1% aqueous TFA). The fraction containing the title compound was alkalized with saturated NaHCO3 and then extracted with chloroform / IPA (3:1) (3x). The combined organic matter was passed through a hydrophobic phase separator, and the solvent was removed to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ7.86 (s, 1H), 7.04 (s, 1H), 5.88 (s, 1H), 5.46 (s, 1H), 4.68 (s, 2H), 4.35(s, 2H), 3.63 (t, J = 5.7 Hz, 2H), 3.10 (t, J = 5.7 Hz, 2H), 2.43 (s, 3H); ES-MS[M + H] + = 330.

[0348] 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6-(2,4-dimethoxybenzyl)-3-ethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound 33). In a reaction vial, 2-(2-cyclopropyl-6,7-dihydrothiazo[5,4- c ]pyridine-5(4H)-yl)-6-(2,4-dimethoxybenzyl)-3-vinyl-6,7-dihydro-5H-pyrrolo[3,4- b Pyridin-5-one (36 mg, 0.07 mmol) was suspended in ethanol (2 mL). The mixture was evacuated and purged with nitrogen (3x). Palladium supported on activated carbon (CAS# 7440-05-3; 8 mg, 0.01 mmol) and palladium hydroxide supported on activated carbon (CAS# 12135-22-7; 10 mg, 0.01 mmol) were added. The resulting mixture was purged with H2 for 1 min. The balloon was removed and the reaction was stirred at 50 °C for 5 h. The suspension was filtered through a Celite® pad and washed with 10% MeOH / DCM. The filtrate was concentrated under reduced pressure and purified by reversed-phase chromatography (15%-65% MeCN / water / 0.05% NH4OH) to give the title compound. 1HNMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.21 (d, J = 8.2 Hz, 1H), 6.49 – 6.37 (m,2H), 4.74 (s, 2H), 4.43 (s, 2H), 4.20 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H),3.52 – 3.45 (m, 2H), 3.05 (s, 2H), 2.71 (q, J = 7.5 Hz, 2H), 2.38 (s, 1H), 1.29(t, J = 7.4 Hz, 3H), 1.21 (s, 2H), 1.10 (s, 2H). ES-MS [M+1] + : 491.

[0349] 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-ethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one (compound 34). 2-(2-cyclopropyl-6,7-dihydrothiazo[5,4- c ]pyridine-5(4H)-yl)-6-(2,4-dimethoxybenzyl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4- b The mixture of pyridin-5-one (12 mg, 0.02 mmol) in trifluoroacetic acid (75 μL, 0.98 mmol) was stirred at 60 °C for 4 h. The reaction mixture was concentrated to give a crude residue, which was purified by reversed-phase chromatography (5%–45% MeCN / water / 0.1% TFA) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 6.06 (s, 1H), 4.49 (s, 2H), 4.36 (s,2H), 3.55 (t, J = 5.7 Hz, 2H), 3.09 (t, J = 5.9 Hz, 2H), 2.74 (q, J = 7.5 Hz, 2H),2.47-2.36 (m, 1H), 1.31 (t, J= 7.5 Hz, 3H), 1.25-1.21 (m, 2H), 1.18-1.13 (m, 2H). ES-MS [M+1] + : 341.

[0350] 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -cyclopentadiene[ b ]Pyridin-5-one (compound 35). 3-Bromo-2-(2-cyclopropyl-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H )-6,7-dihydro-5 H -cyclopentadiene[ b Pyridin-5-one (8.0 mg, 0.02 mmol), cesium carbonate (20 mg, 0.06 mmol), trimethylboroxane (50% wt in THF) (20 µL, 0.06 mmol), Pd(dppf)Cl2 (3.0 mg, 0.004 mmol), and 1,4-dioxane (0.5 mL) were placed in microwave-safe vials. The mixture was evacuated and purged with nitrogen and stirred at 80 °C for 18 h. The reaction mixture was diluted with EtOAc, filtered through Celite®, and concentrated. The crude residue was dissolved in DMSO (1.5 mL) and purified by reversed-phase chromatography (10%–40% MeCN / 0.1% aqueous TFA). The fraction containing the desired product was neutralized 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. 1 H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 4.61(t, J = 1.9 Hz, 2H), 3.66 (t, J = 5.6 Hz, 2H), 3.04 (dt, J = 9.4, 6.0 Hz, 4H), 2.73– 2.66 (m, 2H), 2.36 (d, J = 0.9 Hz, 3H), 2.27 (ddd, J = 13.1, 8.3, 4.9 Hz, 1H), 1.17 – 0.98 (m, 4H). ES-MS [M+1] +: 326.2.

[0351] 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b Pyridin-5-one (compound 36). Prepared in a similar manner to compound 23. 1 H NMR(400 MHz, CDCl3) δ 5.82 (s, 1H), 4.56 – 4.51 (m, 2H), 4.28 (s, 2H), 3.51 (t, J = 5.7 Hz, 2H), 3.04 (t, J = 5.8 Hz, 2H), 2.66 (s, 3H), 2.29 (s, 3H), 1.67 –1.55 (m, 2H), 1.51 – 1.39 (m, 2H). ES-MS [M+1] + : 359.

[0352] 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3,4,6-trimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b Pyridin-5-one (compound 38). Prepared in a similar manner to compound 23. 1 H NMR (400 MHz, CDCl3) δ 4.51 (t, J = 1.8 Hz, 2H), 4.21 (s, 2H), 3.48 (t, J = 5.7 Hz,2H), 3.16 (s, 3H), 3.03 (tt, J = 5.7, 1.8 Hz, 2H), 2.65 (s, 3H), 2.27 (s, 3H), 1.68 – 1.56 (m, 2H), 1.49 – 1.42 (m, 2H). ES-MS [M+1] + : 373.

[0353] The compounds shown in Table 2 can be prepared using the methods shown in the foregoing schemes and examples, with appropriate starting materials.

[0354] Table 2 .

[0355] Bioactivity A. Cell lines expressing muscarinic acetylcholine receptors Using Lipofectamine 2000, human and rat M4 cDNA were combined with chimeric G protein G. qi5 The cells were transfected into Chinese hamster ovary (CHO-K1) cells purchased from the American Type Culture Collection. Transfected cells were treated with selective antibiotics to produce stable cell lines; cells expressing M4 were selected with G418 sulfate (1 mg / mL), and cells expressing G4 were selected with hygromycin B (500 µg / mL). qi5 The cells were further screened to obtain hM4–G. qi5 and rM4–G qi5 Single clones were used for compound screening assays. Stable single clones were cultured in Ham's F-12 medium containing 10% heat-inactivated fetal bovine serum (FBS), 1X antibiotic / antifungal agent, 20 mM HEPES, 500 µg / mL G418 sulfate, and 200 µg / mL hygromycin B in a humidified incubator at 37°C in the presence of 5% CO2.

[0356] B. Cell-based functional assay of muscarinic acetylcholine receptor activity High-throughput assays were used to measure receptor-induced intracellular calcium mobilization to determine compound activity. The test compound was added to cells expressing muscarinic receptors, which were loaded with a calcium-sensitive fluorescent dye. After an incubation period of approximately 2.5 minutes, submaximal (EC50) was added. 20The concentration of acetylcholine was measured, and the response was determined. This kinetic assay allows for the simultaneous screening and potency determination of multiple pharmacological modes of action, including agonist and synergist activities. CHO-K1 cells stably expressing the muscarinic receptor were seeded at 15,000 cells / 20 μL / well in growth medium lacking G418 and hygromycin in clear substrates treated with Greiner 384-well black-walled tissue culture (TC) plates (Greiner Bio-One). Cells were incubated overnight at 37°C and 5% CO2. The next day, calcium assay buffer (Hank's Balanced Salt Solution (HBSS), 20 mM HEPES, 2.5 mM probenecid, 4.16 mM sodium bicarbonate (Sigma-Aldrich, St. Louis, Missouri)) was prepared to dilute the compounds, agonists, and the fluorescent calcium indicator dye Fluo-4-acetylmethoxyester (Fluo-4-AM). The compounds were serially diluted 1:3 in DMSO using a Bravo liquid processor (Agilent Technologies, Santa Clara, CA) to create a 10-point concentration-response profile. The profiles were then transferred to 384-well plates using an Echo acoustic liquid processor (Beckman Coulter, Indianapolis, Indiana) and diluted 2-fold to the final concentration in assay buffer. Agonist plates were prepared as follows: acetylcholine (ACh, Sigma-Aldrich, St. Louis, Missouri) was diluted 5-fold to the final concentration in assay buffer, corresponding to EC50. 20 and EC MAX Response concentration. A 2X dye solution (2.3 µM) was prepared by mixing 2.3 mM Fluo-4-AM stock solution in DMSO with 10% (w / v) pluronicacid F-127 at a 1:1 ratio in assay buffer. Cells were washed three times with assay buffer to remove culture medium using a microplate washer (BioTek, Winuschi, Vermont). After the final wash, 20 μL of assay buffer remained in the cell plate. Then, 20 μL of 2X dye solution (finally 1.15 µM) was added to each well of the cell plate using a Multidrop Combi dispenser (Thermo Fisher, Waltham, MA). After incubating the cells with the dye solution at 37°C in the presence of 5% CO2 for 45 min, the dye solution was removed using a microplate washer and replaced with assay buffer, leaving 20 μL of assay buffer in the cell plate.

[0357] The prepared compounds, agonists, and cell plates were placed in a functional drug screening system uCell (FDSS uCell, Hamamatsu, Japan) to measure calcium flux. Ca kinetics were measured using a triple-add protocol; the test compound and EC were added sequentially. 20 ACh and EC 80 The ACh was used. In short, after establishing a 2-second fluorescence baseline (excitation, 480 nm; emission, 530 nm), 20 µL of the test compound was first added to the cells, followed by measurement of the response for 140 seconds. A second addition was then made; 10 µL of (5X) EC was added. 20 A concentration of ACh agonist was added to the cells, and the cellular response was measured for 125 seconds. A third addition was immediately performed: 12 μL (5X) EC was added. 80 ACh concentration was added, and cellular responses were measured for 90 seconds. The acetylcholine-mediated maximum response (EC50) was measured by adding 1 mM ACh as a third addition to the control wells. max DMSO medium was added to the control wells in the first addition to evaluate ACh EC. 20 EC80 and EC max Response. Calcium fluorescence was recorded as a fold increase over the baseline fluorescence, and the raw data were normalized to the maximum response to the ACh agonist. Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization after compound addition. Positive allosteric modulator activity was analyzed as EC 20 The concentration-dependent nature of the acetylcholine response increases. Antagonist activity is analyzed as EC. 80 The concentration dependence of the acetylcholine response was reduced. Concentration-response curves were generated using a four-parameter logistic equation with either GraphPad Prism (La Jolla, California) or the Dotmatics software platform (Woburn, Massachusetts).

[0358] The above assays were also performed in a second mode, in which an appropriate fixed concentration of the disclosed compound was added to cells approximately 3 seconds after establishing a fluorescence baseline, and the cellular response was measured. After 140 s, an appropriate concentration of the agonist was added, and the calcium response (maximum-local minimum response) was measured. The EC50 of the agonist in the presence of the test compound was determined by nonlinear curve fitting. 50 Value. The EC50 of the agonist decreases with increasing concentration of the disclosed compound. 50 The value (leftward shift of the agonist concentration-response curve) indicates the degree of positive allosteric regulation of the muscarinic type at a given concentration of the disclosed compound. The EC50 of the agonist increases with increasing concentration of the disclosed compound. 50The value (rightward shift of the agonist concentration-response curve) indicates the extent of muscarinic antagonism at a given concentration of the disclosed compound. The second approach also indicates whether the disclosed compound also affects the maximum response of the muscarinic receptor to the agonist.

[0359] C.mAChR M4 cell-based assays of compound activity The compound was synthesized as described above. Its activity was determined in an M4 cell-based functional assay as described above (ECG). 50 and E max The data is shown in Table 3. The compound numbers correspond to the compound numbers used in Table 2.

[0360] Table 3. serial number <![CDATA[Human M4EC 50 (nM)]]> <![CDATA[E max (%)*]]> 1 409 91 2 23 88 3 51 73 4 1264 59 5 707 97 6 70 95 7 727 71 8 4700 74 9 86 75 10 39 79 11 406 73 12 15 96 13 70 79 14 14 88 15 280 72 16 146 66 17 3510 70 18 176 63 19 1166 79 20 9345 66 21 21 97 22 9 89 23 99 72 24 40 69 25 5 71 26 201 66 27 154 74 28 76 84 29 52 72 30 >10,000 42 31 481 80 32 >10,000 56 33 963 44 34 148 78 35 10 98 36 13 96 37 537 68 38 31 95 * Maximum %ACh at 30 μM.

[0361] D. Cellular cAMP assay (cell cAMP G) i Functional evaluation of M4 activator compounds in HTRF assay After M4 receptor activation, it interacts with G... i / o Protein coupling inhibits cAMP production. To measure the inhibitory level of cAMP by the M4 allosteric modulator, homogeneous time-resolved fluorescence (HTRF) was used in CHO cells stably expressing the human or rat M4 receptor. ® cAMP assay. HTRF cAMP assay is a time-resolved resonance energy transfer (TR-FRET) competitive immunoassay. Cell-produced endogenous intracellular cAMP competes with europium-labeled cAMP (europium donor, emitting at 665 nm) for binding to d2-labeled cAMP antibody (d2-receptor, emitting at 620 nm). Therefore, the fluorescence emission ratio (665 nm / 620 nm) is inversely proportional to intracellular cAMP levels. Compound-mediated M4 activation leads to an increase in the HTRF ratio (665 nm / 620 nm), indicating a decrease in intracellular cAMP levels. To monitor agonist activity, ECs that induce submaximal intracellular cAMP levels are used. 80 The compound was added to M4 cells in the presence of a concentration of foscorlin (an adenylate cyclase activator). To assess the synergist activity, EC2 cells were subjected to... 20 In the presence of a certain concentration of acetylcholine, the compound was added to a container containing EC. 80 Concentrations of foscorlin in M4 cells. This functional assay can determine whether it directly activates or enhances G2. i / o - The potency and efficacy of compounds coupled with the M4 receptor.

[0362] By using HTRF cAMP G i / oThis kit measures cAMP levels in Chinese hamster ovary (CHO) cells stably expressing human or rat M4 muscarinic receptors to determine the functional agonist and synergist activities of compounds. Cells were cultured in F12 medium containing 10% FBS, 20 mM HEPES, 1X antibiotic / antifungal agent, and G418 (500 μg / ml) at 37°C in the presence of 5% CO2. The day before the assay, cells were digested with trypsin and resuspended in plating medium (growth medium without G418). Cells were plated in white solid flat-bottomed 384-well plates at densities of 4,000 human M4 cells and 6,000 rat M4 cells / 10 μL / well. The plates were rotated at 100xg for 1 min and then immediately placed in a 37°C incubator overnight in the presence of 5% CO2.

[0363] The next day, the reagents were freshly diluted 2X in the assay buffer using F12 basal medium or stimulation buffer. All assay buffers contained 500 μM IBMX to prevent cAMP degradation. (The last sentence appears to be incomplete and possibly refers to EC.) 80 In cells stimulated with concentrations of forscorin to induce submaximal intracellular cAMP levels, the activation of M4 by the compound was examined. Forscorin EC 80 Concentrations were determined by forscoringin concentration-response curves (CRC), ranging from 1.5 to 2.5 μM. The compound (10 mM) was prepared in 100% DMSO and then further serially diluted in DMSO at 1:3 or 1:5 using a Bravo liquid processor in 384-well microplates to prepare 13-point CRCs.

[0364] The ability of M4 compounds to directly activate the M4 receptor in the absence of an agonist (acetylcholine) was evaluated using an agonist assay. Ten serially diluted compounds (starting at 30 μM and ending at 30 μM) were transferred to compound plates using the Echo plate reformatting protocol. Compounds containing EC... 80 Add 2X assay buffer of forscoringin concentration to the compound plate. Add media (1% DMSO) to the following control wells: baseline cAMP (forscoringin-free), maximum forscoringin, and forscoringin EC. 80 Immediately add 10 μl / well of the prepared 2X assay buffer to the cell plate using a Bravo 384-well pipette tip liquid processor. Immediately rotate the cell plate at 100 xg for 30 seconds and incubate at 37°C with gentle shaking at 50 rpm for 10 min. Also in EC 80 Acetylcholine-induced CRC was performed in the presence of foscorline at a concentration to determine the maximum induction (EC). max ) and Asia's largest (EC20 The cAMP-inhibited acetylcholine concentration was determined to prepare for subsequent synergist mode assays.

[0365] In synergist assay mode, 10 serially diluted compounds (starting at 1.1 μM as the final concentration) were transferred to the compound plate using the Echo plate rearrangement protocol. Compounds containing EC... 80 Concentrations of foscorine and EC 20 2X assay buffer of acetylcholine concentration was added to the compound plate. The medium (1% DMSO) was added to the following: (1) Forscoline control wells: baseline cAMP (without forscoline), maximum forscoline, and forscoline EC. 80 (2) Agonist control wells: containing foscorine EC 80 - Baseline (no agonist) and acetylcholine EC 20 and EC max Immediately using a Bravo 384-well pipette tip liquid processor, 10 μl / well of the prepared 2X assay buffer was added to the cell plate. The cell plate was immediately rotated at 100 xg for 30 seconds and incubated at 37°C with gentle shaking at 50 rpm for 10 min. During the 10-minute incubation period, cAMP Eu-hole compound donor (20X) and anti-cAMP d2 antibody receptor (20X) were diluted in separate tubes with lysis / detection buffer. Immediately after incubation, 10 μl / well of cAMP Eu-hole compound solution and 10 μl / well of anti-cAMP d2 antibody solution were added sequentially to lyse the cells. The cell plate was immediately rotated at 100 xg for 30 seconds and incubated at 25°C with gentle shaking at 50 rpm for 60 min. Immediately after detection incubation, TR-FRET signals were measured in both channels (665 and 620 nm) using an EnVision microplate reader (PerkinElmer). All emissivity (665 / 620) was normalized to the maximum acetylcholine percentage. A single CRC was generated using a four-parameter logic equation from GraphPad Prism (La Jolla, California), and EC... 50 Extract from the fit and determine the maximum response (%AChMax): in A It is the molar concentration of the compound; minimum ( bottom ) and the highest ( top The numbers ) represent the lower and upper plateaus of the concentration-response curve, respectively; the Hill slope is the Hill coefficient describing the steepness of the curve; and EC... 50 It is the molar concentration of the compound required to produce a response between the highest and lowest values.

[0366] Table 4. Materials and Equipment .

[0367] E. In vitro secondary pharmacology Compound 2 was tested using Eurofins LeadProfilingScreen®, a assay that detects potential off-target activity and determines relative selectivity. The screening included 68 major molecular targets, including several CNS targets recommended by the European Medicines Evaluation Agency (EMEA) for assessing drug dependence potential. Compound 70 showed <50% inhibition of each target in LeadProfilingScreen® at 10 µM (binding), except for human muscarinic 2 (58% inhibition at 10 µM).

[0368] F. In vitro and in vivo drug metabolism and pharmacokinetics Compound 2 has been tested in several in vitro assays to investigate both its metabolism and pharmacokinetics. These assays were performed according to known methods generally described in the following references: Conde-Ceide et al. ACS Med. Chem. Lett. [ACS Medical Chemistry Letters] 2015, 6, 716-720; Morris et al. J. Med. Chem. [Journal of Medicinal Chemistry] 2014, 57, 10192-10197; and Bubser et al. ACS Chem. Neurosci. [ACS Chemical Neuroscience] 2014, 5, 920-942. In vitro assays include those listed in the table below.

[0369] Table 5 Measurement result MDCK-MDR1 ER <![CDATA[2.8(P app A→ B:13.8 x 10 -6 cm / s)]]> <![CDATA[Rat F u (plasma)]]> 0.117 <![CDATA[Canine F u (plasma)]]> 0.054 <![CDATA[Human F u (plasma)]]> 0.037 <![CDATA[Rat F u (brain)]]> 0.027 <![CDATA[Rat CL int (mL / min / kg)]]> 83 <![CDATA[Dog CL int (mL / min / kg)]]> 100 <![CDATA[Human CL int (mL / min / kg)]]> 6 <![CDATA[P450 3A4 IC 50 (µM)]]> 5 <![CDATA[P450 2D6 IC 50 (µM)]]> 10 <![CDATA[P450 2C9 IC 50 (µM)]]> >30 <![CDATA[P450 1A2 IC 50 (µM)]]> 5

[0370] Compound 2 has been tested in several in vivo assays, and the pharmacokinetic parameters listed in the table below were determined by pharmacokinetic studies in rats or dogs using known methods generally described in the following references: Garrison et al. J. Med. Chem. [Journal of Medicinal Chemistry] 2022, 65, 6273-6286; Felts et al. J. Med. Chem [Journal of Medicinal Chemistry] 2017, 60, 5072-5085; and Yu et al. J. Med. Chem. [Journal of Medicinal Chemistry] 2021, 64, 4709-4729.

[0371] Table 6 Measurement result <![CDATA[Rat CL p (mL / min / kg)]]> 24.2 <![CDATA[Dog CL p (mL / min / kg)]]> 52.9 <![CDATA[Rat V ss (L / kg)]]> 0.5 <![CDATA[Canine V ss (L / kg)]]> 0.9 <![CDATA[Rat Elim. t 1 / 2 (hr)]]> 0.4 <![CDATA[Canine Elim. t 1 / 2 (hr)]]> 0.2 Rats were orally administered F (oral F) (3 mg / kg). 24% <![CDATA[Rat brain: plasma K p > 0.8 <![CDATA[Rat brain: plasma K p,uu > 0.2

[0372] It should be understood that the above detailed description and the appended examples are illustrative only and should not be construed as limiting the scope of the invention, which is defined only by the appended claims and their equivalents.

[0373] Various variations and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such variations and modifications may be made without departing from the spirit and scope of the invention, including but not limited to those relating to the chemical structure, substituents, derivatives, intermediates, synthesis, composition, formulation, or method of use of the invention.

Claims

1. A compound having formula (I) or a pharmaceutically acceptable salt thereof, in: X 1 It is NR 5 O or CR 5A R 5B ; R 2 It is G 2 –NR 2a R 2b Halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, –OR 2a –NR 2a C(O)R 2b –C(O)OR 2a –C(O)NR 2a R 2b , or hydrogen; R 2a and R 2b 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 3- to 7-membered carbocyclic group, a 5- to 6-membered heteroaryl group containing 1-4 heteroatoms, a phenyl group, or a 4- to 7-membered heterocyclic group containing 1-2 heteroatoms, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 2 Optionally and independently selected from halogen, cyano, C 1-4 Alkyl, C 1-4 fluoroalkyl, 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 group consists of 1-5 substituents; R x Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, or –C 1-3 alkylene–C 3-6 cycloalkyl; G 2a It is C 3-6 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; or R 4A and R 4B Together with the carbon attached to them, they form C 3-6 cycloalkyl; 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 fluoroalkyl, 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, C 3-4 cycloalkyl, or –C 1-3 alkylene–C 3-4 cycloalkyl; G 5 It is a phenyl group, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, a 5- to 6-membered heteroaryl group containing 1-4 heteroatoms, or a C-type heterocyclic 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 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 3-4 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 contain one additional heteroatom, which is O, N, or S, and the heterocycle is optionally 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, C 2-4 alkenyl, –OR 7a –C 1-3 Alkylene – OR 7a CO2R 7a COR 7a or C 3-6 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; 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 x G 2a R 6 R 6a R 7 R 7a and R 8 Each cycloalkyl group at the position is independently 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, R 2 It is G 2 –NR 2a R 2b Halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, –OR 2a –C(O)OR 2a –C(O)NR 2a R 2b , or hydrogen.

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

4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 3- to 7-membered carbon cyclogroup that is optionally substituted.

5. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 5- to 6-membered heteroaryl group that is optionally substituted.

6. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein G 2 yes , , , , , ,or .

7. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 Yes – NR 2a R 2b .

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

9. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 It is halogen.

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

11. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 It is –C(O)OR 2a .

12. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 2 It is –C(O)NR 2a R 2b .

13. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1, 2, 7, or 11-12, wherein R 2a Is it hydrogen or C? 1-6 alkyl.

14. The compound of any one of claims 1, 2, 7, or 12-13, or a pharmaceutically acceptable salt thereof, wherein R 2b It is hydrogen.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R 4A and R 4B It is hydrogen.

16. The compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, wherein X 1 It is NR 5 .

17. The compound of any one of claims 1-16 or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen, C 1-6 Alkyl, G 5 、or –C 1-3 Alkylene–G 5 .

18. The compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, wherein X 1 It is O.

19. The compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, wherein X 1 It is CR 5A R 5B .

20. The compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof, wherein R 6 It is hydrogen.

21. The compound of any one of claims 1-20 or a pharmaceutically acceptable salt thereof, wherein R 7 It is C 1-4 Alkyl, halogen, cyano, or C 3-6 Cycloalkyl.

22. The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof, wherein n is 0.

23. The compound of claim 1, wherein the compound is selected from the group consisting of: 2-(6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 3-Methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 3-Methyl-2-(2-(thien-2-yl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 5-(3-methyl-5-oxo-6,7-dihydro-5-) H -pyrrolo[3,4- b ]pyridin-2-yl)-4,5,6,7-tetrahydrothiazo[5,4- c ]Ethyl pyridine-2-carboxylate; 3-Methyl-2-(2-methyl-6,7-dihydrothiazo[5,4-]) c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 3-Methyl-2-(2-(1-methyl-1-yl) H -pyrazol-5-yl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-amino-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-chloro-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-(tert-butyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 3,6-Dimethyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 6-Cyclopropyl-2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-]) c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 6-Cyclopropyl-3-methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 6-Cyclopentyl-2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-]) c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 6-Cyclopentyl-3-methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 6-Cyclopropyl-2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 6-Cyclopentyl-2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclobutyl-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-3,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclobutyl-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-yl)-3-methylfurano[3,4- b ]Pyridine-5(7 H )-ketone; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3,6-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 3-Methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)furano[3,4- b ]Pyridine-5(7 H )-ketone; 2-(2-Cyclobutyl-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 3-Cyclopropyl-2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-]) c ]Pyridine-5(4 H )-yl)-6-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-6-methyl-5-oxo-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridine-3-carboxynitrile; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-6-methyl-3-vinyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-6-methyl-3-(prop-1-en-2-yl)-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-6-methyl-5-oxo-6,7-dihydro-5 H -pyrrolo[3,4- b ] Methyl pyridine-3-carboxylic acid ester; 5-(3-methyl-5-oxo-6,7-dihydro-5-) H -pyrrolo[3,4- b ]pyridin-2-yl)-4,5,6,7-tetrahydrothiazo[5,4- c ]Pyridine-2-carboxamide; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-6-(2,4-dimethoxybenzyl)-3-ethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-ethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-Cyclopropyl-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3-methyl-6,7-dihydro-5 H -cyclopentadiene[ b ]Pyridin-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3,4-dimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-4-methyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-3,4,6-trimethyl-6,7-dihydro-5 H -pyrrolo[3,4- b ]Pyridin-5-one; Or its pharmaceutically acceptable salt.

24. A pharmaceutical composition comprising the compound of any one of claims 1-23 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. The compound of any one of claims 1-23 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24, 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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